Rule: Human Drugs and Biological Products: Prescription Drug Products Labeling Requirements

Tuesday,
January 24, 2006
Part II
Department of
Health and Human
Services
Food and Drug Administration
21 CFR Parts 201, 314, and 601

Requirements on Content and Format of
Labeling for Human Prescription Drug
and Biological Products and Draft
Guidances and Two Guidances for
Industry on the Content and Format of
Labeling for Human Prescription Drug
and Biological Products; Final Rule and
Notices
rwilkins on PROD1PC63 with RULES_2
VerDate Aug<31>2005 16:08 Jan 23, 2006 Jkt 208001 PO 00000 Frm 00001 Fmt 4717 Sfmt 4717 E:\FR\FM\24JAR2.SGM 24JAR2
3922 Federal Register / Vol. 71, No. 15 / Tuesday, January 24, 2006 / Rules and Regulations
DEPARTMENT OF HEALTH AND Evaluation and Research (HFD–7), ‘‘package circular’’) is a compilation of
HUMAN SERVICES Food and Drug Administration, information about the product,
5600 Fishers Lane, Rockville, MD approved by FDA, based on the agency’s
Food and Drug Administration 20857, 301–594–2041, thorough analysis of the new drug
sadovee@CDER.FDA.GOV. application (NDA) or biologics license
21 CFR Parts 201, 314, and 601 application (BLA) submitted by the
[Docket No. 2000N–1269] (formerly Docket
For information on labeling of applicant. This labeling contains
No. 00N–1269) biological products that are information necessary for safe and
regulated as prescription drugs: effective use. It is written for the health
RIN 0910–AA94 Toni M. Stifano, Center for care practitioner audience, because
Biologics Evaluation and Research prescription drugs require ‘‘professional
Requirements on Content and Format (HFM–600), Food and Drug supervision of a practitioner licensed by
of Labeling for Human Prescription Administration, 1401 Rockville law to administer such drug’’ (section
Drug and Biological Products Pike, Rockville, MD 20856, 301– 503(b) of the act (21 U.S.C. 353(b))).
AGENCY: Food and Drug Administration, 827–6190, stifano@CBER.FDA.GOV, FDA-approved labeling is defined in
HHS. or Kathleen Swisher, Center for section 201(m) of the act (21 U.S.C.
ACTION: Final rule. Biologics Evaluation and Research 321(m)) and is subject to all applicable
(HFM–17), Food and Drug provisions of section 502 of the act (21
SUMMARY: The Food and Drug Administration, 1401 Rockville U.S.C. 352). It satisfies the requirement
Administration (FDA) is amending its Pike, Rockville, MD 20852, 301– of § 201.100(d) (21 CFR 201.100(d)) that
regulations governing the content and 827–6210. ‘‘[a]ny labeling, as defined in section
format of labeling for human SUPPLEMENTARY INFORMATION: 201(m) of the act * * * that furnishes
prescription drug products (including or purports to furnish information for
biological products that are regulated as Table of Contents use or which prescribes, recommends,
drugs). The final rule revises current I. Background or suggests a dosage for the use of the
regulations to require that the labeling II. Overview of the Final Rule Including drug * * * contains * * * [a]dequate
of new and recently approved products Changes to the Proposed Rule information for such use,’’ as further
include highlights of prescribing III. Implementation described in that provision. FDA-
information and a table of contents. The IV. Overview of Agency Initiatives to approved labeling also accompanies
final rule also reorders certain sections, Improve the Content and Format of ‘‘promotional’’ materials, as described
requires minor content changes, and Prescription Drug Labeling in § 202.1(l)(2) (21 CFR 202.1(l)(2)).
sets minimum graphical requirements. V. Implications of This Final Rule for FDA-approved labeling also ‘‘bears
These revisions will make it easier for the Electronic Labeling Initiative adequate information’’ within the
health care practitioners to access, read, VI. Comments on the Proposed Rule meaning of § 201.100(c)(1), which
and use information in prescription VII. Legal Authority applies to ‘‘labeling on or within the
drug labeling. The revisions will VIII. Paperwork Reduction Act of 1995 package from which a prescription drug
enhance the safe and effective use of IX. Environmental Impact is to be dispensed’’, referred to in this
prescription drug products and reduce X. Executive Order 13132: Federalism document as ‘‘trade labeling.’’ In this
the number of adverse reactions XI. Analysis of Economic Impacts document, FDA-approved labeling for
resulting from medication errors due to XII. Executive Order 12988: Civil Justice
prescription drugs is referred to as
misunderstood or incorrectly applied Reform
‘‘labeling’’ or ‘‘prescription drug
drug information. For both new and XIII. References
labeling.’’
recently approved products and older I. Background
products, the final rule requires that all B. Developing the Proposed Rule
In the Federal Register of December
FDA-approved patient labeling be In recent years, there has been an
22, 2000 (65 FR 81082), FDA issued a
reprinted with or accompany the increase in the length, detail, and
proposed rule to revise its regulations
labeling. The final rule also revises complexity of prescription drug
governing the content and format of
current regulations for prescription drug labeling, making it harder for health
labeling for human prescription drug
labeling of older products by clarifying care practitioners to find specific
products, which appear in §§ 201.56
certain requirements. These changes information and to discern the most
and 201.57 (21 CFR 201.56 and
will make the labeling for older critical information. Before issuing the
201.57).1
products more informative for health proposal, the agency evaluated the
care practitioners. A. FDA-Approved Prescription Drug usefulness of prescription drug labeling
DATES: This rule is effective June 30, Labeling for its principal audience to determine
2006. See section III of this document A prescription drug product’s FDA- whether, and how, its content and
for the implementation dates of this approved labeling (also known as format could be improved. The agency
final rule. ‘‘professional labeling,’’ ‘‘package used focus groups, a national physician
FOR FURTHER INFORMATION CONTACT: insert,’’ ‘‘direction circular,’’ or survey, a public meeting, and written
For information on drug product comments to develop multiple
labeling: Janet Norden, Center for 1 Although §§ 201.56 and 201.57 do not prototypes and to ascertain how
Drug Evaluation and Research specifically mention the term ‘‘biologics’’, under the prescription drug labeling is used by
Federal Food, Drug, and Cosmetic Act (the act),
(HFD–40), Food and Drug most biologics are drugs that require a prescription
health care practitioners, what labeling
Administration, 10903 New information practitioners consider most
and thus are subject to these regulations. (See

Hampshire Ave., Bldg. 22, rm. 4202, section VII of this document for legal authority.) For important, and how practitioners
Silver Spring, MD 20993–0002, the purposes of this document, unless otherwise believed labeling could be improved.
specified, all references to ‘‘drugs’’ or ‘‘drug
301–796–2270, products’’ include human prescription drug
The agency developed a prototype based
nordenj@CDER.FDA.GOV, or products and biological products that are also on this accumulated information as the
Elizabeth Sadove, Center for Drug drugs. model for the proposed rule.
Federal Register / Vol. 71, No. 15 / Tuesday, January 24, 2006 / Rules and Regulations 3923
C. The Proposed Rule proposed § 201.80. The agency proposed • An overview of the agency’s
The agency’s proposed changes were to redesignate then-current § 201.57 as prescription drug labeling initiatives
designed to enhance the ability of health § 201.80 to describe labeling (section IV of this document),
care practitioners to access, read, and requirements for older drugs and add • The implications of this rule for the
use prescription drug labeling. new § 201.57 to describe labeling electronic labeling initiative (section V
requirements for new and recently of this document),
1. Proposed Provisions for New and approved drugs. • A discussion of the comments
Recently Approved Drugs
3. Proposed Provisions for All Drugs received on the proposal and the
FDA proposed the following changes agency’s responses to the comments
FDA also proposed certain revisions
for the labeling for prescription drugs (section VI of this document),
to the requirements governing the
that were approved on or after the • A statement of legal authority
content of labeling to help ensure that
effective date of the final rule, drugs that (section VII of this document),
statements appearing in labeling related
had been approved in the 5 years before
to effectiveness or dosage and • A description of the information
the effective date of the final rule, and administration are sufficiently collection provisions of the rule (section
older approved drugs for which an supported. These provisions would VIII of this document),
efficacy supplement is submitted. FDA have applied to all drugs.
believed that applying the revised • An statement on the environmental
• The labeling for all drugs would impact of the rule (section IX of this
content and format requirements only to contain all FDA-approved patient
more recently approved products was document),
labeling (i.e., approved printed patient
appropriate because, among other • A statement on federalism (section
information and Medication Guides) for
reasons, health care practitioners are X of this document),
the drug, not just the information
more likely to refer to the labeling of required by regulation to be distributed • An analysis of the economic
recently approved products (see to patients (see table 2). impacts of the rule (section XI of this
comment 113). • Minor revisions would be made to document),
• The addition of introductory the requirements for labels affixed to • A statement on the impact of the
prescribing information, entitled prescription drug containers and rule on the civil justice system (section
‘‘Highlights of Prescribing Information’’ packaging. XII of this document), and
(Highlights). The proposal called for the • A list of references (section XIII of
• The addition of a table of contents. submission of comments by March 22, this document).
• Reordering and reorganizing to 2001. At the request of the
make the labeling easier to use and read. Pharmaceutical Research and II. Overview of the Final Rule Including
• Minimum graphical requirements Manufacturers of America, and to Changes to the Proposed Rule
for format. provide all interested persons additional
• Certain revisions to the content This final rule amends part 201 (21
time to comment, the comment period CFR part 201) of FDA regulations by
requirements, such as modifying the was reopened until June 22, 2001 (66 FR
definition of ‘‘adverse reaction’’ to make revising the requirements for the
17375, March 30, 2001). After careful content and format of labeling for
the ‘‘Adverse Reactions’’ section of consideration of the comments, FDA has
labeling more meaningful and useful to prescription drug products (see tables 1
revised the proposal and is issuing this
health care practitioners. and 2 of this document). Table 1 lists
final rule.
the sections required for prescription
The following sections of this
2. Proposed Provisions for Older drug labeling before the effective date of
document provide:
Approved Drugs this final rule (and which will remain in
• An overview of the final rule
The agency proposed that older including changes to the proposed rule effect for older products), and, for new
approved drug products would not be (section II of this document), and recently approved products, the
subject to these proposed changes. • A discussion of the implementation sections FDA proposed in 2000 and
These older products would, instead, be requirements for the final rule (section those required by this final rule.
subject to the labeling requirements at III of this document), BILLING CODE 4160–01–S
The final rule requires that any FDA- requirement in effect before the effective ‘‘FDA-approved patient labeling’’ will
approved patient labeling either: (1) date of this final rule, the 2000 proposed be used to refer to any approved printed
Accompany the prescription drug requirement, and the final requirement patient information or Medication
labeling or (2) be reprinted at the end of (see comment 92 for discussion of FDA- Guide, unless a comment is addressing
such labeling (§§ 201.57(c)(18) and approved patient labeling). For the one or the other specifically.
201.80(f)(2)). Table 2 lists the purposes of this document, the term
ER24JA06.000</GPH>
TABLE 2.—FDA-APPROVED PATIENT LABELING WITH PRESCRIPTION DRUG LABELING

Requirement for All Products Before the Ef- Proposed Requirement for All Products Final Requirement for All Products
fective Date of the Final Rule
To be reprinted at the end of labeling: To be reprinted at the end of labeling: To be reprinted at the end of labeling or to
• Full text of FDA-approved patient labeling • Full text of any FDA-approved patient la- accompany the labeling:
that is required to be distributed to patients beling • Full text of any FDA-approved patient la-
beling
In this rulemaking, the agency drugs with pediatric patent protection that labeling in the new format is for a
finalizes many of the provisions in the or exclusivity. The agency added a prescription drug product.
December 2000 proposal. In addition, provision in § 201.56(d)(5) of the final • The ‘‘R’’ symbol in the FPI
the final rule reflects revisions the rule to make clear that any risk (proposed § 201.56(d)(2)), which would
agency made in response to comments information from the have identified the ‘‘References’’
on the December 2000 proposal and ‘‘Contraindications,’’ ‘‘Warnings and section.
revisions made by the agency on its own Precautions,’’ or ‘‘Use in Specific • The ‘‘P’’ symbol in the FPI
initiative. FDA also has made editorial Populations’’ section is ‘‘pediatric (proposed § 201.57(c)(18)), which would
changes to clarify provisions, correct contraindications, warnings, or have identified the ‘‘Patient Counseling
cross-references, and support the precautions’’ within the meaning of Information’’ section.
agency’s plain language initiative. Table section 11 of the BPCA (21 U.S.C.
1. Highlights of Prescribing Information
3 lists the substantive changes made to 355A(l)(2)). By adding § 201.56(d)(5),
the general provisions and Highlights the agency intends to avoid any possible Like the proposed rule, the final rule
and table 4 lists the substantive changes confusion as to what information the requires that the labeling for new and
made to the Full Prescribing agency may require in generic labeling more recently approved products
Information (FPI). that otherwise omits a pediatric include introductory information
indication or other aspect of labeling entitled ‘‘Highlights of Prescribing
A. Content and Format of Labeling for Information’’ (Highlights)
pertaining to pediatric use protected by
New and More Recently Approved (§§ 201.56(d)(1) and 201.57(a)) (see table
patent or exclusivity.
Prescription Drug Products 1).
In addition, the agency declined to
The final rule, like the proposed rule, adopt the use of symbols that were The final rule requires the same
requires that the labeling for new and proposed to emphasize or identify headings for Highlights as proposed,
more recently approved drug products information in prescription drug except that, in response to comments,
comply with revised content and format labeling. Based on comments, FDA FDA moved ‘‘Most Common Adverse
requirements (§ 201.56(d)) (see table 1). declined to use the inverted black Reactions’’ from ‘‘Warnings and
Like the proposed rule, the final rule triangle (see comment 15) and the Precautions’’ (proposed § 201.57(a)(10))
provides that new and more recently exclamation point (!) to emphasize the to a new heading entitled ‘‘Adverse
approved products include drug boxed warning (see comment 43). On its Reactions’’ (§§ 201.56(d)(1) and
products with an NDA, BLA, or efficacy own initiative, for the same reasons that 201.57(a)(11)) (see table 1 and comment
supplement that: (1) Was approved FDA rejected use of the two symbols 28). Like the proposed rule, the final
between June 30, 2001, and June 30, commented upon, FDA declined to use rule requires that Highlights, except for
2006; (2) is pending on June 30, 2006; the following three proposed symbols: the boxed warning, be limited in length
or (3) is submitted anytime on or after • The Rx symbol (proposed to one-half of the page (§ 201.57(d)(8))
June 30, 2006 (§ 201.56(b)(1)). § 201.57(a)(3)) in Highlights. The agency (see comment 104).
On its own initiative, the agency proposed the symbol to identify a The agency is also revising its
added a provision on pediatric risk product that is available only by regulations on supplements and other
information to the general labeling prescription under section 503(b) of the changes to an approved application in
requirements of the final rule. Section act. The agency decided that the Rx §§ 314.70 and 601.12 (21 CFR 314.70
11 of the Best Pharmaceuticals for symbol in Highlights is unnecessary and 601.12) to require applicants to
Children Act (Public Law 107–109) because the new prescription drug obtain prior approval of any labeling
(BPCA), which was signed into law on labeling format is so distinct from the changes to Highlights, except for
January 4, 2001, addresses labeling over-the-counter (OTC) drug labeling identified minor changes (see comment
requirements for generic versions of format that it will be clear to prescribers 5).
TABLE 3.—SUBSTANTIVE CHANGES FROM THE PROPOSED RULE TO THE FINAL RULE: GENERAL PROVISIONS AND TO
HIGHLIGHTS
Description of Change from Proposed Rule
21 CFR Section in
Final Rule See comment or section of this document (identified in parentheses) for more detailed information regarding the
change.
201.55, Container Labels

201.57(c)(4)(v), • Withdrew proposed amendments regarding content of container labels and associated proposed amendments to
201.57(c)(12)(i)(D), the labeling (106 and 107)

and 201.100(b)
TABLE 3.—SUBSTANTIVE CHANGES FROM THE PROPOSED RULE TO THE FINAL RULE: GENERAL PROVISIONS AND TO
HIGHLIGHTS—Continued
Description of Change from Proposed Rule
21 CFR Section in
Final Rule See comment or section of this document (identified in parentheses) for more detailed information regarding the
change.
201.56(a)(2) General Requirement

• Revised to clarify that the labeling must be updated when new information becomes available that causes the la-
beling to become inaccurate, false, or misleading (114)
201.56(d) Product Title

• Deleted proposed § 201.56(d)(4), which permitted a ‘‘Product Title’’ section to be included at the beginning of the
FPI (39)
201.56(d)(4) Format of Contents

• Revised to require that the Contents identify if sections have been omitted (37)
201.56(d)(5) Pediatric Risk Information

• Added, on its own initiative, a provision to make clear that pediatric risk information within the meaning of the
BPCA may be located in the ‘‘Use in Specific Populations’’ section (II.A)
201.57 and 201.80 Unsubstantiated Claims

• Removed the 1-year implementation requirement for provisions in §§ 201.57 and 201.80 that prohibit inclusion of
unsubstantiated claims in labeling (114)
201.57 Promotional Labeling

• Removed, on its own initiative, the reference to statements made in promotional labeling and advertising in pro-
posed 201.57(a) (111)
201.57(a)(1) Highlights Limitation Statement

• Moved the Highlights limitation statement to the beginning of Highlights (35)
201.57(a)(3) Inverted Black Triangle Symbol

• Instead of an inverted black triangle symbol, labeling will state the ‘‘Initial U.S. Approval’’ date (15)
201.57(a)(4) Boxed Warning

• Revised to require that Highlights contain a concise summary of any boxed warning in the FPI (16)
201.57(a)(5) Recent Labeling Changes

• Changed the heading to ‘‘Recent Major Changes’’ and revised to identify only substantive changes to the ‘‘Boxed
Warning,’’ ‘‘Indications and Usage,’’ ‘‘Dosage and Administration,’’ ‘‘Contraindications,’’ and ‘‘Warnings and Pre-
cautions’’ sections and the date of the change(s) (18–22)
201.57(a)(6) Indications and Usage

• Revised to require identification of the pharmacologic class of the drug if it is a member of an established pharma-
cologic class (6)
201.57(a)(8) How Supplied

• Changed the heading to ‘‘Dosage Forms and Strengths’’ (41)
201.57(a)(11) Adverse Reactions

• Moved ‘‘Most Common Adverse Reactions’’ from ‘‘Warnings and Precautions’’ to a new heading: ‘‘Adverse Reac-
tions’’ (28)
• Revised the criteria used for determining which adverse reactions to include in Highlights and that the criteria used
be specified (28)
• Revised to require that the adverse reactions reporting contact statement be included under the ‘‘Adverse Reac-
tions’’ heading of Highlights; deleted proposed § 201.57(c)(6)(v) that would have required that this statement also
be included in the FPI (28 and 30)
• Revised the requirements associated with the adverse reactions reporting contact statement (31 and 32)
201.58 Waiver Provision

• Revised to make clear applicants can request waivers from any requirement under §§ 201.56, 201.57, and 201.80
(104)
2. Full Prescribing Information: preceded by the numerical identifier for made this change for editorial reasons to
Contents the heading or subheading (§ 201.57(b)). correctly reflect the function of the
FDA has revised, on its own initiative, section. In response to comments, FDA
Like the proposed rule, the final rule the heading for this portion of the added certain format requirements for
requires that the labeling for new and labeling to read ‘‘Full Prescribing the Contents (see table 3 and comments
recently approved products include, Information: Contents’’ (Contents) 37 and 101).
after Highlights, a list of headings and instead of proposed ‘‘Comprehensive
subheadings contained in the FPI Prescribing Information: Index.’’ FDA
3. Full Prescribing Information products (see tables 1 and 2). The final requested FDA to clarify these proposed
rule establishes minimum requirements requirements.
FDA has revised, on its own initiative, for key graphic elements, including bold In addition, FDA has revised, on its
the heading for this portion of the type, bullet points, type size, spacing own initiative, ‘‘Contraindications’’ to
labeling to read ‘‘Full Prescribing and use of vertical and horizontal lines. emphasize that the section must only
Information’’ instead of proposed The final rule requires the same sections describe situations in which the
‘‘Comprehensive Prescribing for the labeling of these products as potential risks associated with drug use
Information.’’ FDA made this change to proposed except the major, substantive outweigh any possible benefit. FDA
more accurately reflect that this portion changes listed in table 4, which the believes that including relative or
of prescription drug labeling contains agency made in response to comments hypothetical hazards diminishes the
the information that FDA determined is and, in a few cases as noted, on its own usefulness of the section. For clarity and
necessary for the safe and effective use initiative. In addition, FDA made emphasis, FDA is requiring that ‘‘none’’
of the drug, but may not contain all revisions, none of which changed be stated when no contraindications are
known information about the drug (e.g., substantive requirements, to the known. Similarly, FDA deleted, on its
details of all clinical trials). ‘‘Dosage and Administration,’’ own initiative, proposed
The final rule revises the ‘‘Indications and Usage,’’ ‘‘Overdosage,’’ § 201.57(c)(9)(iii) because it was
requirements for the content and format ‘‘Clinical Pharmacology,’’ and ‘‘Drug redundant with requirements in
of the FPI in former §§ 201.56(d) and Interactions’’ sections. FDA made these ‘‘Warnings and Precautions’’ and
201.57 for new and recently approved changes in response to comments that ‘‘Contraindications.’’
TABLE 4.—SUBSTANTIVE CHANGES FROM THE PROPOSED RULE TO THE FINAL RULE: FULL PRESCRIBING INFORMATION
Description of Change From Proposed Rule
21 CFR Section in Final Rule See comment or section of this document (identified in parentheses) for more detailed information re-
garding the change.
201.57(c)(3) Dosage and Administration

• Revised to make clear that this section must include dosing recommendations based on clinical phar-
macologic data, certain dosage modifications, and specified compliance information (51–54)
201.57(c)(4) and 201.57(c)(17) How Supplied/Storage and Handling

• Reorganized information in proposed ‘‘How Supplied/Storage and Handling’’ (§ 201.57(c)(4)) such that
the information is now contained in two sections: § 201.57(c)(4) retitled ‘‘Dosage Forms and
Strengths’’ and ‘‘How Supplied/Storage and Handling’’ at § 201.57(c)(17) (41)
201.57(c)(7) Adverse Reactions

• Moved the ‘‘Adverse Reactions’’ section (proposed § 201.57(c)(9)) to follow ‘‘Warnings and Pre-
cautions’’ (38)
• Withdrew the proposed definition of adverse reaction and retained the definition at former § 201.57(g)
(designated in this final rule at § 201.80(g)), with a minor modification (68)
• Revised the requirements on how to classify and categorize adverse reactions and how to describe
adverse reaction rates (71-75)
• Revised to require a description of the overall adverse reaction profile based on entire safety data-
base (70 and 77)
201.57(c)(9) Use in Specific Populations

• Withdrew the proposed warning statements at §§ 201.57(c)(8)(i)(A)(4) and (c)(8)(i)(A)(5) for pregnancy
categories D and X and will continue to require the warning statements at former §§ 201.57(f)(6)(i)(d)
and (f)(6)(i)(e) be used (66)
• Withdrew the proposed revisions for the ‘‘Nursing Mothers’’ subsection at § 201.57(c)(8)(iii) and will
continue to use the language at former § 201.57(f)(8) (66)
201.57(c)(13)(ii) and 201.80(b)(2) In Vitro Data for Anti-infectives

• Deferred action on proposed §§ 201.57(c)(13)(ii) and 201.80(b)(2) that would have only permitted in
vitro data for anti-infective drugs not shown by adequate and well-controlled studies to be pertinent to
clinical use be included in labeling if a waiver was granted (81)
201.57(c)(18) and 201.80(f)(2) Patient Counseling Information

• Revised to require that the full text of FDA-approved patient labeling either accompany labeling or be
reprinted at the end of the labeling and clarified the type size requirements that apply (93 and 94)(see
table 7)
201.57(d)(6) Font size

• Revised to require that font for trade labeling be a minimum of 6-point type instead of 8-point type
(102)
201.57(c)(16) and 201.80(l) References

• Clarified requirements for including a reference (89)
B. Content and Format for Older approved patient labeling immediately information’’ on the product label in
Prescription Drug Products following the last section of the cases when it is currently required to be
Like the proposed rule, the final rule prescription drug labeling or having it used. These proposed requirements
redesignates former § 201.57 as § 201.80. accompany such labeling (proposed § 201.57(c)(4)(v) and
New § 201.80 provides content and (§ 201.80(f)(2))(see table 4 and comment (c)(12)(i)(D)) were also withdrawn.
format requirements for labeling of older 93).
• Addition of the font size provision The agency intends to conduct a
prescription drug products (older comprehensive evaluation of
products) that are not subject to the to redesignated § 201.80(f)(2) (on the
agency’s own initiative with information required to be contained on
labeling requirements at new § 201.57 product labels. If necessary, FDA will
(see tables 1 and 2). modifications made in response to
comments) (see table 4 and comments propose changes to these requirements
Section 201.80 is the same as former
93 and 94). after that evaluation has been
§ 201.57 with the following exceptions
that are the same as the changes for new completed.
C. Content of Prescription Drug Product
and more recently approved products: Labels III. Implementation
• Modifications that help ensure that
statements currently appearing in FDA has reconsidered its proposal to The final rule is effective June 30,
labeling for older products relating to revise the requirements for the content 2006. The final rule has the same
effectiveness or dosage and of prescription drug product labels implementation plan as proposed for
administration are sufficiently (proposed §§ 201.55 and 201.100(b)). In the revised labeling content and format
supported (§ 201.80(c)(2)(i), (c)(2)(ii), (j), response to comments, FDA has decided
requirements at §§ 201.56(d) and 201.57
and (m)(1)). to withdraw these proposed revisions at
for new and more recently approved
• Deletion of proposed § 201.80(b)(2) this time (see comments 106 and 107).
products (see table 5). Manufacturers of
regarding in vitro data for anti-infectives The agency had proposed to move
certain information about inactive older products that voluntarily elect to
(see table 4 and comment 81).
revise the format and content of their
• Deletion of ‘‘induced emesis’’ as an ingredients and storage conditions from
example of treatment procedures in the the product label to the prescription labeling to be consistent with
‘‘Overdosage’’ section of labeling. drug labeling and to remove the §§ 201.56(d) and 201.57 may submit a
• Revisions that allow manufacturers requirement to include the statement supplement with proposed labeling at
the option of either reprinting the FDA- ‘‘See package insert for dosage any time (see table 5).
TABLE 5.—IMPLEMENTATION PLAN

Applications (NDAs, BLAs, and Efficacy Supplements) Required to Time by Which Conforming Labeling Must Be Submitted to the
Conform to New Labeling Requirements Agency for Approval
Applications submitted on or after June 30, 2006 Time of submission
Applications pending on June 30, 2006 and applications approved 0 to June 30, 2009
1 year before June 30, 2006
Applications approved 1 to 2 years before June 30, 2006 June 30, 2010
Applications approved more than 5 years before June 30, 2006 Voluntarily at any time
As indicated in the proposed rule, the As the agency proposed (65 FR at drug labeling to make the information in
implementation plan for revised 81099), the provisions requiring FDA- labeling easier for health care
labeling for products approved or approved patient labeling to accompany practitioners to access, read, and use.
submitted for approval under an ANDA labeling (§§ 201.57(c)(18) and Elsewhere in this issue of the Federal
depends on the labeling of the listed 201.80(f)(2) of the final rule) will be Register, the agency is announcing the
drug referenced in the ANDA. In implemented by June 30, 2007. The availability of four guidance documents
accordance with § 314.94(a)(8) (21 CFR agency clarified this provision at on content and format of labeling.2
314.94(a)(8)), the labeling of a drug §§ 201.57 and 201.56(e)(6). These guidances are intended to assist
product submitted for approval under IV. Overview of Agency Initiatives to manufacturers and FDA reviewers in
an ANDA must be the same as the Improve the Content and Format of developing clear, concise, and
labeling of the listed drug referenced in Prescription Drug Labeling
the ANDA, except for changes required 2 The agency announces the availability of
because of differences approved under a The agency is engaged in a broad guidances in the Federal Register. Draft and final
suitability petition (§ 314.93 (21 CFR effort to improve the communication to guidances for the Center for Drug Evaluation and
314.93)) or because the drug product health care practitioners of information Research (CDER)-related information are posted on
the Internet at http://www.fda.gov/cder/guidance/
and the reference listed drug are necessary for the safe and effective use
index.htm. The Center for Biologics Evaluation and
produced or distributed by different of prescription drugs. A major Research (CBER)-related information is posted at
manufacturers. component of this effort is improvement http://www.fda.gov/cber/guidelines.htm (21 U.S.C.
of the content and format of prescription 371(h), 21 CFR 10.115).
accessible prescription drug labeling. The agency is also engaged in an this final rule, could dramatically
The four guidances are as follows: effort to revise the regulations improve the way practitioners obtain
1. A draft guidance entitled ‘‘Labeling concerning the content and format of information about prescription drugs
for Human Prescription Drug and the ‘‘Pregnancy’’ subsection of and, as a consequence, significantly
Biological Products—Implementing the prescription drug labeling (see the improve patient care.
New Content and Format notice of a 21 CFR part 15 hearing to
VI. Comments on the Proposed Rule
Requirements’’ (the new labeling format discuss the pregnancy category
guidance). This guidance, which is requirements (62 FR 41061, July 31, The agency received 97 comments on
intended to assist manufacturers in 1997) and the notice of a public the December 22, 2000, proposal.
complying with the provisions of this advisory committee meeting to discuss Comments were received from
final rule, includes, among other things, possible changes to pregnancy labeling prescription drug manufacturers and
how to determine what information (64 FR 23340, April 30, 1999)). related companies; trade organizations
from the FPI should be included in representing prescription drug
V. Implications of This Final Rule for manufacturers and other interested
Highlights. the Electronic Labeling Initiative
2. A draft guidance entitled parties; professional associations and
‘‘Warnings and Precautions, Developing standards for the organizations representing health care
Contraindications, and Boxed Warning conversion of paper labeling to an practitioners; health care and consumer
Sections of Labeling for Human electronic format is a high priority for advocacy organizations; individual
Prescription Drug and Biological the agency. On December 11, 2003, FDA physicians, pharmacists, and
Products—Content and Format’’ (the published its final rule in the Federal consumers; and others.
Register entitled ‘‘Requirements for
‘‘Warnings and Precautions’’ section A. General Comments on the Proposed
Submission of Labeling for Human
guidance). Rule
Prescription Drugs and Biologics in
3. A guidance entitled ‘‘Adverse Most comments expressed broad
Electronic Format’’ (68 FR 69009). The
Reactions Section of Labeling for agreement that prescription drug
final rule requires the content of
Human Prescription Drug and Biological labeling could be more effective in
prescription drug labeling, including
Products—Content and Format ‘‘ (the communicating drug information to
text, tables, and figures, to be submitted
‘‘Adverse Reactions’’ section guidance). to FDA in an electronic format that the health care practitioners and
The agency issued a draft of this agency can process, review, and archive. overwhelming support for the agency’s
guidance on June 21, 2000 (65 FR The agency views this final rule on goal of improving the content and
38563). the content and format of labeling as an format of prescription drug labeling to
4. A guidance entitled ‘‘Clinical essential step towards the success of its make information easier for health care
Studies Section of Labeling for electronic labeling initiative. The practitioners to access, read, and use.
Prescription Drug and Biological labeling format required by this rule for Many comments expressed approval
Products—Content and Format’’ (the new and more recently approved of all the major features of the proposal,
‘‘Clinical Studies’’ section guidance). products should facilitate transition to indicating that the proposed changes
The agency issued a draft of this an electronic format. The agency represent an important improvement in
guidance on July 9, 2001 (66 FR 35797). believes that an electronic version of the organization, clarity, and overall
The agency is also developing two labeling in the new format, particularly usefulness of prescription drug labeling.
additional guidances on the content and Highlights and Contents, will For example, there was near universal
format of specific sections of labeling— significantly expand health care support for the proposal to place at the
the ‘‘Clinical Pharmacology’’ and practitioners’ ability to access front of labeling those sections that
‘‘Dosage and Administration’’ sections. information in prescription drug practitioners refer to most frequently
In the future, the agency may develop labeling, enable them to rapidly obtain and consider most important, although
guidance for additional sections of answers to questions for a range of drug some comments recommended
prescription drug labeling, if necessary. products, and ultimately facilitate the sequences slightly different from those
FDA has undertaken additional development of a comprehensive proposed by FDA (see section VI.G of
rulemaking related to prescription drug repository for drug labeling. For this document). There was also broad
labeling. The agency published a final example, FDA envisions that an support for restructuring the old
rule in the Federal Register entitled electronic version of the new format ‘‘Precautions’’ section into new sections
‘‘Labeling Requirements for Systemic will eventually enable health care devoted to use in specific populations,
Antibacterial Drug Products Intended practitioners to quickly access labeling drug interactions, and patient
for Human Use’’ that became effective information for all drugs in a counseling information and for
on February 4, 2004 (68 FR 6062, pharmacologic or therapeutic class with combining the remainder of the
February 6, 2003). This rule requires a single electronic query. ‘‘Precautions’’ section with the
that the labeling for all systemic FDA realizes that this final rule will ‘‘Warnings’’ section.
antibacterial drug products (i.e., affect the agency’s existing electronic Comments from manufacturers, while
antibiotics and their synthetic labeling requirements and guidances strongly supportive of the agency’s
counterparts) intended for human use and will work to ensure consistency efforts to improve the content and
include certain statements about using with the electronic labeling initiative.3 format of labeling, generally expressed
antibiotics in a way that will reduce the The agency believes the electronic concerns about some of the major
development of drug-resistant bacterial labeling initiative, in conjunction with elements of the proposal. In particular,
strains. The rule encourages health care this new format for labeling described in as discussed in greater detail in sections
practitioners: (1) To prescribe systemic VI.C and VI.D of this document, many
antibacterial drugs only when clinically 3 See http://www.fda.gov/cder/guidance/ manufacturers were concerned about
indicated and (2) to counsel their index.htm under ‘‘Electronic Submissions’’ and the inclusion of Highlights.
http://www.fda.gov/cber/guidelines.htm for the
patients about the proper use of such most recent guidances on submission of labeling in
Manufacturers also expressed concern
drugs and the importance of taking them an electronic format for drug and biological about the proposed requirements to re-
exactly as directed. products, respectively. evaluate, within 1 year of the effective
date of the final rule, all prescription broad range of health care practitioners proposed format for Highlights is a good
drug labeling to identify and remove that rely on prescription drug labeling, design because it makes use of multiple
any claims for indications and dosing and has determined the optimal formats (e.g., text, tables, bulleted lists)
regimens that are not supported by ordering for labeling sections, as and bolded headings, which make the
substantial evidence and to remove in reflected in this final rule. labeling information more accessible.
vitro data that are not supported by FDA notes that the sections most One comment noted that, because
clinical data. commonly referred to by pharmacists in Highlights contains pointers to the
Specific issues raised by the the cited survey are the same as those location of more detailed information in
comments and the agency’s responses most commonly referred to by the FPI, the pointers will increase the
follow. physicians, although in a somewhat likelihood that health care practitioners
different rank order. FDA believes that, will refer to the FPI. The comment also
B. Comments on the Process for
although the rank order of the sections stated that the user-friendly Highlights
Development of the Proposed Rule
is not identical for the two groups, the format would be likely to increase the
As discussed in detail in the preamble formatting improvements required by frequency with which health care
to the proposed rule, FDA relied on this final rule make the information in practitioners consult the labeling for
focus group testing of physicians, a these sections readily accessible to all drug information and would enhance
national physician survey, and a public health care practitioners who use their ability to use the information.
meeting held in 1995 to develop the prescription drug labeling. Comments opposing inclusion of
labeling prototype that was used as the Highlights stated that manufacturers
basis for the proposal (65 FR 81082 at C. Highlights of Prescribing
would be forced to pick certain
81083 through 81085). Information—General Comments
important warnings listed in the FPI for
(Comment 1) Several comments FDA proposed to require that inclusion in Highlights and, because of
questioned the process that FDA used to prescription drug labeling for products space limitations, exclude other
develop the proposed rule. A number of described in proposed § 201.56(b)(1) important information. These comments
comments expressed concern that (i.e., new and more recently approved maintained that, by extracting from the
health care practitioners other than prescription drug products) contain FPI only selected portions of the
physicians were not surveyed or introductory prescribing information information needed for safe and
otherwise consulted. Two comments entitled ‘‘Highlights of Prescribing effective use, Highlights would omit
indicated that a majority of pharmacists Information’’ (proposed §§ 201.56(d) important information and lack detail
refer to prescription drug labeling at and 201.57(a)). and context, and might, therefore, be
least once a day. The comments cited a (Comment 2) Comments expressed misleading. They contended that these
survey finding that the sections most different opinions about the utility and shortcomings might outweigh any
frequently referred to by pharmacists patient care implications of Highlights. convenience derived from condensing
are, in descending order, ‘‘Dosage and Physicians, pharmacists, other health information into Highlights. One
Administration,’’ ‘‘Adverse Reactions,’’ care practitioners, health care advocacy comment maintained that the FPI is
‘‘Contraindications,’’ ‘‘Indications and groups, and professional societies and itself a condensation of a complex body
Usage,’’ ‘‘Warnings and Precautions,’’ organizations representing health care of information and that it is problematic
and ‘‘How Supplied/Storage and practitioners expressed unequivocal and illogical to try to further condense
Handling.’’ The comments urged FDA to enthusiasm about and uniform support the information from the FPI into
consult with all relevant audiences to for Highlights. Manufacturers, with Highlights.
revise prescription drug labeling and some exceptions, were opposed, or Several comments from
labels. strongly opposed, to the inclusion of manufacturers stated that the limited
FDA recognizes the important roles Highlights. content of Highlights is of concern
that health care practitioners other than Comments supporting Highlights because practitioners would have a
physicians play in the health care stated that it would be an excellent tendency to rely only on the information
delivery system and recognizes that vehicle for drawing attention to the in Highlights when making prescribing
prescription drug information is relied most important information about a decisions, even though that information
upon by health care practitioners other product, a useful and convenient source alone would not be an adequate basis
than physicians. The agency focused its for quick reminder information in for making such decisions. Some of
research efforts on how physicians use routine prescribing situations, and a these comments maintained that there is
labeling, because they are the principal useful vehicle to efficiently direct a lack of evidence to support the
intended audience (i.e., they use practitioners to the more detailed premise that Highlights will facilitate
labeling for prescribing decisions). The information in the FPI. Several practitioners’ access to more detailed
agency also sought input from all comments stated that Highlights is information in the FPI. They asserted
interested parties in the development of probably the most important innovation that there is a high likelihood that
the proposed rule, especially those in the proposed rule. One comment Highlights would be the only part of the
whose use of labeling could be expected stated that Highlights is the element of labeling read by practitioners.
to impact patient safety. Panelists and the proposal that will most enhance the Another comment stated that, rather
participants in the 1995 public meeting clinical utility of prescription drug than requiring inclusion of Highlights in
included nurse practitioners, labeling. Several comments stated that labeling, the agency and manufacturers
pharmacists, and physician assistants. by making prescription drug labeling should work together to make the FPI
Their comments and observations easier to navigate, Highlights would better.
directly contributed to refining the third help to make labeling easier for patients FDA has determined that the
version of FDA’s prototype into the and health care practitioners to Highlights provisions of the final rule
version that was the basis for the understand. are an essential element of the agency’s
proposed rule. Moreover, the agency has Several comments endorsed the efforts to improve the accessibility,
carefully reviewed and considered all Highlights format as a means of making readability, and usefulness of
comments received on the proposed labeling information more accessible. information in prescription drug
rule, which included comments from a Some comments stated that the labeling and reduce the number of
adverse reactions resulting from large amounts of complex information. (Comment 3) Some comments stated
medication errors due to misunderstood Highlights summarizes the information that FDA should do additional testing to
or incorrectly applied drug information. from the FPI that is most important for determine whether Highlights is
By means of focus group testing, a prescribing the drug safely and necessary to accomplish FDA’s goal of
nationwide physician survey, and a effectively and organizes it into logical making information in prescription drug
public meeting, the agency carefully groups, or ‘‘chunks,’’ to enhance labeling more useful and accessible or
evaluated the drug information needs of accessibility, retention, and access to whether the other proposed format
physicians and ways to best address the more detailed information. This changes, without Highlights (i.e., an
those needs in prescription drug design, combined with the use of index, reordering of the sections of the
labeling. Some of the principal findings multiple formats (e.g., tables, bulleted FPI, and enhanced formatting) would be
were that: (1) The relative importance of lists) and graphic emphasis (e.g., bolded adequate to accomplish the agency’s
information in labeling varies, (2) text), improves visual and cognitive goal. One comment requested that FDA
physicians typically refer to labeling to access to the information so that evaluate whether simply reordering the
answer a specific question, (3) practitioners can more easily find sections of the prescribing information
physicians have considerable difficulty information, and improves recall of the would be adequate to accomplish the
locating the information they need to information. agency’s goal. Some comments stated
make prescribing decisions, and (4) Importantly, Highlights must include that the agency should test whether the
physicians strongly prefer to have a identifying numbers indicating where in proposed format would change
separate introductory summary of the the FPI to find details of the information prescriber behavior as intended and
most important information contained that is cited or concisely summarized in lead to a reduction in medication errors.
in the full prescribing information, Highlights. In the final rule, FDA has The agency believes it is unnecessary
located at the beginning of labeling, to revised proposed § 201.57(a)(17) to compare the prototype labeling with
make it easier to find the information (§ 201.56(d)(3) in the final rule) to Highlights to the prototype labeling
necessary to prescribe the drug safely require that any information referenced without Highlights (i.e., a version with
and effectively (65 FR 81082 at 81083 in Highlights, not just subheadings, be a table of contents, reordered sections in
through 81085; see also Ref. 11). Many accompanied by the identifying number the FPI, and enhanced graphics, or a
of the comments submitted in response corresponding to the location of the version with only reordered sections
to the proposed rule concur with these information in the FPI. The agency and enhanced graphics). The
findings, particularly those from health requirements of this final rule are built
believes that these identifying numbers
care practitioners and their on extensive testing conducted by FDA,
will facilitate access to the detailed
organizations. established principles of cognitive
information in the FPI.
This preference for highlighting the processing, previous research conducted
most important information that is part The Highlights design—a broad array by FDA for OTC drug labeling, and
of a larger body of information is of important information in a discrete, evaluation of comments submitted in
consistent with good risk visually accessible location—also response to this proposal. FDA has
communication practices and with well- increases the variety of information that determined that Highlights, because it
established cognitive principles. The a practitioner is exposed to in a typical will efficiently and effectively convey
agency employed these principles in labeling referral. That is, the Highlights information about a drug product and
designing Highlights. design increases the likelihood that will help to facilitate the transition to
For example, cognitive research has practitioners will be exposed to and electronic labeling, is a vital component
shown that, because there is a limit to retain critical information about a drug of the efforts to reduce the numbers of
the amount of information that an in addition to the information that the adverse reactions from medication
individual can hold in memory at one practitioner sought in referring to the errors due to misunderstood or
time, individuals tend to organize labeling, such as the recommended incorrectly applied drug information.
similar information into ‘‘chunks’’ to: dose. The practitioner therefore is likely (Comment 4) In the proposed rule,
(1) Increase the amount of available to know more about a drug after FDA specifically sought comment on
space in memory and (2) facilitate exposure to labeling with Highlights whether, and under what
retrieval of information (Refs. 1 through than after exposure to labeling without circumstances, it might be inappropriate
3). ‘‘Chunking’’ complex information Highlights. In addition, by making to include the proposed Highlights in
into smaller, more manageable units labeling easier to use and an overall the labeling of a particular drug or drug
makes it easier to remember and process better source of drug information, the class.
information efficiently and effectively Highlights design is likely to increase The vast majority of comments
(decreases ‘‘cognitive load’’). the frequency with which practitioners supported Highlights for all products or
FDA research conducted during rely on labeling for prescription drug no products. One comment stated that if
development of new rules for OTC drug information. In a survey regarding the agency retains the requirement to
labeling demonstrated that ‘‘chunking’’ labeling for vaccines, 71 percent of include Highlights, all products
information in a standardized format physicians surveyed indicated that they required to have the new format should
with graphic emphasis on the most would increase their use of labeling if a be required to have Highlights. One
important information helped summary of prescribing information comment stated it would not be useful
individuals make correct product use were included in labeling (65 FR 81082 to include Highlights if the entire
decisions, decreased reading time, and at 81084). Highlights should result in labeling is very short (e.g., one page).
increased the individuals’ confidence in health care practitioners being better The agency concludes that there
their ability to use that information (Ref. informed about prescription drugs. should be no exceptions to the
4). This research supports the approach Therefore, the agency concludes that Highlights requirement for drugs subject
adopted in this final rule for prescription drug labeling with to the new content and format
prescription drug labeling. Highlights more effectively requirements at §§ 201.56(d) and 201.57.
In designing Highlights, the agency communicates drug information to The agency acknowledges that
employed established techniques to prescribers than labeling without prescription drug labeling for some
enhance effective communication of Highlights. drugs may be very short and that this
may result in short Highlights. However, about the difficulty involved in TABLE 6.—LOCATION OF STATEMENTS
as discussed previously, the agency has summarizing the complex and often REQUIRED TO BE INCLUDED IN LA-
determined that Highlights improves the lengthy information in the FPI (see e.g., BELING—Continued
usefulness, readability, and accessibility comments 16, 23 and 27), the agency
of information in prescription drug believes that it is essential for FDA to Location—Old
labeling and is consistent with good risk Location—New Format
review and approve most proposed Format
communication practices. changes to the information in
(Comment 5) Several comments stated Highlights. Accordingly, the agency is Precautions (Spe- Use in Specific Popu-
that there should be more specific cific Populations) lations
revising its regulations on supplements
criteria for selecting information for and other changes to an approved Precautions (Infor- Patient Counseling In-
inclusion in Highlights to ensure application. Under §§ 314.70(b)(2)(v)(C) mation for pa- formation
consistency for all drug products. These and (c)(6)(iii), and 601.12(f)(1) and tients)
comments stated that, without specific (f)(2)(i), applicants are required to
criteria, the information in Highlights obtain prior approval of any labeling How Supplied (or How Supplied/Storage
for different drugs within the same drug changes to Highlights, except for after How Sup- and Handling
class may be different, and these plied)
editorial or similar minor changes,
differences could be used to the including removal of a listed section(s)
competitive advantage or disadvantage Where statements are required in
from ‘‘Recent Major Changes’’ or a labeling but not in a specific labeling
of some products. Some comments change to the most recent revision date
stated that the agency should designate section, the agency may specify the
of the labeling. Sections 314.70(d)(2)(x)
location in the FPI for the statements for
the precise information that must be
and 601.12(f)(3)(i)(D) allow these the drug or class of drugs to ensure
included in Highlights. One comment
editorial and similar minor changes inconsistency within drug classes.
said that, for products with class
the labeling to be reported in an annual
Whether a specific statement required
labeling, FDA must designate which
report. by regulation must appear in Highlights
class labeling statements must be
included in Highlights to ensure will be determined by the agency.
In addition, as noted, the agency is
consistency among drugs in the class. making available guidance to assist (Comment 6) Several comments stated
Another comment stated that the manufacturers and FDA reviewers in that Highlights should mention the
relative importance of drug information, developing prescription drug labeling.drug’s therapeutic or pharmacologic
and, as a result, the basis for selecting This guidance addresses, among other class. They maintained that this
information for inclusion in the section, things, how to select information for information is informative to
can vary depending on a drug’s inclusion in Highlights (section IV ofpractitioners when the drug is a member
indication. The comment maintained this document). of an established class because it puts
that Highlights would have to provide the drug in a context with other
In some instances, a statement for a
therapies and helps prevent duplicative
for differences in safety profiles for drug or class of drugs is currently
drugs with multiple indications and therapy.
required by regulation to be included in The agency agrees that information
those that are used in different a specific section of prescription drug
populations. about a drug’s therapeutic or
labeling (e.g., § 201.21). In these cases,
pharmacologic class is important and
The agency believes that these
when converting labeling to the new appropriate for inclusion in Highlights.
concerns are not unique to Highlights.
format, the statements must be included
If a drug is a member of an established
The agency agrees that, for a given drug,
if there are significant differences in in the corresponding section in the new
therapeutic or pharmacologic class, the
safety profiles or dosing considerations format (e.g., a statement required to be
identity of that class can provide a
for different indications or populations, included in the ‘‘Boxed Warning’’ practitioner with important information
Highlights must reflect these section in the old format must be about what to expect from that product
differences. The agency also agrees that included in the ‘‘Boxed Warning’’ and how it relates to other therapeutic
it is critical to ensure accuracy and section in the new format). However, options. The agency also agrees with the
consistency in the information included some statements are currently requiredcomment that making the identity of a
in Highlights because it contains a to be included in labeling sections that
drug’s class more prominent could
summary of the most important have been altered or eliminated by this
reduce the likelihood of prescribers
information for prescribing the drug final rule. In these instances, the placing a patient on more than one
safely and effectively. statements must be located in the FPI as
therapy within the same class when
In general, however, the agency outlined in table 6. such use would not be appropriate.
believes that it would not be The agency believes that information
appropriate, or possible, to specify in TABLE 6.—LOCATION OF STATEMENTS about drug class is an important
the final rule the precise content of REQUIRED TO BE INCLUDED IN LA- supplement to the information
Highlights. Judgment will continue to be BELING contained in a drug’s ‘‘Indications and
necessary to determine what Usage’’ section and should be placed
information from the broad range of Location—Old under that heading in Highlights.
Location—New Format
information necessary for the safe and Format Accordingly, the agency has revised
effective use of the prescription drug proposed § 201.57(a)(6) to require that
appearing in the FPI must also appear Warnings Warnings and Pre- when a drug is a member of an
in Highlights (e.g., differences in safety cautions established pharmacologic class, the
profiles or dosing considerations for class must be identified in the
Precautions (Gen- Warnings and Pre-

differing indications or populations). eral) cautions ‘‘Indications and Usage’’ section in
However, because Highlights is a Highlights.
summary of the most important Precautions (Drug Drug Interactions (Comment 7) One comment stated
information for prescribing decisions interactions) that Highlights should also include
and some comments expressed concerns information about managing drug
overdose (recommended a new section which sections they reference most D. Comments on Product Liability
entitled ‘‘Toxicity and Overdose’’) and frequently. Implications of the Proposed Rule
characteristics by which a tablet can be The agency believes that the order of
identified (color, markings, shape, etc.). In the proposal, FDA requested
information in Highlights required by comments on the product liability
The agency acknowledges the the final rule gives sufficient
importance of information about implications of revising the labeling for
prominence to risk information. The prescription drugs.
managing drug overdose and agency also believes that the formatting
characteristics by which a tablet can be (Comment 12) In comments, some
requirements, the one-half page length manufacturers expressed concerns that,
identified and took care to make this restriction for Highlights (excluding
information prominent in the FPI. by highlighting selected information
space for a boxed warning, if one is from the FPI to the exclusion of
However, space for Highlights is limited required) (§ 201.57(d)(8)), and the
and the agency has made judgments information not highlighted, they make
limitations on the amount of themselves more vulnerable to product
about which information is most information that can be included in
important for safe and effective use and liability claims. Some of these
Highlights will ensure that all the comments also stated that the Highlights
thus must appear in Highlights. The information in Highlights has adequate
agency has concluded that information limitation statement, which states that
prominence and is visually accessible. Highlights does not contain all the
about managing overdose or product
identification characteristics (except (Comment 10) One comment information needed to prescribe a drug
scoring) will not be required in expressed concern about the safely and effectively and that
Highlights. The agency has retained implications of Highlights for FDA’s practitioners should also refer to the
scoring in Highlights because this initiative to improve pregnancy FPI, would not constitute an adequate
information is needed to appropriately labeling. The comment stated that the legal defense in a case alleging failure to
tailor a dose for some patients (e.g., a preliminary format FDA has discussed provide adequate warning of a drug’s
patient is unable to take two tablets of in public meetings (which would risks.
a drug because of a particular side replace the pregnancy category Based on the agency’s research and
effect, but is able to take one-and-one- designations) could not be readily analysis in developing the prototype
half tablets). condensed into an informative single labeling that was the basis for the
(Comment 8) One comment stated sentence in Highlights. The comment proposed rule (see comment 2), the
that the information presented in suggested that electronic labeling could agency has concluded that a labeling
Highlights should be in bulleted format potentially solve this problem by format that includes Highlights is more
to the extent possible to avoid linking to additional information about effective than a format that omits
redundancy with the information in the prescribing in specific patient Highlights. In response to the comments
FPI. populations and by linking to pregnancy and as discussed in the response to
FDA agrees that information registry databases and tertiary specialty comment 35, FDA has taken steps to
presented in Highlights, not otherwise texts as well. enhance the prominence of the
required to be bulleted under The agency anticipates that the Highlights limitation statement. FDA
§ 201.57(d)(4), should be succinctly planned revisions to the requirements believes the statement will be effective
summarized and in a format (e.g., for the ‘‘Pregnancy’’ subsection of in reminding prescribers that the
bulleted) that calls attention, and labeling are unlikely to affect the information in the Highlights should not
provides easy access, to the more information in Highlights about use of be relied on exclusively in making
detailed information in the FPI. drugs during pregnancy. The agency prescribing decisions and that it is
Highlights is not a verbatim repetition of agrees that the electronic labeling important to consult the more detailed
selected information contained in the initiative holds great promise for information in the FPI. We also believe
FPI. providing rapid access to related that this limitation statement will help
(Comment 9) One comment requested information of varying levels of to ensure that the labeling will be
that the sections in Highlights be complexity and detail, including considered in its entirety in any product
reordered to lend more prominence to information about drug exposure during liability action. FDA acknowledges the
risk information. The comment stated pregnancy. comment’s concerns and, as discussed
that all risk information, including more fully in response to comment 13,
(Comment 11) Several comments believes that under existing preemption
contraindications and drug interactions,
should be placed before the ‘‘Dosage recommended that there be an principles such product liability claims
and Administration’’ and ‘‘How educational campaign in conjunction would be preempted.
Supplied’’ sections. with the publication of the final rule to
(Comment 13) Some comments stated
ensure that practitioners understand that the new format requirements might
The order of the sections in Highlights
tracks the order of the corresponding that Highlights contains only limited have product liability implications for
sections in the FPI. The agency believes information and should not be relied on drugs that are not subject to the new
the order of information in Highlights without reference to the FPI. requirements. These comments
must be consistent with the FPI so that The agency agrees that there should expressed concern that labeling in the
practitioners can efficiently navigate be, and it plans to initiate, an old format might be characterized by
from Highlights to the corresponding educational campaign to familiarize plaintiffs as inferior to labeling in the
section of the FPI. As discussed in more health care practitioners with the new new format and, as a result, could be
detail in the preamble to the proposed labeling format. The agency also agrees used as evidence that a manufacturer
rule (65 FR 81082 at 81084), the revised that an important component of the did not provide adequate warnings.
order of the sections in the FPI was educational message should be that They requested that the agency state in
based on extensive focus group testing Highlights alone does not contain all the the final rule that FDA approval of
and surveys of physicians to determine information FDA has determined is labeling, whether it be in the old or new
which sections they believe are most needed to use a drug safely and format, preempts conflicting or contrary
important to prescribing decisions and effectively. State law, regulations, or decisions of a
court of law for purposes of product scientific information to monitor the of these cases, the court determined that
liability litigation. safety of products and to incorporate the State law claim could not proceed,
FDA believes that under existing information into the product’s labeling on the ground that the claim was
preemption principles, FDA approval of when appropriate. preempted by Federal law,5 or was not
labeling under the act, whether it be in Changes to labeling typically are properly before the court by operation of
the old or new format, preempts initiated by the sponsor, subject to FDA the doctrine of primary jurisdiction.6 In
conflicting or contrary State law. review, but are sometimes initiated by some cases, however, the court has
Indeed, the Department of Justice (DOJ), FDA. Under FDA regulations, to change permitted the claim to proceed.7
on behalf of FDA, has filed a number of labeling (except for editorial and other State law actions can rely on and
amicus briefs making this very point. In minor revisions), the sponsor must propagate interpretations of the act and
order to more fully address the submit a supplemental application fully FDA regulations that conflict with the
comments expressing concern about the explaining the basis for the change agency’s own interpretations and
product liability implications of revising (§§ 314.70 and 601.12(f) (21 CFR 314.70 frustrate the agency’s implementation of
the labeling for prescription drugs, we and 601.12(f))). FDA permits two kinds its statutory mandate. For example,
believe it would be useful to set forth in of labeling supplements: (1) Prior courts have rejected preemption in State
some detail the arguments made in approval supplements, which require law failure-to-warn cases on the ground
those amicus briefs. The discussion that FDA approval before a change is made that a manufacturer has latitude under
follows, therefore, represents the (§§ 314.70(b) and 601.12(f)(1)); and (2) FDA regulations to revise labeling by
government’s long standing views on ‘‘changes being effected’’ (CBE) adding or strengthening warning
preemption, with a particular emphasis supplements, which may be statements without first obtaining
on how that doctrine applies to State implemented before FDA approval, but permission from FDA. (See, e.g., Eve v.
laws that would require labeling that after FDA notification (§§ 314.70(c) and Sandoz Pharm. Corp., 2002 U.S. Dist.
conflicts with or is contrary to FDA- 601.12(f)(2)). While a sponsor is LEXIS 23965 (S.D. In. Jan. 28, 2002);
approved labeling. permitted to add risk information to the Ohler v. Purdue Pharma, L.P., 2002 U.S.
Under the act, FDA is the expert FPI without first obtaining FDA Dist. LEXIS 2368 (E.D. La. Jan. 22,
Federal public health agency charged by approval via a CBE supplement, FDA 2002); Motus v. Pfizer Inc., 127 F. Supp.
Congress with ensuring that drugs are reviews all such submissions and may 2d 1085 (C.D. Cal. 2000); Bansemer v.
safe and effective, and that their labeling later deny approval of the supplement, Smith Labs., Inc., 1988 U.S. Dist. LEXIS
adequately informs users of the risks and the labeling remains subject to 16208 (E.D. Wis. Sept. 12, 1988);
and benefits of the product and is enforcement action if the added McEwen v. Ortho Pharm Corp., 528 P.2d
truthful and not misleading. Under the information makes the labeling false or 522 (Ore. 1974).) In fact, the
act and FDA regulations, the agency misleading under section 502(a) of the determination whether labeling
makes approval decisions based not on act (21 U.S.C. 352). Thus, in practice, revisions are necessary is, in the end,
an abstract estimation of its safety and manufacturers typically consult with squarely and solely FDA’s under the act.
effectiveness, but rather on a FDA prior to adding risk information to A manufacturer may, under FDA
comprehensive scientific evaluation of labeling. As noted in response to regulations, strengthen a labeling
the product’s risks and benefits under comment 5, however, a sponsor may not warning, but in practice manufacturers
the conditions of use prescribed, use a CBE supplement to make most typically consult with FDA before doing
recommended, or suggested in the changes to Highlights. so to avoid implementing labeling
labeling (21 U.S.C. 355(d)). FDA Since the proposed rule was changes with which the agency
considers not only complex clinical published, FDA has learned of several ultimately might disagree (and that
issues related to the use of the product instances in which product liability therefore might subject the
in study populations, but also important lawsuits have directly threatened the manufacturer to enforcement action).
and practical public health issues agency’s ability to regulate manufacturer Another misunderstanding of the act
pertaining to the use of the product in dissemination of risk information for encouraged by State law actions is that
day-to-day clinical practice, such as the prescription drugs in accordance with FDA labeling requirements represent a
nature of the disease or condition for the act. In one case, for example, an minimum safety standard. According to
which the product will be indicated, individual plaintiff claimed that a drug many courts, State law serves as an
and the need for risk management manufacturer had a duty under appropriate source of supplementary
measures to help assure in clinical California State law to label its products safety regulation for drugs by
practice that the product maintains its with specific warnings that FDA had encouraging or requiring manufacturers
favorable benefit-risk balance. The specifically considered and rejected as to disseminate risk information beyond
centerpiece of risk management for scientifically unsubstantiated.4 In some that required by FDA under the act.
prescription drugs generally is the (See, e.g., Brochu v. Ortho Pharm. Corp.,
labeling which reflects thorough FDA 4 Dowhal v. SmithKline Beecham Consumer
642 F.2d 652 (1st Cir. 1981); Salmon v.
review of the pertinent scientific Healthcare, 2002 Cal. App. LEXIS 4384 (Cal. Ct. Parke-Davis and Co., 520 F.2d 1359 (4th
evidence and communicates to health App. 2002), reversed, 2004 Cal. LEXIS 3040 (Cal.
April 15, 2004). Cir. 1975); Caraker v. Sandoz Pharm.
care practitioners the agency’s formal, 5 E.g., Ehlis v. Shire Richwood, Inc., 233 F. Supp. Corp., 172 F. Supp. 2d 1018 (S.D. Ill.
authoritative conclusions regarding the 2d 1189, 1198 (D.N.D. 2002), aff’d on other grounds,
conditions under which the product can 367 F.3d 1013 (8th Cir. 2004). 7 Dowhal v. SmithKline Beecham Consumer
be used safely and effectively. FDA 6 E.g., Bernhardt v. Pfizer, Inc., 2000 U.S. Dist. Healthcare, 2002 Cal. App. LEXIS 4384 (Cal. Ct.
carefully controls the content of labeling LEXIS 16963 (S.D.N.Y. Nov. 16, 2000). This App. 2002), reversed, 2004 Cal. LEXIS 3040 (Cal.
doctrine allows a court to refer a matter to an April 15, 2004); Bernhardt v. Pfizer, Inc., 2000 U.S.
for a prescription drug, because such administrative agency for an initial determination Dist. LEXIS 16963 (S.D.N.Y. November 16, 2000);
labeling is FDA’s principal tool for
where the matter involves technical questions of Motus v. Pfizer, Inc., 127 F. Supp. 2d 1085 (C.D.
educating health care professionals fact and policy within the agency’s jurisdiction. If Cal. 2000), summary judgment granted, 196 F.
about the risks and benefits of the a court finds that the agency has primary Supp. 2d 984, 986 (C.D. Cal. 2001), aff’d, 2004 U.S.
jurisdiction, the court stays the matter and instructs App. LEXIS 1944 (9th Cir. February 9, 2004); In re
approved product to help ensure safe the plaintiff to initiate an action with the agency. Paxil Litigation, 2002 U.S. Dist. LEXIS 16221 (C.D.
and effective use. FDA continuously See, e.g., Israel v. Baxter Labs., Inc., 466 F.2d 272, Cal. August 16, 2002), transferred, 296 F. Supp. 2d
works to evaluate the latest available 283 (D.C. Cir. 1972); see also 21 CFR 10.60. 1374 (J.P.M.L. 2003).
2001); Mazur v. Merck & Co., Inc., 742 encourage, and in fact require, lay that the doctrine of preemption
F. Supp. 239 (E.D. Pa. 1990); In re judges and juries to second-guess the precluded the plaintiff’s claim from
Tetracycline Cases, 747 F. Supp. 543 assessment of benefits versus risks of a proceeding.8 The practice of addressing
(W.D. Mo. 1989).) In fact, FDA interprets specific drug to the general public—the conflicting State requirements through
the act to establish both a ‘‘floor’’ and central role of FDA—sometimes on participation in litigation (including
a ‘‘ceiling,’’ such that additional behalf of a single individual or group of product liability cases) in which the
disclosures of risk information can individuals. That individualized Government is not a party is not new.
expose a manufacturer to liability under reevaluation of the benefits and risks of For example, DOJ participated on FDA’s
the act if the additional statement is a product can result in relief—including behalf in favor of pre-emption in Jones
unsubstantiated or otherwise false or the threat of significant damage awards v. Rath Packing Company, 430 U.S. 519
misleading. Given the or penalties—that creates pressure on (1977), Grocery Manufacturers of
comprehensiveness of FDA regulation of manufacturers to attempt to add America, Inc. v. Gerace, 755 F.2d 993
drug safety, effectiveness, and labeling warnings that FDA has neither approved (2d Cir. 1985), Eli Lilly & Co., Inc. v.
under the act, additional requirements nor found to be scientifically required. Marshall, 850 S.W.2d 155 (Tex. 1993),
for the disclosure of risk information are This could encourage manufacturers to and Buckman Co. v. Plaintiffs’ Legal
not necessarily more protective of propose ‘‘defensive labeling’’ to avoid Comm., 531 U.S. 341, 352–53 (2001).
patients. Instead, they can erode and State liability, which, if implemented, FDA believes that State laws conflict
disrupt the careful and truthful could result in scientifically with and stand as an obstacle to
representation of benefits and risks that unsubstantiated warnings and achievement of the full objectives and
prescribers need to make appropriate underutilization of beneficial purposes of Federal law when they
judgments about drug use. Exaggeration treatments. purport to compel a firm to include in
of risk could discourage appropriate use FDA has previously preempted State labeling or advertising a statement that
of a beneficial drug. law requirements relating to drugs in FDA has considered and found
State law requirements can rulemaking proceedings. For example: scientifically unsubstantiated. In such
undermine safe and effective use in • In 1982, FDA issued regulations cases, including the statement in
other ways. In the preamble requiring tamper-resistant packaging for labeling or advertising would render the
accompanying the proposal, FDA noted OTC drugs. In the preamble drug misbranded under the act (21
that liability concerns were creating accompanying the regulations, FDA U.S.C. 352(a) and (f)). The agency
pressure on manufacturers to expand stated its intention that the regulations believes that State law conflicts with
labeling warnings to include speculative preempt any State or local requirements and stands as an obstacle to
risks and, thus, to limit physician that were ‘‘not identical to * * * [the achievement of the full objectives and
appreciation of potentially far more rule] in all respects’’ (47 FR 50442 at purposes of Federal law if it purports to
significant contraindications and side 50447, November 5, 1982). preclude a firm from including in
effects (65 FR 81082 at 81083). FDA has • In 1986, FDA issued regulations labeling or advertising a statement that
previously found that labeling that requiring aspirin manufacturers to is included in prescription drug
includes theoretical hazards not well- include in labeling a warning against labeling. By complying with the State
grounded in scientific evidence can use in treating chicken pox or flu law in such a case and removing the
cause meaningful risk information to symptoms in children due to the risk of statement from labeling, the firm would
‘‘lose its significance’’ (44 FR 37434 at Reye’s Syndrome. In the accompanying be omitting a statement required under
37447, June 26, 1979). Overwarning, just preamble, FDA said the regulations § 201.100(c)(1) as a condition on the
like underwarning, can similarly have a preempted ‘‘State and local packaging exemption from the requirement of
negative effect on patient safety and requirements that are not identical to it adequate directions for use, and the
public health. (See section X of this with respect to OTC aspirin-containing omission would misbrand the drug
document.) Similarly, State-law products for human use’’ (51 FR 8180 at under 21 U.S.C. 352(f)(1). The drug
attempts to impose additional warnings 8181, March 7, 1986). might also be misbranded on the ground
can lead to labeling that does not • In 1994, FDA amended 21 CFR that the omission is material within the
accurately portray a product’s risks, 20.63 to preempt State requirements for meaning of 21 U.S.C. 321(n) and makes
thereby potentially discouraging safe the disclosure of adverse event-related the labeling or advertising misleading
and effective use of approved products information treated as confidential under 21 U.S.C. 352(a) or (n).
or encouraging inappropriate use and under FDA regulations (59 FR 3944, Consistent with its court submissions
undermining the objectives of the act. January 27, 1994). (See also 47 FR and existing preemption principles,
(See, e.g., Dowhal v. SmithKline 54750, December 3, 1982) (‘‘FDA FDA believes that at least the following
Beecham Consumer Healthcare, 2002 believes that differing State OTC drug
Cal. App. LEXIS 4384 (Cal. Ct. App. pregnancy-nursing warning 8 The DOJ submissions in these cases relied on
2002) (allowing to proceed a lawsuit requirements would prevent the doctrine of implied preemption or primary
jurisdiction. Although the act itself contains no
involving a California State law accomplishment of the full purpose and general express pre-emption provision for drugs, a
requiring warnings in the labeling of objectives of the agency in issuing the provision of legislation amending the drug
nicotine replacement therapy products regulation and that, under the doctrine provisions addresses the relationship of the
that FDA had specifically found would of implied preemption, these State legislation to State law. Section 202 of the Drug
Amendments of 1962 (Public Law 87-781, Title II,
misbrand the products under the act), requirements are preempted by the section 202, 76 Stat. 793 (October 10, 1962))
reversed, 2004 Cal. LEXIS 3040 (Cal. regulation as a matter of law.’’) provides: ‘‘Nothing in the amendments made by
April 15, 2004).) As noted previously, DOJ has made this Act to the Federal Food, Drug, and Cosmetic
State law actions also threaten FDA’s submissions to courts in a number of Act shall be construed as invalidating any provision
of State law which would be valid in the absence
statutorily prescribed role as the expert cases in which private litigants asserted
of such amendments unless there is a direct and

Federal agency responsible for a State law basis for challenging the positive conflict between such amendments and
evaluating and regulating drugs. State adequacy of risk information provided such provision of State law.’’ The existence of a
legislative provision addressing pre-emption does
actions are not characterized by by manufacturers for drugs in not bar the operation of ordinary principles of
centralized expert evaluation of drug accordance with FDA requirements implied preemption (Geier v. American Honda
regulatory issues. Instead, they under the act. In each case, DOJ argued Motor Co., Inc., 529 U.S. 861, 869 (2000)).
claims would be preempted by its 495 (1996) (holding that the presence of by a new route of administration, or
regulation of prescription drug labeling: a State law damages remedy for with a novel drug delivery system.
(1) Claims that a drug sponsor breached violations of FDA requirements does not (Comment 15) Several comments
an obligation to warn by failing to put impose an additional requirement upon opposed, or expressed reservations
in Highlights or otherwise emphasize medical device manufacturers but about, the use of an inverted black
any information the substance of which ‘‘merely provides another reason for triangle to identify a product,
appears anywhere in the labeling; (2) manufacturers to comply with * * * indication, or dosage form that has been
claims that a drug sponsor breached an federal law’’); id. at 513 (O’Connor, J., approved for less than 3 years. There
obligation to warn by failing to include concurring in part and dissenting in were concerns that the symbol is not
in an advertisement any information the part); id)). But see Buckman Co. v. universally understood and could
substance of which appears anywhere in Plaintiffs’ Legal Comm., 531 U.S. 341, therefore be confusing to practitioners.
the labeling, in those cases where a 352–53 (2001) (holding that ‘‘fraud on One comment stated that use of icons to
drug’s sponsor has used Highlights the FDA’’ claims are preempted by convey public health information has
consistently with FDA draft guidance Federal law); 21 U.S.C. 337(a) historically been unsuccessful. Some of
regarding the ‘‘brief summary’’ in direct- (restricting the act enforcement to suits the comments stated that if the inverted
to-consumer advertising (‘‘Brief by the United States); In re Orthopedic black triangle were retained, the agency
Summary: Disclosing Risk Information Bone Screw Prods. Liability Litig., 159 would need to conduct an extensive
in Consumer-Directed Print F.3d 817, 824 (3d Cir. 1998) (‘‘Congress educational campaign to educate
Advertisements,’’ 69 FR 6308 (February has not created an express or implied practitioners about its meaning and
2004)) (see comment 112); (3) claims private cause of action for violations of purpose. Some comments also
that a sponsor breached an obligation to the FDCA or the MDA [Medical Device expressed the concern that labeling
warn by failing to include Amendments]’’). containing the symbol could be in
contraindications or warnings that are circulation much longer than 3 years
E. Highlights—Comments on Specific after approval, which would undermine
not supported by evidence that meets
Provisions the significance of the symbol. One
the standards set forth in this rule,
including § 201.57(c)(5) (requiring that The agency received comments on the comment stated that the symbol implies,
contraindications reflect ‘‘[k]nown following provisions of the proposed without basis, that newer drugs are
hazards and not theoretical rule relating to the content of inherently less safe than older drugs.
possibilities’’) and (c)(7); (4) claims that Highlights: Some comments stated that the criteria
a drug sponsor breached an obligation to • Drug names, dosage form, route of for when a new indication would
warn by failing to include a statement administration, and controlled extend the time for which a product
in labeling or in advertising, the substance symbol (proposed must have the inverted black triangle
substance of which had been proposed § 201.57(a)(1)) are not clear.
Two comments stated that a bold
to FDA for inclusion in labeling, if that In proposed § 201.57(a)(1), FDA
approval date might be more
statement was not required by FDA at specified the information concerning
informative than the inverted black
the time plaintiff claims the sponsor had the identity of the product that would
triangle. Another comment
an obligation to warn (unless FDA has be included at the beginning of recommended using the designation
made a finding that the sponsor Highlights. ‘‘New-Rx’’ to identify a product that has
withheld material information relating (Comment 14) One comment been approved for less than 3 years.
to the proposed warning before plaintiff recommended that this information be Other comments expressed strong
claims the sponsor had the obligation to moved above the title ‘‘Highlights of support for the inverted black triangle as
warn); (5) claims that a drug sponsor Prescribing Information’’ in Highlights. a mechanism to prompt practitioners to
breached an obligation to warn by The agency does not agree that the more carefully scrutinize the labeling of
failing to include in labeling or in information required by § 201.57(a)(1) newer products and more diligently
advertising a statement the substance of should be placed above the title report adverse events. The comments
which FDA has prohibited in labeling or ‘‘Highlights of Prescribing Information.’’ maintained that use of the inverted
advertising; and (6) claims that a drug’s The agency believes that the title of each black triangle could lead to earlier
sponsor breached an obligation to of the three major portions of detection of rare, serious adverse
plaintiff by making statements that FDA prescription drug labeling (‘‘Highlights reactions and, thus, could potentially
approved for inclusion in the drug’s of Prescribing Information,’’ ‘‘Full save lives. One comment suggested
label (unless FDA has made a finding Prescribing Information: Contents,’’ and extending the time that the inverted
that the sponsor withheld material ‘‘Full Prescribing Information’’) should black triangle would be required to 5
information relating to the statement). be placed at the beginning of the years.
Preemption would include not only corresponding information so that the The agency has reconsidered its
claims against manufacturers as title is readily apparent to users. proposal to require use of the inverted
described above, but also against health • Inverted black triangle (proposed black triangle to identify products that
care practitioners for claims related to § 201.57(a)(2)) have been marketed for less than 3
dissemination of risk information to FDA proposed to require that years. The agency continues to believe
patients beyond what is included in the products that contain a new molecular strongly in the goals of the inverted
labeling. (See, e.g., Bowman v. Songer, entity, new biological product, or new black triangle—to help ensure that
820 P.2d 1110 (Col. 1991).) combination of active ingredients have prescribers use a product with
FDA recognizes that FDA’s regulation in their labeling an inverted black particular care during its initial years of
of drug labeling will not preempt all triangle to indicate that the drug or drug marketing and to make prescribers more
State law actions. The Supreme Court combination had been approved in the diligent in reporting suspected adverse
has held that certain State law United States for less than 3 years reactions for newer products. However,
requirements that parallel FDA (proposed § 201.57(a)(2)). This proposal the agency agrees with comments that,
requirements may not be preempted also applied to marketed products in prescription drug labeling, the
(Medtronic, Inc. v. Lohr, 518 U.S. 470, approved for a new indication, for use inverted black triangle is not universally
understood, could be confusing to the that alerting a practitioner to the fact warnings be summarized concisely in
prescriber (even with a concerted that a drug has been marketed for an Highlights.
educational effort) and therefore may extended period could provide some (Comment 17) Several comments
not serve its intended purpose. The added assurance about the drug’s safety stated that inclusion of the full boxed
agency acknowledges that the margin based on cumulative, safe warning in Highlights and in the FPI
recommended ‘‘New-Rx’’ designation experience with the product. Therefore, was needlessly duplicative and
may be more informative than the the requirement to include the initial recommended that the boxed warning
inverted black triangle, but is concerned date of U.S. approval in Highlights will be included in only one location. One
that the ‘‘New-Rx’’ designation might not lapse 3 years after approval of the comment maintained the boxed warning
also be confusing because practitioners product for marketing. should appear only in the ‘‘Warnings
are not familiar with it. • Boxed warnings or and Precautions’’ section in the FPI.
The agency agrees with comments contraindications (proposed As discussed in the response to the
that use of the initial date of approval § 201.57(a)(4)) previous comment, the boxed warning
in the United States would be a better FDA proposed to require that the full in Highlights is required to be a
mechanism than the inverted black text of boxed warning(s) or summary of the complete boxed
triangle to call attention to the relative contraindication(s) required by warning in the FPI. Thus, the boxed
newness of a product. Therefore, the proposed § 201.57(c)(1) be included in warning in Highlights will not duplicate
final rule requires that Highlights Highlights unless the boxed warning the boxed warning in the FPI. The
include the year in which a drug was was longer than 20 lines, in which case agency believes that a summarized
initially approved in the United States. a summary of the contents of the boxed boxed warning must be included in
Highlights must contain the phrase warning would be required (proposed Highlights to ensure that practitioners
‘‘Initial U.S. Approval’’ followed by the § 201.57(a)(4)). The agency specifically are exposed to critical information at the
four-digit year of initial approval in bold sought comment on whether the full beginning of prescription drug labeling
face type (§ 201.57(a)(3) and (d)(5)). text of a boxed warning should be and that the complete boxed warning is
Because this statement takes up more included in Highlights, regardless of needed to expand on the summary in
space than the proposed inverted black length. Highlights.
triangle, the final rule requires that the (Comment 16) Some comments The agency does not agree that the
statement be placed on its own line supported the proposed 20-line complete boxed warning in the FPI
directly below the established name of limitation on the length of a boxed should be placed in the ‘‘Warnings and
the product (proper name of the product warning in Highlights. Other comments Precautions’’ section rather than at the
for biological products) rather than on recommended that the boxed warning in beginning of the FPI. Placement of the
the same line as the proprietary name Highlights always be a summarized complete boxed warning at the
(§ 201.57(a)(3)). version of the boxed warning in the FPI. beginning of the FPI, where it can be
In contrast to the proposed rule, the Others expressed concern that easily located, is consistent with good
final rule does not require identification summarizing boxed warnings might risk communication practices, as well as
of the initial date of U.S. approval of a result in the omission of key health care practitioner preferences
new indication for a new population, information or lead to articulated in public comments and
new route of administration, or novel misinterpretations of the warning. They FDA’s physician surveys and focus
delivery system. The agency agrees with stated that the boxed warning is already group research.
comments that expressed concerns that succinct and the language is carefully • Recent labeling changes (proposed
also requiring the inverted black triangle negotiated with FDA and, therefore, that § 201.57(a)(5))
for new indications, routes of the boxed warning should always be FDA proposed to require in Highlights
administration, and novel delivery included in its entirety in Highlights. a heading entitled ‘‘Recent Labeling
systems could diminish the significance The agency has retained the 20-line Changes’’ that identifies the sections in
of the inverted black triangle and could length limitation on boxed warnings in the FPI that contain recent FDA-
be confusing to practitioners. Similarly, Highlights. The agency believes that 20 approved or authorized substantive
the agency believes that referring to lines is sufficient space to alert labeling changes (proposed
multiple dates, including the date of practitioners to the critical risk § 201.57(a)(5)).
initial approval of a new indication, information contained in a boxed (Comment 18) In general, comments
new route of administration, or a novel warning and to refer them to more supported the addition of a ‘‘Recent
delivery system for a drug would be detailed information in the FPI Labeling Changes’’ heading to labeling
confusing and would diminish the (complete boxed warning and other and many comments thought the
significance of these references. The sections in the FPI). information would be very useful to
agency is, therefore, limiting The agency agrees with the comments practitioners. However, one comment
identification of the initial date of U.S. that stated that manufacturers should recommended that the proposed
approval to new molecular entities, new always be required to present heading ‘‘Recent Labeling Changes’’ be
biological products, or new summarized boxed warning information changed to ‘‘Sections Revised’’ to
combinations of active ingredients in Highlights. The agency has accommodate changes that, although no
because this is sufficient to accomplish determined that information from boxed longer truly recent, would be important
the goals of increasing prescriber warnings can readily be condensed to call to the attention of practitioners
vigilance and reporting of suspected without omitting critical risk for an extended period of time (e.g.,
adverse reactions when using newer information. The agency believes a through multiple labeling revisions).
products. summarized boxed warning in Another comment recommended that
The agency believes the date of initial Highlights, with references to more the heading be changed to ‘‘Last
U.S. approval will continue to be detailed information in the FPI, is the Labeling Revisions’’ to accommodate
informative throughout a product’s life most effective way to communicate changes that could no longer reasonably
cycle. Although the agency does not critical risk information to practitioners. be considered recent (e.g., a situation in
subscribe to the view that newer drugs The agency has revised proposed which years elapse between labeling
are inherently less safe, it does believe § 201.57(a)(4) to require that boxed changes).
The agency agrees that the proposed calendar year, some comments subheadings (proposed § 201.57(a)(6)).
heading should be changed to better recommended that each change This information would include major
reflect the function of including the appearing under ‘‘Recent Major limitations of use (e.g., particular
information. Thus, the final rule Changes’’ be dated in a month/year subsets of the populations, second line
requires the heading ‘‘Recent Major format so that practitioners can readily therapy status). The agency specifically
Changes’’ (§ 201.57(a)(5)). FDA believes identify the most recent changes. sought comment on whether the
that it is important to characterize the The agency agrees that it would be information required under the
changes listed under the heading as useful to date the labeling changes ‘‘Indications and Usage’’ heading of
both ‘‘recent’’ and ‘‘major’’ to draw identified under this heading. The Highlights should be presented verbatim
attention to the relative newness of the agency has, therefore, revised proposed from the FPI or summarized in a
changes and to let practitioners know § 201.57(a)(5) to require that sections of bulleted format.
that identified changes are significant to prescription drug labeling listed under (Comment 23) Several comments
clinical use of the drug (i.e., ‘‘Recent Major Changes’’ be followed by stated that it was important to
substantive), and not merely editorial. the month and year in which the change reproduce the ‘‘Indications and Usage’’
(Comment 19) In the proposal, the was incorporated in the labeling. section verbatim to prevent confusion or
agency specifically sought comment on (Comment 21) One comment misinterpretations. Other comments
whether there should be a time limit by recommended that the rule specify that maintained that there should be
which information under the proposed changes should be listed flexibility to reproduce the information
heading (now ‘‘Recent Major Changes’’) chronologically beginning with most in the ‘‘Indications and Usage’’ section
must be removed. Some comments recent. verbatim or summarize it in a bulleted
supported a 1-year time limit for The agency does not agree. Where format, depending on factors such as the
inclusion of information under the there are multiple recent changes and amount of information in the
proposed heading. Other comments those changes appear in more than one ‘‘Indications and Usage’’ section and
stated that there should be no fixed time section, to avoid confusion, the order in whether the information can be
limit for removal of information which the sections are listed under summarized and still effectively
identified as a recent labeling change. ‘‘Recent Major Changes’’ should be communicate what a practitioner should
These comments expressed concern that consistent with the order of the sections know about a drug’s indications. Other
requiring labeling to be revised for the in the FPI. FDA has revised proposed comments recommended that there be
sole purpose of removing information § 201.57(a)(5) accordingly. bulleted summaries of the indications in
from under the heading would lead to (Comment 22) Some comments all cases. One of these comments
unnecessary expense, and that such requested that the agency clarify how it suggested that each bullet be preceded
information be removed at the next will determine whether a labeling by an index number that corresponds
substantive labeling revision. Other change is substantive and thus required with the index number of the full
comments stated that no time limit to be included under ‘‘Recent Major description of the indication in the FPI.
should be imposed for removal, but that Changes.’’ The agency has determined that the
removal should occur at the first The agency recognizes that a product amount of information that must be
convenient opportunity after 1 year may have a large number of labeling included in Highlights from the
from the date of the labeling change. changes ranging from inclusion of very ‘‘Indications and Usage’’ section of the
Another comment stated that important new risk information to FPI will vary. In most cases, the
information should remain under the typographical or editorial changes. ‘‘Indications and Usage’’ section can be
‘‘Recent Major Changes’’ heading for 1 Identifying all these changes under readily condensed (e.g., bulleted format)
to 3 years after the change to keep ‘‘Recent Major Changes’’ would obscure to provide prescribers with an accurate
practitioners up-to-date on labeling the most significant changes and would and informative summary, even if there
changes. not be informative for practitioners. is space available in Highlights to
The agency agrees that, although there Therefore, the agency has revised reproduce the ‘‘Indications and Usage’’
should not be a rigid time limit for proposed § 201.57(a)(5) to require that section from the FPI in its entirety (i.e.,
removal of information from ‘‘Recent only substantive labeling changes in the the one-half page limit requirement
Major Changes,’’ the information should ‘‘Boxed Warning,’’ ‘‘Indications and would not be exceeded).
not remain in Highlights indefinitely. Usage,’’ ‘‘Dosage and Administration,’’ The agency recognizes that for some
The purpose of the heading is to alert ‘‘Contraindications,’’ and ‘‘Warnings products with many indications, it may
practitioners to recent substantive and Precautions’’ sections be included not be possible to limit Highlights to
labeling changes. The agency is under ‘‘Recent Major Changes.’’ These one-half page in length (§ 201.57(d)(8)),
concerned that the information might be would include only those changes that even using a summarized version of the
ignored by practitioners if it often are significant to the clinical use of the ‘‘Indications and Usage’’ section. In
identifies changes that are no longer drug and, therefore, have significant such cases, FDA may waive the one-half
recent. The agency will, therefore, clinical implications for practitioners page requirement and approve the
require that labeling changes identified (i.e., substantive changes). Thus, labeling with slightly longer Highlights
under this heading be deleted at the first ‘‘Recent Major Changes’’ would not (see comment 104).
reprinting of the labeling after the include any changes in the sections • Dosage and administration
change has been in labeling for 1 year. subject to this requirement that are (proposed § 201.57(a)(7))
This requirement should ensure that typographical or editorial. FDA proposed that Highlights
labeling changes identified under the • Indications and usage (proposed include, under a ‘‘Dosage and
‘‘Recent Major Changes’’ heading are § 201.57(a)(6)) Administration’’ heading, the most
current without imposing unnecessary FDA proposed to require that important information in the ‘‘Dosage
costs on industry by requiring labeling Highlights include an ‘‘Indications and and Administration’’ section of the FPI
revisions solely for the purpose of Usage’’ heading that contains a concise (proposed § 201.57(a)(7)).
removing the information. statement of each of the product’s (Comment 24) One comment
(Comment 20) Because there could be indications, as specified in proposed recommended that ‘‘Dosage and
multiple changes to labeling in a § 201.57(c)(2), with any appropriate Administration’’ in Highlights include,
in addition to the usual recommended about how to adjust dosages for various Precautions’’ section of the FPI. Rather,
doses, a range of doses known to be specific populations would in many they are more likely to be discussed in
effective, and in particular, doses lower cases require a great deal of space. the ‘‘Adverse Reactions’’ section of the
than the usual recommended doses. The Therefore, FDA is not requiring that FPI. The comment recommended that
comment stated that 76.2 percent of all such information be included in the most common adverse reactions be
adverse reactions are dose-related and Highlights. listed under a separate section in
many patients respond to lower doses • Warnings and precautions Highlights immediately following the
than those recommended in labeling. (proposed § 201.57(a)(10)) contact information for reporting
Therefore, the comment suggested, FDA proposed to require that suspected serious adverse reactions.
lower doses may prevent adverse Highlights include, under a ‘‘Warnings The agency agrees that it may be
reactions. and Precautions’’ heading, a concise confusing to include under the
FDA agrees that it is important to summary of the most clinically ‘‘Warnings and Precautions’’ heading in
include in labeling the full range of significant aspects of the ‘‘Warnings and Highlights information that is derived
doses that FDA has concluded are Precautions’’ section of the FPI from both the ‘‘Warnings and
effective. The agency has revised (proposed § 201.57(a)(7)). The Precautions’’ and ‘‘Adverse Reactions’’
proposed § 201.57(a)(7) to clarify the information chosen from the FPI would sections of the FPI. The agency is,
range of doses to be included under the include those warnings and precautions therefore, revising proposed § 201.57(a)
‘‘Dosage and Administration’’ heading that affect prescribing because of their by adding to Highlights a heading
in Highlights. severity and consequent influence on entitled ‘‘Adverse Reactions’’
(Comment 25) Several comments the decision to use the drug, because (§ 201.57(a)(11)) that is required to
supported tabular presentation of monitoring of them is critical to safe use follow the ‘‘Warnings and Precautions’’
dosage and administration information of the drug, or because measures can be section. Information under the ‘‘Adverse
in Highlights. One comment proposed taken to prevent or mitigate harm. Reactions’’ heading must include: (1) A
the use of a titration dose column (a (Comment 27) Some comments listing of the most frequently occurring
visual tool to depict a drug’s titration requested clarification of the scope of adverse reactions identified in the
regimen) in Highlights for drugs for information to be included in Highlights ‘‘Adverse Reactions’’ section in the FPI
which titration is relevant. One under the ‘‘Warnings and Precautions’’ and (2) contact information for reporting
comment maintained that the dosage heading. Comments expressed concern suspected adverse reactions. The
adjustment statement in the prototype that summarizing selected safety sequence in which the information is
that accompanied the proposed rule information from the ‘‘Warnings and presented in Highlights—the most
should be highlighted and enlarged. Precautions’’ section of the FPI might frequently occurring adverse reactions
FDA agrees with the comment that cause some important safety followed by contact information for
supported use of a tabular format for information to be omitted from reporting suspected adverse reactions—
‘‘Dosage and Administration’’ in Highlights. is unchanged from the proposed rule.
Highlights. However, because a tabular ‘‘Warnings and Precautions’’ in (Comment 29) One comment
format or a titration dose column may Highlights serves to: (1) Identify the requested clarification about whether
not be appropriate for all drug products, most clinically significant risks only information that is supported by
FDA is not requiring use of these discussed in the ‘‘Warnings and clinical data would be appropriate for
formats under the ‘‘Dosage and Precautions’’ section in the FPI, (2) inclusion in Highlights.
Administration’’ heading. concisely summarize the salient features In most cases, the risk information in
With respect to highlighting and of those risks, and (3) direct the Highlights would be based on clinical
enlarging the dosage adjustment practitioner to the more detailed data. However, risk information derived
statement in the prototype, FDA discussion of risks in the FPI. from animal data could be appropriate
believes that bolded type is sufficient to Information under the ‘‘Warnings and for inclusion in Highlights. For
draw attention to particularly important Precautions’’ heading in Highlights will example, warnings about a drug’s risks
dosage adjustment statements and that typically include those risks that: (1) in pregnancy could be based entirely on
enlarging the statement is not necessary. Affect decisions about whether to animal data and might be appropriate
Enlarging only dosage adjustment prescribe a drug, (2) require monitoring for inclusion in Highlights. In such
information in Highlights would make of patients to ensure safe use of the cases, Highlights must present only the
this information appear more significant drug, or (3) require that measures be clinically significant conclusions about
than other information in Highlights, taken to prevent or mitigate harm. The risk in pregnancy (e.g., significant
which would not be appropriate. agency has revised § 201.57(a)(10) to teratogen) and not include a discussion
Therefore, FDA is not requiring that make clear the scope of information to of the animal data that are the basis for
dosage adjustment statements in include under this heading. the risk information presented.
Highlights be in larger font than other Because the risks identified under the • ADR reporting contacts (proposed
information in Highlights. ‘‘Warnings and Precautions’’ heading in § 201.57(a)(11))
(Comment 26) One comment Highlights will refer the prescriber to FDA proposed (proposed
requested that when the labeling states the full discussion in the ‘‘Warnings and § 201.57(a)(11)) to require that
that there may be a need for dosage Precautions’’ section of the FPI, the Highlights include, for drug products
adjustments in patients with renal or agency believes that important risk other than vaccines, a statement
hepatic impairment, it also specify how information will not be overlooked by following the information under the
to adjust the dose or dosing interval. practitioners. ‘‘Warnings and Precautions’’ heading:
Highlights identifies important (Comment 28) One comment stated ‘‘To report SUSPECTED SERIOUS
information about the need for dosage that it would be misleading to include ADRs, call (insert name of
adjustments in specific populations and the most common adverse reactions manufacturer) at (insert manufacturer’s
refers to the section of the FPI where under ‘‘Warnings and Precautions’’ in phone number) or FDA’s MedWatch at
more detailed information about how to Highlights because the most common (insert the current FDA MedWatch
adjust doses can be obtained. FDA adverse reactions are not likely to be number).’’ For vaccines, the following
believes that complete information discussed in the ‘‘Warnings and statement would be required: ‘‘To report
SUSPECTED SERIOUS ADRs, call reporting contact information. The to also include the phone number of the
(insert name of manufacturer) at (insert agency does not believe that also FDA review division that approved the
manufacturer’s phone number) or including contact information in the drug. FDA review divisions are not the
VAERS at (insert the current VAERS FPI, even if moved to the beginning of initial point of contact for postmarketing
number).’’ The agency specifically the FPI, would result in meaningfully adverse reaction reports; therefore,
requested comment on whether it is expanding the number of practitioners manufacturers and practitioners should
necessary to include a contact number who become aware of the contact not send these reports to the review
for reporting suspected adverse information. Therefore repeating the divisions for processing. It is critical
reactions in both Highlights and the contact information in the FPI would that these reports be directed to the
‘‘Warnings and Precautions’’ section of not have a meaningful effect on the location(s) in FDA that are responsible
the FPI. extent to which practitioners report for receiving and processing these
(Comment 30) Some comments stated adverse events. The agency also does reports so that they are evaluated and
that the contact information should be not believe that placing the contact analyzed in an appropriate manner.
in both Highlights and FPI to make it information for reporting suspected The agency agrees with comments
more convenient to access and increase adverse reactions only in the FPI would recommending that, in addition to their
the likelihood that practitioners will be afford the information adequate phone number, manufacturers include
prompted to report suspected adverse prominence. Accordingly, the final rule the direct link to the section of their
reactions. Other comments stated that it was revised to delete the proposed Web site for voluntary reporting of
would not be necessary to include requirement at § 201.57(c)(6)(v) that adverse reactions. The agency has
contact information in both places contact information for adverse reaction revised proposed § 201.57(a)(11) to
because prominent placement of the reporting be included in the ‘‘Warnings require the address of the Web site, if
information in Highlights alone would and Precautions’’ section in the FPI. The one is available. The agency will not
be sufficient to encourage practitioners agency believes it is unnecessary to require that manufacturers create a Web
to report adverse reactions. Some further increase the prominence of the site to meet this requirement.
comments agreed that one location adverse reaction reporting contact The agency has also decided to
would be sufficient, but because those information. Its current location— require that the adverse reaction
comments also opposed inclusion of immediately following the listing of the reporting contact information include
Highlights in labeling, they most common adverse reactions—is the the FDA Web site address for voluntary
recommended including the contact appropriate location, and the bolding reporting of adverse reactions
information in the FPI. Other comments and use of capitalization are sufficient (currently, http://www.fda.gov/
suggested locating the contact to call attention to the information and medwatch for drug products except
information at the beginning of the distinguish it from adjacent information. vaccines and http://www.fda.gov/vaers
labeling or in a ‘‘box’’ to increase its The agency does not agree that the for vaccines). This Web site has become
prominence. One comment adverse reaction reporting contact an increasingly important source of
recommended that the information be information should be omitted from adverse reaction reports. The agency has
included only once and in close labeling because it is not considered concluded that providing practitioners
proximity to the name and address of prescribing information. Including with the convenience of being able to
the manufacturer in the FPI. The adverse reaction reporting contact submit an adverse reaction report
comment maintained that it is not information in labeling enables electronically may encourage reporting
intuitive to look for adverse reaction practitioners to report adverse reactions of adverse reactions that might not
reporting contact information under to FDA promptly. The agency monitors otherwise be reported. Thus, the agency
‘‘Warnings and Precautions.’’ One these reports and analyzes the adverse believes it is very important to require
comment objected to inclusion of any reactions data to determine whether identification of this Web site address in
adverse reaction reporting contact labeling revisions are necessary for safe labeling, in addition to the FDA
information in labeling. That comment and effective use. telephone number.
maintained that contact information is (Comment 31) Some comments (Comment 32) Two comments stated
not prescribing information and thus recommended that only the that all adverse reactions should be
not appropriate for inclusion in labeling manufacturer’s phone number be reported, and not just serious adverse
and, moreover, that there is no evidence included in prescription drug labeling, reactions.
that inclusion of such information in while others agreed that including the The agency agrees that practitioners
labeling will facilitate reporting of MedWatch phone number is important should not be discouraged from
adverse reactions. because manufacturers’ phone numbers reporting adverse reactions that might
The agency agrees with the comments are subject to change. One comment not be considered serious. Certain
that support inclusion of contact requested that a telephone number for adverse reactions that are not
information for reporting adverse the relevant FDA review division also considered serious can be clinically
reactions only in Highlights. Because be included. Two comments significant. Moreover, practitioners may
the contact information is featured recommended including the not always be able to determine whether
prominently in Highlights—bolded and manufacturer’s Web site in the reporting an adverse reaction meets the regulatory
set apart from other information—the contact information. definition of serious (21 CFR 310.305(b),
agency believes that this is sufficient to The agency agrees that it is important 21 CFR 312.32(a), 21 CFR 314.80(a), and
make practitioners aware of the to include both the manufacturer’s 21 CFR 600.80(a)). Also, there are
appropriate contacts to report adverse phone number and FDA’s phone limitations on the extent to which a
reactions and to encourage them to number for voluntary reporting of drug’s risks (serious and nonserious
report suspected adverse reactions. The adverse reactions. The agency believes adverse reactions) can be delineated
agency also believes that as prescribers that providing practitioners two options before marketing. The agency, therefore,
become familiar with the content of for reporting adverse reactions will help believes that practitioners should be
Highlights, they will become ensure that they always have someone encouraged to submit all suspected
increasingly aware of and familiar with to contact about an adverse reaction. adverse reactions to the manufacturer or
the location of the adverse reaction The agency believes it is not appropriate FDA, without regard to the seriousness
of the reaction, to facilitate faster and result, may be confusing. Decisions it is necessary to require both an index
more accurate characterization of a about use of a drug in pregnancy should and Highlights. As discussed in section
drug’s risk profile. Accordingly, FDA be based on careful consideration of II of this document, the agency has
has revised proposed § 201.57(a)(11) to available data, not simply on a reference decided, on its own initiative, to change
require that the statement for adverse to the pregnancy category. the title (now ‘‘Full Prescribing
reaction reporting contact information • Highlights limitation statement Information: Contents’’) to better reflect
refer to all suspected adverse reactions, (proposed § 201.57(a)(15)) the function of this portion of the
not just serious ones. FDA proposed (proposed labeling.
• Drug interactions (proposed § 201.57(a)(15)) to require that (Comment 36) Most comments
§ 201.57(a)(12)) Highlights include the statement: supported inclusion of an index
FDA proposed to require that ‘‘These highlights do not include all the (hereafter Contents). They maintained
Highlights contain a ‘‘Drug Interactions’’ information needed to prescribe (insert that Highlights alone cannot be relied
heading that would include, with any name of drug product) safely and upon to help locate all drug information
appropriate subheadings, a concise effectively. See (insert name of drug in the FPI because Highlights is not
summary of the drug interaction product)’s comprehensive prescribing comprehensive (Highlights includes
information in the FPI (i.e., prescription information provided below.’’ information from only certain sections
or over-the-counter drugs or foods that (Comment 35) Several comments of the FPI). They stated that a table of
interact in clinically significant ways recommended that the Highlights contents is necessary to quickly and
with the product)(proposed limitation statement be made more easily direct the reader to sections of the
§ 201.57(a)(12)). prominent by moving the statement to FPI that are not referred to in Highlights.
(Comment 33) Several comments the beginning of Highlights. In addition, Other comments stated that, despite the
strongly supported inclusion of ‘‘Drug several comments recommended distinct purposes served by Highlights
Interactions’’ as a separate heading in revisions to the language of the and Contents, the agency should
Highlights. One comment recommended statement, such as including that consider consolidating them to save
requiring separate subheadings for drug- practitioners ‘‘must’’ consult the space. Some comments stated that there
drug, drug-food, drug-laboratory, and comprehensive prescribing information, need not be both because they have
possibly drug-herbal interactions. in addition to Highlights, to use a drug similar functions and recommended
FDA will not require that ‘‘Drug safely and effectively. that Contents be deleted if Highlights is
Interactions’’ in Highlights include The agency agrees that it is important retained. One comment recommended
specific subheadings depending on to emphasize to prescribers that that prescription drug labeling include
whether the interaction is a drug-drug, Highlights does not include all the neither Contents nor Highlights. The
drug-food, drug-herbal, or drug- information needed to use a drug safely comment stated that the reordered and
laboratory interaction. Use of these and effectively and that placement of reformatted FPI itself is adequate to
subheadings is typically most the statement at the beginning of facilitate practitioners’ access to
appropriate when a drug has a large Highlights increases the prominence of information in labeling.
number of interactions in each of these this message. Therefore, FDA has FDA continues to believe that
categories. In other cases, it is unlikely revised proposed § 201.57(a)(15) to Highlights and Contents serve different
to provide additional clarification require that the statement appear at the purposes and has determined that both
sufficient to justify use of space for the beginning of Highlights (§ 201.57(a)(1)). should be retained. Highlights presents
subheadings. The agency does not agree, however, a succinct summary of the information
• Use in specific populations that it is necessary to revise the in the FPI that is most crucial for safe
(proposed § 201.57(a)(13)) language of the Highlights limitations and effective use, with cross-references
FDA proposed to require that statement. Recognizing that FDA cannot to direct prescribers to more details in
Highlights contain a ‘‘Use in Specific require practitioners to consult the FPI, the FPI. In contrast, Contents serves as
Populations’’ heading (proposed the agency believes that the language in a navigational tool that references all the
§ 201.57(a)(13)). The agency proposed this statement, with two minor editorial sections and subsections in the FPI,
that this heading include, with any changes, very clearly states the some of which will not be referenced in
appropriate subheadings, a concise limitations of Highlights. Highlights. Therefore, the agency
summary of information from this believes Contents has a unique and
section of the FPI on any clinically F. Comments on the Index (Proposed meaningful function in making
important differences in response or use § 201.57(b)) information in the FPI accessible to
of the drug in specific populations. FDA proposed to require that practitioners.
(Comment 34) One comment prescription drug labeling for products In addition, Highlights and Contents
requested that the agency specify that described in proposed § 201.56(b)(1) both figure prominently in FDA’s plans
the pregnancy category designation be (i.e., new and more recently approved to convert prescription drug labeling to
included under the ‘‘Use in Specific prescription drug products) contain an an electronic format (see section V of
Populations’’ heading in Highlights index entitled ‘‘Comprehensive this document). The Contents will
because the pregnancy category quickly Prescribing Information: Index’’ provide hyperlinks to all sections and
communicates whether use of a drug is (proposed § 201.57(b)). The index would subsections of the FPI, enabling
appropriate during pregnancy. list the subheadings required under practitioners to navigate the labeling
The agency does not agree that proposed § 201.56(d)(1), if not omitted more easily. Highlights will provide
pregnancy category designations are under proposed § 201.56(d)(3), and each hyperlinks to the most frequently
appropriate for inclusion in Highlights optional subheading included in the FPI referenced and, typically, most
or that they are effective in quickly under proposed § 201.56(d)(5). Each important prescribing information,
communicating whether use of a drug is subheading would be required to be allowing rapid access to more detailed
appropriate during pregnancy. The preceded by its corresponding index information on these critical topics.
agency believes the pregnancy category, number or identifier. (Comment 37) One comment
in isolation, tends to oversimplify the In the proposal, the agency recommended that, for sections of
risks of drugs in pregnancy and, as a specifically sought comment on whether labeling that are omitted from the FPI
because they are not applicable, the groups, public comments, and its own information in the section will be
agency consider including the section experience) to be most important to, and related to risk. The section is, therefore,
number and heading in Contents most commonly referenced by, health more appropriately placed among the
followed by the statement ‘‘not care practitioners. For example, other labeling sections related to risk. In
applicable,’’ rather than omitting the proposed § 201.57(c)(1) would require addition, the agency believes that all
section number and heading. The that any boxed warning(s) be the first dosing information should be
comment noted that the prototype substantive information to appear in the consolidated in a single section. If there
labeling in the proposed rule omitted a FPI, proposed § 201.57(c)(2) would are specific recommendations for dosage
section and also omitted the listing of require that the ‘‘Indications and Usage’’ regimen modifications for use in
the section heading in Contents, and section follow any boxed warnings in specific populations, those
that this omission might confuse the FPI, and proposed § 201.57(c)(3) modifications must be described in the
practitioners. would require that the ‘‘Dosage and ‘‘Dosage and Administration’’ section
The purpose of Contents is to set forth Administration’’ section follow the (see § 201.57(c)(3)).
the sections and subsections included in ‘‘Indications and Usage’’ section in the (Comment 39) One comment
the FPI. For many drug products, some FPI. requested that the agency require a
sections and subsections are not (Comment 38) Virtually all the ‘‘Product Title’’ section at the beginning
applicable (e.g., ‘‘Drug Abuse and comments supported the proposed of the FPI. The comment maintained
Dependence,’’ ‘‘References’’). Currently, reordering of the FPI to give greater that the title is short and repeating it
these sections are, in most cases, simply prominence to the sections that would be useful to practitioners to avoid
omitted from the labeling without practitioners consider most important confusion.
discussion in accordance with former and refer to most often. Many comments The option to include a ‘‘Product
§ 201.56(d)(3). The agency believes that agreed that the reordering, by better Title’’ section is a vestige of the
this practice should continue, but reflecting the way the information in the prescription drug labeling rule finalized
recognizes that because identifying FPI is used, would make the FPI more in 1979 (44 FR 37434, June 26, 1979).
numbers are now required to be used for useful and accessible to practitioners. The optional ‘‘Product Title’’ section
labeling of new and recently approved Some comments, while supportive of was incorporated in the labeling
products, this practice may initially be the reordering generally, recommended regulations at that time in response to a
confusing for some. The agency certain changes to the sequence of the comment to the proposed rule that was
considered the comment’s suggestion sections. One comment requested that the basis for the 1979 final rule (44 FR
that the section identifying number and the ‘‘Adverse Reactions’’ section be 37440). The comment stated that the
heading be included in Contents moved from its present location proposed labeling requirements did not
followed by the statement ‘‘not following the ‘‘Use in Specific require identification of the product at
applicable’’ for labeling that omits a Populations’’ section and be placed the beginning of labeling. Instead, the
required section or subsection, but immediately after the ‘‘Warnings and first required element in the proposed
believes that this is not the best Precautions’’ section. The comment also labeling regulations was the
approach because of space recommended that the ‘‘Use in Specific ‘‘Description’’ section. The comment
considerations. Instead, to minimize any Populations’’ section be moved from its recommended, and the agency agreed,
potential confusion regarding omitted location following the ‘‘Drug that certain sections of the
sections, the agency has revised Interactions’’ section and be placed ‘‘Description’’ section could be pulled
proposed § 201.56(d)(3) (designated in immediately after the ‘‘Dosage and out of that section and used as a
this final rule as § 201.56(d)(4)) to Administration’’ section. The comment ‘‘Product Title’’ section at the beginning
require in these cases that the Contents maintained that use in specific of labeling.
heading be followed by an asterisk and populations frequently involves Under this final rule, a ‘‘Product
that the following statement be included modifications to dose or dosage Title’’ section is not needed for labeling
at the end of Contents: ‘‘* Sections or regimen, so it would be logical to place subject to the requirements of new
subsections omitted from the full the section in close proximity to the § 201.57, because under final
prescribing information are not listed.’’ ‘‘Dosage and Administration’’ section. § 201.57(a)(2), Highlights includes the
In addition, for legal clarity, FDA The agency agrees that it would be name of the drug, dosage form, and
revised proposed § 201.56(d)(3) and advantageous to group together the two route of administration and, for
(e)(3) (§ 201.56(d)(4) and (e)(3) in this major risk information sections—the controlled substances, the controlled
final rule) to make clear that clearly ‘‘Warnings and Precautions’’ and substance symbol. Because this
inapplicable sections, subsections, or ‘‘Adverse Reactions’’ sections. Placing information will appear at the beginning
specific information are omitted from the two sections sequentially of labeling and is similar to the
labeling. consolidates risk information in one information required under the
location and helps put in context the ‘‘Product Title’’ section, the agency
G. Full Prescribing Information— relative seriousness of the adverse believes it is not necessary or useful to
Comments on the Reorganization reactions discussed in labeling. Thus, provide the option to include a
FDA proposed to revise, for products FDA has revised proposed § 201.57(c) to ‘‘Product Title’’ section at the beginning
described in proposed § 201.56(b)(1) require that the ‘‘Adverse Reactions’’ of the FPI. Accordingly, the agency has
(new and more recently approved section follow the ‘‘Warnings and deleted proposed § 201.56(d)(4) from the
prescription drug products), the content Precautions’’ section. requirements for products described in
and format requirements of prescription The agency does not agree with the § 201.57(b)(1) (new and more recently
drug labeling at then-current recommendation to place the ‘‘Use in approved drug products). This revision
§§ 201.56(d) and 201.57. These revisions Specific Populations’’ section does not have any effect on the ‘‘Product
included, in proposed §§ 201.56(d) and immediately after the ‘‘Dosage and Title’’ provision in current regulations
201.57(c), reordering the information in Administration’’ section. Although (§ 201.56(e)(4)), which this final rule
the FPI to make more prominent those some of the information in the ‘‘Use in retains for products subject to § 201.80.
sections that the agency identified Specific Populations’’ section will have (Comment 40) One comment stated
(based on the physician surveys, focus implications for dosing, most of the that, if the agency retains the
requirement for the boxed warning in section toward the end of the labeling agency recognizes the complexity of
both Highlights and the FPI, the boxed (§ 201.57(c)(17)). (See comments 55 and these issues and, therefore, is making
warning in the FPI should be placed in 107 for discussion of revisions (i.e., available the new labeling format
the ‘‘Warnings and Precautions’’ section addition of imprinting as an example of guidance to assist in determining how to
rather than at the beginning of the FPI. an identifying characteristic and reorganize existing labeling information
The agency disagrees. The agency deletion of proposed § 201.57(c)(4)(v)).) into the new format (see section IV of
believes that the summary sections in FDA also has decided to require that this document).
Highlights should appear in the same information identified by prescribers as
order as the corresponding sections in H. Full Prescribing Information—
frequently referenced (i.e., dosage forms
the FPI to facilitate access to the more Comments on Specific Provisions
and strengths and some product
detailed information contained in the identification information) be included As noted previously, for products
corresponding sections in the FPI. The in a section entitled ‘‘Dosage Forms and described in proposed § 201.56(b)(1)
risk information presented in a boxed Strengths’’ (§ 201.57(c)(4)) following the (new and more recently approved
warning is of such importance that it ‘‘Dosage and Administration’’ section. prescription drug products), FDA
warrants placement in the most The agency believes that moving the proposed to revise the content and
prominent locations. ‘‘How Supplied/Storage and Handling’’ format requirements at then-current
(Comment 41) Some comments section toward the end of labeling will § 201.57 (proposed § 201.57(c)). A
recommended that the ‘‘How Supplied/ make it easier for pharmacists to locate discussion of the comments pertaining
Storage and Handling’’ section be kept product identification, packaging, and to these provisions and the agency’s
at the end of the FPI, rather than moved storage information. Retaining critical responses follow.
toward the front of the FPI, as proposed. prescribing information in the ‘‘Dosage • Boxed warning (proposed
The comments expressed concern that, Forms and Strengths’’ section will § 201.57(c)(1))
because of the variable length of the continue to meet the needs of FDA proposed to require that a boxed
three labeling sections that precede the prescribers by keeping available dosage warning in the FPI be preceded by an
‘‘How Supplied/Storage and Handling’’ forms and strengths information exclamation point (!) for indexing
section, it would not be in a consistent together with information about dosage purposes (proposed § 201.57(c)(1)). The
location; therefore, practitioners would and administration. Under this final agency specifically requested comment
have more difficulty locating the section rule, some product identification on the different types of icons that could
than if it were always at the end of the information (e.g., shape, color, coating, be used to signal the boxed warning and
FPI. One comment stated that scoring, and imprinting) may be on the costs and benefits of different
pharmacists frequently access this required to appear in both the ‘‘Dosage icon types.
section for information about storage Forms and Strengths’’ and ‘‘How (Comment 43) Several comments
conditions and that it would be more Supplied/Storage and Handling’’ stated that an icon is unnecessary
appropriate to place the section just sections. FDA believes that the product because practitioners are familiar with
before the ‘‘Patient Counseling identification information should be the meaning of a boxed warning and the
Information’’ near the end of the included in both sections to preserve box itself is sufficient to call attention
labeling, where pharmacists are the integrity and comprehensibility of to the warning. Some comments
accustomed to finding it. each section. observed that the exclamation point was
The proposed placement of the ‘‘How (Comment 42) One comment not a sufficiently distinct symbol
Supplied/Storage and Handling’’ section requested that the agency clarify the because it could be confused with the
following the ‘‘Dosage and conditions under which it would be numeral 1 and might be particularly
Administration’’ section was based on appropriate, when amending existing difficult to recognize in small font.
input from physicians who were labeling to the new labeling format, to Some comments expressed concern
surveyed about which information in move certain information from a section about using any icon that is not
labeling is most important and in old labeling to a different section in universally understood. One comment
frequently referenced. Physicians new labeling. For example, the recommended that a stop sign be used
indicated that their use of the ‘‘Dosage comment asked what criteria would be as it has a universally recognized
and Administration’’ section and the used to determine whether information meaning. Other comments expressed
‘‘How Supplied/Storage and Handling’’ on use in specific populations, currently concern about added printing and
section is linked. Physicians commonly contained in the ‘‘Clinical software costs associated with any icon
refer to the ‘‘Dosage and Pharmacology’’ section, should be requirement.
Administration’’ section for dosing moved to the new ‘‘Use in Specific FDA has reconsidered requiring an
information and then to the ‘‘How Populations’’ section. exclamation point, or any other icon, to
Supplied/Storage and Handling’’ section The agency expects that, in many identify a boxed warning. FDA agrees
for available dosage strengths and cases, amending labeling to meet new that the single black line box around the
dosage forms. For this reason, the § 201.57(c) will involve rearranging warning information is understood by
agency believes that keeping dosing and large segments (sections and practitioners in the United States and is
dosage forms and strengths information subsections) of information in existing sufficient to draw attention to the
together in the labeling is important. labeling without substantially changing warning information. Therefore, the
However, the agency recognizes that, the content. In some cases, however, it agency is not requiring an exclamation
under proposed § 201.57(c)(4), the will be necessary to parse information point or any other icon preceding the
‘‘How Supplied/Storage and Handling’’ from several parts of the existing boxed warning in the FPI. Sections
section would often have contained labeling into a new section. When 201.56(d)(1), 201.57(a)(4), and (c)(1) of
lengthy lists of available packaging and information is to be consolidated into a the final rule have been revised to
product identification information that new section, or when information is remove the requirement.
may distract prescribers from other required in several places, there may be • Indications and usage (proposed
important information. For this reason, uncertainty about how the information § 201.57(c)(2)(i))
and in view of the comments received, should be divided into portions for FDA proposed to require that the
the agency has decided to move this clarity and to avoid redundancy. The ‘‘Indications and Usage’’ section of the
FPI (proposed § 201.57(c)(2)(i)) contain require that this section of the FPI who need a drug (e.g., microbe
the same information as required at identify specific tests needed for susceptibility testing). The comment
then-current § 201.57(c)(1) except that selection or monitoring of the patients stated that it is not practical to
outdated examples of indications were who need the drug and describe, if recommend specific microbial
removed. available, information on the susceptibility testing when empirical
(Comment 44) One comment approximate kind, degree, and duration diagnosis is common.
recommended that the ‘‘Indications and of improvement to be anticipated. Specific tests for selecting and
Usage’’ section be retitled ‘‘Food and (Comment 46) One comment monitoring patients would be described
Drug Administration—Approved Uses.’’ requested that the ‘‘Indications and when they are necessary for safe and
The comment stated that the phrase Usage’’ section specify the type of effective use. Therefore, the requirement
‘‘indications and usage’’ is regulatory clinical trial that has been conducted to in final § 201.57(c)(2)(i)(C) that the
jargon that is not meaningful to support each indication (e.g., placebo- ‘‘Indications and Usage’’ section
practitioners or patients. controlled, active-controlled). identify specific tests needed for
The agency does not believe it would The agency believes that the ‘‘Clinical selecting and monitoring patients does
be worthwhile to change the title of the Studies’’ section is the appropriate not require that the ‘‘Indications and
section in the manner recommended by section of labeling to discuss the details Usage’’ section routinely state that
the comment. The agency does not agree (e.g., trial design, outcome) of clinical microbial susceptibility testing must be
that ‘‘indications and usage’’ is jargon trials, not the ‘‘Indications and Usage’’ done. The requirement addresses
and not meaningful to practitioners. section. The agency has concluded that situations in which a drug is indicated
FDA believes practitioners are familiar greater clarity about the scope of the for a specific therapeutic niche that can
with the section heading and information to be included in the be identified by microbe susceptibility
understand that the uses described in ‘‘Indications and Usage’’ section is testing. For example, the ‘‘Indications
this section are those for which FDA has warranted and has revised proposed and Usage’’ section might specify that a
found to be safe and effective. § 201.57(c)(2) accordingly. This revision drug is indicated to treat penicillin-
(Comment 45) One comment stated is consistent with having, as stated in resistant pneumococci. The description
that the ‘‘Indications and Usage’’ section the preamble to the proposed rule, a of the drug’s activity provides critical
should include approved uses in more focused ‘‘Indications and Usage’’ prescribing information.
pregnancy. section (65 FR 81082 at 81091). • Indications and usage—lack of
The agency agrees, in part. Uses that (Comment 47) FDA received one evidence statement (proposed
have been specifically studied for comment that strongly supported the § 201.57(c)(2)(iv)(D))
conditions unique to pregnancy and for proposed modification of the FDA proposed to revise then-current
which a drug has been demonstrated to ‘‘Indications and Usage’’ section to § 201.57(c)(3)(iv), which provided that
be safe and effective (e.g., to induce require that limitations in usefulness or in situations where there is a common
labor) would be appropriate for in data supporting approval be belief that a drug may be effective for a
inclusion in the ‘‘Indications and specified. One comment stated that the certain use or condition or the drug is
Usage’’ section. Ordinarily, however, requirement should be modified to commonly used for that condition but
special considerations about the use of specifically require discussion of the preponderance of the evidence
a drug in pregnancy for indications that differential drug effects in shows the drug is ineffective, the
do not differ from the general subpopulations with varying genetic ‘‘Indications and Usage’’ section must
population would be placed in the ‘‘Use characteristics. state that the drug is ineffective
in Specific Populations’’ section. FDA agrees that the ‘‘Indications and (proposed § 201.57(c)(2)(iv)(D)). The
• Indications and usage—scope of Usage’’ section must discuss differences revision proposed to expand this
information (proposed in drug effectiveness in subgroups for requirement to situations in which a
§ 201.57(c)(2)(iv)(A)) which there is substantial evidence for drug may be effective for a use but the
FDA proposed to revise the such differences. The proposed preponderance of the evidence shows
requirement at then-current language was not intended to limit the that the therapeutic benefits of the
§ 201.57(c)(3)(i) to state that if evidence scope of the requirement to particular product do not generally outweigh its
is available to support the safety and subgroups. The provision applies to any risks. In such situations, under sections
effectiveness of the drug only in identifiable subgroup with a clearly 201(n) (21 U.S.C. 321) and 502(a) of the
selected subgroups of the larger different response to a drug. The agency act, the agency can require that the
population with the disease or believes the language in final ‘‘Indications and Usage’’ section state
condition (e.g., patients with mild § 201.57(c)(2)(i)(B) and (c)(2)(i)(D) that there is a lack of evidence that the
disease or patients in a special age makes clear that the section must drug is effective or safe for that use.
group) or if evidence to support the discuss differential drug effects for all (Comment 49) One comment
indication is based on surrogate types of patient subgroups for which requested that the agency provide
endpoints, then the available evidence there is substantial evidence examples to clarify what it intends by
and the limitations on the usefulness of establishing differences in effects. If this new requirement.
the drug (or in the case of surrogate dosage modification is necessary based Anti-arrhythmia drugs are an example
endpoints, the limitations of the on genetic characteristics, this must be of a category of drugs to which the new
supporting efficacy data) must be described in the ‘‘Dosage and requirement in final § 201.57(c)(2)(ii)
described succinctly in the ‘‘Indications Administration’’ section. FDA has could apply. They are typically effective
and Usage’’ section (proposed revised proposed § 201.57(c)(3) in restoring or maintaining normal sinus
§ 201.57(c)(2)(iv)(A)). FDA proposed, accordingly (see § 201.57(c)(3)(i)(H) of rhythm for a variety of types of rhythm
further, to require reference to the final rule). disturbances, but because of the
‘‘Clinical Studies’’ section of the FPI (Comment 48) One comment potential for pro-arrhythmic effects,
(proposed § 201.57(c)(15)) for a detailed requested that FDA make clear when the they are typically indicated for only the
discussion of the methodology and ‘‘Indications and Usage’’ section must more serious clinical situations in
results of clinical studies relevant to include specific tests needed for which their benefits outweigh their
such limitation(s). FDA also proposed to selection and monitoring of patients risks. For example, an anti-arrhythmic
drug may be indicated for sustained interaction be included in the ‘‘Dosage include a statement indicating that there
ventricular arrhythmia, but specifically and Administration’’ section. is no such information.
not indicated for premature ventricular (Comment 52) One comment The agency agrees that information
contractions. requested that all intravenous dosing about appropriate time of day to take a
• Dosage and administration regimens in labeling be expressed in medication or other dosing
(proposed § 201.57(c)(3)) rates of milligrams per hour. The considerations must be included in the
FDA proposed to require that the comment pointed out that rates are ‘‘Dosage and Administration’’ section if
‘‘Dosage and Administration’’ section of expressed in milligrams per minute and this information is necessary for safe
the FPI (proposed § 201.57(c)(3)) contain milligrams per hour. The comment and effective use (e.g., if a significant
the same information as required in maintained that expressing all such amount of a therapeutic effect is lost if
then-current § 201.57(j), except that the rates in milligrams per hour would the drug is not taken on an empty
section must include efficacious or toxic avoid the need to recalculate rates and stomach). Therefore, the agency has
drug or metabolite concentration ranges thus reduce the likelihood of revised proposed § 201.57(c)(3) to
and therapeutic concentration windows medication errors. require that clinically significant dosing
for drug or metabolite(s) where The agency does not agree that always information (e.g., clinically significant
established and when clinically requiring rates of administration for food effects) be included in the ‘‘Dosage
important. FDA proposed to require intravenous medications to be expressed and Administration’’ section. Similarly,
information on therapeutic drug in milligrams per hour would avoid the the agency has revised proposed
concentration monitoring (TDM), when need to recalculate rates of infusion and § 201.57(c)(13)(i)(B) of the ‘‘Clinical
clinically necessary. The proposed thus reduce medication errors. The Pharmacology’’ section to clarify that
provision also specified that dosing agency believes that these rates should certain recommendations regarding
regimens must not be implied or be expressed per time unit that is most pharmacodynamic effects included in
suggested in other sections of labeling if appropriate to the interval over which a other sections of labeling, such as the
medication is to be administered. This ‘‘Dosage and Administration’’ section,
not included in this section. FDA has
approach will eliminate, to the extent must not be repeated in the ‘‘Clinical
retained this provision in the final rule
possible, the need to recalculate rates Pharmacology’’ section.
with some editorial revisions
and should, therefore, minimize error. The agency agrees that rigid
(§ 201.57(c)(3)). (Comment 53) One comment stated compliance with the dosage regimen
(Comment 50) One comment asked that, with respect to clinically important can be critical to safe and effective drug
the agency to clarify whether the effectiveness and/or toxic drug and/or therapy and information about how to
language in proposed § 201.57(c)(3), metabolite concentration ranges and manage noncompliance is important for
‘‘upper limit beyond which safety and therapeutic concentration windows in practitioners. Therefore, FDA has
effectiveness have not been the ‘‘Dosage and Administration’’ revised proposed § 201.57(c)(3) to make
established,’’ is referring to maximum section, effectiveness information other clear that important considerations
tolerated dose. than information on TDM would more concerning compliance with the dosage
The language does not refer to the appropriately be placed in the ‘‘Clinical regimen must be included.
maximum tolerated dose. The upper Pharmacology’’ section. The comment The agency believes that the labeling
limit beyond which safety and further stated that, if the concentration should not include a separate section
effectiveness have not been established range concerned safety, it would more devoted to the importance of
would ordinarily refer to: (1) The largest appropriately be included in the compliance with a drug’s dosage
dose demonstrated to be safe and ‘‘Warnings and Precautions’’ section. regimen or information on what to do
effective in controlled clinical trials, (2) The ‘‘Dosage and Administration’’ about missed doses, because this
the largest dose evaluated that showed section must identify efficacious or information is most appropriately
an increase in effectiveness (i.e., where toxic concentration windows of the drug contained in other sections of the
studied larger doses provided no or its metabolites, if established and labeling (e.g., ‘‘Dosage and
additional benefit), or (3) the largest clinically significant, and information Administration,’’ ‘‘Clinical
dose beyond which safety has not been on TDM, when TDM is necessary. Pharmacology,’’ ‘‘Patient Counseling
established or an unacceptable risk has Clinically relevant background Information’’). The agency believes that
been demonstrated. information supporting the need for it would not be useful to include a
(Comment 51) One comment TDM could appear in other sections of statement in the labeling indicating that
requested that the agency make it clear labeling as appropriate (e.g., ‘‘Clinical there is no information available about
that any dosage adjustments discussed Pharmacology,’’ ‘‘Clinical Studies,’’ management of noncompliance (e.g.,
in the ‘‘Drug Interactions’’ section ‘‘Adverse Reactions’’). missed doses).
should also be presented in the ‘‘Dosage (Comment 54) Two comments • How supplied/storage and handling
and Administration’’ section. recommended including instructions on (proposed § 201.57(c)(4))
The agency agrees that when there is the appropriate time of day to take a FDA proposed to require that the
specific information about how to adjust drug and other dosing conditions (e.g., ‘‘How Supplied/Storage and Handling’’
dosage because of a drug interaction, take with food, take on an empty section of the FPI (proposed
this information must be included in the stomach) in the ‘‘Dosage and § 201.57(c)(4)) contain the same
‘‘Dosage and Administration’’ section. Administration’’ section of the labeling. information as required at then-current
The ‘‘Dosage and Administration’’ One comment requested that the § 201.57(k), except that a new provision
section should also refer the reader to labeling include a section concerning was added at proposed § 201.57(c)(4)(v).
the more detailed discussion of the drug the importance of compliance with the Proposed § 201.57(c)(4)(v) would
interaction in the ‘‘Drug Interactions’’ dosage regimen and instructions on require a statement specifying the type
and ‘‘Clinical Pharmacology’’ sections. what to do about missed doses and of container to be used by pharmacists
In response to this comment, FDA has noncompliance in general. The in dispensing the product. Comments
modified proposed § 201.57(c)(3) to comment requested that, in the absence pertaining to proposed § 201.57(c)(4)(v)
require that information on dosage of data to support instructions on what are addressed in section VI.J of this
adjustments needed because of a drug to do about noncompliance, the labeling document (‘‘Comments on Revisions to
Container Labels’’; see comments 106 Precautions’’ section. The comments adverse reactions in the ‘‘Warnings and
through 110). Comment 41 addresses agreed with FDA’s findings, based on Precautions’’ section from ‘‘serious’’ to
relocation of the ‘‘How Supplied/ physician surveys and focus testing, that ‘‘clinically significant’’ adverse
Storage and Handling’’ section to the distinction between warnings and reactions. There was concern that the
§ 201.57(c)(17) and the retention of precautions is not meaningful to significance of the adverse reactions
critical prescribing information in the practitioners who use labeling. The discussed in the ‘‘Warnings and
‘‘Dosage Forms and Strengths’’ section comments stated that the combined Precautions’’ section would be diluted
at § 201.57(c)(4). A comment pertaining section would make the discussion of by the inclusion of less serious adverse
to the format for and type of information risk information in labeling less reactions in the section, thus
contained in these sections is discussed repetitive, less confusing, and more undermining the value of the section.
here. accessible. Other comments expressed concern that
(Comment 55) One comment (Comment 56) In the proposal, the ‘‘clinically significant’’ is subject to
recommended including product agency specifically sought comment on interpretation and could, in application,
identity markings in this section. The whether there should be standardized result in inconsistency across labeling
comment also recommended bulleted or headings for categories of adverse for different products.
tabular presentation of product identity reactions in the proposed ‘‘Warnings As discussed in the preamble
markings, color, flavor, package sizes, and Precautions’’ section and, if there accompanying the proposed rule (65 FR
strengths, storage conditions, etc., to should be, what standardized headings 81082 at 81092), ‘‘serious’’ was changed
make such information more accessible. would be appropriate. to ‘‘clinically significant’’ to expand the
FDA agrees with the comment that Comments uniformly opposed scope of the ‘‘Warnings and
product identity markings are useful for standardized headings to categorize Precautions’’ section to allow for
practitioners and, therefore, now adverse reactions in the ‘‘Warnings and inclusion of adverse reactions that may
includes imprinting as an example of an Precautions’’ section. Comments not meet the regulatory definition of
identifying characteristic in both the expressed concern that standardized ‘‘serious’’ (§ 312.32(a)), but nonetheless
‘‘Dosage Forms and Strengths’’ and the headings would not provide sufficient have a significant impact on clinical use
‘‘How Supplied/Storage and Handling’’ flexibility to accommodate the diversity of the drug. The agency believes that
sections of the final rule. FDA also of risk information that might be information on both types of adverse
agrees that presenting information about appropriate for inclusion in the reactions is necessary for practitioners
product identity markings, color, flavor, ‘‘Warnings and Precautions’’ section. to prescribe products safely and
package sizes, strengths, storage FDA agrees that standardized effectively and must, therefore, be
conditions, and other identifying headings should not be required in the included in the ‘‘Warnings and
information in a bulleted or table format ‘‘Warnings and Precautions’’ section Precautions’’ section. The agency
will make the information more because a requirement to place risk acknowledges that inclusion of less
accessible, particularly where the information under prescribed headings serious but clinically significant adverse
product has many dosage forms and could make the information less clear or reactions may add to the overall length
strengths. However, because the amount more difficult to find. of the ‘‘Warnings and Precautions’’
and content of information can vary (Comment 57) One comment section of labeling for certain drugs. The
significantly from product to product, requested clarification of the agency does not agree, however, that the
FDA is not requiring a specific format. requirement in proposed effect will be to dilute or deemphasize
• Warnings and precautions § 201.57(c)(6)(iii) that the ‘‘Warnings the importance of serious adverse
(proposed § 201.57(c)(6)) and Precautions’’ section identify any reactions contained in the section. The
FDA proposed to revise the content of laboratory tests that ‘‘may be helpful’’ in agency believes that limiting inclusion
the ‘‘Warnings’’ and ‘‘Precautions’’ following a patient’s response or of nonserious adverse reactions to only
sections. First, FDA proposed to require identifying possible adverse reactions. those that have significant impact on
that information on drug interactions, The comment maintained that the therapeutic decisionmaking (e.g., may
information on specific populations language ‘‘may be helpful’’ is too vague reduce compliance with drug therapy)
(i.e., pregnancy, labor and delivery, and recommended that the language be ensures that the intended scope of the
nursing mothers, pediatric, and geriatric changed to specify that only laboratory ‘‘Warnings and Precautions’’ section is
use information), and information for tests that ‘‘have been shown to be preserved.
patients be moved from the helpful’’ be required in the ‘‘Warnings (Comment 59) One comment
‘‘Precautions’’ section to three new and Precautions’’ section. recommended that the agency describe
sections (described in proposed The agency is concerned that limiting parameters upon which to base
§ 201.57(c)(7), (c)(8), and (c)(17) the scope of laboratory testing decisions about the sequence in which
respectively). Second, FDA proposed to recommendations identified in labeling adverse reactions are presented in the
require that the remainder of the to only those tests that have been ‘‘Warnings and Precautions’’ section.
information in the ‘‘Precautions’’ ‘‘shown to be helpful’’ in monitoring There are multiple factors that could
section, with the information from the patients could exclude sensible and influence the sequence in which
‘‘Warnings’’ section, be combined into a potentially important laboratory testing adverse reactions should be presented
new section entitled ‘‘Warnings and recommendations. The agency agrees, in the ‘‘Warnings and Precautions’’
Precautions’’ (proposed § 201.57(c)(6)). however, that ‘‘may be helpful’’ is a section. The most significant include
FDA also proposed to require that the vague standard and, therefore, has the relative seriousness of the adverse
‘‘Warnings and Precautions’’ section amended the provision to require reaction, the ability to prevent or
include information on contacts for identifying any laboratory tests mitigate the adverse reaction, the
adverse reaction reporting (proposed ‘‘helpful’’ in following a patient’s likelihood the adverse reaction will
§ 201.57(c)(6)(v)). See comment 30 response or identifying possible adverse occur, and the size of the population
regarding deletion of proposed reactions. affected. In general, the sequence of the
§ 201.57(c)(6)(v). (Comment 58) Several comments adverse reactions should reflect the
Several comments supported expressed concern about the proposal to relative public health significance, and
reorganizing the ‘‘Warnings and change the criteria for inclusion of the seriousness of the adverse reaction
should weigh more heavily than the included in the ‘‘Clinical ranked by order of the strength of the
likelihood of occurrence or the size of Pharmacology’’ section. Thus, the data supporting the existence of an
the affected population. The agency has agency has revised proposed interaction.
added clarifying language to this § 201.57(c)(7)(i) and (c)(13)(i)(D) to FDA believes that relative clinical
requirement to assist in selecting and provide this clarification (see significance of the drug interaction
organizing information in this section. § 201.57(c)(8)(i) and (c)(13)(i)(C)). would ordinarily be the most reasonable
The agency is also making available (Comment 61) One comment stated basis for determining the order of
guidance on the ‘‘Warnings and that the labeling example published presentation of drug interactions.
Precautions’’ section, which provides with the proposed rule included Because, for certain products, this
recommendations on sequencing of recommended dosage adjustments for section can be lengthy and complex, the
adverse reactions (see section IV of this drug interactions that are not based on agency will not designate a specific
document). clinical experience and requested order in the regulations.
In addition, the final rule clarification about whether the (Comment 64) One comment
(§ 201.57(c)(6)(i)) states that FDA may manufacturer must include speculative recommended that, in the following
require labeling to include a specific interactions and dosage adjustments in language from the proposed provision
warning relating to a use that is not this section. The comment also asked to for the ‘‘Drug Interactions’’ section, the
provided for under the ‘‘Indications and what extent sponsors would be required word ‘‘patients’’ be replaced with the
Usage’’ section if the drug is commonly to develop clinical data to support word ‘‘humans’’: ‘‘Information in this
prescribed for a disease or condition dosage adjustments for drug section must be limited to that
and such usage is associated with interactions. pertaining to clinical use of the drug in
clinically significant risk or hazard. Manufacturers must not speculate in patients.’’ The comment maintained that
FDA deleted language from proposed labeling. Information from clinical drug interaction studies often involve
§ 201.57(c)(6)(i), (i.e., ‘‘and there is a experience is clearly the most healthy volunteers, rather than patients,
lack of substantial evidence of persuasive, but other relevant data, such and the language in the regulation
effectiveness for that disease or as pharmacokinetic data, in vitro data, should reflect the nature of the study
condition’’) because the requirement for and data from other drug products in participants.
a warning is based on an assessment of the same pharmacologic or chemical The agency has revised final
risk. In addition, FDA also clarified that class, may reliably predict the § 201.57(c)(8)(i) to clarify the scope of
its authority under this provision must likelihood of an interaction with the the information to be included in this
be exercised in accordance with drug or provide a basis for a dosage section and this sentence was deleted.
sections 201(n) and 502(a) of the act. adjustment recommendation. Therefore, (Comment 65) One comment
• Drug interactions (proposed it would not be appropriate to limit the requested that the agency clarify the
§ 201.57(c)(7)) scope of the drug interactions and requirement in the proposed ‘‘Drug
FDA proposed to require a ‘‘Drug dosage adjustment information in Interactions’’ section to briefly describe
Interactions’’ section (proposed labeling to only those interactions or the mechanism of interaction for drugs
§ 201.57(c)(7)) containing the same dosage adjustments for which there are and drug classes that interact with a
information as required by the ‘‘Drug clinical data. drug in vivo. The comment maintained
interactions’’ subsection of the (Comment 62) One comment stated that the mechanism is not always
‘‘Precautions’’ section at then-current that including discussions of dosage understood and requested that the rule
§ 201.57(f)(4). adjustments to address drug interactions specify that the requirement to describe
(Comment 60) Most comments in both the ‘‘Drug Interactions’’ and the mechanism applies only if the
supported creation of a distinct section ‘‘Dosage and Administration’’ sections mechanism is understood.
for drug interactions. These comments would add unnecessarily to the length The agency agrees. Proposed
maintained that the new section would of the labeling. § 201.57(c)(7) (§ 201.57(c)(8)(i) in this
improve the safety of drugs for patients FDA does not agree that discussing final rule) has been revised to state that
on multiple medications. One comment dosage adjustments for drug interactions the mechanism of an interaction must
asked FDA to clarify whether in both the ‘‘Drug Interactions’’ section be briefly described, if it is known.
discussions of drug interaction and the ‘‘Dosage and Administration’’ • Use in specific populations
pharmacokinetic studies should be section would be unnecessary or (proposed § 201.57(c)(8))
repeated in the ‘‘Clinical Pharmacology’’ repetitive because the purposes of the FDA proposed to require a new
section. sections are distinct (see comment 51). section entitled ‘‘Use in Specific
How to divide information on drug The ‘‘Drug Interactions’’ section alerts Populations’’ (proposed § 201.57(c)(8))
interactions between the ‘‘Clinical the prescriber to the existence of to include the information on specific
Pharmacology’’ and ‘‘Drug Interactions’’ interactions and provides a place for populations required in the
sections is a matter of judgment. substantive discussion of the nature of ‘‘Pregnancy,’’ ‘‘Labor and delivery,’’
Manufacturers must not include a the identified interactions, including ‘‘Nursing mothers,’’ ‘‘Pediatric use,’’ and
detailed discussion of drug interaction practical advice about preventing or ‘‘Geriatric use’’ subsections of the
pharmacokinetic studies in both the limiting interactions. The ‘‘Dosing and ‘‘Precautions’’ section at then-current
‘‘Drug Interactions’’ and the ‘‘Clinical Administration’’ section provides § 201.57(f)(6) through (f)(10). The
Pharmacology’’ sections. Ordinarily, specific information about how to agency also proposed to revise certain
clinically significant results and modify the dose to minimize the risk of required warning language in the
conclusions of such studies must appear drug interactions when such labeling of drugs in pregnancy
in the ‘‘Drug Interactions’’ section and information is available, but does not categories D and X (proposed
clinically significant information on provide the details that are discussed in § 201.57(c)(8)(i)(A)(4) and
dosing modifications in the ‘‘Dosage and the ‘‘Drug Interactions’’ section. (c)(8)(i)(A)(5)). The proposal would have
Administration’’ section. If additional (Comment 63) One comment replaced the following language from
details about the design or conduct of recommended revising the ‘‘Drug then-current § 201.57(f)(6)(i)(d) and
the studies are relevant to the clinical Interactions’’ section to require the (f)(6)(i)(e): ‘‘If this drug is used during
use of the drug, the information must be presentation of drug interaction data pregnancy, or if the patient becomes
pregnant while taking this drug, the the pregnancy labeling with this guidance to clarify these concepts and
patient should be apprised of the rulemaking to revise the requirements of conduct an educational campaign to
potential hazard to the fetus.’’ The prescription drug labeling generally. explain the meaning and significance of
proposed alternative language, which The comment maintained that the the new definition. Several comments
was intended to address the concern pregnancy labeling requirements need maintained that the definition of an
that any woman with reproductive to be changed expeditiously to require adverse reaction in then-current
potential should be apprised of the risk that the labeling address the likelihood § 201.57(g) is a more accurate
associated with taking the category D of harm to the fetus based on timing of description of the events that should be
and X drugs during pregnancy, read: ‘‘If exposure, pharmacokinetic changes in included in labeling.
this drug is administered to a woman pregnant women, and the relevance of One comment expressed concern that
with reproductive potential, the patient animal data to humans. the proposed definition of adverse
should be apprised of the potential The agency does not agree that the reaction could result in excluding
hazard to a fetus.’’ two initiatives should be combined. The adverse events that should be included
FDA also proposed some changes in pregnancy labeling initiative focuses in the labeling because there is a lack of
terminology to the ‘‘Nursing mothers’’ exclusively on revising the content guidance for determining ‘‘reasonable
subsection (proposed § 201.57(c)(8)(iii)). requirements for the pregnancy causality’’ to identify which adverse
For example, FDA proposed to change subsection of labeling to meaningfully reactions to list. The comment said that
the term ‘‘nursing mothers’’ to ‘‘lactating describe the risks associated with fetal it is commonly known that prescription
women.’’ Other proposed changes and maternal exposure to a drug and the drug labeling lists all adverse reactions
included making assessments based on clinical implications of those risks. In that occurred in trials, with definite,
‘‘clinically significant adverse contrast, this final rule is focused on probable, possible, and remote
reactions’’ rather than ‘‘serious adverse revising the format and content of causality. The comment recommended
reactions.’’ labeling to increase its usefulness for that significant adverse reactions be
(Comment 66) Several comments health care practitioners. listed in Highlights and reinforced in
supported creation of a section devoted • Adverse reactions—definition of the full prescribing information. The
to information about use in specific adverse reaction (proposed comment also stated that all other
populations. The comments indicated § 201.57(c)(9)) events that occurred should still be
that placing all the information on FDA proposed to revise the definition listed, perhaps last in the
specific populations in one labeling of ‘‘adverse reaction’’ to mean a comprehensive ‘‘Adverse Reactions’’
section would make the information ‘‘noxious and unintended response to section, because the loss of a
much easier to locate. However, one any dose of a product for which there comprehensive listing of all reported
comment stated that the revised is a reasonable possibility that the events could be detrimental to patient
warning statement for drugs in product caused the response, i.e., the safety.
pregnancy categories D and X no longer relationship cannot be ruled out’’ Some comments stated that the
makes clear that a pregnant woman (proposed § 201.57(c)(9)). proposed new definition for an adverse
receiving the drug should be apprised of (Comment 68) Several comments reaction was a marked improvement
the potential hazard to the fetus. The objected to the revised definition of an because it would narrow the scope of
comment expressed concern that the adverse reaction in proposed the ‘‘Adverse Reactions’’ section. These
phrase ‘‘women with reproductive § 201.57(c)(9). The comments comments contended that narrowing the
potential’’ could be interpreted as maintained that this definition would be scope of events considered adverse
referring only to women with the too restrictive and could result in reactions for purposes of the ‘‘Adverse
potential to become pregnant and not to omission of important information. Reactions’’ section would help address
those who actually are pregnant. Comments expressed particular concern long-standing practitioner concerns that
The agency is developing a proposal that the terms ‘‘noxious’’ and the section is not very informative
that would revise the requirements for ‘‘unintended’’ could be applied to because it contains excessively long lists
the ‘‘Pregnancy,’’ ‘‘Labor and delivery,’’ exclude important adverse reactions. of reactions, many of which are not
and ‘‘Nursing mothers’’ subsections of They also stated that important relevant to clinical use of the drug.
prescription drug labeling. For this information could be excluded from the The agency has reconsidered the
reason, the agency has reconsidered the ‘‘Adverse Reactions’’ section because proposed definition of an adverse
need to make minor, interim changes to manufacturers could narrowly construe reaction, which was intended to
the warning statements for pregnancy whether the drug caused the event. conform to the definition of adverse
categories D and X in this final rule and Comments maintained, for example, drug reaction for safety reporting in the
has decided to retain the language at that an adverse reaction that affects International Conference on
former § 201.57(f)(6)(i)(d) and (f)(6)(i)(e). compliance could be considered Harmonisation of Technical
This language clearly addresses use of clinically meaningful and thus merit Requirements for Registration of
the drug by pregnant women and discussion in the ‘‘Warnings and Pharmaceuticals for Human Use (ICH)
obviates the need for the changes Precautions’’ section, but be excluded guidance ‘‘E2A Clinical Safety Data
advocated by the comment. from the ‘‘Adverse Reactions’’ section Management: Definitions and Standards
FDA also decided not to make interim because it is not considered noxious or for Expedited Reporting’’ (60 FR 11284
changes to the ‘‘Nursing mothers’’ unintended. Some comments requested at 11285, March 1, 1995).
subsection of the labeling and will clarification of elements of the Upon consideration of the comments
retain the language at former definition—in particular ‘‘noxious,’’ submitted in response to this proposal,
§ 201.57(f)(8) for this subsection. The ‘‘unintended,’’ and ‘‘injurious to the agency concluded that it should not
agency believes that it is best to address health.’’ One comment recommended require use of a new definition of
all changes to the content of these that ‘‘unintended’’ be changed to adverse reaction for labeling of new and
subsections at one time. ‘‘unexpected,’’ stating that recently approved products. The agency
(Comment 67) One comment ‘‘unexpected’’ may more accurately believes that the language in the
requested that the agency combine the reflect the intent of the definition. One definition of adverse reaction at former
initiative to revise the requirements for comment requested that FDA issue § 201.57(g) (designated in the final rule
as § 201.57(c)(7)), in particular ‘‘an The concerns expressed in these this section is organized and presented
undesirable effect, reasonably associated comments are based on the proposed across different drug products. To
with use of a drug, that may occur as adverse reaction definition. Because the address this problem, the agency
part of the pharmacological action of the agency is not adopting this definition recommends, in the ‘‘Adverse
drug or may be unpredictable in its for the purposes of labeling, FDA Reactions’’ section guidance, an
occurrence’’ is appropriate for labeling, believes that the concerns expressed in organization for the typical components
but that it requires clarification, as these comments are no longer of the ‘‘Adverse Reactions’’ section.
described in the next paragraph, to applicable. Thus, FDA continues, as
minimize including information in • Adverse reactions— recommended by the comment, to
labeling that does not help prescribers characterization of adverse reactions provide general requirements in
use the drug safely and effectively (i.e., (proposed § 201.57(c)(9)(ii)) regulation and detailed
adverse events that are not related to use FDA proposed to retain the language recommendations in guidance. The
of the drug), and that may result in from then-current § 201.57(g)(2) in ‘‘Adverse Reactions’’ section guidance
diluting the usefulness of clinically proposed § 201.57(c)(9)(ii): provides recommendations for how to
meaningful information. Thus, FDA In this listing, adverse reactions may be select information for inclusion in this
will, as recommended by several categorized by organ system, by severity of section, how to characterize the
comments, continue to use its existing the reaction, by frequency, or by toxicological information, and how to further
definition for adverse reaction. mechanism, or by a combination of these, as organize it (see section IV of this
The agency believes, as previously appropriate. If frequency information from document).
indicated, that the definition of adverse adequate clinical studies is available, the (Comment 71) One comment
categories and the adverse reactions within recommended that manufacturers be
reaction at former § 201.57(g) requires each category must be listed in decreasing
clarification. For this purpose, FDA has order of frequency. An adverse reaction that
required to specify in the ‘‘Adverse
revised this definition to make clear that is significantly more severe than the other Reactions’’ section what categorization
it is specific to prescription drug reactions listed in a category, however, must scheme was employed for listing of the
labeling and does not include all be listed before those reactions, regardless of adverse reactions.
adverse events observed during use of a its frequency. If frequency information from The agency believes that, in most
drug, but only those adverse events for adequate clinical studies is not available, the cases, the basis for the categorization of
which there is some basis to believe categories and adverse reactions within each ‘‘Adverse Reactions’’ section will be
there is a causal relationship between category must be listed in decreasing order of readily apparent to readers. In rare
the drug and the occurrence of the severity.* * * instances in which the basis for
adverse event. There are many factors to (Comment 70) One comment categorization is not apparent, it would
consider in assessing the association requested that the agency reconcile be appropriate to identify the
between a drug and a reported adverse apparent inconsistencies between the categorization scheme employed. The
event and determining whether a draft of the ‘‘Adverse Reactions’’ section agency has, therefore, determined that it
reported event is an adverse reaction guidance in development and the is not necessary to require in regulation
that should be included in labeling. The language in the ‘‘Adverse Reactions’’ that the basis for categorization of
agency has included clarifying language section of the proposed rule. The adverse reactions be identified for all
in this final rule to assist in selecting comment maintained that the labeling.
and organizing reactions. To further recommended organization in the draft The agency has revised, for the
assist manufacturers and reviewers, ‘‘Adverse Reactions’’ section guidance is reasons described in the response to
FDA is making available the ‘‘Adverse not consistent with the organization of comment 70, proposed § 201.57(c)(9)(ii)
Reactions’’ section guidance (see section the ‘‘Adverse Reactions’’ section in the (designated in this final rule as
IV of this document). proposed rule. This comment advocated § 201.57(c)(7)(ii)) to provide clarification
(Comment 69) One comment that important points regarding adverse for this part of the ‘‘Adverse Reactions’’
expressed concern that inclusion of an reactions be discussed in both the section. The agency changed the term
adverse reaction in the ‘‘Adverse proposed rule and the ‘‘Adverse ‘‘organ system’’ to ‘‘body system.’’
Reactions’’ section under the proposed Reactions’’ section guidance, with Although the two terms have been used
definition would be tantamount to an extensive detail provided in the interchangeably, currently, the term
admission that the event was caused by guidance document. ‘‘body system’’ is used most often.
a drug for product liability purposes. Based on this comment and on In addition, the agency deleted the
Another comment stated that having comments received on the draft option to categorize adverse reactions by
two definitions for adverse reactions ‘‘Adverse Reactions’’ section guidance, toxicological mechanism. After
(i.e., the definition in proposed the agency has revised the regulation on reviewing the 1975 proposed and 1979
§ 201.57(c)(9) for new and recently the ‘‘Adverse Reactions’’ section at final rules, the agency concluded that
approved drugs and the definition in proposed § 201.57(c)(9) (designated in the term is not clear; therefore,
redesignated § 201.80(g) for older drugs) this final rule as § 201.57(c)(7)) to clarify categorization by toxicological
may have implications for product the scope of information for this section mechanism is not an appropriate option
liability. One comment stated that of labeling. See comments 71 through for the ‘‘Adverse Reactions’’ section.
application of the proposed adverse 75. The agency also made clear that,
reactions definition to drugs that have to The agency recognizes that the however categorized, adverse reactions
revise their labeling to implement the ‘‘Adverse Reactions’’ section has must be listed in order of decreasing
new format would require reevaluation evolved over time to a point where it frequency.
of clinical data and a new safety review now typically contains several different FDA also removed the requirement
by the agency. One comment requested components (e.g., information from that significantly more severe reactions
the agency clarify whether controlled clinical trials, uncontrolled be listed before other reactions
manufacturers would now have to clinical trials, and postmarketing regardless of frequency. In most cases,
reclassify or otherwise reassess adverse experience). The agency also recognizes frequency information is paramount, but
reactions profiles of products with that there exists considerable in other cases, severity information may
existing labeling. inconsistency in how information in be more important or a combination of
the two may be the best approach. The estimation of incidence calculations from one indication or population to
categorization scheme selected for the difficult. another, the differences are drug related,
‘‘Adverse Reactions’’ section should be Because these differences and the data have important clinical
appropriate to the drug’s safety database significantly affect the interpretation of implications. On the other hand, where
and reflect the relative public health these complementary sets of data, the differences are relatively minor and not
importance of the information. agency believes it is important to clinically meaningful, separate
The agency also clarified that if data separate in labeling adverse reactions presentations for multiple indications
are available and important for adverse identified in clinical trials from adverse would not be informative and would
reactions with significant clinical reactions identified from domestic and detract from more important
implications, details about the nature, foreign spontaneous reports. For information.
frequency, and severity of the reaction precisely these reasons, in the draft (Comment 74) One comment
must be included. This provision makes ‘‘Adverse Reactions’’ section guidance, requested that the ‘‘Adverse Reactions’’
clear that, in many cases, in addition to FDA suggested segregating adverse section discuss differences in adverse
lists of adverse reactions, descriptive reactions from spontaneous reports in reaction rates among different
information is appropriate for inclusion this section of the labeling. Thus, the demographic subgroups (e.g., men,
in the ‘‘Adverse Reactions’’ section. agency has revised proposed women, blacks, renally-impaired).
(Comment 72) One comment § 201.57(c)(9)(ii) (§ 201.57(c)(7) in this The agency agrees that the ‘‘Adverse
requested that the agency require that final rule) by creating a separate listing Reactions’’ section must include
adverse reactions identified from for each set of adverse reactions within information on differences in adverse
postmarketing experience be listed the ‘‘Adverse Reactions’’ section. reactions among demographic
separately from adverse reactions The agency clarifies that this subgroups where sufficient data are
identified from clinical trials. distinction is between adverse reactions available and important. Thus, the
The agency agrees that adverse identified in clinical trials and those agency has revised proposed
reactions identified from domestic and identified from domestic and foreign § 201.57(c)(9) (designated in this final
foreign spontaneous reports after a drug spontaneous reports after a drug is rule as § 201.57(c)(7)) to require such
is marketed should be listed separately marketed. Adverse reactions that are information in the ‘‘Adverse Reactions’’
from adverse reactions identified in identified in clinical trials conducted section.
clinical trials. Adverse reaction data after a drug is marketed would be listed • Adverse reactions—frequency
from clinical trials and spontaneous under adverse reactions identified from information (proposed § 201.57(c)(9)(ii))
reports communicate different clinical trials. FDA proposed to retain the language
information to practitioners. In clinical (Comment 73) One comment from then-current § 201.57(g)(2) in
trials, subjects are specifically queried requested that, for drugs with multiple proposed § 201.57(c)(9)(ii):
about and evaluated for occurrence of doses or indications, the ‘‘Adverse The approximate frequency of each adverse
adverse events and clinical investigators Reactions’’ section have a separate reaction must be expressed in rough
have requirements for identifying and presentation of adverse reactions for estimates or orders of magnitude essentially
reporting such events (21 CFR each dose or indication. as follows:
312.64(b)). Data from clinical trials The agency agrees that it is important The most frequent adverse reaction(s) to
inform practitioners about the range of for the ‘‘Adverse Reactions’’ section to (name of drug) is (are) (list reactions). This
(these) occur(s) in about (e.g., one-third of
adverse reactions that may occur. In call attention to adverse reactions for patients; one in 30 patients; less than one-
addition, because there is typically a which there are clinically significant tenth of patients). Less frequent adverse
comparison to a control group, these dose-response relationships. reactions are (list reactions), which occur in
data provide an estimate of the Thus, the agency has revised approximately (e.g., one in 100 patients).
incidence and the ability to identify proposed § 201.57(c)(9) (designated in Other adverse reactions, which occur rarely,
events that, because they are likely to be this final rule as § 201.57(c)(7)) to in approximately (e.g., one in 1,000 patients),
causally related, represent adverse require manufacturers to include details are (list reactions).
reactions. about the relationship of adverse Percent figures may not ordinarily be used
Postmarketing experience with a drug reactions to drug dose where sufficient unless they are documented by adequate and
permits observation of suspected well-controlled studies as defined in
data are available and necessary to
§ 314.126(b) of this chapter (except for
adverse reactions in a larger, often more prescribe the drug safely and effectively. biological products), they are shown to
diverse, patient population. This The agency does not believe, however, reflect general experience, and they do not
experience may provide an opportunity that it needs to require that separate falsely imply a greater degree of accuracy
to identify low frequency reactions and presentations of adverse reactions than actually exists.
reactions not previously observed always be included for different doses. For biological products, such figures
because the susceptible population was If there are important differences in must be supported by substantial
either excluded from the controlled adverse reaction rates for different evidence.
trials or only included in small doses, the section can include a single (Comment 75) One comment asked
numbers. But, to interpret this table that directly compares the adverse the agency to clarify an apparent
information accurately, a practitioner reactions rates for different doses. inconsistency between the proposed
must be mindful that postmarketing Presenting rates for different doses side rule and the draft ‘‘Adverse Reactions’’
experience, although more closely by side in a table, for example, is an section guidance concerning how to
reflective of clinical practice, lacks the effective way to make a dose-response characterize the incidence of adverse
structure of a clinical trial setting that relationship apparent. reactions. The comment pointed out
permits increased precision. For The agency also does not believe that that the proposed rule (which used the
postmarketing reporting, the impetus for it needs to require a separate same language as in the 1979 final rule)
reporting, the frequency with which a presentation of adverse reactions for recommended grouping adverse
suspected adverse reaction is reported, each indication. Such information could reactions by rough orders of magnitude
and the number of exposures to the drug be appropriate for a drug with multiple and encouraged use of the terms
compared to the number of suspected indications, however, when the adverse ‘‘frequent,’’ ‘‘infrequent,’’ and ‘‘rare’’ in
reactions reported are unknown, making reaction profile differs substantially conjunction with orders of magnitude
appropriate for a given drug’s safety a clearer way to communicate rough subsections—‘‘Mechanism of action,’’
database. The comment observed that rates of incidence for a group of adverse ‘‘Pharmacodynamics,’’ and
agency guidance discouraged use of reactions. Therefore, the agency has ‘‘Pharmacokinetics.’’ Proposed
these terms when grouping by rough revised proposed § 201.57(c)(9) to § 201.57(c)(13) also provided for an
orders of magnitude. require that adverse reactions for which optional subsection for incorporation of
The agency agrees that clarification is meaningful percentage rates cannot be other clinical pharmacology information
needed regarding presentation of reliably determined (e.g., adverse that does not fit into one of the specified
incidence information for adverse reactions were observed only in the subsections.
reactions. The language in the proposed uncontrolled trial portion of the overall (Comment 78) One comment
rule is not sufficiently precise to safety database), be grouped within recommended that the ‘‘Clinical
accurately reflect current practices in specified frequency ranges as Pharmacology’’ section be revised to
characterizing the incidence of adverse appropriate to the safety database of the require discussion of a drug’s
reactions associated with the use of a drug (e.g., adverse reactions occurring at elimination half-life, indicate
drug product. The preamble to the 1975 a rate of less than 1/100, adverse differences in elimination half-life as a
proposed rule indicates that precise reactions occurring at a rate of less than function of age or other subpopulation,
percent figures would be appropriate if 1/500) or descriptively identified, if and specify the enzyme involved in
there is scientific evidence from well- frequency ranges cannot be determined. metabolism (e.g., CYP450).
controlled trials substantiating such (Comment 76) One comment Under the final rule, elimination half-
figures and when inclusion of percent requested clarification on how life of drugs and differences in the
figures does not falsely imply a greater percentages should be used to elimination half-life as a function of
degree of accuracy than actually exists characterize the frequency of adverse specific populations (including age-
(40 FR 15392 at 15393, April 7, 1975). reactions when percentages are derived related populations) must be reported in
The science of clinical trials has from studies that evaluated greater the ‘‘Pharmacokinetics’’ subsection of
progressed so substantially over time doses than the approved dose. The the ‘‘Clinical Pharmacology’’ section of
that ascertaining such rates is typically comment asked whether, in this the labeling (§ 201.57(c)(13)(i)(C)). In
part of virtually all drug development circumstance, rates of adverse reactions addition, if there are clinically
programs. should be omitted from the ‘‘Adverse significant differences in elimination
Under current labeling practices, rates Reactions’’ section. half-lives among specific populations
of incidence for most adverse reactions The agency will determine, during and those differences require special
identified in controlled clinical trials review of an application, whether monitoring or alternate dosing regimens,
are expressed as percentages. Current adverse reaction rates derived from such information must be included in
labeling also typically includes doses greater than recommended doses other sections, such as ‘‘Use in Specific
percentage rates for comparison groups would be informative for practitioners Populations,’’ ‘‘Warnings and
in clinical trials (e.g., placebo group) and not misleading, and thus Precautions,’’ and ‘‘Dosage and
where inclusion of such rates would not appropriate for inclusion in labeling. Administration.’’ Information about
be misleading. Broader frequency ranges Where there are adverse reaction data drug metabolism, including metabolic
are used only when meaningful from studies using different doses, pathways and the enzyme systems
percentage rates cannot be determined. including doses greater than involved, is also required in the
Therefore, the agency has revised recommended doses, the agency will ‘‘Pharmacokinetics’’ subsection of the
proposed § 201.57(c)(9) (designated in evaluate whether pooling or otherwise ‘‘Clinical Pharmacology’’ section.
this final rule as § 201.57(c)(7)) to make combining adverse reaction data would (Comment 79) One comment
it clear that when meaningful adverse more accurately describe the frequency requested that FDA clarify the statement
reaction rates can be derived (for drug of adverse reactions. in proposed § 201.57(c)(13)(i)(B): ‘‘If
treatment group and comparison (Comment 77) One comment pharmacokinetic/pharmacodynamic
groups) and presentation of comparator requested clarification on whether relationships are not demonstrated or
rates would not be misleading, they manufacturers are required to identify are unknown, the labeling must contain
must be included in labeling. the total number of patients enrolled in a statement about the lack of
The agency also believes it is clinical trials in the ‘‘Adverse information.’’ The comment asked that
inappropriate to use nonspecific terms Reactions’’ section. FDA clarify whether the provision is
such as ‘‘frequent,’’ ‘‘infrequent,’’ and FDA has revised proposed referring to concentration versus
‘‘rare’’ when presenting adverse reaction 201.57(c)(9)(i) (designated in this final response relationships generally.
information. The agency believes the rule as 201.57(c)(7)(i)) to clarify that the In response to this comment, the
science of clinical trials has evolved total number of subjects or patients agency has rephrased this provision, as
such that use of those terms in the exposed to the drug, and the extent of follows: ‘‘Exposure-response
manner recommended by the 1979 rule exposure, must be identified in the relationships (e.g., concentration-
is confusing because the terms do not ‘‘Adverse Reactions’’ section, so that response, dose-response) and time
necessarily refer to the same frequency practitioners can interpret the course of pharmacodynamic response
range across different drug products. For significance of the data in this section. (including short-term clinical response)
example, for product A, ‘‘rare’’ might The ‘‘Adverse Reactions’’ section must be included if known.’’ (See final
mean an incidence of less than 1/500, guidance provides recommendations on § 201.57(c)(13)(i)(B).)
but for product B, ‘‘rare’’ might mean an how to describe the database from (Comment 80) One comment stated
incidence of less than 1/1000. Moreover, which the adverse reaction data in this that the three new subsections in the
the terms are imprecise and, even if section are derived (see section IV of ‘‘Clinical Pharmacology’’ section will
precise meanings were defined, would this document). make it easier to find information in the
reinforce the misconception that • Clinical pharmacology (proposed section.

frequency is synonymous with § 201.57(c)(13)) One comment requested that in vitro
seriousness. FDA proposed to require that the data supporting the ‘‘Mechanism of
The agency believes that identifying ‘‘Clinical Pharmacology’’ section action’’ subsection in the ‘‘Clinical
the numerical frequency range alone is (proposed § 201.57(c)(13)) contain three Pharmacology’’ section be permitted to
be included in the subsection because process by which a waiver could be inclusion in labeling of in vitro data not
such information is helpful in granted. supported by clinical data and how to
understanding a drug’s physiologic Several comments expressed concern use such data in making prescribing
activity and in differentiating a drug about the implications of removing in decisions.
from other therapeutic agents. vitro data for devising susceptibility At this time, the agency will continue
The agency agrees that the three new tests for new anti-infective drugs. They to rely on the algorithm in its current
subsections should make information stated that these data are relied on by guidance on clinical development and
easier to find. Because 201.56(d)(2) FDA (the Center for Devices and labeling of anti-infectives for
(proposed 201.56(d)(5)) permits Radiological Health) and by determining when to include in vitro
additional nonstandard subsections, manufacturers of in vitro susceptibility data in the ‘‘Clinical Pharmacology’’
FDA deleted ‘‘12.4 other clinical tests in selecting appropriate organisms section of labeling. As part of the
pharmacology information’’ (proposed for which to devise tests. In addition, comprehensive evaluation of the way in
201.57(c)(13)(i)(D)) from the final rule. comments stated the data are used to which anti-infective therapies are
The ‘‘Mechanism of action’’ develop quality control mechanisms for, currently developed and labeled (see
subsection must include information and to help develop criteria for use in response to comment 81), the agency
based on in vitro data if the information the review and clearance of, may reconsider use of the algorithm and
is essential to a description of the susceptibility test devices. Some make any changes that may be needed.
established mechanism of action and comments maintained that removal of in For this reason, the agency will not at
the information is clinically relevant. vitro data would cause manufacturers this time undertake an educational
Where in vitro information about not to develop susceptibility tests for campaign to educate prescribers about
mechanism of action is included, the organisms for which such tests would the basis for inclusion of in vitro data
information must not be used as the be desirable. in labeling.
One comment supported exclusion of (Comment 83) Several comments
basis for a clinical comparison (i.e., to
in vitro data from labeling. The recommended retaining in vitro data for
differentiate the drug from other
comment stated that exclusion of in
therapeutic agents). anti-infective drugs in the ‘‘Clinical
vitro data that are not adequate to
(Comment 81) Many comments Pharmacology’’ section and
support therapeutic decisionmaking
opposed the proposal (proposed strengthening the current in vitro
will improve anti-infective therapy and
§ 201.57(c)(13)(ii) to revise the current disclaimer statement that indicates that
help prevent inappropriate use of
‘‘Clinical Pharmacology’’ section to the clinical significance of the in vitro
antibiotics.
require that in vitro data related to the The agency has reconsidered its data is unknown.
activity or effectiveness of an anti- proposal to exclude from the ‘‘Clinical Until FDA has developed a
infective drug be included in the section Pharmacology’’ section in vitro data for comprehensive plan to address the
only if a waiver is granted under anti-infectives that are not supported by broad range of issues confronting
§ 201.58 or § 314.126(c) (21 CFR clinical data. The agency is considering development and labeling of anti-
314.126(c)). While comments conceded a broad range of issues concerning the infective products, the agency will defer
that in vitro data have their limitations, development and labeling of anti- any decisions about the content of the
the comments maintained that in vitro infective products, including the types disclaimer that accompanies in vitro
data for anti-infective agents can be an of data that should be obtained to data indicating that the clinical
important component of the total support indications, the way that significance of the data is unknown.
information available for making indications and anti-infectives data (Comment 84) One comment
prescribing decisions in some should be presented in labeling, and requested that the agency clarify the
situations, including: (1) In the absence ways to meaningfully address resistance scope of the proposed exclusion of in
of susceptibility testing, (2) in treating to anti-infective drugs. The agency vitro data to make clear that it does not
drug resistant pathogens (e.g., drug- believes a comprehensive and encompass in vitro data with clinical
resistant pneumococci), and (3) in coordinated approach is needed to substantiation. The comment
treating rare infections. Some comments address these issues. Thus, FDA is maintained that in vitro susceptibility
stated that preventing inclusion of in deferring any action on the in vitro data data from large scale clinical trials
vitro data that indicate a drug is inactive proposals in the ‘‘Clinical would provide some basis for making an
against a microorganism could result in Pharmacology’’ section of labeling at informed decision about possible
selection of inappropriate antibiotics §§ 201.57(c)(13)(ii) and 201.80(b)(2) effectiveness in the absence of
and poor clinical outcomes. One until the agency has developed a susceptibility testing (e.g., while
comment maintained that some comprehensive plan. At that time, the awaiting such testing) and that this
physician organizations effectively agency may repropose changes to the information is especially important for
endorse use of in vitro data by having way in which in vitro data are presented antiviral drugs.
guidelines that recommend use of in in labeling. In vitro data that are supported by
vitro data as an adjunct to making (Comment 82) Several comments clinical data have certain problems in
educated empirical judgments about maintained that the algorithm in the common with in vitro data not
appropriate anti-infective therapy. agency’s current guidance for industry supported by clinical data (e.g.,
Several comments stated that the (‘‘Clinical Development and Labeling of antimicrobial susceptibilities are
absence of in vitro data will make it Anti-Infective Drug Products,’’ 1992) for constantly changing and vary by
difficult for practitioners to identify determining when it is appropriate to location). In vitro and animal data not
appropriate broad spectrum agents include in labeling in vitro data not supported by clinical data were the
when broad coverage is needed. One supported by clinical data contains focus of the agency’s proposal to
comment requested that in the event the adequate safeguards and should exclude in vitro and animal data from
agency decides to go forward and continue to be used for determining the ‘‘Clinical Pharmacology’’ section
exclude in vitro data related to when to include such data. One (§ 201.57(c)(13)(ii)). As discussed
effectiveness unless a waiver has been comment suggested that labeling users previously, the agency has reconsidered
granted, the agency explain in detail the be educated about the criteria for its proposal to exclude such data from
labeling and will defer any action until extent and limitation of the product’s and Usage’’ or ‘‘Dosage and
it has developed a comprehensive plan. benefits, how the drug was used in Administration’’ sections, are intended
(Comment 85) Several comments clinical trials, who was studied, and for informational purposes only (i.e., not
recommended that in vitro critical parameters that were monitored. to suggest claims).
susceptibility data for anti-infectives be (Comment 87) One comment One comment asked that the agency
retained in labeling and be placed in a requested that the agency clarify the make clear that the limitation on
new labeling section entitled ‘‘Clinical extent to which secondary endpoint inclusion of information in labeling
Microbiology.’’ data, quality of life data, and about unapproved doses and regimens
The agency believes that a labeling pharmacoeconomic data would be would not preclude discussion of a dose
section devoted specifically to clinical permitted in the ‘‘Clinical Studies’’ ranging study that supports approval
microbiology data is not needed at this section. and includes dosage regimens that were
time. As a result of its ongoing The ‘‘Clinical Studies’’ section must not approved for use.
comprehensive evaluation of anti- describe those studies that facilitate an One comment agreed with the
infectives drug development and understanding of how to use a drug proposed revision to exclude from the
labeling practices, the agency may safely and effectively. Generally, this ‘‘Clinical Studies’’ section data and
reconsider the need for a separate means those studies that were essential information concerning indications and
section on clinical microbiology. to establishing the drug’s effectiveness dosing that are not consistent with the
• Nonclinical toxicology (proposed for the purpose of obtaining marketing information in the ‘‘Indications and
§ 201.57(c)(14)) approval. Usage’’ and ‘‘Dosage and
FDA proposed to require a new If studies were appropriately designed
section in the FPI entitled ‘‘Nonclinical Administration’’ sections. The comment
to evaluate secondary endpoints, it may
Toxicology’’ (proposed § 201.57(c)(14)) maintained that inconsistent
be appropriate to include a discussion
to contain information from then- information about indications and
of these secondary endpoints in the
current § 201.57(f)(5) (the dosing creates confusion and
section.
‘‘Carcinogenesis, mutagenesis, The agency would evaluate the contributes to uncertainty and distrust
impairment of fertility’’ subsection) and appropriateness of including quality of of information in the labeling.
then-current § 201.57(l) (the ‘‘Animal life and pharmacoeconomic data Some comments stated that if the
Pharmacology and/or Animal according to the same standard. The agency has concerns about the
Toxicology’’ section). data could be appropriate for inclusion implications of labeling on product
(Comment 86) One comment in the section if all of the following promotion, these can be addressed
requested that FDA provide guidance apply: (1) The data are from adequate through its existing legal authority and
clarifying when it would be appropriate and well-controlled trials that should be addressed as a separate issue.
to omit the ‘‘Nonclinical Toxicology’’ incorporated quality of life or The agency requires that claims in
section. pharmacoeconomic endpoints in their any section of labeling, expressed or
Although the final rule provides that design and carried out appropriate implied, be supported by substantial
any section of labeling would be analyses, (2) for pharmacoeconomic evidence (§ 201.56(a)(3)). This
omitted if it is clearly inapplicable (see studies, the findings are reasonably requirement would not preclude
§ 201.56(d)(4)), it is unlikely that the generalizable to most clinical discussing in labeling an adequate and
‘‘Nonclinical Toxicology’’ section, in its environments, not just the ones studied, well-controlled clinical study, including
entirety, would ever be inapplicable. and (3) the information would be a dose ranging study that has treatment
Animal data are often the only practical important to a practitioner’s arms with dosing regimens that are not
and ethical means to understand a understanding of how to use the drug in recommended, if the data for the use of
product’s potential for certain kinds of a clinical setting. The ‘‘Clinical Studies’’ such regimens are important to a
toxicity (e.g., carcinogenicity, section guidance contains FDA’s practitioner’s understanding of how to
mutagenicity, reproductive and recommendations on what studies are use the drug safely and effectively. For
developmental toxicity). In addition, appropriate for inclusion in the instance, it might be important to
even if carcinogenicity data are not ‘‘Clinical Studies’’ section (see section include such data if the data indicate
available, the labeling must state that IV of this document). that a particular dosage regimen is not
these studies were not done (Comment 88) Some comments effective, is minimally active, provides
(§ 201.57(c)(14)(i)). The final rule requested that the agency reconsider its no benefit compared to lower doses, or
provides, however, that the ‘‘Animal proposal to bar, in the ‘‘Clinical is associated with an unacceptable level
toxicology and/or pharmacology’’ Studies’’ section, inclusion of data of toxicity. If data that include dosage
subsection must include certain data concerning indications and doses that regimens other than recommended
that do not appear elsewhere in the are not consistent with the approved regimens are discussed in the ‘‘Clinical
labeling. This means that this indications and dosing regimens. Studies’’ section, the data must be
subsection would be omitted if all the Comments maintained that such accompanied by a statement
required information appears in one or information can be important to a appropriately qualifying the data and
more of the other labeling sections practitioner’s understanding of a indicating that those dosage regimens
(§ 201.57(c)(14)(ii)). product’s clinical and safety profile, as have not been found safe and effective
• Clinical studies (proposed well as to an understanding of the by FDA, if such a statement is necessary
§ 201.57(c)(15)) approved indication. Some comments for the labeling to be truthful and not
FDA proposed to require a section in stated that all studies that are misleading.
the FPI entitled ‘‘Clinical Studies’’ scientifically sound and provide The agency agrees that advertising
(proposed § 201.57(c)(15)). The section medically relevant information should and promotional labeling regulations
would be required to contain a be included in the ‘‘Clinical Studies’’ address product promotion issues and
discussion of clinical studies that are section. One comment stated that that this final rule is not an appropriate
important to a prescriber’s practitioners understand that data context for discussion of these issues.
understanding of the basis for approval presented in the ‘‘Clinical Studies’’ • References (proposed
of the drug product, including the section, as opposed to the ‘‘Indications § 201.57(c)(16))
FDA proposed to permit references to ‘‘Precautions’’ section (required under labeling. Under part 208 (21 CFR part
be included in labeling in place of a then-current § 201.57(f)(2)) be made a 208), FDA can require a Medication
detailed discussion of a subject that is separate section entitled ‘‘Patient Guide for a prescription drug product
of limited interest, but nonetheless Counseling Information’’ (proposed that FDA determines poses a serious
important (proposed § 201.57(c)(16)). § 201.57(c)(17)). The section would be and significant public health concern
The proposed provision stated that the placed at the end of the FPI. requiring distribution of FDA-approved
reference must be based on an adequate The agency also proposed to require patient information (§ 208.1(a)).
and well-controlled clinical in proposed § 201.57(c)(17) that any Medication Guides are subject to
investigation under § 314.126(b) or, for approved printed patient information or specific content and format
a biological product, upon substantial Medication Guide be referenced in the requirements (§ 208.20).
evidence of effectiveness. ‘‘Patient Counseling Information’’ (Comment 93) Some comments
(Comment 89) One comment section and that the full text of the supported the proposed requirement to
maintained that requiring that all approved printed patient information or reprint FDA-approved patient labeling
information contained in the Medication Guide be reprinted at the end of the ‘‘Patient Counseling
‘‘References’’ section be based on immediately following the section. Information’’ section so that this
adequate and well-controlled trials will (Comment 91) One comment information is readily accessible for
result in omission of important supported the proposal to put healthcare practitioners. Other
references for many anti-infective information for patients in its own comments requested that the agency
products, including references for section and change the name from reconsider the proposal to require that
standardized test methodology in in ‘‘Information for patients’’ to ‘‘Patient FDA-approved patient labeling be
vitro studies. Counseling Information.’’ The comment printed at the end of the FPI. Some
The agency believes that inclusion of stated that the name change is important comments asked whether attaching
a reference to clinical data will be because it emphasizes the need to prescription drug labeling without FDA-
unusual. Any clinical data that are counsel patients on their medications approved patient labeling to trade
important to a prescriber’s and not just provide printed materials. packaging and attaching the FDA-
understanding of the safe and effective As described in the proposed rule, approved patient labeling separately
use of the drug must be summarized in FDA determined to change the heading would satisfy the requirement. Some
the ‘‘Clinical Studies’’ section, rather of the information required under then- comments expressed concern that
than referenced in the ‘‘References’’ current § 201.57(f)(2) from ‘‘Information prescription drug labeling with the
section. The ‘‘References’’ section may for patients’’ to ‘‘Patient Counseling FDA-approved patient labeling
cite an authoritative scientific body, Information’’ to clarify that the reprinted at the end may make it more
standardized methodology, scale, information under this section is not difficult for patients to find and read the
technique, or similar material important intended to be distributed to patients, patient information. One comment
to prescribing decisions that are but is intended to help practitioners stated that patient information typically
mentioned in another section of communicate important drug uses larger fonts and may use color and
labeling, but cannot readily be information to patients. illustrations, making it difficult and
summarized. The agency has revised (Comment 92) Some comments costly to reprint in the prescription drug
proposed §§ 201.57(c)(16) and 201.80(l) requested that the agency clarify the labeling. Some comments also
to make this clear and to delete the meaning of ‘‘any approved printed expressed concern that inclusion of
requirement that limits the ‘‘References’’ patient information.’’ One comment also FDA-approved patient labeling would
section to references to adequate and asked that the agency clarify make the labeling too long and impose
well-controlled clinical studies. ‘‘Medication Guide.’’ additional costs because it could
(Comment 90) One comment noted FDA has revised the terminology in necessitate redesign and enlarging of
that, even though the conditions for the final rule to clarify the meaning of trade packaging. One comment asked
including references in the proposed ‘‘any approved printed patient whether it would be sufficient to
rule are essentially the same as in the information’’ and ‘‘Medication Guide.’’ provide only a reference to FDA-
requirements for old labeling, there are The term ‘‘FDA-approved patient approved patient labeling in the
substantial differences in the way these labeling’’ refers to any labeling that has ‘‘Patient Counseling Information’’
conditions are applied across new drug been reviewed and approved by the section instead of reprinting the
reviewing divisions. agency that provides information for information in the section.
As discussed in the response to the patients and is for distribution to FDA believes that it is crucial that
previous comment, in this final rule, the patients who are prescribed a drug. This prescribers have ready access to FDA-
agency has clarified the conditions term includes approved printed patient approved patient labeling so that they
under which it is appropriate to include information specifically required by are aware that the information exists,
a reference in prescription drug regulation (e.g., for oral contraceptives can familiarize themselves with the
labeling. The agency appreciates the (21 CFR 310.501) and estrogens (21 CFR content of that information, and can
comment’s concern about inconsistent 310.515)) and patient labeling that is explain the information to their
application of the criteria for inclusion submitted voluntarily to FDA by patients. The agency believes this
of references across different new drug manufacturers and approved by the objective can best be accomplished by
review divisions. As part of its internal agency. FDA-approved patient labeling requiring that this information be
efforts to implement this final rule and may have different functions reflected reprinted at the end of prescription drug
related labeling initiatives, the agency in the type of information conveyed to labeling. Thus, it would be insufficient
intends to make considerable efforts to patients. For example, some FDA- to provide only a reference to FDA-
ensure consistent application of the approved patient labeling contains risk approved patient labeling in the
requirements. information, and some contains only ‘‘Patient Counseling Information’’

• Patient counseling information detailed instructions about how to section.
(proposed § 201.57(c)(17)) administer a drug product. However, the agency is persuaded
FDA proposed that the ‘‘Information Medication Guides are a specific that reprinting the FDA-approved
for patients’’ subsection of the category of FDA-approved patient patient labeling at the end of the
labeling is not the only approach that drug labeling, additional costs will be § 201.57). For Medication Guides to be
would successfully address the need to incurred by the manufacturer. To help distributed to patients, the type size
familiarize prescribers with this minimize the added cost, FDA has requirements set forth at § 208.20 apply.
information. Therefore, the agency has revised proposed § 201.57(c)(18) to With regard to the labeling for products
revised the requirements at specify that the same type size subject to § 201.80, the agency clarifies
§§ 201.57(c)(18) and 201.80(f)(2) to requirements that apply to prescription at § 201.80(f)(2) that the font size
require that FDA-approved patient drug labeling (§ 201.57(d)(6)) also apply requirement for Medication Guides in
labeling either accompany the to FDA-approved patient labeling that is § 208.20 does not apply to a Medication
prescription drug labeling or be printed at the end of the labeling or Guide that is printed in prescription
reprinted at the end of such labeling accompanies labeling, unless a drug labeling unless it is intended to
(i.e., immediately following the ‘‘Patient Medication Guide is to be distributed to
comply with § 208.24 (i.e., the
Counseling Information’’ section of the patients in compliance with § 208.24
(see table 7 of this document). In most requirement to distribute Medication
FPI for products subject to
§ 201.57(c)(18) or after the last section of cases, this will be a minimum type size Guides to patients). Thus, for these
labeling for products subject to of 8 points. For trade labeling, this will products, there is no minimum font size
§ 201.80(f)(2)). be a minimum type size of 6 points (see requirement for FDA-approved patient
The agency acknowledges that, in response to comment 102 for discussion labeling that is included with labeling
cases for which FDA-approved patient of 6-point minimum type size for trade but not for distribution to patients (see
labeling is included with prescription labeling for products subject to table 7).
TABLE 7.—TYPE SIZE REQUIREMENTS FOR LABELING AND FDA-APPROVED PATIENT LABELING INCLUDED WITH LABELING
Type Size Requirements for
Type Size Require-
Labeling FDA-Approved Patient Labeling Included with Labeling FDA-Approved Patient La-
ments for Labeling beling
New Format (§ 201.57)
Trade Labeling (i.e., labeling Minimum 6-point type FDA-approved patient labeling that is not for distribution Minimum 6-point type
on or within the package to patients
from which the drug is to
be dispensed)
Any FDA-approved patient labeling except a Medication Minimum 6-point type

Guide that is for distribution to patients
Medication Guide that is for distribution to patients Minimum 10-point type
Other Labeling (e.g., label- Minimum 8-point type FDA-approved patient labeling that is not for distribution Minimum 8-point type
ing accompanying pro- to patients
motional materials)
Any FDA-approved patient labeling except a Medication Minimum 8-point type

Old Format (§ 201.80)
Trade Labeling and Other No minimum require- FDA-approved patient labeling that is not for distribution No minimum requirement
Labeling ment to patients
Any FDA-approved patient labeling except a Medication No minimum requirement

(Comment 94) One comment asked prescription drug labeling in a way that The agency does not mean for
whether the agency meant for the would facilitate it being torn off (e.g., prescription drug labeling with the
prescription drug labeling with the along a perforation line) would satisfy FDA-approved patient labeling
FDA-approved patient labeling these requirements. One comment noted reprinted at the end to replace the
reprinted at the end to replace the that if the FDA-approved patient stand-alone FDA-approved patient
stand-alone FDA-approved patient labeling is appended to the prescription labeling required to be distributed to
labeling required to be distributed to drug labeling as a perforated patients. FDA has long stressed the
patients. The comment asked if the attachment, it might be more difficult importance of providing such
combined document would satisfy the for the patient to receive information at information to consumers.
requirement to distribute the FDA- the pharmacy because the pharmacist However, if the FDA-approved patient
approved patient labeling to patients would have to separate the patient labeling is appended to the prescription
who have been prescribed the drug. information from the prescription drug drug labeling (e.g., as a perforated
Other comments asked whether FDA- labeling. attachment that can be torn off and
approved patient labeling attached to given to patients) and is formatted as
required for distribution to patients Including only the FDA-approved products that will be required to have a
(§ 208.20), it would meet the patient labeling in the ‘‘Patient ‘‘Patient Counseling Information’’
requirement to provide information to Counseling Information’’ section is not section will already have an
patients. For example, for a product sufficient to meet the requirements of ‘‘Information for patients’’ subsection in
subject to § 201.57 with a Medication this section. This section, like the other their existing labeling on which to base
Guide, trade labeling for the product sections of prescription drug labeling, is the ‘‘Patient Counseling Information’’
would be required to be in at least 6- specifically written for health care section. Thus, this new requirement is
point type (see comment 102 of this practitioners. Its purpose is to inform anticipated to impose minimal burdens
document), while the Medication Guide, practitioners about what information is on manufacturers.
if reprinted as a perforated attachment important to convey to the patient at the
I. Comments on the Format
to the labeling for distribution to time of prescribing for the drug to be
Requirements (Proposed § 201.57(d))
patients, would be required to be in a used safely and effectively. FDA-
minimum 10-point type (see table 7). approved patient labeling, in contrast, is FDA proposed new format
For products subject to § 201.80 with a specifically written for a lay audience requirements for prescription drug
Medication Guide, there is no minimum and is intended to be read by patients. labeling (proposed § 201.57(d)). The
font size requirement for the labeling, The agency emphasizes how proposed provisions set forth minimum
while the Medication Guide, if reprinted important it is that prescribers be standards and requirements for many of
as a perforated attachment to the informed about what they should the key graphic elements of labeling
labeling for distribution to patients, communicate to their patients. On the (e.g., type size, letter and line spacing,
would be required to be in a minimum basis of a series of national telephone and contrast).
10-point type (see table 7). The agency surveys conducted by FDA to assess (Comment 98) Some comments
does not agree that distributing how patients receive information about recommended implementation of the
prescription drug labeling with the their prescription medicines, the agency proposed changes solely or primarily as
FDA-approved patient labeling determined that the prescribing part of the electronic labeling initiative.
appended as a perforated attachment physician is the primary source of drug Some comments requested that the new
will make it more difficult for the information for patients (Ref. 5). The format requirements not be
patient to receive information at the most recent survey, conducted in 1998, implemented for prescription drug
pharmacy because the pharmacists showed that more patients received labeling required to be distributed with
would have to detach the patient verbal prescription medicine a drug in trade packaging. They pointed
information. information at their physician’s office out that using an electronic format
(Comment 95) One comment sought (69 percent) than at the pharmacy (43 would permit use of larger print size,
clarification of what information should percent) (Ref. 5). In addition, although hypertext linking to all sections of
be included in the ‘‘Patient Counseling 74 percent of patients reported receiving labeling, links to newly revised sections
Information’’ section. The comment written information at the pharmacy, of of labeling, key word searches, and links
expressed concern about how the those who received written information to patient information without affecting
information in this section is to be at the pharmacy, 85 percent received the size of trade packaging. The
communicated to patients. instruction sheets and 83 percent comments maintained that larger trade
The ‘‘Patient Counseling Information’’ received stickers on the medicine packaging will be required to
section contains information that the container, but only 38 percent received accommodate larger labeling that will
practitioner may decide to convey to the brochures about the medicine. These result from the new format
patient at the time of prescribing for the results indicate that most consumers requirements.
drug to be used safely and effectively who receive product information, other The agency agrees that use of the
(e.g., warnings about driving if the than instructions for use or the sticker required format in conjunction with an
product causes drowsiness, or the information, receive it orally from their electronic medium may have benefits
concomitant use of other substances that physicians during an office visit. over paper labeling. As discussed in
may have harmful additive effects). The (Comment 97) One comment asked section V of this document, the agency
information in this section will vary whether products with existing labeling believes that, in the future, the Internet
depending on the safety and efficacy that will be required to convert to the and other electronic sources for labeling
characteristics of the product and how new labeling format will be required to will most likely be the primary means
it is taken. have a ‘‘Patient Counseling for delivering drug information to
FDA believes that requiring a separate Information’’ section if the product’s practitioners. At the present time,
‘‘Patient Counseling Information’’ existing labeling does not contain an however, some practitioners may not
section and a reminder message in ‘‘Information for patients’’ subsection in have the requisite computer equipment
Highlights directing practitioners to this its ‘‘Precautions’’ section. or skills to access prescription drug
section will make patient counseling If a product that does not have an labeling in an electronic format. The
information in labeling more accessible ‘‘Information for patients’’ subsection agency anticipates that it will be several
to health care practitioners. These becomes subject to the new content and years before the phase-out of paper
requirements will increase the format requirements at § 201.57, the labeling as the major source of
accessibility of the section and should product’s manufacturer would be prescribing information can begin.
reinforce the need for practitioners to required to develop a ‘‘Patient Therefore, the agency believes that it is
counsel their patients, thereby fostering Counseling Information’’ section for the important to establish minimum format
communication between practitioners product’s prescription drug labeling requirements for paper labeling.
and patients about prescribed drugs. unless a ‘‘Patient Counseling (Comment 99) One comment
(Comment 96) One comment asked Information’’ section would be clearly recommended the use of more blank
whether including the FDA-approved inapplicable (see § 201.56(d)(4)) and space among sections of Highlights. The
patient labeling in the ‘‘Patient thus not required. The agency comment expressed concern that,
Counseling Information’’ section would anticipates that few products would because Highlights contains a
be sufficient to meet the content qualify for such an exception. The significant amount of information in a
requirements for the section. agency believes that the vast majority of constrained space and uses a variety of
formatting techniques, the overall effect the requirement in proposed section titles and subheadings in each
would be confusing. One comment § 201.57(d)(5) to bold the information section, underlining section titles,
stated that the placement of the ‘‘Patient required by proposed § 201.57(a)(1) indenting subheadings under each
Counseling Information Statement’’ through (a)(4), (a)(11), and (a)(15) (i.e., section title, and providing more blank
above the ‘‘Highlights Limitation the following information in Highlights: space between each section. Another
Statement’’ in Highlights is not ideal Drug names, dosage form, route of comment also recommended indenting
because it appears that the ‘‘Patient administration, and controlled the subheadings under the major
Counseling Information Statement’’ is substance symbol; the inverted black sections to more readily distinguish
the title of the limitation statement. The triangle symbol; the prescription drug between the major sections and the
comment also requested that the FPI be symbol; boxed warnings or subheadings within the sections.
required to be in a two-column format contraindications; adverse reaction The agency agrees that all the
because such a format enables users to reporting contacts; and Highlights recommended revisions to the format of
stay better aware of the overall limitation statement) would ensure the Contents could make the information
information structure, as well as read visual prominence of the bolded easier to read and use. Because of cost
individual sections more easily. information or whether different and space constraints, however, the
The agency believes that use of more highlighting methods would be more agency believes that it is impractical to
blank space in Highlights would not be effective. implement all of the recommended
feasible because additional blank space (Comment 100) Most comments changes. FDA has revised the format
would increase the length of Highlights expressed satisfaction that bolding was requirements at proposed § 201.57(d) to
and of labeling generally. The one-half adequate to ensure the visual now require that the subheadings under
page length limitation for Highlights is prominence of the specified each section heading in Contents be
based on the strong preferences of information. Some comments stated that indented (§ 201.57(d)(10). In addition,
physicians surveyed in developing the capitalization, italics, and underlining, the final rule now requires that only the
prototype for the new labeling format in also effective methods of ensuring headings in Contents be bolded, not the
the proposed rule. Physicians reacted prominence and flexibility, should be subheadings (§ 201.57(d)(10)). The
negatively to prototype Highlights that maintained. Some comments expressed agency believes these changes make the
were one or one and one-half pages concern that possible alternative Contents easier to read and use without
long. They indicated that the utility of methods of ensuring visual prominence increasing its length or attendant costs.
Highlights decreased significantly as its (e.g., color printing) would add (Comment 102) In the proposal, the
length increased. In addition, there was unnecessary costs. One comment agency specifically sought comment on
significant concern from manufacturers requested that, if color is required, whether the proposed requirement
about the costs associated with adding specific Pantone colors be assigned to (proposed § 201.57(d)(6)) for a minimum
to the length of labeling. specific types of information to ensure type size of 8 points for all typeface
The agency also believes that the consistency in all product labeling. information in labeling is sufficient or
formatting techniques used in The agency recognizes that use of whether a minimum type size of 10
Highlights help make the information different methods to ensure prominence points would be more appropriate.
accessible, notwithstanding the density may decrease their impact and Currently, prescribing information is
of the section. Therefore, the agency significance. Therefore, FDA concludes usually printed in 6- or 7-point type.
does not believe that it is necessary to that bolding alone is adequate to One manufacturer stated that 6-point
include more blank space in Highlights. achieve visual prominence for the type was generally adequate for
The agency agrees that the formatting specified information in Highlights. The prescribing information, and another
and placement of the ‘‘Patient agency also agrees that color printing manufacturer stated that it typically
Counseling Information Statement’’ and would add cost and impose an uses 4- to 6-point type. Some
the ‘‘Highlights Limitation Statement’’ additional burden on manufacturers that manufacturers were concerned that a
in Highlights could be improved to would not be offset by meaningful minimum 8-point type would increase
better communicate the discrete improvement in visual prominence. the length of labeling to such an extent
information provided by each statement. Therefore, § 201.57(d)(5) requires the that trade packaging would have to
For this reason, and in response to following Highlights information to be increase in size to accommodate the
comments recommending greater in bold type: Highlights limitation longer labeling and the increase in size
prominence for the ‘‘Highlights statement; drug names, dosage form, would impose substantial costs. One
Limitation Statement,’’ the agency route of administration, and controlled comment recommended that prescribing
moved this statement to appear at the substance symbol; the initial U.S. information that accompanies trade
beginning of Highlights (see comment approval statement and year of this packaging not be subject to the 8-point
35). The agency also removed the approval; boxed warnings; adverse type minimum, while prescribing
requirement at proposed § 201.57(d)(3) reaction reporting contacts; and the information that is distributed in other
that the ‘‘Patient Counseling patient counseling information contexts, where it is more likely to be
Information Statement’’ be presented in statement. referenced by the prescriber (e.g.,
the center of a horizontal line, so that it (Comment 101) One comment prescribing information in electronic
does not appear to be a section title. requested that the agency revise the format, prescribing information
The agency agrees that a two-column format of Contents to make it easier to accompanying promotional materials
format is effective, but believes other read and use. The comment stated that and product samples), be required to be
formats may be equally effective in the information in Contents is not as in at least 8-point type. Some
conveying prescription drug accessible as it could be because it uses manufacturers stated that 8-point type
information and, therefore, is not straight columns, which make it hard to was adequate for prescribing
requiring a two-column format for the distinguish the major labeling sections information included in trade
FPI. (e.g., ‘‘Use in Specific Populations’’) packaging, but that a minimum 10-point
• Bolding (Proposed § 201.57(d)(5)) from subsections (e.g., ‘‘Pregnancy’’). type would increase the length of
In the proposal, the agency The comment recommended use of labeling to such an extent that trade
specifically sought comment on whether contrasting font types and sizes for the packaging would have to increase in
size to accommodate the larger size requirement is satisfactory for such there are alternatives that would be
prescribing information. labeling. FDA’s telephone survey of more appropriate and under what
Some consumers and health care office-based physicians showed that the circumstances such alternatives should
advocacy organizations requested that prescribing information in trade labeling be considered.
the agency reconsider whether the is referred to by physicians substantially Some comments stated that the one-
increase to an 8-point minimum type less frequently than other sources of half page length restriction should be
size was sufficient to achieve the prescribing information (Ref. 11, p. 30). required for all products (i.e., there are
agency’s goal of improving the Because manufacturers could incur no circumstances in which the
readability of the prescribing substantial costs in converting trade limitation should be waived). Other
information. They stated that, to labeling to 8-point type and the public comments maintained that it might be
improve readability, labeling should be health benefits of such conversion may difficult to consistently accommodate
printed in a type size larger than 8 not justify these costs, the agency the information required to be in
points and with more white space. They believes it is reasonable to allow a 6- Highlights within one-half page. These
urged the agency to test prototypes to point minimum type size for trade comments stated that the final rule
compare the relative readability of 8- labeling (see comment 124). Thus, should allow for some flexibility in the
point versus 10-point type. Some proposed § 201.57(d)(6) was revised to length of Highlights in those cases
comments advocated that the minimum permit a 6-point minimum type size for where one-half page may not be
type size should be at least 10 points, trade labeling. practical or possible. These comments
and preferably 12 points, for all patient The agency disagrees with the indicated that some manufacturers had
information. comment that recommended use of type done mockups of Highlights and had
In the preamble accompanying the sizes smaller than 6 points because such been unable to get the required
proposed rule, FDA summarized studies labeling would not be sufficiently information on one-half page. Some
that demonstrated the importance of readable. The final rule on OTC drug comments stated that the length
type size in evaluating readability of labeling requirements summarized restriction should be flexible enough to
written information and its effect on research on smaller font sizes, noting accommodate as many disclaimers and
visibility and reading speed (see 65 FR that a significant portion of the adult qualifying messages as are necessary to
81082 at 81096 and Refs. 6 through 9). population is not able to read OTC drug guide the physician to the more detailed
Type size combined with other product labeling with 4.5-point type discussion of the desired information in
graphical elements (e.g., letter and line size (see 64 FR 13254 at 13264 and the FPI. These comments maintained
spacing, contrast, print and background 13265, March 17, 1999). that the limitation on length could
color, and type style) also affect The agency acknowledges those result in increased medication errors
readability (Ref. 10). comments that urge even larger because important information would
The agency carefully considered the minimum type sizes to further increase be too compressed or might be excluded
literature, the comments submitted in readability. The agency agrees that, from Highlights.
response to the font size proposal, and absent any cost or space constraints, a The agency believes that a one-half
the estimated costs of using various font 10- or 12-point minimum type size page Highlights is adequate for the vast
sizes for labeling, and has determined would be preferable to 8-point. majority of products. As discussed
that permitting different font sizes for However, the agency believes that the 8- previously, Highlights provides
trade labeling (i.e., labeling on or within point minimum type size requirement introductory information to the more
the package from which the drug is to for all labeling except trade labeling and detailed FPI. The agency does not agree
be dispensed) and labeling disseminated the variety of formatting techniques that multiple disclaimers or qualifying
in other settings (e.g., labeling that incorporated into the new labeling statements would be useful or
accompanies prescription drug format will substantially improve the appropriate.
promotional materials) best achieves the readability of labeling without imposing The agency acknowledges, however,
agency’s objective of ensuring an unreasonable costs on manufacturers. that there may be situations in which it
acceptable base level of readability for Moreover, this final rule establishes may not be possible to accommodate all
prescription drug labeling while, at the minimum type sizes, but does not the information that should go into
same time, minimizing costs to prevent manufacturers from printing Highlights within one-half page. In such
manufacturers. Even though a larger labeling in larger type sizes. cases, the agency may waive the one-
font size may improve readability, the (Comment 103) One comment half page requirement and approve the
agency believes that an 8-point requested that the agency require labeling with slightly longer Highlights.
minimum type size, combined with Roman typeface in labeling for optimal Accordingly, FDA has revised § 201.58
other required graphical elements (e.g., legibility. The comment stated that in this final rule to make clear that FDA
bold type, bullets, demarcation lines), is Roman is a major improvement over can waive any of the requirements
adequate for prescription drug labeling currently used sans serif, and that sans under § 201.56 or § 201.57.
disseminated in settings where it is serif is only appropriate in applications The agency strongly believes that
likely to be referred to by prescribers where appearance is more important limiting the length of Highlights is
(e.g., labeling that accompanies drug than legibility (e.g., advertising). critical to preserving its usefulness. In
promotional materials). The agency The agency does not agree that FDA the physician surveys relied on by the
believes that the 8-point minimum type should require a specific typeface for all agency in developing and refining the
size reasonably balances the agency’s prescription drug labeling. The agency new labeling format, 80 percent of
objective of improving the readability of believes that any typeface that is clear physicians indicated that a summary or
labeling with the costs associated with and legible should be acceptable in highlights section should be no more
the resultant increase in the length of labeling. than one-half page. The surveys found
the labeling. (Comment 104) In the proposal, the that the perceived usefulness of
The agency also agrees with the agency specifically sought comment on Highlights declined considerably with
comments requesting that there be an whether the requirement in proposed increasing length. Accordingly, the
exception for trade labeling. FDA § 201.57(d)(8) for a one-half page limit labeling format was designed to
believes that a minimum 6-point type on Highlights is adequate or whether accommodate, on a single page, a one-
half page Highlights and a one-half page explanatory footnote with the asterisk overcrowding on prescription drug
Contents. To test the feasibility of would not overcome the confusion labels by removing certain information
limiting Highlights to one-half of a page, arising from use of an asterisk for from the container label.
the agency did numerous mockups of multiple purposes in labeling. Current § 201.100(b)(2) requires that
Highlights for a wide range of products The agency acknowledges that a the label on a prescription drug
and found that the one-half page limit vertical line in the margin might not be container bear a statement of the
provided adequate space in each case. universally understood as an indication recommended or usual dosage. Where it
Thus, the agency anticipates that the that the text adjacent to the mark has is not possible to present an informative
length restriction will be feasible in the been changed. The agency believes, or useful statement about the
vast majority of cases. however, that a significant percentage of recommended or usual dosage in the
(Comment 105) In the proposal, the practitioners have had some experience space available on the container label,
agency specifically sought comment on with commercial word processing current § 201.55 states that the
whether there are means other than a software and thus some exposure to requirements of § 201.100(b)(2) may be
vertical line that would facilitate access revision marks, including the use of the met by including the statement ‘‘See
to, and identification of, new labeling vertical line to identify changed text. package insert for dosage information.’’
information in the FPI. The agency also intends to develop for The agency proposed to eliminate
Some comments agreed that it was practitioners a comprehensive § 201.55. The agency also proposed to
highly desirable to call attention to new educational campaign to accompany the eliminate the requirement in
information in the FPI and that the introduction of the revised labeling § 201.100(b)(5) that the label of a
vertical line is adequate to identify the format. This educational campaign will prescription drug for other than oral use
new information. Other comments address, among other issues, the must bear the names of all inactive
stated that it was desirable to call significance of the vertical line in the ingredients. The agency proposed to
attention to new information, but that a margin. eliminate the requirement in
vertical line in the FPI might not be the The agency does not believe the § 201.100(b)(7) that the container label
best mechanism because it might not be vertical line will unnecessarily call bear a statement directed to the
understood as a revision mark by attention to minor changes in labeling. pharmacist specifying the type of
practitioners. Some comments The vertical line will be applied only to container to be used in dispensing the
maintained that use of a vertical line substantive changes that are identified product to maintain its identity,
would make the printing and graphics in the ‘‘Recent Major Changes’’ (‘‘Recent strength, quality, and purity. The agency
process for labeling more complex and Labeling Changes’’ in the proposed rule) proposed to require instead that these
costly. One comment recommended section in Highlights. In response to instructions be placed in the ‘‘How
italicizing new or revised text in the comments requesting that the agency Supplied/Storage and Handling’’ section
FPI. One comment recommended use of clarify what is meant by substantive of prescription drug labeling (proposed
an asterisk to identify changes, along changes, the agency specified in the § 201.57(c)(4)(v)).
with a footnote explaining what was final rule that only significant changes (Comment 106) Several comments
changed. Some comments maintained in the ‘‘Boxed Warning,’’ ‘‘Indications opposed the proposal to eliminate the
that identifying recent changes in and Usage,’’ ‘‘Dosage and requirement that the label of a
narrative in a section of the FPI devoted Administration,’’ ‘‘Contraindications,’’ prescription drug product for other than
to labeling changes or in the proposed and ‘‘Warnings and Precautions’’ oral use bear the name of all inactive
‘‘Recent Labeling Changes’’ section in sections of the FPI be listed in the ingredients. The comments stated that
Highlights (now called ‘‘Recent Major ‘‘Recent Major Changes’’ section. identification of inactive ingredients is
Changes’’) would alone be adequate to Nonsubstantive changes such as important because of their potential to
call attention to changes in the FPI. typographical or editorial changes be allergens. Some comments
Some comments stated that the vertical should not be identified. The agency maintained that manufacturers should
line will call unnecessary attention to believes that focusing on substantive be able to list on product labels selected
minor changes. Some comments stated changes in only these sections will inactive ingredients (e.g., ingredients
that, by stressing labeling changes, the avoid calling unnecessary attention to that are known allergens or are
identification of changes in the FPI minor changes and will ensure that the associated with adverse reactions). One
could dilute the significance of significance of unmarked text is not comment recommended listing the
unmarked text. diluted. diluent that should be used for
The agency has retained the proposed The agency believes that it would not admixture or those diluents that are
requirement at § 201.57(d)(9) to mark be adequate to identify labeling changes contraindicated. Two comments
major changes in the FPI with a vertical only in a section of the labeling devoted supported eliminating the list of
line in the left margin. The agency to changes. The agency believes it is inactive ingredients from the container
agrees that it is highly desirable to call important to also identify the specific label of products for other than oral use.
attention to new information in the FPI text that has been changed so that They agreed that the presence of such
and that the vertical line is adequate to practitioners will be able to locate information in the ‘‘Description’’ section
identify the new information. The changes and access the complete text. of prescription drug labeling would be
agency considered bolding, underlining, sufficient and that eliminating the
and italicizing as means to emphasize J. Comments on Revisions to Container information from the container label
changes. These formatting techniques Labels could make other information on the
are all currently used in labeling to add In addition to revising its regulations label more accessible and legible.
emphasis for purposes other than governing the content and format of Several comments also opposed the
identifying new information, so they labeling for prescription drugs, the proposal to eliminate the requirement
would not be readily understood as agency also proposed certain revisions that the label of a prescription drug
identifying labeling changes. Asterisks to the information required to appear on product bear a statement directed to the
are also used in labeling for purposes prescription drug product labels pharmacist specifying the type of
other than identifying labeling changes. (proposed § 201.100). The proposed container to be used in dispensing the
The agency believes that use of an revisions were intended to lessen product to maintain its identity,
strength, quality, and purity. The and Handling’’ section the type of statutory (section 502(c) of the act) and
comments maintained that eliminating container to be used in dispensing a regulatory provisions (§ 201.15)
dispensing information from the product to maintain a product’s requiring that information on product
container label, and placing it in identity, strength, quality, and purity labels be prominent and conspicuous so
prescription drug labeling, would make (information formerly presented on the as to render it likely to be read and
the information less accessible to product label) should apply only if the understood by the ordinary individual
pharmacists and would thus be product cannot be dispensed in the under customary conditions of purchase
inefficient and frustrating for standard amber vial. The comment and use provide the agency adequate
pharmacists. The comments were maintains that limiting the scope of the authority to ensure that the symbol is
concerned that making information on requirement to situations in which visually accessible. The agency does not
storage and handling less accessible exceptional storage conditions are believe it is necessary to specify the
could lead to inappropriate storage and required would serve to highlight the location of the symbol or its font size to
handling. Some comments urged that need for special considerations when ensure that the symbol achieves
the label at least be required to state any dispensing. adequate prominence.
special or unusual conditions for As discussed in the previous (Comment 110) One comment
storage. One comment recommended comment, the agency has reconsidered expressed concern about the
mandatory use of a symbol that signifies its proposed changes to the container proliferation of artwork on label
when a product requires special label, including the proposal to remove containers and the potential for that
handling. Two comments supported from the container label information artwork to make the label more difficult
removal of information on storage and directed at the pharmacist concerning to read and cause medication errors.
handling from product labels, agreeing the appropriate container in which to The agency acknowledges the
that less information on the container dispense a product. The agency will potential for artwork to obscure
label could make other information on continue to require that dispensing important information on the label. The
the label more accessible and legible. instructions appear on the container agency believes, however, that its
One comment maintained that label. Accordingly, proposed existing authority under 502(c) of the
manufacturers should be able to remove § 201.57(c)(4)(v) was deleted from the act and § 201.15 is adequate to ensure
from the label the statement referring final rule. Storage and special handling that artwork does not compromise the
practitioners to the full prescribing conditions have to be specified in prominence and conspicuousness of
information for dosage information labeling consistent with the information required to be on the label.
before the manufacturer is required to requirements of § 201.57(c)(17)(iv) of
revise its label in accordance with this this final rule. K. Miscellaneous Comments
final rule. (Comment 108) One comment (Comment 111) One comment
The agency has reconsidered its requested that the container label also requested that the agency clarify how
proposals to eliminate from container be required to disclose when the the content and format of the brief
labels: (1) The list of inactive container or some component of the summary required to accompany
ingredients for products other than for container contains latex or polyvinyl prescription drug advertising under
oral use, (2) the statement directed to chloride (PVCs). § 202.1 would be affected by the
the pharmacist concerning the type of As discussed in the response to
proposed revisions to prescription drug
container in which a product should be comment 106, the agency intends to
labeling. Another comment suggested
dispensed, and (3) the statement conduct a comprehensive evaluation of
that the agency entertain the idea that
referring practitioners to the package the product label and may repropose
Highlights could serve as an alternative
insert for dosage information in changes in the content of the product
to the brief summary because the agency
situations in which it is not possible to label at a later time, including changes
has noted that Highlights contains the
include information about the concerning the presence of latex and
most important information about drug-
recommended or usual dose on the PVCs in drug containers.
(Comment 109) One comment urged related risks.
label. The agency decided to withdraw
that there be a mandatory location for The proposed regulations were not
these proposed revisions to container
the ‘‘Rx Only’’ symbol on the main part designed to affect either the content or
labels. The agency believes that what is
of the label and that there be a specified the format of the brief summary of
appropriate content for product
minimum font size for the symbol. prescribing information required to
container labels and how to make that
In rulemaking (initiated under section accompany prescription drug
information as accessible as possible
126 of the Food and Drug advertisements under § 202.1 (21 U.S.C.
need to be further evaluated. The agency
Administration Modernization Act of 352(n)). As discussed in the proposed
intends to conduct a comprehensive
1997), the agency amended its rule (65 FR 81082 at 81087), statements
evaluation of information required to be
regulation requiring that container made in promotional labeling and
included on container labels and, if
labels contain the statement ‘‘Caution: advertisements must be consistent with
necessary, will propose changes to these
Federal law prohibits dispensing all information included in labeling
requirements at that time.
At this time, the agency will not without prescription’’ by replacing the under proposed § 201.57(c) to comply
require placement of a symbol on the statement with the symbol ‘‘Rx Only’’ with current §§ 201.100(d)(1) and
container label indicating that the (67 FR 4904, February 1, 2002). 202.1(e).9 The agency does believe,
product has special storage and Comments submitted to the agency in however, that Highlights communicates
handling requirements. The agency will response to this proposed change important information about a drug. The
consider this possibility during its requested that FDA specify the font size agency therefore will explore further, in
evaluation of the content of product and the location of the symbol on the conjunction with other prescription
labels. It would be premature to adopt container label. The agency declined drug advertising initiatives, the concept
such a symbol at this time. this request in the final rule of February 9 This requirement at proposed § 201.57(a) has
(Comment 107) One comment 1, 2002, and declines it again in this been removed because it is not pertinent to the
requested that the proposed requirement final rule. As discussed in the preamble contents of § 201.57 and is redundant with
to specify in the ‘‘How Supplied/Storage to the February 2002 final rule, existing provisions at §§ 202.1 and 201.100.
that Highlights could serve as a brief L. Comments on the Proposed the implementation plan also apply to
summary (see also FDA’s response to Implementation Plan all drugs that are among the 150 most
comment 112 about the brief summary For new and more recently approved frequently prescribed drugs that would
for consumer directed advertisements). drugs, FDA proposed a staggered not otherwise be covered by the
(Comment 112) Some comments implementation schedule for the implementation plan. The comment
stated that prescription drug labeling labeling requirements, with revised maintained that under the proposed
should be written in language that a lay labeling required for newer products implementation plan only 1 of the
audience can comprehend. The first (proposed § 201.56(c)). The current top 15 drugs used in the elderly
comments noted that consumers need to schedule is being finalized as proposed would be required to implement the
be able to read and understand the (see table 5 in section III of this revised content and format.
labeling because it accompanies the Some comments expressed concern
document). Revised labeling for ANDA
product, and because it is often used to that having different labeling formats
products depends on the labeling for the
provide information for direct-to- would be confusing to physicians. One
reference listed drug. The agency
consumer (DTC) advertisements. comment expressed concern that having
proposed to implement no later than 1
The purpose of prescription drug two different formats might impact
year after the effective date of the final prescribing behavior, arguing that
labeling is to provide health care rule the revised content requirements
practitioners information necessary for prescribers might favor newer, more
regarding unsubstantiated claims in expensive drugs. Some comments
safe and effective use. The agency labeling for newer and older drugs. The
believes that use of medical and maintained that a single standard format
agency also proposed to implement by is needed to facilitate access to labeling
scientific terminology is necessary to 1 year after the effective date of the final
effectively communicate to practitioners in electronic formats. One comment also
rule the requirement that any FDA- questioned FDA’s underlying
information about a product’s risks and approved patient labeling be reprinted
benefits as required under 21 U.S.C. assumption that there is a lesser need
immediately following the ‘‘Patient for improved labeling for older products
352(n) and § 201.100. Requiring that Counseling Information’’ section of the because practitioners are more familiar
language used in prescription drug FPI for newer products or immediately with older products and refer to older
labeling be tailored to a lay audience following the last section of the labeling product labeling less frequently than
would result in a loss of the clarity and for older products. The agency also newer product labeling. The comment
precision needed to effectively proposed to implement by 1 year after maintained that newer practitioners
communicate to practitioners a the effective date of the final rule the would need to refer to the labeling of
product’s benefits and risks. For requirement that in vitro or animal data older drugs to the same extent as for
example, if a drug is associated with a related to activity or efficacy of a drug newer drugs. One comment suggested
risk of a specific type of blood disorder, that have not been shown by adequate that manufacturers be given the option
the disorder must be identified by its and well-controlled studies to be to revise labeling for older products.
technical name (e.g., thrombotic pertinent to clinical use be removed Some comments from manufacturers
thrombocytopenic purpura) so the from the labeling unless a waiver is maintained that it would be most
practitioner can more quickly diagnose granted. practical to apply the new format
and treat the disorder when symptoms In the proposal, the agency requirements only to products whose
present. Scientific terminology may specifically sought comment on whether applications are submitted on or after
help to identify types of patients that the revised content and format the effective date of the final rule. They
might be at increased risk or otherwise requirements should be applied, as stated that broader implementation
manage the risk of that blood disorder. proposed, to drug products with an would place a substantial burden on
If the risk can only be described in NDA, BLA, or efficacy supplement that FDA resources and could interfere with
terms that a lay audience can is pending at the effective date of the review of new drugs. One comment
comprehend (e.g., blood disorder), the final rule, that was submitted on or after stated that the new format should apply
labeling would lack the precision the effective date of the final rule, or only to drugs that are not a member of
needed to communicate the specific risk that has been approved from 0 up to and an existing drug class (i.e., products that
to prescribers. including 5 years prior to the effective would be considered the original
For many products, the final rule will date of the final rule, or whether member of a drug class) or that are a
improve the usefulness of the brief alternative application criteria should new and novel member of an existing
summary to consumers and health care be used. drug class and whose applications are
practitioners by improving the (Comment 113) Several comments submitted on or after the effective date
usefulness of the prescription drug agreed with the categories of of the final rule. The comment
labeling, on which the brief summary is prescription drugs that would be subject maintained that having different
based. To this end, FDA has issued a to the new labeling content and format labeling formats for similar drugs within
draft guidance document entitled ‘‘Brief requirements in the agency’s proposed the same drug class would be a
Summary: Disclosing Risk Information implementation plan. Other comments competitive disadvantage for one format
in Consumer-Directed Print expressed concern that the proposed or the other.
Advertisements’’ that describes various implementation plan is too narrow. The agency believes the
options for presenting this information These comments maintained that the implementation plan as proposed for
in DTC print advertisements (69 FR new format is superior to the old format new and more recently approved drug
6308, February 10, 2004). By providing and the scope of the proposed products is the best option for
recommendations on use of alternatives implementation of the new format implementing the new format
to prescription drug labeling to fulfill would leave large numbers of products requirements. The agency agrees that it
the brief summary requirement, FDA is with inferior labeling. Some comments is desirable for all prescription drugs to
encouraging manufacturers to develop requested that the revised content and be subject to the same labeling rules.
brief summaries for use in consumer- format requirements eventually be However, the agency has carefully
directed advertisements using language applied to all marketed prescription considered the costs and benefits of
they can understand. drugs. One comment recommended that implementing the revised labeling
format and determined that requiring implementation plan did not encompass labeling for unsubstantiated claims and
broader implementation (e.g., to all all prescription drugs. remove all such claims from labeling
prescription drugs) of the new format FDA is cognizant that the presence of within 1 year of the effective date of the
requirements would be an excessive two labeling formats will present final rule. The agency agrees that a
regulatory burden. important challenges when requirement to scrutinize all existing
This initiative will require substantial implementing electronic labeling but is labeling within that timeframe would
resource allocation by the agency and confident that these challenges can be place substantial burdens on
industry for a period of several years. successfully addressed. For example, manufacturers and the agency and that
The agency’s proposed implementation the ways in which information will be such burdens might not be justified. In
plan, which is being finalized in this formatted, tagged, and stored in the the preamble to the proposed rule, the
rule as proposed, is intended to make contemplated electronic format will agency estimated that no more than 25
the best use of these resources. As permit access to labeling information in percent of labeling for drugs other than
discussed in the preamble to the both the old and new labeling formats. antibiotics might contain
proposed rule (65 FR 81082 at 81098), The agency does not agree that the unsubstantiated claims. Based on a
the plan targets newer products because new format should be applied only recent review of a sample of
practitioners are more likely to refer to prospectively or that it should be prescription drug labeling, however, the
the labeling for newer products. In optional for the currently approved agency believes the percentage of
FDA’s survey of physicians, newness of drugs that would be subject to the new products whose labeling might contain
the product was a reason rated by 87 format requirements under the proposed such claims is considerably lower than
percent of physicians as very likely to implementation plan. This narrower 25 percent and not high enough to
trigger a labeling referral for a drug (Ref. application of the new format justify a requirement that manufacturers
11, p. 35). In addition, the labeling for requirements would fail to reach a scrutinize all existing labeling to
newer products is typically longer and significant number of products whose identify those claims, particularly in a
more complex and, thus, more likely to labeling is frequently referenced and short timeframe.
could benefit from the new format The agency is eliminating only the
benefit from a new format that makes
requirements. requirement that manufacturers
the information more accessible. The
(Comment 114) Several comments scrutinize all labeling for the presence
implementation plan will also capture objected to the proposed requirement
many older products that would not of unsubstantiated claims within 1 year
that, within 1 year of the effective date of the effective date of the final rule.
otherwise be covered by the plan when of the final rule, manufacturers review
manufacturers seek new indications for The language in proposed § 201.57(c)(2),
all existing labeling and remove any (c)(3), and (c)(15) and § 201.80(c)(2), (j),
their products (i.e., submit an efficacy express or implied unsubstantiated and (m)(1) remains in the final rule,
supplement). For these reasons, the claims from the ‘‘Indications and requiring that the ‘‘Indications and
agency believes the implementation as Usage,’’ ‘‘Dosage and Administration,’’ Usage,’’ ‘‘Dosage and Administration,’’
proposed is the most reasonable ‘‘Clinical Pharmacology,’’ and ‘‘Clinical and ‘‘Clinical Studies’’ sections must
approach to maximizing the public Studies’’ sections. Some comments not imply or suggest uses not supported
health benefit and best utilizing maintained that this requirement would by substantial evidence and/or dosing
available resources in requiring the new be very burdensome for industry and regimens not included in the ‘‘Dosage
content and format for labeling. In the agency. They disagreed with the and Administration’’ section. This
addition, manufacturers of older agency’s contention in the preamble to language accurately reflects the existing
products not covered by the the proposed rule that the labeling regulatory standard for claims presented
implementation plan may voluntarily changes to remove unsubstantiated in prescription drug labeling.
revise, and submit for review, labeling claims could usually be accomplished While the agency will not require a
for their products in the new format at without prior approval by the agency systematic evaluation of all existing
any time. (i.e., with a ‘‘Changes Being Effected’’ labeling to identify unsubstantiated
The agency does not believe that an labeling supplement). They stated that claims within 1 year of the effective date
implementation plan based on volume these changes would more often than of the final rule, the agency wishes to
of prescriptions would be prudent. not require prior approval and extensive make it clear that manufacturers have an
Prescription volume can fluctuate negotiations between the agency and a ongoing obligation to ensure that claims
considerably over time, and the agency manufacturer. Some comments in labeling have adequate substantiation
is not aware that there are standardized maintained that there would be a and are not false or misleading. When
prescription volume data that are substantial number of requests for new information comes to light that
generally accepted as accurate. Thus, waivers under § 201.58 or § 314.126(c) causes information in labeling to
the agency believes it would be very and these requests would also be a become inaccurate, manufacturers must
difficult to fairly implement and enforce burden on the agency. Some comments act to change the content of their
an implementation plan based on agreed with the requirement to remove labeling, in accordance with §§ 314.70
prescription volume. unsubstantiated claims from existing and 601.12 (21 CFR 314.70 and 21 CFR
The agency also acknowledges that labeling, but stated that 1 year was not 601.12). To clarify this obligation, the
the existence of two different labeling enough time for manufacturers to agency has revised § 201.56 to specify
formats may lead to some frustration accomplish the task. One comment that manufacturers must act to correct
among practitioners. The agency maintained that the burden on the labeling that, in light of new
believes, however, that any potential agency would compromise the drug information, has become inaccurate (see
confusion can be minimized. approval process. One comment § 201.56(a)(2)).
Practitioners are already aware of the requested that the agency clarify what (Comment 115) One comment
content and format of existing labeling. types of statements would have to be recommended an implementation
The agency intends to engage in a removed. period of 3 years, rather than 1 year as
comprehensive educational campaign to The agency has reconsidered the proposed, to append any FDA-approved
educate practitioners about the major proposed requirement to have patient labeling to the end of the
features of the new format and why the manufacturers scrutinize all existing labeling for trade packages. The
comment maintained that additional exclusivity. This final rule does not comment requested that the agency
time was needed for reconfiguration and change the requirement to exclude any amend the rule to include labeling that
replacement of packaging equipment. condition of use or indication from the is distributed with prescription drug
The agency believes that the proposed labeling of a generic product when samples. The comment maintained that
implementation plan is appropriate and necessary (e.g., when the reference free prescription drug samples do not
in the best interest of public health. listed drug has patent protection or contain adequate information in their
Including the FDA-approved patient market exclusivity for an indication), packaging to keep consumers safe from
labeling in prescription drug labeling nor does it prevent, as described at harm.
ensures that this information is § 314.127(a)(7), approval of an ANDA FDA has often emphasized the
available to health care practitioners to when the reference listed drug has importance of providing patients with
reinforce the discussions they have with protected labeling. useful written prescription drug
their patients concerning the risks and In the scenario described, the information (e.g., FDA-approved patient
benefits of prescription drugs. The reference listed drug and the generic labeling) in a variety of settings (see e.g.,
agency considers improving physician- product would both be required to use 63 FR 66378, December 1, 1998; 68 FR
patient communication crucial for the new labeling format. The NDA 33724, June 5, 2003). Prescription drug
public health. Furthermore, the agency holder could not prevent the samples must be accompanied by trade
believes that this requirement should manufacturer of the generic product labeling (§ 201.100(c)), which is subject
not place an undue burden on from using the new labeling format of to this final rule. If FDA-approved
manufacturers because of the the reference listed drug, but the NDA patient labeling for a product is required
approximately 200 products that would holder would still have exclusivity for to be distributed to the patient, the
be affected by this provision of the final the new indication. manufacturer or distributor of that
rule, the labeling of more than 60 (Comment 117) One comment product must provide it with the
percent of them already conform with recommended that all generic drugs samples.
the requirement (see section XI.C.1 of pending approval or approved on or
this document). after the effective date of the final rule M. Comments on Environmental Impact
(Comment 116) Manufacturers of be required to submit labeling based on (Comment 120) One comment
products subject to an ANDA (generic the new format. The comment maintained that FDA failed to
products) expressed concern that NDA maintained that the content of labeling adequately consider the environmental
holders will use the rule’s is not significantly changed, just impact of the additional paper that will
implementation provisions as a reordered, so this requirement would be required for labeling and the increase
mechanism to delay approval of not be burdensome for manufacturers of in size of packaging and shipping
generics. The specific concern was that generic products and the information in containers.
NDA holders will obtain approval for a the labeling of the reference listed drug As stated in section IX of the
new indication near the end of their product and the generic product would proposed rule (65 FR 81082 at 81103),
marketing exclusivity for their drug’s still be essentially the same. the agency determined that it is not
original indication, revise the labeling The agency does not believe that required to do an environmental
for the drug to the new format, and manufacturers of generic products assessment or an environmental impact
receive 3 years’ marketing exclusivity should be required to provide labeling statement. This is an action excluded
for the new indication. The comments in the new format when seeking under § 25.30(h) and (k) (21 CFR
asked FDA to make it clear that, in such approval for their product if the 25.30(h) and (k)) (i.e., does not
situations, manufacturers of generic reference listed drug product is not individually or cumulatively have a
products would be permitted to base required to have its labeling in the new significant effect on the human
their labeling on the old format until the format. As discussed in the response to environment). The changes made to the
marketing exclusivity for the new comment 115, the act and regulations proposal in this final rule do not change
indication has expired. currently require that a generic product this conclusion. Therefore, neither an
The agency wishes to make clear that have the same labeling as the reference environmental assessment nor
the requirement to revise the labeling of listed drug product. Moreover, the environmental impact statement is
a reference listed drug in the new format agency believes that, to avoid confusion, required.
does not have any impact on the the labeling of a generic product should
duration of exclusivity for the drug and, be in the same format as the labeling of VII. Legal Authority
therefore, does not prevent a the reference listed drug. In this rule, FDA is addressing legal
manufacturer of a generic product from (Comment 118) One comment urged issues relating to the agency’s action to
using the revised labeling of the FDA to compile a list of products that revise the regulations prescribing
reference listed drug. Under section would be subject to the new format content and format requirements for
505(j)(2)(A)(v) of the act (21 U.S.C. requirements and make the list publicly prescription drug labeling.
355(j)(2)(A)(v)) and §§ 314.94(a)(8) and available.
314.127(a)(7) (21 CFR 314.127(a)(7)) of FDA does not believe that it is A. Statutory Authority
the agency’s regulations, the labeling of necessary to compile such a list. FDA’s revisions to the content and
a drug product submitted for approval Manufacturers can readily determine format requirements for prescription
under an ANDA must be the same as the whether their products are subject to drug labeling are authorized by the act
labeling of the listed drug referenced in these requirements by referring to the and by the Public Health Service Act
the ANDA, except for changes required implementation plan and the effective (the PHS Act). Section 502(a) of the act
because of differences approved under a date of the rule (see section III of this deems a drug to be misbranded if its
suitability petition (§ 314.93), because document). labeling is false or misleading ‘‘in any
the generic drug product and the (Comment 119) Some comments particular.’’ Under section 201(n) of the
reference listed drug are produced or requested that the agency clarify act, labeling is misleading if it fails to
distributed by different manufacturers, whether this final rule has implications reveal facts that are material with
or because aspects of the listed drug’s for labeling that is distributed with respect to consequences which may
labeling are protected by patent or prescription drug samples. One result from the use of the drug under the
conditions of use prescribed in the they are reasonably related to the supplied information, is necessary
labeling or under customary or usual government’s interest in ensuring the because it provides adequate directions
conditions of use. Section 502(f) of the safe and effective use of prescription for use. Because not all of the
act deems a drug to be misbranded if its drug products and because they do not information required in labeling clearly
labeling lacks adequate directions for impose ‘‘unjustified or unduly is necessary to prevent the labeling from
use and adequate warnings against use burdensome’’ disclosure requirements. being false or misleading, it is necessary
in those pathological conditions where (See Zauderer v. Office of Disciplinary for FDA to apply the remaining parts of
its use may be dangerous to health, as Counsel, 471 U.S. 626, 651 (1985); see the Central Hudson analysis.
well as adequate warnings against also Ibanez v. Florida Dep’t of Bus. and FDA’s interest in protecting the public
unsafe dosage or methods or duration of Prof’l Regulation, 512 U.S. 136, 146 health has been previously upheld as a
administration or application, in such (1994).) The information required by the substantial government interest under
manner and form, as are necessary for final rule to appear in labeling is the Central Hudson. (See Pearson v.
the protection of users. Section 502(j) of information necessary to provide facts Shalala, 164 F.3d 650, 656 (D.C. Cir.
the act deems a drug to be misbranded that are material with respect to 1999) (citing Rubin v. Coors Brewing
if it is dangerous to health when used consequences which may result from Co., 514 U.S. 476, 484–85 (1995).) The
in the dosage or manner, or with the the use of the drug under the conditions final rule’s labeling requirements
frequency or duration, prescribed, of use prescribed in the labeling or directly advance this interest, thereby
recommended, or suggested in its under customary or usual conditions of satisfying the third part of Central
labeling. use (sections 201(n) and 502(a) of the Hudson, because by requiring disclosure
In addition, the premarket approval act); adequate directions for use and of complete information on the
provisions of the act authorize FDA to adequate warnings (section 502(f) of the conditions under which a product can
require that prescription drug labeling act); and information on the conditions be used safely and effectively, the
provide the practitioner with adequate of use in which the product would be requirements help to ensure that
information to permit safe and effective dangerous (section 502(j) of the act). In prescription drug products will be
use of the drug product. Under section addition, pursuant to section 505 of the prescribed properly by health care
505 of the act, FDA will approve an act, the labeling sets forth information practitioners and will be used safely and
NDA only if the drug is shown to be on the conditions in which the product effectively by patients.
both safe and effective for use under the is safe and effective. By its terms, the Finally, under the fourth part of the
conditions set forth in the drug’s final rule requires disclosure of the Central Hudson test, there are not
labeling. Section 701(a) of the act (21 essential scientific information numerous and obvious alternatives (in
U.S.C. 371(a)) authorizes FDA to issue necessary for safe and effective use of fact, there are no reasonable
regulations for the efficient enforcement the labeled drug product. Consequently, alternatives) (Cincinnati v. Discovery
of the act. FDA believes the final rule passes Network, 507 U.S. 410, 418 n.13 (1993))
Under 21 CFR 314.125, FDA will not muster under the First Amendment. to the content and format requirements
approve an NDA unless, among other In Central Hudson Gas & Electric of this final rule that directly advance
things, there is adequate safety and Corporation v. Public Service the government’s interest but are less
effectiveness information for the labeled Commission 447 U.S. 557 (1980), the burdensome to speech. Health care
uses and the product labeling complies Supreme Court established a four-step practitioners are accustomed to looking
with the requirements of part 201. analysis for assessing the to the prescription drug labeling as their
Under § 201.100(d) of FDA’s constitutionality of government primary source of information about a
regulations, prescription drug products restrictions on the content of product, and patients rely for their drug
must bear labeling that contains commercial speech. information primarily on practitioners.
adequate information under which [First,] we must determine whether the Neither a public education campaign,
licensed practitioners can use the drug expression is protected by the First nor encouraging sponsors to provide
safely for their intended uses. This final Amendment. For commercial speech to come information on the risks and benefits of
rule amends the regulations specifying within that provision, it at least must concern drugs but not requiring such
the format and content for such labeling. lawful activity and not be misleading. information, would ensure that
Section 351 of the PHS Act (42 U.S.C. [Second,] we ask whether the asserted practitioners have the information they
262) provides legal authority for the governmental interest is substantial. If both
inquiries yield positive answers, we must
need about the conditions in which
agency to regulate the labeling and determine [third] whether the regulation prescription drugs can be used safely
shipment of biological products. directly advances the government interest and effectively. Requiring disclosures
Licenses for biological products are to asserted, and [fourth,] whether it is not more meets the fourth part of the test.
be issued only upon a showing that they extensive than is necessary to serve that Accordingly, the agency believes it
meet standards ‘‘designed to insure the interest. has complied with its burdens under the
continued safety, purity, and potency of This rule also survives scrutiny under First Amendment to support the content
such products’’ prescribed in the four-part test in Central Hudson. and format requirements for
regulations (section 351(d) of the PHS FDA believes that much information prescription drug labeling.
Act). The ‘‘potency’’ of a biological required to appear in prescription drug
labeling is necessary for labeling to be VIII. Paperwork Reduction Act of 1995
product includes its effectiveness (21
CFR 600.3(s)). Section 351(b) of the PHS nonmisleading. The risk information The final rule contains information
Act prohibits false labeling of a contained in such labeling, for example, collection provisions that are subject to
biological product. FDA’s regulations in constitutes material facts within the review by the OMB under the
part 201 apply to all prescription drug meaning of sections 201(n) and 502(a) of Paperwork Reduction Act of 1995 (44
products, including biological products. the act. Risk information can also U.S.C. 3501–3520). The title,
qualify as warnings compelled by description and respondent description

B. First Amendment section 502(f) and (j) of the act. Other of the information collection provisions
FDA’s requirements for the content information, such as information on are shown below with an estimate of the
and format of prescription drug labeling indications for the product, dosage and reporting burdens. Included in the
are constitutionally permissible because administration information, and how estimate is the time for reviewing
instructions, searching existing data Prescribing Information.’’ Highlights they were previously incurred to
sources, gathering and maintaining the provides a concise extract of the most produce existing labeling.
data needed, and completing and important information required under
2. Annual Burden for Labeling Design,
reviewing each collection of § 201.57(c) (the FPI), as well as certain
Testing, and Submitting to FDA for
information. The OMB and FDA additional information important to
NDAs Submitted on or After the
received no comments concerning the prescribers. Section 201.57(b) requires a
information collection provisions of the Effective Date of the Final Rule
table of contents to prescribing
proposed rule. (§§ 201.56 and 201.57)
information, entitled ‘‘Full Prescribing
Title: Requirements on Content and Information: Contents,’’ consisting of a New drug product applicants must:
Format of Labeling for Human list of each heading and subheading (1) Design and create prescription drug
Prescription Drug and Biological along with its identifying number to labeling containing Highlights,
Products facilitate health care practitioners’ use Contents, and FPI, (2) test the designed
Description: The final rule amends of labeling information. Section labeling (e.g., to ensure that the
FDA’s regulations governing the format 201.57(c) specifies the contents of the designed labeling fits into carton-
and content of labeling for human FPI. The final rule reorders information enclosed products), and (3) submit it to
prescription drug products. It revises required at former § 201.57, makes FDA for approval.
current regulations to require that the minor content changes, and provides Based on information received from
labeling of new and recently approved standardized identifying numbers for the pharmaceutical industry, FDA
products contain highlights of the required information. Section estimated that it took applicants
prescribing information, a table of 201.57(d) mandates new minimum approximately 3,200 hours to design,
contents for prescribing information, specifications for the format of test, and submit prescription drug
reordering of certain sections, minor prescription drug labeling and labeling to FDA as part of an NDA or
content changes, and minimum establishes minimum requirements for BLA under former labeling requirements
graphical requirements. The final rule key graphic elements such as bold type, (see row 1 of table 8a). FDA estimates
does not subject older drugs to the bullet points, type size, and spacing.
revised labeling requirements. However, that it will take an additional 149 hours
it does require, as for new and recently In accordance with the final rule, to generate Highlights and Contents and
approved products, that FDA-approved older drugs not subject to the revised otherwise comply with the additional
patient labeling accompany or be labeling content and format requirements of the final rule (see row
reprinted immediately following the last requirements in § 201.57 remain subject 2 of table 8a). Therefore, it will take a
section of prescription drug labeling. to labeling requirements at former total of approximately 3,349 hours to
As discussed in section VII of this § 201.57, which is redesignated as design, test, and submit new labeling.
document, FDA’s legal authority to § 201.80 by this final rule. Section Approximately 85 applicants would
amend its regulations governing the 201.80 contains minor clarifications. In submit approximately 107 new
content and format of labeling for addition, § 201.80(f)(2) requires that applications (NDAs and BLAs) to FDA
human prescription drugs derives from within 1 year, any FDA-approved per year, totaling 358,343 hours (see
sections 201, 301, 502, 503, 505, and patient labeling be referenced in the Total of table 8a).
701 of the act and from section 351 of ‘‘Precautions’’ section of the labeling of 3. Burden Associated with Labeling
the PHS Act. older products and either accompany or Supplements for Applications
be reprinted immediately following the Approved Within 5 Years Prior to the
A. Summary of Prescription Drug labeling.
Labeling Content and Format Effective Date of the Rule (§ 201.57)
Requirements in this Final Rule That B. Estimates of Reporting Burden The final rule requires that
Contain Collections of Information prescription drug applications approved
1. The Reporting Burdens for the
Section 201.56 requires that General Requirements (§ 201.56) during the 5 years before, or pending on,
prescription drug labeling contain the effective date conform to format and
certain information in the format The reporting burdens for the general content requirements at § 201.57. For
specified in either § 201.57 or § 201.80, requirements in § 201.56(a) are the same these products, applicants must
depending on when the drug was as those for former § 201.56(a) through redesign and negotiate the labeling,
approved for marketing. Section (c) and are estimated in tables 8a and 8b including Highlights and Contents, test
201.56(a) sets forth general labeling as part of the burdens associated with the redesigned labeling, and prepare
requirements applicable to all § 201.57. Section 201.56(b) and (c) sets and submit that labeling to FDA for
prescription drugs. Section 201.56(b) forth the categories of affected drugs and approval. Based on information
specifies the categories of new and more their implementation schedule, provided in the ‘‘Analysis of Economic
recently approved prescription drugs generating no reporting burdens. Impacts’’ (economic analysis) (see
subject to the revised content and Section 201.56(d) sets forth the required section XI.D.2.a of this document),
format requirements in §§ 201.56(d) and sections and subsections associated labeling supplements for a total of
201.57. Section 201.56(c) sets forth the with the revised format in § 201.57; approximately 344 innovator products
schedule for implementing these revised therefore, its associated reporting would be submitted to the FDA over a
content and format requirements. burdens are estimated in tables 8a and 5-year period (beginning in year 3 and
Section 201.56(e) specifies the sections 8b under the requirements at § 201.57. ending in year 7 after the effective date
and subsections, required and optional, Sections 201.56(e) and 201.80 codify of the rule). Approximately 172
for the labeling of older prescription former labeling requirements at applicants would submit these labeling
drugs not subject to the revised format §§ 201.56(d) and (e) and 201.57, with supplements. The time required for
and content requirements. minor clarifications, for older redesigning, testing, and submitting the
Section 201.57(a) requires that prescription drugs. The requirements in labeling to FDA is estimated to be
prescription drug labeling for new and these sections impose no new reporting approximately 196 hours per
more recently approved prescription burdens (except those accounted for in application, totaling 67,424 hours (see
drug products include ‘‘Highlights of section VIII.B.6 of this document), as row 1 of table 8b).
4. Burden Associated with Revised 5. Burden Associated with Revised or be reprinted immediately following
Labeling Efficacy Supplements Labeling for Efficacy Supplements for the prescription drug labeling
Submitted on or After the Effective Date Generic Drug Products (§ 201.57) (§§ 201.57(c)(18) and 201.80(f)(2)). As
of the Rule (§§ 201.56(d) and 201.57) The reporting burden for generic indicated in the economic analysis
products subject to the requirements of (section XI.D.1 of this document), an
Efficacy supplemental applications the final rule has only been estimated estimated 80 products will need to
for older drugs submitted on or after the for those products requiring revisions to revise labeling as a result of this
effective date of the final rule are subject their existing labeling. Reporting requirement. Approximately 18
to the content and format requirements burdens for generating newly approved applicants would be subject to this
at §§ 201.56(d) and 201.57. To meet labeling for generic products requirement. The agency estimates
these requirements, applicants must (§ 314.94(8)) is already approved under approximately 38 hours per product as
revise the existing labeling for these OMB control number 0910–0001. a one-time labeling revision, totaling
products. Each year an increasing According to the data in the economic 3,040 hours (see row 4 of table 8b).
number of innovator drug labeling will analysis, beginning in year 3 and
have been revised, and over time, very continuing throughout the 10-year C. Capital Costs
few efficacy supplements independently period analyzed, approximately 42
generic applications per year must A small number of carton-enclosed
will generate labeling revisions as a
submit labeling supplements to comply products may require new packaging to
result of this final rule. According to
with the final rule (see section XI.D.2.a accommodate longer inserts (see section
information in the economic analysis,
of this document). For purposes of this XI.D.2.c and comment 124 of this
the total number of affected efficacy
analysis, approximately 336 already document). As described in more detail
supplements over 10 years is estimated
approved generic drug applications in the economic analysis (section
at 324, with a decreasing number each
must submit labeling supplements over XI.D.2.c.ii), up to 5 percent of the
year over the 10-year period (see section
the 10-year period after the effective existing products affected by the rule
XI.D.2.a. of this document). For
date of the rule (see section XI.D.2.a of (i.e., products with new efficacy
purposes of this analysis, the total
this document). The time required to supplements, products approved in the
burden for efficacy supplements is revise and submit this labeling to FDA 5 years prior to the effective date of the
summarized in row 2 of table 8b. Over would be approximately 27 hours per rule, and affected ANDAs) may require
10 years, approximately 172 applicants application, totaling 9,072 hours (see equipment changes at an estimated cost
will trigger approximately 324 efficacy row 3 of table 8b). In addition to this of $200,000 each product. As shown in
supplements, each one requiring burden, a minimal reporting burden table 17, the estimated value of
approximately 196 hours to revise the associated with a very small number of equipment changes totals $7.2 million
labeling in the application, totaling generic applications referencing older and $8.7 million over 10 years
63,504 hours. In addition to this burden, drugs may continue indefinitely.
discounted at 7 and 3 percent,
a minimal annual reporting burden,
6. Requirement That FDA-Approved respectively.
probably even lower than the 7 per year
Patient Labeling Accompany Description of Respondents: Persons
estimated in year 10 of table 13 of this Prescription Drug Labeling Within 1
document, will continue indefinitely. and businesses, including small
Year (§§ 201.57 and 201.80) businesses and manufacturers.
Within 1 year, all FDA-approved
patient labeling must either accompany
TABLE 8A.—ESTIMATED REPORTING BURDEN FOR NEW DRUG APPLICATIONS1
Number of Number of Responses Total Hours
Category (21 CFR section) Total Hours
Respondents per Respondent Responses per Response
Annual burden associated with

former labeling requirements
(former 201.56(d) and 201.57) 85 1.26 107 3,200 342,400
Additional annual burden associ-

ated with requirements of this
final rule (201.56(d) and
201.57) 85 1.26 107 149 15,943
Total 3,349 358,343

1 There are no capital costs or operating and maintenance costs associated with this collection of information.
TABLE 8B.—ESTIMATED REPORTING BURDENS FOR LABELING REVISIONS TO ALREADY-APPROVED DRUG PRODUCTS1
Number of
Year(s) In Which Bur- Number of Responses Total Re- Hours per Total Total Capital
Category (21 CFR section) dens Occur Following Respond- per Re- sponses Response Hours Costs
Rule’s Effective Date ents spondent
Burden associated with re- Beginning year 3, 172 2.0 344 196 67,424 $3.3 million
vised labeling for applica- ending year 7
tions approved within 5
years prior to the rule’s ef-
fective date (201.57)
Burden associated with re- Beginning year 1, di- 172 1.88 324 196 63,504 $2.5 million
vised labeling for efficacy minishing over time
supplements submitted on
or after the rule’s effective
date (201.56(d) and 201.57)
Burden associated with re- Beginning year 3, 42 8 336 (for years 27 9,072 $2.5 million
vised labeling for efficacy continuing annually 1–10)
supplements for generic thereafter
drug products (201.57)
Burden as a result of having Year 1 only 18 4.44 80 38 3,040 $400,000

FDA-approved patient label-
ing accompany drug label-
ing within 1 year
(201.57(c)(18) and
201.80(f)(2))
Total 143,040 Up to $8.7

million (see
table 17)
1 There are no operating and maintenance costs associated with this collection of information.
The information collection provisions the Federal statute.’’10 Here, FDA has An NDA must include the ‘‘proposed
in this final rule have been approved determined that the exercise of State text of the labeling,’’ together with
under OMB control number 0910–0572. authority conflicts with the exercise of ‘‘annotations to the information in the
This approval expires December 31, Federal authority under the act. summary and technical sections of the
2008. An agency may not conduct or The act gives FDA comprehensive application that support the inclusion of
sponsor, and a person is not required to authority over drug safety, effectiveness, each statement in the labeling * * *’’
respond to, a collection of information and labeling. FDA is the expert Federal (21 CFR 314.50(c)(2)(i)). The proposed
unless it displays a currently valid OMB agency charged by Congress with labeling must also provide ‘‘adequate
ensuring that drugs are safe and directions for use’’ (section 502(f) of the
control number.
effective and that product labeling is act). FDA by regulation has defined this
IX. Environmental Impact truthful and not misleading (sections to mean ‘‘directions under which the
505(d) and 903(b)(2)(B) of the act (21 layman can use a drug safely * * *’’ (21
The agency has determined under 21 U.S.C. 393(b)(2)(B))). According to the CFR 201.5). Because a prescription drug,
CFR 25.30(h) and (k) that this action is act, a manufacturer of a drug must by definition, cannot be used safely by
of a type that does not individually or submit an NDA containing ‘‘full reports a layperson without professional
cumulatively have a significant effect on of investigations which have been made supervision, FDA regulations afford an
the human environment. Therefore, to show whether or not such drug is safe exemption from the statutory
neither an environmental assessment for use and whether such drug is requirement of adequate directions for
nor an environmental impact statement effective in use’’ (section 505(b)(1)(A) of use for a prescription drug whose
is required. the act; see also 21 CFR 314.50; see also labeling includes ‘‘any relevant hazards,
United States v. Rutherford, 442 U.S. contraindications, side effects, and
X. Executive Order 13132: Federalism 544, 555 (1979) (‘‘Few if any drugs are precautions under which practitioners
We have analyzed this final rule in completely safe in the sense that they licensed by law to administer the drug
may be taken by all persons in all can use the drug safely and for the
accordance with the principles set forth
circumstances without risk. Thus, the purposes for which it is intended
in Executive Order 13132. Section 4(a)
Commissioner generally considers a * * *’’ (§ 201.100(c)(1)). If labeling
of the Executive order requires agencies
drug safe when the expected therapeutic lacks this information, or is otherwise
to ‘‘construe * * * a Federal statute to
gain justifies the risk entailed by its false or misleading in any particular,
preempt State law only where the use’’ (citations omitted))). FDA is authorized to refuse to approve
statute contains an express preemption the NDA (section 505(d) of the act; 21
provision or there is some other clear 10 Because we have determined that the act
CFR 314.125(b)(6) and (b)(8)).
evidence that the Congress intended preempts State law because the exercise of State The FDA review process for an NDA
preemption of State law, or where the authority conflicts with the exercise of Federal
authority under that statute, we need not construe
is thorough and scientifically rigorous.
exercise of State authority conflicts with our statutory rulemaking authority as required by An NDA must contain proposed
the exercise of Federal authority under section 4(b) of the Executive order. labeling and all information about the
drug (whether favorable or unfavorable) they need to prescribe the drug safely and commerce without having submitted the
that is pertinent to evaluating the effectively for the care of patients. required premarket information has
application and that is received or (65 FR 81082 at 81082 and 81083). What violated the act (section 505(a) of the
otherwise obtained by the applicant distinguishes the prescription drug act) and is subject to FDA enforcement
from any source (21 CFR 314.50 and labeling from other information action. Similarly, if a manufacturer fails
601.2(a)). FDA scientists evaluate this available to practitioners about a to submit information required by 21
information, and may request additional prescription drug is that the CFR 314.80 and 314.81, it is subject to
information as necessary to provide a prescription drug labeling ‘‘is intended enforcement action under 21 U.S.C.
complete and accurate picture of the to provide physicians with a clear and 331(e). FDA is authorized to investigate
product. FDA may supplement the concise statement of the data and suspected fraud using its general
expertise of its in-house scientific information necessary for the safe and statutory investigative authority (section
personnel with advice from scientific effective use of the drug.’’ Moreover, the 702 of the act (21 U.S.C. 372)). The
advisory committees of outside experts act ‘‘permits labeling statements with agency is also empowered to address
(21 CFR 14.171). respect to safety only if they are fraud by seeking injunctive relief and
Under the act and FDA regulations, supported by scientific evidence and are civil penalties (21 U.S.C. 332,
the agency determines that a drug is not false or misleading in any 333(g)(1)(A)), and has authority to
approvable based not on an abstract particular’’ (44 FR 37434 at 37435 and invoke the general federal prohibition
estimation of its safety and 37441). on making false statements to the
effectiveness, but rather on a Under this final rule, risk information Federal Government (18 U.S.C. 1001). In
must appear in different sections of the sum, FDA has a variety of enforcement
comprehensive scientific evaluation of
prescription drug labeling in a options that allow it to make a
the product’s benefits and risks under
particular order and must be based on calibrated response to suspected
the conditions of use prescribed,
data derived from human experience violations of the act’s information
recommended, or suggested in the
whenever possible. For example, submission requirements.
labeling (section 505(d) of the act). FDA
information included in the The agency carefully reviews all the
considers not only complex clinical
contraindications section of prescription information submitted by a sponsor in
issues related to the use of the product
drug labeling must include only a marketing application to make its
in study populations, but also important
‘‘[k]nown hazards and not theoretical statutorily required judgment as to
and practical public health issues
possibilities’’ (§ 201.57(c)(5)). The whether the product is safe and effective
pertaining to use of the product in day- adverse reactions section must include
to-day clinical practice, such as the and otherwise in compliance with the
those adverse events for which there is act. It also reviews adverse event
nature of the disease or condition for some basis to believe there is a causal
which the product will be indicated, information submitted after marketing
relationship between the event and the approval and determines what action, if
and the need for risk management drug (§ 201.57(c)(7)).
measures to help assure in clinical any, should be taken. In rare cases, FDA
The act and FDA regulations prescribe finds that the information supports a
practice that the product maintains its several procedures to ensure that FDA
favorable benefit-risk balance. The determination to withdraw the product
receives information about risks that from the market (section 505(e) of the
centerpiece of risk management for become apparent after approval.
prescription drugs generally is the act; 21 CFR 601.5(b)(1)). In other
Because clinical trials involve time- instances, FDA uses other risk
labeling, which reflects thorough FDA limited administration of the
review of the pertinent scientific management techniques. One such
investigational product to a relatively technique is incorporating additional
evidence and communicates to health small and homogeneous population of
care practitioners the agency’s formal, risk information into, or otherwise
study subjects, adverse events that were modifying, the prescription drug
authoritative conclusions regarding the not observed during clinical trials may
conditions under which the product can labeling (§ 201.57(e)). In many cases,
be recognized or identified following review of the submitted reports does not
be used safely and effectively in approval. The act provides that a
accordance with the act. lead to any change, e.g., because FDA
manufacturer must establish and determines that the event reported is not
FDA carefully controls the content of maintain such records, and make such
prescription drug labeling, because such causally related to the product.
reports, as FDA may require by Changes to prescription drug labeling
labeling is FDA’s principal tool for regulation (section 505(k) of the act). To typically are initiated by the sponsor,
educating health care practitioners implement this provision, FDA has subject to FDA review, but are
about the risks and benefits of the issued regulations requiring prompt sometimes initiated by FDA. Under FDA
approved product to help ensure safe reports of serious, unexpected drug regulations, to change prescription drug
and effective use. As FDA noted in the experiences and periodic reports of all labeling (except for editorial and other
preamble accompanying the December information relating to the safety and minor revisions), the sponsor must
2000 proposed rule amending the 1979 effectiveness of the drug (21 CFR 314.80 submit a supplemental application fully
physician labeling regulations: and 314.81). Manufacturers may also
The part of a prescription drug product’s
explaining the basis for the change
approved labeling directed to health care commit to conduct additional safety and (§§ 314.70 and 601.12(f)). FDA permits
practitioners * * * is the primary effectiveness studies following approval two kinds of labeling supplements: (1)
mechanism through which FDA and drug and submit data from these studies to Prior approval supplements, which
manufacturers communicate essential, the agency. (See section 506B of the act require FDA approval before a change is
science-based prescribing information to (21 U.S.C. 356b).) made (§§ 314.70(b) and 601.12(f)(1)),
health care professionals. This part of The statutory and regulatory and (2) CBE supplements, which may be
approved labeling is a compilation of requirements for the submission of implemented before FDA approval, but
information based on a thorough analysis of

the new drug application (NDA) or biologics
information to FDA are accompanied by after FDA notification (§§ 314.70(c) and
license application (BLA) submitted by the statutory provisions addressing the 601.12(f)(2)). Labeling changes to the
applicant * * * . [T]he primary purpose of failure of a sponsor to comply with FPI to add or strengthen a warning,
prescription drug labeling is to provide these requirements. A manufacturer that precaution, contraindication, or adverse
practitioners with the essential information introduces a new drug into interstate reaction statement are within the
category of changes for which CBE more detail above, it preempts state law Section 202(a) of the Unfunded
supplements are required by FDA only to the extent required to preserve Mandates Reform Act of 1995 requires
regulations (§§ 314.70(c)(6)(iii) and Federal interests. Section 4(d) of that agencies prepare a written
601.12(f)(2)(i)) (see comment 5). While a Executive Order 13132 states that when statement of anticipated costs and
sponsor is permitted to add risk an agency foresees the possibility of a benefits before proposing any rule that
information to the FPI without first conflict between State law and federally may result in an expenditure by State,
obtaining FDA approval via a CBE protected interests within the agency’s local, and tribal governments, in the
supplement, FDA reviews all such area of regulatory responsibility, the aggregate, or by the private sector, of
submissions and may later deny agency ‘‘shall consult, to the extent $100 million in any one year (adjusted
approval of the supplement, and the practicable, with appropriate State and annually for inflation).
labeling remains subject to enforcement local officials in an effort to avoid such The agency believes that this rule is
action if the added information makes a conflict.’’ Section 4(e) of Executive consistent with the regulatory
the labeling false or misleading under Order 13132 adds that, when an agency philosophy and principles identified in
section 502(a) of the act. To mitigate this proposes to act through adjudication or Executive Order 12866 and in these two
risk, manufacturers often consult with rulemaking to preempt State law, the statutes. The final rule would amend
FDA before adding risk information to agency ‘‘shall provide all affected State current requirements for the format and
labeling. As noted in response to and local officials notice and an content of human prescription drug
comment 5, however, a sponsor may not opportunity for appropriate product labeling. Although the
use a CBE supplement to make most participation in the proceedings.’’ effectiveness of the revised labeling in
changes to Highlights. FDA sought input from all achieving time savings and reductions
As FDA has long recognized, its role stakeholders on new requirements for in adverse reactions is uncertain, based
is not to regulate medical practice. The the content and format of prescription on the following analysis as
agency’s actions nevertheless affect drug labeling through publication of the summarized in table 9, FDA projects
medical practice in a variety of ways. proposed rule in the Federal Register. that the present value of the quantifiable
For example, FDA approval decisions Although the proposed rule did not benefits of the final rule over 10 years
affect the availability of drugs and propose to preempt state law, it did range from $330 million to $380 million
medical devices. Also, FDA decisions as solicit comment on product liability and from $420 million to $480 million
to the content and format of prescription issues. FDA received no comments on at a 7 and 3 percent discount rate,
drug labeling affect health care the proposed rule from State and local respectively. Direct costs of the final
practitioners’ communications with governmental entities. rule are projected to range from
patients, to the extent such labeling is Officials at FDA consulted with a
approximately $7 million to $17 million
relied upon by such practitioners to number of organizations representing
in any one year, for a total present value
guide their discussions of risk with the interests of state and local
of approximately $90 million and $120
patients. FDA strongly believes that governments and officials about the
million over 10 years at a 7 and 3
health care practitioners should be able interaction between FDA regulation of
percent discount rate, respectively. The
to rely on prescription drug labeling for prescription drug labeling (including
agency thus concludes that the benefits
authoritative risk information and that this rule) and state law.
of this final rule outweigh the costs.
health care practitioners should not be In conclusion, the agency believes
Furthermore, the agency has determined
required to convey risk information to that it has complied with all of the
that the final rule is not an economically
patients that is not included in the applicable requirements under
significant rule as described in the
labeling. Executive Order 13132 and has
If State authorities, including judges Executive order, because annual
determined that this final rule is
and juries applying State law, were impacts on the economy are
consistent with the Executive order.
permitted to reach conclusions about substantially below $100 million.
the safety and effectiveness information XI. Analysis of Economic Impacts Because the rule does not impose any
disseminated with respect to drugs for FDA has examined the impacts of the mandates on State, local or tribal
which FDA has already made a series of final rule under Executive Order 12866, governments, or the private sector that
regulatory determinations based on its the Regulatory Flexibility Act (5 U.S.C. will result in an expenditure in any one
considerable institutional expertise and 601–612), and the Unfunded Mandates year of $100 million or more, FDA is not
comprehensive statutory authority, the Reform Act of 1995 (Public Law 104–4). required to perform a cost-benefit
federal system for regulation of drugs Executive Order 12866 directs agencies analysis according to the Unfunded
would be disrupted. Where a drug has to assess all costs and benefits of Mandates Reform Act. The current
not been reviewed by FDA and available regulatory alternatives and, inflation-adjusted statutory threshold is
decisions with respect to safety, when regulation is necessary, to select about $115 million.
effectiveness, and labeling have not regulatory approaches that maximize The agency believes that this rule
been made by the agency, expert net benefits (including potential would not have a significant impact on
determinations would not yet have been economic, environmental, public health most small entities. However, it is
made by FDA, and such disruption and safety, and other advantages; possible that some small firms that
would not occur. distributive impacts; and equity). Under produce several affected drugs, or small
Section 4(c) of Executive Order 13132 the Regulatory Flexibility Act, unless firms that might be required to
instructs us to restrict any Federal the agency certifies that the rule is not undertake packaging modifications, may
preemption of State law to the expected to have significant economic be significantly affected by this rule.
‘‘minimum level necessary to achieve impact on a substantial number of small Therefore, the following analysis, in
the objectives of the statute pursuant to entities, an agency must consider conjunction with the preamble,
which the regulations are promulgated.’’ alternatives that would minimize any constitutes the agency’s final regulatory
This final rule meets the preceding significant impact of the rule on small flexibility analysis as required by the
requirement because, as discussed in entities. Regulatory Flexibility Act.
TABLE 9.—SUMMARY OF PROJECTED QUANTIFIABLE BENEFITS AND COSTS OVER 10 YEARS1

Present Value ($ million)
Total ($ million)
3 percent 7 percent
Benefits:
Health Care Practitioner Time Saved 150 120 90
Cost of Adverse Drug Events Avoided 360 to 430 300 to 360 240 to 290
Total Potential Benefits 510 to 580 420 to 480 330 to 380
Costs:
Design and Produce Trade Labeling; Modify Packaging Equipment 42 36 29
Reformat and Produce Labeling Not Accompanying Drug Products 36 30 25
Print Longer PDR 59 49 39
Total Costs 140 120 90

1 Numbers may not sum due to rounding.
A. Purpose of the Final Rule Although our analysis did not stated that because the proposal has the
The purpose of the final rule is to separate administrative costs from other potential to substantially affect larger
make it easier for health care labeling design costs, the agency companies (could double the length of
practitioners to find and read anticipated that manufacturers would labeling and require extensive re-
information important for the safe and require some ‘‘detailed discussions and engineering and re-design of packaging
effective use of prescription drugs. As drug-specific decisions’’ during the lines and ancillary equipment), its
described elsewhere in this preamble, design phase of labeling (e.g., regarding impact would be even greater on smaller
the agency has found that the current exactly which adverse reactions should companies.
format of prescription drug labeling can be listed in Highlights) (65 FR 81082 at Although the agency had requested
be improved to more optimally 81106). Currently, manufacturers input from small companies that might
communicate important drug submitting new applications (i.e., NDAs be affected by the rule, all comments on
information (see section I of this and BLAs) and efficacy supplements this question came from large
document). Enhanced communication have to negotiate the content of labeling companies. FDA believes it is difficult
of drug information to physicians as part of the review process. Because to predict the effect of the rule on small
should make them better informed any information in Highlights is also in firms. While small firms may have
prescribers. The final rule is designed to the FPI, the agency does not agree that lower sales volume over which to
achieve these objectives by amending negotiating the content of Highlights spread the fixed costs of compliance,
the current content and format of the will impose significant administrative some industry consultants have found
labeling for certain human prescription costs beyond what is currently incurred that small pharmaceutical firms have
drug products to, among other things, by these manufacturers. As noted, to less organizational layers and incur
highlight frequently accessed and new facilitate this process, the agency is lower costs for the same activity than
information, include a table of contents making available guidance to assist large pharmaceutical firms (Ref. 12).
for the detailed information in labeling, manufacturers in selecting information Table 22 in section XI.E.2 of this
and reorder this detailed information. for inclusion in Highlights (section IV of document illustrates the potential
this document). impact that the final rule might have on
B. Comments on the Economic Impact On the other hand, manufacturers of small firms.
Analysis recently approved innovator drugs (i.e., (Comment 123) One comment
Most comments on the economic approved within 5 years prior to the maintained that there is no support for
analysis of the proposed rule came from effective date of the final rule) will incur FDA’s identified benefit of reducing the
pharmaceutical manufacturers. costs to: (1) Prepare and submit their time it takes a prescriber to use labeling
Although many manufacturers redesigned labeling to FDA for approval, by 15 seconds. The comment argued
expressed concerns that the agency had which may include negotiations that Highlights, because it contains
significantly underestimated the costs to concerning the content of Highlights, incomplete information, would actually
industry, especially the additional and (2) replace existing labeling with increase physician reading time and
packaging costs that would be necessary redesigned labeling. To account for asserts that FDA’s assumption would be
with labeling printed in 8 points, only these additional actions, the one-time true only if physicians read just
a few provided detailed information design costs for labeling of recently Highlights.
about the potential burden they approved products are estimated to be The agency acknowledges that there is
expected the rule to impose. The agency about 50 percent higher than for not direct empirical support for the
welcomes these comments and, labeling of new products (see section estimate of 15 seconds time savings, but
whenever possible, has incorporated XI.D.2 of this document). is persuaded based on consultation with
data from these examples in the final (Comment 122) The agency sought physicians that the labeling changes
analysis of economic impacts. specific comment on whether the would save time. The agency consulted
(Comment 121) Several comments potential impact of the proposed rule on physicians in a national survey, focus
argued that manufacturers would incur small entities has been accurately groups, and a public meeting to design
significant administrative costs when estimated by the agency, and whether labeling that provides easier and faster
negotiating the content of Highlights small business concerns have been access to the most important and
with FDA. adequately addressed. One comment commonly referenced prescribing
information (65 FR 81082 at 81083 points, on average, trade labeling is in impact of each of these requirements
through 81085; see also Ref. 11). Using 6 points, and thus requiring a minimum separately.
a standard format with frequently type size of 6-point will not increase the Within 1 year of the effective date of
accessed sections at the beginning of size of most trade labeling. However for the final rule, any FDA-approved
labeling will help physicians find the few products currently printed in 4 patient labeling must either be reprinted
important information quickly and points, labeling will require immediately following the end of
retain that information. Inclusion of approximately 33 percent more paper to labeling or accompany the labeling
Contents and references in Highlights to conform with the 6-point minimum size (§§ 201.57(c)(18) and 201.80(f)(2)). An
the full prescribing information that is requirement at § 201.57(d)(6). The estimated 150-square inches of surface
cited or concisely summarized will agency believes that the additional area would be needed to print this
speed access to detailed information in resources associated with longer information, adding an additional 75-
the FPI. In the absence of quantitative labeling are warranted by the ease of use square inches to the size of the labeling
evidence suggesting a different estimate and speed of comprehension by having (65 FR 81082 at 81109). The agency
of time savings, the agency is retaining labeling printed in 6 rather than 4 identified up to 200 products with some
15 seconds as a conservative estimate of points. form of FDA-approved patient labeling
the amount of time health care Highlights and Contents will increase that will be affected by the final rule. A
practitioners can save when seeking trade labeling by approximately 40 sample of these affected products shows
drug product information in labeling. square inches, requiring an additional that the labeling of more than 60 percent
(Comment 124) Some comments 20 square inches of paper. already conforms to this provision of the
argued that FDA’s estimate significantly Manufacturers submitting NDAs and final rule. For the final analysis, the
underestimates increased costs for trade BLAs have not yet designed product agency increased the estimate of the
packaging, shipping containers, and labeling or packaging. Thus, the agency number of affected products from 50 to
new packaging and shipping equipment does not agree that the final rule will 80, thus increasing the incremental
to accommodate the larger labeling that impose additional packaging costs on printing costs for this provision of the
will result from the new format. Some these manufacturers. In contrast, final rule to $0.4 million annually (see
comments argued that the agency’s manufacturers submitting efficacy section XI.D.1 of this document).
initial estimate of $200,000 to adjust or supplements or having existing labeling More space will be needed to print
retool existing packaging equipment for drug products affected by the final longer trade labeling and labeling
underestimates the impact on industry rule will need to determine if their distributed with promotional materials
by almost fourfold. Moreover, one redesigned trade labeling fits on or for new and recently approved
comment stated it could cost large within existing packaging. products. The length will depend on the
manufacturers with many product lines The final rule will affect less than 15 minimum type size requirements for the
up to $40 million to change all percent of existing products in the labeling. For trade labeling printed in a
packaging lines. Several comments United States.11 The agency agrees that minimum of 6 points, an estimated 20
stated that increases of this magnitude some packaging lines of these products square inches of paper is necessary to
will require retooling or replacing will require adjustment to accommodate accommodate Highlights and Contents.
existing equipment, increasing longer trade labeling, but disagrees that In contrast, product labeling distributed
containers to accommodate longer this will be necessary for all packaging with promotional materials must be
outserts, or, in some cases, adding a lines. Based on an analysis of printed in a minimum 8-point type size,
carton. Comments also stated that longer ophthalmic products, the agency requiring about 93 square inches of
labeling would increase administrative increased the proportion of existing paper (65 FR 81082 at 81107).
costs. products expected to incur one-time Furthermore, for labeling with FDA-
FDA allows each manufacturer some production costs from 1 to 5 percent approved patient labeling which is not
flexibility to determine the size and (see section XI.D.2.c.ii of this currently appended to the product
shape of a product’s trade labeling and document). labeling, after all provisions of the final
packaging. A survey of labeling printed (Comment 125) One comment insisted rule are implemented, product labeling
in the Physicians’ Desk Reference (PDR) that FDA’s estimate of 92.6 square will be approximately 168 square inches
for 200 products showed that, on inches of additional labeling space is or 65 square inches longer when printed
average, labeling requires 200 square not sufficient to accommodate the in 8-point or 6-point type, respectively.
inches of surface area when printed in proposed new labeling sections, (Comment 126) One comment asked
6.5-point type size. Since prescription increase in white space, increase in type the agency to consider the impact of the
drug labeling is printed on both sides of increased number of calls on
size, and inclusion of patient
the paper, these findings suggest that companies, and possible increases in
information in the FPI. The comment
current trade labeling averages 100 personnel to process calls, as a result of
suggested that FDA’s presentation of
square inches. From this baseline, the requiring companies to include their
how much additional labeling space
agency calculates that about an phone number in the package inserts.
would be needed was confusing.
additional 92.6 square inches of paper The implementation schedule to add Another comment raised concerns that
would be needed to print labeling in 8- FDA-approved patient labeling to requiring corporate telephone numbers
point type size and to add Highlights prescription drug labeling differs from for reporting of serious adverse
and Contents to the labeling. the implementation schedule for the reactions in Highlights would require
To reduce the burden on industry, the formatting and content changes affecting companies to change their labeling with
final rule requires that trade labeling be labeling for new and recently approved each change of their corporate telephone
printed in at least 6-point type size (see products (i.e., approved within 5 years number.
comment 102), similar to the size of the The agency believes that health care
of the effective date of the final rule).

baseline case used in the original Consequently, the agency analyzed the
practitioners have varied access to
analysis and a size generally supported company information via the Internet
by industry comments on the proposed 11 Data derived from information in ‘‘Approved and other sources, thus including the
rule. Even though some trade labeling is Drug Products with Therapeutic Equivalence phone number is unlikely to overly
currently printed in a size as small as 4 Evaluations,’’ December 2001. burden a company’s ability to handle
incoming calls. The agency believes that Moreover, comments from a pharmacy manufacturers agreed that including a
changes in corporate phone numbers are association, submitted in response to comprehensive table of contents and
an ordinary business expense. the proposed rule, reported that a recent reordering of the detailed information
informal survey of pharmacists found would improve clarity of the labeling
C. Benefits of Regulation
that 30 percent refer to prescription and quickly direct the reader to the
The expected economic benefits of drug labeling several times each day, 36 appropriate section of the FPI, but
this final rule are the sum of the present percent refer at least once per day, and expressed reservations about the utility
values of: (1) The reduced time needed 34 percent refer at least once per week. of Highlights (see comment 2).
by health care practitioners to seek If representative, these findings suggest Comments, including one by an
desired information in prescription drug that the average pharmacist in the expert in human cognition, supported
labeling; (2) the increased effectiveness United States seeks information from Highlights as a way to improve the
of drug treatment; and (3) the avoided prescription drug labeling at least 257 accessibility of the most heavily used
costs of treating drug-related errors due times each year.13 To put this estimate information (see comment 2). Moreover,
to misunderstood or incorrectly applied in perspective, approximately 2.85 by including references in Highlights to
drug information. billion prescriptions were dispensed by specific sections of the FPI, Highlights
We acknowledge that the information retail pharmacies in 2001 (Ref. 17). will also enhance the effective use of the
to estimate the benefits of this rule is About 60 percent of the 212,660 information in the detailed sections of
quite limited. In particular, we do not pharmacists in the United States work the labeling. Therefore, based on
have direct estimates of how much time in retail pharmacies (Refs. 18 and 19) comments from health care
practitioners might save by using the and cumulatively seek information from practitioners, professional organizations
new labeling, or how the new labeling prescription drug labeling about 32.8 and consumer groups, the agency
might improve doctors’ understanding million times each year (212,660 believes that the new format will reduce
of risks of prescription drugs. There is pharmacists x 0.6 x 257 labeling the time physicians, pharmacists, and
no formal study that tested how consultations per year), approximately other practitioners must spend seeking
alternative labeling formats affect 12 times for every 1,000 prescriptions specific information in prescription
physicians’ speed or quality of dispensed. drug labeling and increase the extent
comprehension of information related to For the analysis of the proposed rule, they rely on labeling for drug
potential adverse effects of drugs. FDA was aware of no data estimating information.
the total time physicians spend reading A recent study in Oregon found that
1. Decreased Health Care Practitioner
prescription drug labeling. It also had primary care physicians on average will
Time
no estimates of how much time savings consult two sources of information, one
Prescription drug labeling is a major might result from possible changes in of which is usually the PDR, and spend
source of information about the risks drug labeling. It therefore conservatively an average of 12 minutes seeking
and benefits of prescription drugs. Each assumed that physicians could save an information to answer patient questions
year health care practitioners spend average of 15 seconds each time they (Ref. 16). Another study in Finland
considerable time seeking medical refer to prescription drug labeling in the logged the time physicians spent
knowledge about the therapeutic risks new format (65 FR 81082 at 81104). One searching a computerized set of
and benefits of the drugs prescribed to comment from a pharmaceutical guidelines, the ‘‘Physicians’ Desk
treat patients. However, only a few manufacturing organization requested Reference and Database,’’ and found the
studies have focused on the justification for this assumption (see average time needed to find and read an
information-seeking behavior of health comment 123). The comment stated that article was 4.9 minutes (Ref. 20).
care practitioners. Four studies using rather than save time, the new format Although these studies may not be
family practice physicians reported that with Highlights would lengthen the representative of the average
the PDR, a compilation of prescription time practitioners spend looking for practitioner in the United States, they
drug labeling, was the most frequently information. suggest that the agency’s estimate of a
used reference book in a clinical setting The agency disagrees it will take 15-second time savings with the new
(Refs. 13 through 16). In one study health care practitioners more time to format (once drug labeling is at hand) is
published in 1990, physicians reported find information with the new format plausible and conservative in that it is
using the PDR almost daily (Ref. 13). In compared to the old format. As only a small improvement relative to
addition to the PDR, physicians receive described elsewhere in the preamble, time currently spent for most labeling
prescription drug labeling directly from the agency solicited input from health referrals. If the new format were
drug manufacturers and their care practitioners to develop a format implemented for all prescription drug
representatives. that presents complex drug information products, the nation’s 625,100
A 1994 FDA survey of physicians in a manner that will enable them to physicians active in patient care (Ref.
found that 42 percent referred to find information more rapidly, 21) could save a total of about 552,100
prescription drug labeling at least once improving the communication of the hours per year (625,100 physicians x
a day, 33 percent less often than once risks and benefits of the drug (see 212 labeling consultations per year x 15
a day but more often than once a week, section I of this document). In seconds saved per labeling consultation/
and 25 percent once a week or less (Ref. comments on the proposed rule, 3600 seconds per hour). Likewise,
11, pp. 30–31). These findings suggest organizations representing health care pharmacists could save an additional
that a physician seeks drug information practitioners and consumer groups 227,700 hours per year (212,660
from prescription drug labeling on strongly supported the new format as pharmacists x 257 labeling
average 212 times each year.12 being easier and quicker to use (see consultations per year x 15 seconds
comment 2). Comments from many drug saved per labeling consultation/ 3,600
12 On average, physicians work 47 weeks per year

seconds per hour).
and consult prescription drug labeling 4.51 times 13 On average, it is assumed that pharmacists
The final rule only applies to new and
each week [(7 consultations per week x 42 percent) work 50 weeks per year and consult labeling 5.14
+ (4 consultations per week x 33 percent) + (1 times per week [(10 consultations per week x 30
recently approved products. Moreover,
consultation per week x 25 percent)] (65 FR 81082 percent) + (5 consultations per week x 36 percent) implementation for recently approved
at 81104 through 81105). + (1 consultation per week x 34 percent)]. products is phased in over several years.
Thus, the final rule will initially apply remain unchanged (65 FR 81082 at To estimate the monetary value of the
only to a small percentage of 81104). This analysis, therefore, time saved, an hourly loaded wage for
prescription drug labeling. The rule’s assumes that the rule will begin physicians is calculated using data from
focus on newer products includes the affecting the length of time needed for the American Medical Association
prescription drug labeling that health prescription drug labeling consultations (AMA) on the average net annual
care practitioners consult most in the second year of implementation, income of all non-Federal physicians
frequently. In FDA’s survey of only affecting 5 percent of all (excluding residents), the average
physicians, newness of the product was consultations in that year. The weekly workload, average number of
the factor most often rated by physicians percentage of reformatted prescription weeks worked per year and benefits
as ‘‘very likely’’ to trigger referral to drug labeling consulted by physicians is adjusted by the proportion of self-
prescription drug labeling (Ref. 11, p.
assumed to increase to 10, 15, and 25 employed physicians (Refs. 22 and 23).
35). Similarly, the pharmacy
percent in years 3, 4, and 5 respectively. The loaded wage for pharmacists is
association’s survey found that
pharmacists were most likely to consult Thereafter, it is assumed to increase an calculated from Bureau of Labor
labeling if the drug was recently additional 5 percent each year, reaching Statistics data (Ref. 18). At $88.16 per
approved (48 percent). 50 percent in year 10. Thus, in year 10, hour for physicians ([$194,400 x (1 +
Although the average practitioner the time savings for physicians and 0.2)] / [47 weeks x 56.3 hours / week])
regularly prescribes from 40 to 100 pharmacists is projected to equal about and $46.75 per hour for pharmacists
pharmaceutical products (Ref. 24), the 276,000 and 113,900 hours, ($33.39 / hour x (1 + 0.4)), table 10
proportion of these that are new drugs respectively. FDA has not attempted to shows the annual monetary value of
is unknown. Because the agency project impacts beyond 10 years, due to time saved and indicates that the
received no comments and has no other the uncertainty of the longer term present value over 10 years equals
information on the percentage of technological changes that would affect approximately $90 million or $120
reformatted labeling that practitioners these estimates (see section V of this million using a 7 or 3 percent discount
will consult, the initial assumptions document). rate, respectively.
TABLE 10.—VALUE OF HEALTH CARE PRACTITIONER TIME SAVED1

Current Value ($ million) Present Value ($ million)
Year
Physicians Pharmacists Total Total Discounted at 3 percent Total Discounted at 7 percent
1 0 0 0 0 0
2 2 1 3 3 3
3 5 1 6 5 5
4 7 2 9 8 7
5 12 3 15 13 11
6 15 3 18 15 12
7 17 4 21 17 13
8 19 4 24 19 14
9 22 5 27 20 15
10 24 5 30 22 15
Total 120 30 150 120 90

2. Improved Effectiveness of Treatment Highlights would emphasize those The initial U.S. approval date will
characteristics of drugs that physicians alert practitioners to newer products
The final rule will improve report are the most important for that should be used with greater
prescription drug labeling to make it decisionmaking. With the Contents and vigilance. There are over 100 NDAs,
easier to find and use information about references to the FPI in Highlights, including about 30 new molecular
the product. More effective
practitioners can more quickly find all entities, approved every year in the
communication of drug information will
relevant facts about the drug that are United States. Initial approval is based
better inform practitioners about the
specific to their patients. Each format on data from clinical trials conducted to
risks and benefits of drugs prescribed to
change required by the final rule is determine the safety and effectiveness of
patients. Prescription drug labeling can
contain hundreds of facts about a drug, intended, therefore, to present the a product. These trials typically include
increasing the time needed to find complex drug information contained in only enough subjects to detect 1 adverse
specific information, relative to simpler labeling in a way that will improve the reaction in every 300 to 500 patients
labeling. For example, labeling of the ability of practitioners to select and (Ref. 25). It is not uncommon for drugs
drug cisapride contains over 470 facts prescribe drugs to their patients safely to have significant adverse effects that
(Ref. 24). Under the final rule, and effectively. occur at lower frequencies than can be
detected in premarketing clinical trials. labeling follow a standardized format dollars. If all hospitals incur similar
Adding contact information where will better inform health care costs for preventable adverse events, the
practitioners can report suspected practitioners about the drugs that are potentially preventable annual costs
adverse reactions will facilitate the prescribed to patients, improve the from this source could total from
collection of drug safety information effectiveness of treatment, and reduce between $1.4 billion to $2.2 billion
and make it easier for the agency and the number of preventable adverse nationally (in 2000 dollars).
manufacturers to identify significant reactions experienced by patients. Few studies on adverse reactions in
safety concerns that can emerge after a No national study on the incidence or outpatient or long-term care settings
drug is marketed and a much larger associated costs of adverse reactions has have been conducted. A report from a
population is exposed to the product. been conducted. Furthermore, it is multidisciplinary conference held in
Moreover, by identifying those sections difficult to compare published studies 2000 to discuss a national research
of the labeling in which there have been because they are either too limited in agenda for ambulatory patient safety
important recent changes, the new scope or differ in methodology. described a diverse and complex
format will also alert practitioners to Nevertheless, studies of hospitalized outpatient system that was prone to the
significant new safety concerns and patients suggest that the rate of same types of errors observed in
other significant changes to labeling preventable adverse events that occur hospital studies (Ref. 32). In 1995, FDA
once a product has been approved. during hospitalization is approximately estimated that hospitalizations
In addition, any FDA-approved 1.2 to 1.8 adverse events per 100 associated with outpatient adverse
patient labeling must be printed at the patients admitted (Refs. 27 through 29). reactions cost $4.4 billion per year (60
end of the labeling, or accompany the Moreover, 1 of these studies conducted FR 44182 at 44232; August 24, 1995),
labeling, regardless of when the product in the early 1990s in the northeastern equaling $5.2 billion in 2000 dollars. If
was approved. Including patient United States found that a majority of the causes of errors in the outpatient
information enhances the likelihood preventable adverse events (about 1 setting are similar to the causes in
that physicians will communicate adverse event per 100 hospital hospitals, half of these costs are related
important information to patients,
admissions) were related to errors or to physician ordering errors. Thus,
improving patient understanding and
miscalculations in physician ordering, about $2.6 billion (in 2000 dollars) per
adherence to treatment
the stage most likely to be affected by year in additional hospital costs result
recommendations. FDA is unable to
improved prescription drug labeling from errors likely to be influenced by
quantify the magnitude of these
information (Ref. 28). A more recent improved prescribing information.
expected improvements in treatment
study conducted in the southwestern FDA lacks data to estimate the actual
effectiveness and health outcomes, but
United States reported 4.2 adverse proportion of the adverse reaction costs
the agency believes they could be
events per 100 patients, of which only that would be prevented under the final
significant.
15 percent where deemed preventable rule. Combining the projected hospital
3. Decrease in Costs to Treat Avoidable (Ref. 29). Given the approximately 36 costs attributable to preventable in-
Adverse Reactions million annual hospitalizations in the hospital and outpatient adverse
Although there are multiple causes of United States (Ref. 30), these data reactions, from $4.0 billion to $4.8
adverse reactions, some are potentially suggest that between 229,000 and billion per year may be potentially
preventable and can result from 364,000 adverse reactions among avoided through measures that provide
misunderstood or incorrectly applied hospitalized patients are potentially better information to doctors, such as
drug information (e.g., prescribing too preventable each year. prescription drug labeling. If the final
high a dose for a patient with poor A number of studies show that the rule reduced these costs by even 1
kidney function, or prescribing a drug to occurrence of an adverse event in a percent, between $40 million and $48
a patient with known hospitalized patient increases the costs million of the costs of hospitalization
contraindications). According to a 2000 of caring for the patient by an average could be prevented each year. Over 10
GAO report on adverse drug events, of between $2,162 and $2,595 (Refs. 28, years, the present value of these avoided
standardized packaging is one of many 29, and 31). Costs associated with costs would total from $240 million to
approaches that can be adopted to preventable adverse events were even $290 million with a 7 percent discount
reduce medication errors (Ref. 26). higher, averaging about $4,685 per rate, and from $300 to $360 with a 3
Requiring that prescription drug patient (Ref. 31), or $6,075 in 2000 percent discount rate (table 11).
As illustrated in table 12, the percent, the total present value of value of the compliance costs for the
magnitude of the potential benefits of avoided hospital costs for preventable final rule at both 3 and 7 percent
the final rule will be sensitive to the in-hospital and outpatient adverse drug discount rates.
assumed level of effectiveness. At 0.4 events will exceed the total present
TABLE 12.—IMPACT OF DIFFERENT EFFECTIVENESS LEVELS ON THE TOTAL PRESENT VALUE OF AVOIDED HOSPITAL
COSTS TO TREAT PREVENTABLE ADVERSE DRUG EVENTS1
Discounted at 3 percent Discounted at 7 percent
($ million) ($ million)
Effectiveness Estimate (percent)
From: To: From: To:
0.1 30 36 24 29
0.42 120 140 97 120
0.5 150 180 120 150
1.0 300 360 240 290
5.0 1,500 1,800 1,200 1,500

2 Correspondsto the breakeven point where over 10 years, the total present value of hospital costs avoided exceeds the total present value of
the compliance costs of the final rule.
When compared with other published be quite large. Using a restrictive 33). In contrast, a 2001 revision of the
studies, the agency’s estimate of the cost definition of adverse events and 1995 Johnson and Bootman cost-of-
of adverse reactions is likely less than including direct and indirect costs, a illness model used current costs
the total social cost of such events. In large study of hospital discharge records whenever possible and predicted that
particular, FDA’s estimates include only conducted by Thomas and others in drug-related illness occurring in
hospital costs, and exclude the Utah and Colorado was published in ambulatory care settings cost about
willingness to pay of patients to reduce 1999 and estimated that preventable $177.4 billion each year, or more than
these risks. Because these risks include adverse events cost society at least $17 40 times the estimate of avoided costs
fatality risks, the willingness to pay may billion (in 1996 dollars) each year (Ref. that was used in the rest of this analysis
ER24JA06.001</GPH>
(Refs. 34 and 35). While we including any equipment adjustments, inches to the length of trade labeling
acknowledge that we have no direct (3) layout and artwork for labeling not when printed on two sides (65 FR 81082
evidence about how the rule would accompanying drug products, (4) at 81109). Updating the unit printing
reduce preventable adverse reactions, if producing longer labeling for labeling costs for inflation, this additional length
the final rule avoided at least one-tenth not accompanying drug products, and would increase the incremental printing
of a percent of the costs predicted by the (5) printing longer labeling in the PDR. costs by approximately $6.84 for 1,000
Thomas study, annual benefits of the pieces of labeling (75-square inches per
1. Labeling Changes for All Approved
rule would approximately equal annual piece x $0.0000912 per square inch x
Prescription Drug Products
costs. 1,000 pieces) (68 FR 6062 at 6074). For
a. Affected products. The agency will the final analysis, FDA estimates that for
D. Costs of Regulation require that FDA-approved patient affected products, up to 650,000 pieces
Except as noted below, the methods labeling accompany the prescription of trade labeling would be distributed
used to estimate costs for the proposed drug labeling, or be printed following each year (section XI.D.2.c.i of this
rule remain the same for the final the last section of the prescription drug document). For each of the affected
impact analysis (65 FR 81082 at 81103 labeling within 1 year after the effective products, manufacturers will incur
through 81112). When possible, unit date of the final rule. The agency annual incremental costs averaging
costs have been updated. identified up to 200 products with some about $4,440 to print the longer trade
The proposed rule would have form of FDA-approved patient labeling labeling (650,000 pieces per product per
required two broad types of changes to that will be affected by the final rule. A year x $6.84 per 1,000 pieces). For all
the labeling of prescription drug sample of these affected products shows 80 affected products, annual
products. First, labeling of that the labeling of more than 60 percent incremental printing costs for trade
approximately one-third of products already conforms to this provision of the labeling will increase by $0.4 million.
already approved for marketing would final rule. Therefore, the labeling of an Furthermore, manufacturers distributing
have been revised to delete or add estimated 80 products will need to be longer prescription drug labeling with
information within 1 year. Several revised. promotional materials and samples will
comments argued that these changes b. Prescription drug labeling design spend up to an additional $5,125 in
would be quite costly relative to the costs. On average, prescription drug annual incremental printing costs each
limited benefits that would be derived manufacturers will incur about $2,220 year for 3 years (750,000 pieces per year
and difficult to accomplish in the per product in design and x $6.84 per 1,000 pieces (approximation
proposed implementation period (see implementation costs to append FDA- based on information in footnote 17 in
comment 114). In response to these approved patient labeling to existing section XI.D.2.e of this document)).
comments, the agency removed the prescription drug labeling. Because Therefore, industry will incur
requirements to delete certain changes must be made within 1 year of additional printing costs with a present
information from all existing the effective date of the final rule, not value of approximately $3.6 million or
prescription drug labeling. Only those all firms will have sufficient time to $4.2 million over 10 years at a 7 or 3
products with existing labeling that deplete their inventories of existing percent discount rate, respectively (table
have FDA-approved patient labeling prescription drug labeling. With a 12- 13).
will be required to revise the labeling month implementation period, FDA d. Physicians’ Desk Reference (PDR)
within 1 year. consultants estimate per product Costs. The agency estimates that 75
Second, the proposed rule would inventory losses of approximately $630. percent of prescription drug products
have revised the content and established Thus, including excess inventory losses, have labeling already printed in the
format requirements for labeling of new the cost to change prescription drug PDR. In 2002, an additional page in the
and recently approved applications. labeling is estimated at $2,850 per PDR costs manufacturers $9,750.14
Although the agency modified some product (65 FR 81082 at 81109; and 68 Thus, the per product annual cost to
specific content and format FR 6062 at 6074, reflecting updated print two additional pages is about
requirements, the staggered costs). As shown in table 13, in the first $19,500 ($9,750 x 2). For the estimated
implementation schedule and most year firms may incur one-time costs of 60 affected products (80 products x
provisions were retained for the final $0.2 million to add FDA-approved 0.75), the annual PDR costs would
rule. Therefore, direct costs incurred to patient labeling to the labeling of the increase by $1.2 million ($19,500 x 60),
change prescription drug labeling affected products. equaling a present value of
include the costs of: (1) Designing or c. Incremental printing costs for approximately $8.2 million or $10.0
revising prescription drug labeling and prescription drug labeling. Printed million over 10 years with a 7 or 3-
submitting the new labeling to FDA, (2) patient information would add an percent discount rate, respectively (table
producing longer trade labeling estimated 2 pages or about 75-square 13).
TABLE 13.—COSTS TO INCLUDE FDA-APPROVED PATIENT LABELING WITH LABELING OF EXISTING PRESCRIPTION
PRODUCTS1, 2
One-Time Labeling Annual Incremental Annual PDR Costs Total Costs
Year Revision Costs Printing Costs ($ million) ($ million)
1 0.2 0.8 1.2 2.2

2 0.0 0.8 1.2 1.9
14 Not all of these costs to manufacturers are selling additional pages at more than its true opportunity cost. The excess is a transfer, but we
social costs, as the PDR publisher is presumably do not know its magnitude.
TABLE 13.—COSTS TO INCLUDE FDA-APPROVED PATIENT LABELING WITH LABELING OF EXISTING PRESCRIPTION
PRODUCTS1, 2—Continued
One-Time Labeling Annual Incremental Annual PDR Costs Total Costs
Year Revision Costs Printing Costs ($ million) ($ million)
3 0.0 0.8 1.2 1.9
4 0.0 0.4 1.2 1.5
5 0.0 0.4 1.2 1.5
6 0.0 0.4 1.2 1.5
7 0.0 0.4 1.2 1.5
8 0.0 0.4 1.2 1.5
9 0.0 0.4 1.2 1.5
10 0.0 0.4 1.2 1.5
Total Cost 0.2 4.8 11.7 16.7
Present Value of Total Discounted at 3 per-

cent 0.2 4.2 10.0 14.4
Present Value of Total Discounted at 7 per-

cent 0.2 3.6 8.2 12.0
2 This estimate assumes that products with Medication Guides already conform to this requirement of the final rule.
2. Labeling Changes for New and This rule does not cover labeling for The initial analysis of impacts did not
Recently Approved Prescription Drug OTC products (including those include estimates of the number of
Products approved under an NDA). generic products that would be affected
a. Affected products. The final rule Estimates of the number of new because the period of exclusivity for
would require that prescription drug applications that would be affected by most innovator products covered by the
labeling conform to format and content the rule are updated and based on rule would extend beyond the 10-year
requirements for three categories of application approvals since 1997. horizon. However, a subsequent
products: (1) All NDAs, BLAs, and During this period, an average of 97 analysis of data from ‘‘Approved Drug
efficacy supplements submitted to FDA NDAs and 10 BLAs were approved each Products with Therapeutic Equivalence
on or after the effective date, (2) NDAs, year. FDA assumes that this average rate Evaluations’’ (the Orange Book) found
BLAs, and efficacy supplements will continue. The number of affected that some older innovator products with
approved over the 5 years preceding the products approved within 5 years before generic equivalents have recent
effective date or pending on the the effective date are estimated as the approvals of efficacy supplements or
effective date of the final rule, and (3) number of NDAs approved during the 5-
NDAs for new dosage strengths that
any ANDA that references a listed drug year period from 1997 through 2001
could trigger revision of the labeling of
with labeling conforming to the without subsequent efficacy
supplements. some reference listed drugs. Although
requirements of the final rule. For the
the overall number of older innovator
first category of products, the Most efficacy supplements are filed
and approved within 5 years of the products affected by the final rule is
prescription drug labeling requirements
would apply when a sponsor files an approval date of their original anticipated to be small, normally there
NDA, BLA or efficacy supplement. application. Over time, prescription are multiple generic products for each
Products in the second category must drug labeling of most products affected reference listed drug. Therefore,
file supplemental applications within 3 by the final rule will already conform to beginning in year 3, the final rule is
to 7 years of the issuance of the rule, the requirements of the final rule when estimated to affect an average of 42
according to the implementation plan an efficacy supplement is submitted. generic products annually. Table 14
described in the preamble (see Table 5). Beginning in year 3, therefore, the shows the number of products projected
For ANDA products (generic products), number of labeling revisions as a result to be affected by the final rule during
the implementation schedule for the of an efficacy supplement will decline the 10-year period following the
affected reference listed drug applies. over time. effective date.
TABLE 14.—ESTIMATED NUMBER OF AFFECTED PRODUCTS BY APPLICATION TYPE

Approvals 5 Years
Year New NDAs and BLAs Efficacy Supplements ANDAs Total
Prior to Effective Date
1 107 69 0 0 176
TABLE 14.—ESTIMATED NUMBER OF AFFECTED PRODUCTS BY APPLICATION TYPE—Continued

Approvals 5 Years
Year New NDAs and BLAs Efficacy Supplements ANDAs Total
Prior to Effective Date
2 107 69 0 0 176
3 107 52 69 42 270
4 107 39 69 42 257
5 107 29 68 42 246
6 107 22 69 42 240
7 107 16 69 42 234
8 107 12 0 42 161
9 107 9 0 42 158
10 107 7 0 42 156
Total 1,070 324 344 336 2,074
b. Prescription drug labeling design Highlights and Contents does not labeling frequently during the first 5
costs. The cost of designing prescription increase this time burden on years a product is marketed. During this
drug labeling that conforms to the final manufacturers or the agency. Therefore, period, the agency anticipates that
format and content requirements will the time required to revise labeling manufacturers would remove recent
depend heavily on when, during a conforming to the requirements of the major changes from Highlights at the
product’s life cycle, labeling design final rule will fall between the time same time they voluntarily change
occurs. Costs will be highest for required to design a novel patient labeling and, thus, would incur no
products already marketed with information guide and time required to additional costs. After 5 years on the
approved prescription drug labeling that redesign a guide. Although sponsors of market, however, some manufacturers
otherwise would not be changed. new applications and efficacy would incur additional costs to remove
Conversely, design costs will be lowest supplements would incur many of the recent major changes in the timeframe
for products that are closely related to same design costs as sponsors of specified by the final rule. The earliest
a prior product application that has existing innovator products, they would this might occur is in year 7 after the
already had its prescription drug experience no additional testing, initial redesign of the labeling.15 Based
labeling changed to the new format or preparation, and application costs. For on the agency’s experience with
for generic drug labeling. Costs for the initial analysis, it was anticipated products that have been on the market
currently marketed products that would that manufacturers would incur one- for more than 5 years, up to 10 percent
be undergoing relabeling for other time costs up to $5,000 for each new of the products affected by the final rule
reasons (e.g., related to an efficacy product and $7,500 for each existing might be required to remove recent
supplement) will be in between these product to conform to the format and major changes in year 7 or later, at a per
extremes. content provisions of the rule (65 FR product cost of approximately $1,600.
FDA has previously estimated that it 81082 at 81106 through 81107). These Over 10 years, the present value of these
takes about 2 months of full-time effort one-time per product costs are updated costs could equal about $0.1 million
to design a novel patient information to $6,190 and $8,700, respectively. with either a 7 percent or 3 percent
guide (for the first prescription drug in Modifying prescription drug labeling for discount rate.
a therapeutic class), but less than 1 ANDAs is anticipated to cost generic As shown in table 15, the total first-
week to redesign a guide following a drug manufacturers about $1,300 per year costs would amount to $1.1
previously approved prototype (i.e., product, including $830 in labor costs million. Costs increase to a high of $1.6
innovator drugs in the same therapeutic and $470 in material costs for artwork million in years 3 and 4. After the
class for which patient information was and scrap (68 FR 6062 at 6074). seventh year, when all products
already developed) (60 FR 44232). The Once product labeling contains approved within 5 years prior to the
final rule requires reordering of the Highlights, any substantive revisions of rule’s effective date or pending on the
detailed information in the prescription key sections of the labeling must be effective date have redesigned
drug labeling and addition of Highlights listed in the recent major changes prescription drug labeling, the costs
and Contents. Although FDA designates section along with the month and year decline to about $0.8 million per year.
the new order, detailed discussion and the revision was incorporated. However, As a result, the estimated total present
drug-specific decisions (e.g., regarding the final rule also requires that after 1 value of the costs of redesigning
exactly what should be listed in year, the information about recent major prescription drug labeling over 10 years
Highlights) may be necessary. Because changes must be removed the next time is about $8.8 million and $10.5 million
negotiation of labeling is a routine part the labeling is reprinted. Manufacturers with a 7 and 3 percent discount rate,
of the review process, including voluntarily change drug product respectively.
15 Recent major changes must remain in the after year 5 would therefore remain on the labeling
Highlights for at least 1 year. Any major change through year 6 or later.
TABLE 15.—ESTIMATED PRESCRIPTION DRUG LABELING DESIGN COSTS1

Year Approvals 5 Years

NDAs and Efficacy Total Discounted Total Discounted
Prior to Effective ANDAs Total
BLAs Supplements at 3 percent at 7 percent
Date
1 0.7 0.4 0.0 0.0 1.1 1.1 1.0
2 0.7 0.4 0.0 0.0 1.1 1.0 1.0
3 0.7 0.3 0.6 0.1 1.6 1.5 1.3
4 0.7 0.2 0.6 0.1 1.6 1.4 1.2
5 0.7 0.2 0.6 0.1 1.5 1.3 1.1
6 0.7 0.1 0.6 0.1 1.5 1.2 1.0
7 0.7 0.1 0.6 0.1 1.5 1.2 0.9
8 0.7 0.1 0.0 0.1 0.8 0.7 0.5
9 0.7 0.1 0.0 0.1 0.8 0.6 0.4
10 0.7 0.0 0.0 0.1 0.8 0.6 0.4
Total 6.7 2.0 3.0 0.4 12.2 10.5 8.8

c. Costs associated with producing requirements of the final rule will with 2,900 generic products.16 Using
longer labeling accompanying drug lengthen trade labeling by 650,000 pieces per innovator product
products and drug samples (trade approximately 20 square inches when and 370,000 pieces per generic product,
labeling). The proposed rule would have printed on two sides. Longer at a cost of $0.18 and $0.19 per 100
required that trade labeling be printed prescription drug labeling increases the pieces, respectively, yields annual per
in 8-point minimum type size, almost cost of paper, ink, and other ongoing product cost estimates of $1,165 and
doubling the current average length for incremental printing costs. As discussed $700, respectively. Table 16 shows the
the labeling. Several comments from below, even in 6 points, a small number estimated number of revised labelings
pharmaceutical manufacturers stated of products are still expected to incur and annual incremental printing costs
that the agency had underestimated the some equipment costs (e.g., different over 10 years.
retooling and packaging line costs that insert-folding machinery). Trade labeling must also accompany
would be incurred to include this longer drug product samples. However, the
i. Incremental printing costs for trade
trade labeling (see comment 124). A few number of samples distributed for a
large firms estimated that new labeling. U.S. retail pharmacies
dispense about 3.3 billion prescriptions specific product depends on a
equipment would cost between manufacturer’s marketing strategy and
$135,000 and $700,000 per packaging per year, of which an estimated 790
million are for unit-of-use products that may vary from year to year. Although
line and could total up to $40 million IMS Health (IMS) reported that the
for a large firm if trade labeling of all include prescription drug labeling
within the package (65 FR 81082 at volume of samples distributed in the
products were affected. As discussed in United States between 1997 and 2000
section XI.F of this document 81107, updated using IMS data at http://
www.ims-health.com). If the non-unit- ranged from 860 million to 920 million
(‘‘Alternatives Considered’’), the agency (Ref. 36), sales representatives normally
recognized that including all products of-use prescriptions average one piece of
labeling per 3.3 prescriptions, the total leave one piece of labeling for every 10
in the final rule would substantially samples they distribute. Even though
increase costs to industry and, therefore, number of labelings accompanying
retail products equals roughly 1.5 new products are sampled more often
limited the final rule to new and than older products, some
recently approved products (see section billion. Further, adding hospital
pharmaceutical volume, estimated at manufacturers continue to distribute
XI.F.3 of this document). Furthermore, samples throughout the life cycle of
approximately half of the affected approximately 54 percent of retail
volume, yields an annual total of 2.4 their product. While the actual number
products shown in table 14 will be new of samples including reformatted trade
approvals that have not yet established billion pieces of trade labeling
accompanying prescribed products. labeling is uncertain, we anticipate that
packaging. Nevertheless, based on the
Allowing 10 percent for wastage manufacturers may spend up to $0.2
potential economic impact the larger
type size might have on pharmaceutical indicates that manufacturers distribute
16 Derived from ‘‘Approved Drug Products with
manufacturers, for the final rule the roughly 2.6 billion pieces of labeling
Therapeutic Equivalence Evaluations,’’ CDER, FDA,
agency reduced the minimum size with prescribed products each year.
2001. The estimate is a count of all branded

requirement for trade labeling to 6 Since 60 percent of all prescriptions are products marketed under an NDA and
points, a size generally reported as for branded products, about 1.6 billion differentiated by active ingredient, therapeutic
pieces of labeling are currently included equivalence, dosage form, or manufacturer, not
acceptable in comments from including multiple dosage strengths. Although not
manufacturers (see comment 102). Thus, with about 2,440 branded products and counted, adding biologicals would not significantly
the new format and content about 1.0 billion pieces are included alter results.
million annually to print longer trade labeling to accompany drug samples

(table 16).
ii. Equipment costs. The original new packaging equipment. However, in final analysis, 5 percent of existing
analysis estimated that 1 percent of a few cases where existing labeling is products affected by the rule (i.e.,
affected existing products would be printed in type sizes between 4.5 points products with new efficacy
required to adjust packaging equipment and 6 points, firms may need to adjust supplements, products approved in the
with trade labeling printed in 8 points. packaging lines for longer labeling. 5 years prior to the effective date of the
According to several comments, trade Since the labeling of many ophthalmic rule, and affected ANDAs) will incur
labeling is currently printed in type drug products is printed in type sizes costs of $200,000 each product. As
sizes of 4.5 points and larger (see smaller than 6 points, the proportion of shown in table 17, the estimated present
comment 102). Thus, it is unlikely that recent approvals for ophthalmic value of equipment changes totals $7.2
the minimum type size requirement of products was used as a proxy for the million and $8.7 million over 10 years
the final rule (i.e., 6 points for trade proportion of affected products that will discounted at 7 and 3 percent
labeling) will require firms to purchase incur some equipment costs. For the respectively.
TABLE 17.—COST OF ADJUSTMENTS TO PACKAGING LINES TO ACCOMMODATE LONGER TRADE LABELING1, 2

Estimated Number of Affected Total Cost
Year Products ($ million) Total Discounted at 3 Percent Total Discounted at 7 Percent
1 3 0.7 0.7 0.6
2 3 0.7 0.7 0.6
3 8 1.6 1.5 1.3
4 8 1.5 1.3 1.1
5 7 1.4 1.2 1.0
6 7 1.3 1.1 0.9
7 6 1.3 1.0 0.8
8 3 0.5 0.4 0.3

9 3 0.5 0.4 0.3
10 2 0.5 0.4 0.2

ER24JA06.002</GPH>
TABLE 17.—COST OF ADJUSTMENTS TO PACKAGING LINES TO ACCOMMODATE LONGER TRADE LABELING1, 2—Continued
Estimated Number of Affected Total Cost
Total 50 10.0 8.7 7.2

2 For products with labeling printed in type sizes smaller than 6 points, the final rule may require that some packaging lines be retooled. Based
on NDA, ANDA or efficacy supplements approvals for ophthalmic drug products between 1997 and 2001, an estimated 5 percent of the existing
products affected by the rule will require some change to packaging equipment at an average cost of $200,000 per product.
d. Layout and design costs for prescription drug labeling for a product will print labeling in different type
prescription drug labeling not in the same type size (8 points or larger) sizes. However, if all new and recently
accompanying drug products. The final will incur no additional design costs. approved innovator products are
rule specifies a minimum type size of 6 However, if trade labeling is printed in affected, the total present value of the
points for trade labeling and 8 points for a type size smaller than 8 points, a firm additional design costs is approximately
all other prescription drug labeling will incur additional costs of $810 per $1.0 million or $1.2 million over 10
distributed by a manufacturer (e.g., product to change and proof read the years discounted at 7 or 3 percent
labeling required to be distributed with layout, and to prepare artwork for the respectively (table 18).
promotional materials or in promotional labeling not accompanying the drug
settings). Firms choosing to print all product. It is uncertain how many firms
TABLE 18.—ESTIMATED ONE-TIME LAYOUT AND DESIGN COSTS FOR LABELING NOT ACCOMPANYING DRUG PRODUCTS1,2
Number of Affected Total Costs
1 176 0.1 0.1 0.1
2 176 0.1 0.1 0.1
3 228 0.2 0.2 0.2
4 215 0.2 0.2 0.1
5 204 0.2 0.1 0.1
6 198 0.2 0.1 0.1
7 192 0.2 0.1 0.1
8 119 0.1 0.1 0.1
9 116 0.1 0.1 0.1
10 114 0.1 0.1 0.0
Total 1,738 1.4 1.2 1.0

1 Firms are expected to only print this type of labeling for 3 years after the launch of a new innovator drug product.
e. Costs associated with producing labeling annually. Because most approval of a new drug.17 As shown in
longer prescription drug labeling not detailing involves relatively new table 19, annual total costs peak at $4.4
accompanying drug products. In products, the products most affected by million in year 5. Over 10 years with a
contrast to trade labeling, with the new this rule, FDA assumed that 7 or 3 percent discount rate, the present
content and format requirements the manufacturers would incur additional value of the incremental printing costs
length of current labeling will increase printing costs for all of this labeling,
an average of about 93 percent when amounting to about $0.4 million 17 For each approval, it was assumed that all
printed in 8-point type size. At this annually. physicians involved in primary care and 25 percent
of physicians practicing a medical specialty would
length, the incremental printing costs Finally, FDA estimated that about receive two mailings per year, or an estimated
will increase by $0.85 per 100 pieces. 730,000 pieces of prescription drug 646,150 pieces (i.e., (222,400 x 2) + (0.25 x 402,700
To calculate the annual cost to print labeling per approval would be x 2)), for 3 years following product launch. An
prescription drug labeling not additional 10 percent or 64,615 pieces are estimated
distributed each year by mail or at to be distributed annually for 3 years to other health
accompanying drug products, FDA conferences to physicians, other health care practitioners or consumers. Furthermore, FDA
estimated that pharmaceutical care practitioners, consumers, retail assumes that 55,581 retail pharmacy outlets and
representatives detailing drug products 8,020 hospital pharmacies would receive 1 mailing
pharmacy outlets, and hospital to announce the launch of a new innovator product
would distribute approximately 50 pharmacies for 3 years following in the year of approval (65 FR 81082 at 81108,
million pieces of prescription drug updated).
for longer prescription drug labeling not about $24 million or $29 million,
accompanying drug products would be respectively.
f. Physicians’ Desk Reference (PDR) pharmaceutical industry via publishing prescription drug labeling changes made
Costs. FDA estimates that the new fees paid to Medical Economics. The as a result of the 5-year rule
Highlights, including any boxed agency assumed that 75 percent of the (applications approved in the 5 years
warnings, and Contents would add new drugs and efficacy supplements preceding the effective date of the final
about a half page to the PDR labeling of would be published in the PDR (some rule) would not be included in the PDR
each affected prescription drug product. smaller firms decline to publish labeling supplements. Based on these
Based on conversations with Medical in the PDR). FDA also assumed that 90 assumptions, the estimated cost of
Economics (the publisher of the PDR) on percent of the new drugs published publishing the extended prescription
the cost per printed page, FDA estimates would be included in the PDR drug labeling in the PDR would be about
that the annual publishing costs of the supplements and 33 percent of the
$1.2 million for year 1. These costs
extra space required for printing the published efficacy supplements would
would continue to increase over time as
expanded prescription drug labeling be included in the PDR supplements
all drug approvals after the effective
would be about $5,550 for each affected (about half are actually included, but
product, plus an additional cost if the only two-thirds of these include full date of the rule would have longer PDR
product was included in one of two prescription drug labeling; the listings. The estimated annual and total
annual supplements. FDA assumed that remainder include only the added costs of printing longer PDR listings are
these costs would be incurred by the indication). FDA also assumed that the shown in table 20.
TABLE 20.—COST TO PRINT LONGER LISTINGS IN THE PDR1, 2

Year
PDR Bound PDR Supplement Total Costs Total Discounted at 3 Percent Total Discounted at 7 Percent
1 0.7 0.5 1.2 1.2 1.1

2 1.5 0.5 2.0 1.8 1.7
3 2.4 0.5 2.9 2.6 2.4

ER24JA06.003</GPH>
TABLE 20.—COST TO PRINT LONGER LISTINGS IN THE PDR1, 2—Continued

Year
PDR Bound PDR Supplement Total Costs Total Discounted at 3 Percent Total Discounted at 7 Percent
4 3.3 0.5 3.8 3.3 2.9
5 4.2 0.4 4.6 4.0 3.3
6 5.0 0.4 5.4 4.5 3.6
7 5.8 0.4 6.2 5.0 3.9
8 6.3 0.4 6.7 5.3 3.9
9 6.8 0.4 7.2 5.5 3.9
10 7.2 0.4 7.6 5.7 3.9
Total 43.1 4.5 47.6 39.1 30.5

2 Printed in 6.5-point type size at an average per page cost of $9,755.
Table 21 summarizes the estimated

compliance costs for the three major
cost categories over a 10-year period.
TABLE 21.—COMPLIANCE COSTS OVER 10-YEAR PERIOD1

Cost Category ($ million) Total
Year Costs
Design and Producing Trade Labeling; Reformat and Producing Labeling Not Printing PDR ($ million)
Modify Packaging Equipment Accompanying Drug Products
1 3.1 1.7 2.4 7.3
2 3.1 2.8 3.1 9.0
3 4.9 4.2 4.1 13.2
4 4.6 4.4 4.9 13.9
5 4.6 4.6 5.8 15.0
6 4.8 4.4 6.6 15.8
7 5.0 4.3 7.4 16.6
8 3.8 3.6 7.9 15.3
9 4.0 3.1 8.3 15.5
10 4.0 2.7 8.8 15.5
Total Current Value 42.0 35.9 59.3 137.2
Total Present Value Dis-

counted at 3 Percent 35.7 30.5 49.0 115.3
Total Present Value Dis-

counted at 7 Percent 29.2 24.9 38.8 92.9
E. Impacts on Small Entities specific information about a drug. and use labeling information about
Therefore, practitioners expend time prescription drug products. The agency
1. The Need for and the Objective of the
that could be spent with patients and believes that having better access to
Rule
may miss critical information about the critical information will improve the
Developments in recent years have safe and effective use of prescription use of prescription drugs and lead to a
contributed to an increase in the length drug products. The objective of the decrease in the number of preventable
and complexity of prescription drug requirements is to improve prescription adverse reactions that occur in the
labeling, making it more difficult for drug labeling by making it easier for United States each year.
health care practitioners to quickly find health care practitioners to access, read,
2. Description and Estimate of the approved 5 years prior to the effective small firms with a single, low-volume
Number of Small Entities Affected date of the final rule must submit product would have lower costs of
reformatted prescription drug labeling compliance, but the incremental cost
This final rule would affect all small
for approval. Only six firms will have per unit sold would be higher.
entities required to design their
more than two existing products Although the agency solicited
prescription drug labeling to comply affected by the rule. Of these six, four
with this rule. The Small Business comment on the initial regulatory
firms will have two products affected in flexibility analysis from small entities,
Administration (SBA) considers the same year and one firm will have
Pharmaceutical Preparation the only comments submitted
three products affected in a single year. specifically about the impact on small
Manufacturing firms (NAICS 325412) The compliance requirements for
and Biological Product Manufacturing entities were from large firms (see
small entities under this final rule are comment 122). The following examples
firms (NAICS 325414) with fewer than the same as those described above for
750 and 500 employees, respectively, to illustrate possible impacts on small
other affected entities. Compliance entities with different production
be small. U.S. Census reports in 1999 primarily involves: (1) designing
there were 265 biological product volumes. Prescription drug labeling
prescription drug labeling that conforms
manufacturing firms (Ref. 37) and 749 costs are estimated for a small firm with
to the content and format requirements,
pharmaceutical preparation a single carton-enclosed product
and (2) once the labeling is approved by
manufacturing firms (Ref. 38). However, (marketed under an NDA) that must: (1)
FDA, ensuring that all future printed
employment size classes for Have its labeling reformatted in year 3
prescription drug labeling is in the new
pharmaceutical preparation of the rule and (2) add patient
format with the required minimum type
manufacturing do not correspond to information in year 1. Table 22 outlines
size. Because manufacturers already
SBA size categories. Nevertheless, 1999 the projected per-unit and total costs to
submit labeling with NDAs, BLAs and
Census data suggest that approximately the firm with 3 different levels of
efficacy supplements to FDA, no
94 percent of biological product production: 1,000, 10,000, and 100,000
additional skills will be required to
manufacturing firms and at least 87 comply with the final rule. units produced per year.
percent of the pharmaceutical The group of small entities likely to In addition to the costs identified in
preparation manufacturing firms could bear the highest total costs under this table 22, a very small number of small
be considered small. Despite the large final rule are those firms that have: (1) firms might incur equipment costs to
number of small manufacturers, large Existing products with prescription include longer prescription drug
companies manufacture most drug labeling that must be revised in the labeling in carton-enclosed products. It
prescription drug products. Although first year or (2) more than one affected is likely, however, that this one-time
the agency cannot predict the number of high-volume product per year, such as capital cost (estimated at $200,000) will
new approvals granted to small entities, a small firm with two or three recently affect a total of no more than two or
the following estimates are based on 5 approved, high-volume products that three small firms in the 10 years
years of recent submissions (65 FR must undergo prescription drug labeling following implementation of the rule.
81082 at 81110, updated for 1997– reformatting simultaneously in the same Based on this analysis, FDA believes
2001). On average, 17 small entities will year. However, the high-cost small that the final rule would not have a
receive product approvals each year. In entities are also the small firms with the significant impact on most small entities
addition, about 64 small entities will be highest sales of affected product; thus, in this industry, but it is possible that
affected during years 3 to 7 of the rule, their incremental cost per unit sold is a few small firms may be significantly
when applicants with products likely to be relatively low. In contrast, affected by the final rule.
TABLE 22.—ESTIMATED COSTS FOR HYPOTHETICAL SMALL FIRM WITH A SINGLE PRODUCT, UNDER THREE ALTERNATIVE
LEVELS OF PRODUCTION1
Number of Units Produced and Sold Each Year
Cost Category
100,000 10,000 1,000
Example 1—Revise labeling of product approved less than 1 year prior

to effective date:
Prescription drug labeling redesign/application $8,700 $8,700 $8,700
Printing trade labeling2 $200 $20 $2
Printing prescription drug labeling not accompanying drug products3 $1,050 $105 $10
Total $9,950 $8,825 $8,712
Additional cost per unit sold $0.10 $0.88 $8.71
Example 2—Add printed patient information to existing labeling for a

product:
Prescription drug labeling redesign $2,850 $2,850 $2,850
Printing trade labeling4 $750 $75 $8
Printing longer PDR5 $19,500 $19,500 N/A
Total $23,100 $22,425 $2,858

Additional cost per unit sold $0.23 $2.24 $2.86

1 Numbersmay not sum due to rounding.
2 Numberof pieces of trade labeling printed is calculated as units produced/year plus 10 percent wastage factor, at an incremental printing cost
of $0.001791 per labeling.
3 To calculate the cost for printing labeling not accompanying drug products, the number of units is adjusted by the ratio of the average num-
ber of pieces printed for mailings to the average number printed as trade labeling (i.e., 1.126), and multiplied by the incremental printing cost of
$0.0085 per piece.
4 Number of pieces of trade labeling printed is calculated as units produced/year plus 10 percent wastage factor, at an incremental printing cost
of $0.006837 per labeling.
5 Assume that prescription drug labeling is already being printed in the PDR. Most low-volume products (i.e., less than 10,000 units per year)
will not have labeling in the PDR.
F. Alternatives Considered for trade labeling instead of the 6-point gradual implementation schedule of up
requirement in the final rule. At 6 to 7 years to reduce the cost impact of
1. Do Nothing
points, the average revised labeling will the rule, especially on small entities.
The agency considered and rejected increase by about 20-square inches.
this option. The current prescription XII. Civil Justice Reform
Requiring the larger minimum size
drug labeling is complex, requiring would take another 70-square inches of This rule has been reviewed under
health care practitioners to spend paper and cost industry about $6,000 Executive Order 12988, Civil Justice
unnecessary time seeking information per million pieces of trade labeling. Reform. This regulation meets the
they need for the safe and effective use Because this requirement would be applicable standards set forth in
of drug products by their patients. burdensome on industry, the agency sections 3(a) and 3(b)(2) of Executive
Preventable adverse reactions have rejected the 8-point minimum type size. Order 12988.
many causes and are a serious public XIII. References
health issue. Changing prescription drug 3. Alternative Categories of Affected
labeling to meet the needs of health care Products The following references have been
practitioners that use it is one of many Three alternative categories of placed on display in the Division of
public health initiatives aimed at products to be covered by the rule were Dockets Management (HFA–305), Food
reducing these adverse reactions and considered: (1) All drugs, (2) a set of and Drug Administration, 5630 Fishers
improving health care. innovator and generic drugs on a ‘‘top Lane, rm. 1061, Rockville, MD 20857,
200 most prescribed’’ list, and (3) the and may be seen by interested persons
2. Formatting Alternatives between 9 a.m. and 4 p.m., Monday
‘‘top 100’’ or ‘‘top 200’’ drugs with the
FDA has considered numerous most adverse reactions. The agency through Friday. (FDA has verified the
alternative formats, including a longer believes including only labeling of new Web site addresses, but FDA is not
Highlights. Highlights is limited to one- and more recently approved drug responsible for any subsequent changes
half page in 8 points to respond to products is the best option for to the Web sites after this document
health care practitioners’ concerns about implementing the new format publishes in the Federal Register.)
length as well as to reduce the 1. Miller, G. A., ‘‘The Magical Number
requirements (see comment 113). Even
Seven, Plus or Minus Two: Some Limits on
incremental printing costs to this limited set of products will require Our Capacity for Processing Information,’’
manufacturers. substantial resources from both industry Psychological Review, 101(2):343–352, 1994.
The agency also considered requiring and the agency for a period of several 2. Shiffrin, R. M., and R. M. Nosofsky,
larger minimum type sizes. A 10-point years. The agency’s proposed ‘‘Seven Plus or Minus Two: A Commentary
minimum size requirement would implementation plan, which is being On Capacity Limitations,’’ Psychological
increase the amount of paper needed to finalized in this rule as proposed, is Review, 101(2):357–361, 1994.
print the average reformatted labeling by intended to make the best use of these 3. Allen, P. A., and L. C. Crozier, ‘‘Age and
about 200-square inches at an Ideal Chunk Size,’’ Journal of Gerontology:
resources. Because there is a lack of Psychological Sciences, 47(1):47–51, 1992.
incremental cost of $18,000 per million standardized data on prescription 4. Food and Drug Administration,
pieces. Over 10 years, the total present volume and volumes can fluctuate ‘‘Consumer Comprehension and Preference
value of producing longer trade labeling considerably over time, the agency does for Variations in the Proposed Over-the-
in 10 points compared to 6 points not believe that categories based on Counter Drug Labeling Format,’’ in OTC vol.
would equal $95 million or $120 volume would be prudent or feasible. 28, Docket No. 96N–0420, Division of
million with a 7- or 3-percent discount As discussed in the preamble to the Dockets Management.
rate, respectively. In addition to higher 5. National Surveys of Prescription
proposed rule (65 FR 81082 at 81098), Medicine Information Received by
incremental printing costs, requiring 10- the plan targets newer products because Consumers, http://www.fda.gov/cder/ddmac/
point minimum type size would make practitioners are more likely to refer to y2ktable.htm.
labeling so large that many the labeling for newer products. Internal http://www.fda.gov/cder/ddmac/
manufacturers would be forced to agency analysis finds that fully 40 y2kTITLE.htm.
modify or replace packaging equipment. percent of adverse reaction reports 6. Kripalani, S., ‘‘The Write Stuff: Simple
The agency therefore rejected this submitted to the FDA are for drugs Guidelines Can Help You Write and Design
option because the potential benefits of Effective Patient Education Materials,’’ Texas
approved within the last 3 years.
Medicine, 91:40–45, 1995.
the larger type size did not outweigh the Therefore, the agency rejected these 7. Backinger, C. L., and P. A. Kingsley,
costs. three alternative categories in order to ‘‘Write It Right: Recommendations for
The agency also considered and focus efforts on recently approved drug Developing User Instructions for Medical
rejected a 10-point minimum size products whose labeling is more likely Devices Used in Home Health Care,’’
requirement for labeling not to be consulted by physicians. Department of Health and Human Services,
accompanying drug products. Compared Publication No. FDA 93–4258, 1993.
to the minimum requirement of 8 points 4. Alternative Implementation Schedule 8. Mettger, W., and J. Mara, ‘‘Clear &
in the final rule, this larger type size FDA considered a shorter Simple: Developing Effective Print Materials
for Low-Literate Readers,’’ Bethesda, MD,

would have taken about 100-square implementation schedule of 3 years National Cancer Institute, Publication No.
inches more paper at an incremental after the effective date for all NIH 95–3594, 1994, http://oc.nci.nih.gov/
cost of $9,000 per million pieces. applications and efficacy supplements services/Clear_and_Simple/HOME.htm.
Finally, the agency proposed a approved 5 years prior to the effective 9. Silver, N. C., and C. C. Braun,
minimum size requirement of 8 points date. The agency selected the more ‘‘Perceived Readability of Warning Labels
with Varied Font Sizes and Styles,’’ Safety Drug Events,’’ Journal of the American authority delegated to the Commissioner
Science, 16:615–625, 1993. Medical Association, 274(1):29–34, 1995. of Food and Drugs, 21 CFR parts 201,
10. Wilkins, A. G., and M. I. Nimmo-Smith, 28. Classen, D. C. et al., ‘‘Adverse Drug 314, and 601 are amended as follows:
‘‘The Clarity and Comfort of Printed Text,’’ Events in Hospitalized Patients: Excess
Ergonomics, 30:1705–1720, 1987. Length of Stay, Extra Costs, and Attributable PART 201—LABELING
11. Transcript of public meeting on Mortality,’’ Journal of the American Medical
prescription drug labeling, Docket No. 95N– Association 277(4):301–306, 1997. ■ 1. The authority citation for 21 CFR
0314, October 30, 1995. 29. Senst, B. L. et al., ‘‘Practical Approach part 201 continues to read as follows:
12. Eastern Research Group, Inc., ‘‘Cost to Determining Costs and Frequency of
Impacts of the Over-the-Counter Adverse Drug Events in a Health Care Authority: 21 U.S.C. 321, 331, 351, 352,
Pharmaceutical Labeling Rule,’’ appendix A, Network,’’ American Journal of Health- 353, 355, 358, 360, 360b, 360gg–360ss, 371,
March 5, 1999. Systems Pharmacy, 58:1126–1132, 2001. 374, 379e; 42 U.S.C. 216, 241, 262, 264.
13. Connelly, D. P. et al., ‘‘Knowledge 30. 2000 hospital discharges data from the ■ 2. Section 201.56 is revised to read as
Resource Preferences of Family Physicians,’’ Agency for Health Care Policy and Research follows:
Journal of Family Practice, 31(2):121–122, (AHCPR), June 25, 1998, http://
1990. www.ahrq.gov/HCUPnet.htm (last viewed 8/ § 201.56 Requirements on content and
14. Ely, J. W. et al., ‘‘What Clinical 13/02). format of labeling for human prescription
Information Resources Are Available in 31. Bates, D. W. et al., ‘‘The Costs of drug and biological products.
Family Physicians’ Offices?’’ Journal of Adverse Drug Events in Hospitalized (a) General requirements. Prescription
Family Practice, 48(2):135–139, 1999. Patients,’’ Journal of the American Medical
15. Ely, J. W. et al., ‘‘The Information
drug labeling described in § 201.100(d)
Association, 277(4):307–311, 1997. must meet the following general
Needs of Family Physicians: Case-Specific 32. Medical Group Management
Clinical Questions,’’ Journal of Family Association, AHRQ, CMS and Partnership for
requirements:
Practice, 35(3):265–269, 1992. Patient Safety, ‘‘Ambulatory Patient Safety: (1) The labeling must contain a
16. Gorman, P., ‘‘Information Needs in What Do We Know?’’ An Agenda for summary of the essential scientific
Primary Care: A Survey of Rural and Research in Ambulatory Patient Safety— information needed for the safe and
Nonrural Primary Care Physicians,’’ Medinfo, Synthesis of a Multidisciplinary Conference, effective use of the drug.
10 (Pt. 1):338–342, 2001. 2000, http://www.ahcpr.gov/about/cpcr/ (2) The labeling must be informative
17. National Association of Chain Drug ptsafety/ambpts2.htm (last viewed 10/10/02). and accurate and neither promotional in
Stores, ‘‘Industry Facts-at-a-Glance—Rx Sales 33. Thomas, E. J. et al., ‘‘Costs of Medical
2001,’’ http://www.nacds.org/
tone nor false or misleading in any
Injuries in Utah and Colorado,’’ Inquiry, particular. In accordance with §§ 314.70
wmspage.cfm?parm1=507#rx (last viewed 8/ 36:255–264, 1999.
27/02). and 601.12 of this chapter, the labeling
34. Johnson, J. A., and J. L. Bootman,
18. U.S. Department of Labor, Bureau of must be updated when new information
‘‘Drug-Related Morbidity and Mortality: A
Labor Statistics, ‘‘2000 National Cost-of-Illness Model,’’ Archives of Internal
becomes available that causes the
Occupational Employment and Wage labeling to become inaccurate, false, or
Medicine, 155:1949–1956, 1995.
Estimates—29–1051 Pharmacists,’’ http:// misleading.
35. Ernst, F. R., and A. J. Grizzle, ‘‘Drug-
www.bls.gov/oes/2000/oes291051.htm (last (3) The labeling must be based
Related Morbidity and Mortality: Updating
viewed 8/27/02). whenever possible on data derived from
the Cost-of-Illness Model,’’ Journal of the
19. U.S. Department of Labor, Bureau of
American Pharmaceutical Association, human experience. No implied claims
Labor Statistics, Occupational Outlook
Handbook, 2002–03, Pharmacists (occupation
41(2):192–199, 2001. or suggestions of drug use may be made
36. IMS Health, ‘‘Product Sampling if there is inadequate evidence of safety
code 29–1051), 2002, http://www.bls.gov/
Continues to Spike in U.S.,’’ 2001, http:// or a lack of substantial evidence of
oco/ocos079.htm (last viewed 9/13/02).
www.imshealth.com/public/structure/ effectiveness. Conclusions based on
20. Jousimaa, J. et al., ‘‘Physicians’ Patterns
dispcontent/1,2779,1362–1362–
of Using a Computerized Collection of animal data but necessary for safe and
Guidelines for Primary Care,’’ International 143626,00.html (last viewed 9/23/02).
37. U.S. Census Bureau, ‘‘Statistics of U.S. effective use of the drug in humans
Journal of Technology Assessment in Health must be identified as such and included
Care, 14(3):484–493, 1998. Businesses; 1999; Pharmaceutical
preparation mfg, United States,’’ http:// with human data in the appropriate
21. U.S. Census Bureau, ‘‘Table 153,
www.census.gov/epcd/susb/1999/us/ section of the labeling.
Physicians by Selected Activity: 1980 to
1999,’’ Statistical Abstract of the United US325412.htm (last viewed 9/12/02). (b) Categories of prescription drugs
States: 2001, p. 106. 38. U.S. Census Bureau, ‘‘Statistics of U.S. subject to the labeling content and
22. U.S. Census Bureau, ‘‘Table 157, Businesses; 1999; Biological product (except format requirements in §§ 201.56(d) and
Medical Practice Characteristics by Selected diagnostic) mfg, United States,’’ http:// 201.57. (1) The following categories of
Specialty: 1985 to 1998,’’ Statistical Abstract www.census.gov/epcd/susb/1999/us/ prescription drug products are subject to
of the United States: 2001, p. 108. US325414.htm (last viewed 9/12/02). the labeling requirements in paragraph
23. American Medical Association, List of Subjects (d) of this section and § 201.57 in
‘‘Medical Education FAQs,’’ http:// accordance with the implementation
www.ama-assn.org/ama/pub/category/ 21 CFR Part 201 schedule in paragraph (c) of this section:
3627.html (last viewed 9/13/02).
Drugs, Labeling, Reporting and (i) Prescription drug products for
24. Woosley, R. L., ‘‘Drug Labeling
Revisions—Guaranteed to Fail?’’ Journal of recordkeeping requirements. which a new drug application (NDA),
the American Medical Association, biologics license application (BLA), or
21 CFR Part 314 efficacy supplement was approved by
284(23):3047–3049, 2000.
25. Friedman, M. A. et al., ‘‘The Safety of Administrative practice and procdure, the Food and Drug Administration
Newly Approved Medicines: Do Recent Confidential business information, (FDA) between June 30, 2001 and June
Market Removals Mean There Is a Problem?’’ Drugs, Reporting and recordkeeping 30, 2006;
Journal of the American Medical Association, requirements. (ii) Prescription drug products for
281(18):1728–1734, 1999. which an NDA, BLA, or efficacy
26. U.S. General Accounting Office, 21 CFR 601
supplement is pending on June 30,
‘‘Adverse Drug Events: The Magnitude of Adminstrative practice and

Health Risk Is Uncertain Because of Limited 2006; or
Incidence Data,’’ GAO/HEHS–00–21,
procedure, Biologics, Confidential (iii) Prescription drug products for
January, 2000. business information. which an NDA, BLA, or efficacy
27. Bates, D. W. et al., ‘‘Incidence of ■ Therefore, under the Federal Food, supplement is submitted anytime on or
Adverse Drug Events and Potential Adverse Drug, and Cosmetic Act and under after June 30, 2006.
(2) Prescription drug products not following headings and subheadings prescribing information must be
described in paragraph (b)(1) of this and in the following order: accompanied by the identifying number
section are subject to the labeling Highlights of Prescribing Information (in parentheses) corresponding to the
requirements in paragraph (e) of this Product Names, Other Required location of the information in the full
section and § 201.80. Information prescribing information.
(c) Schedule for implementing the (4) Omit clearly inapplicable sections,
labeling content and format Boxed Warning subsections, or specific information. If
requirements in §§ 201.56(d) and Recent Major Changes sections or subsections required under
201.57. For products described in Indications and Usage paragraph (d)(1) of this section are
paragraph (b)(1) of this section, labeling Dosage and Administration omitted from the full prescribing
conforming to the requirements in Dosage Forms and Strengths information, the heading ‘‘Full
paragraph (d) of this section and Contraindications Prescribing Information: Contents’’ must
§ 201.57 must be submitted according to Warnings and Precautions be followed by an asterisk and the
the following schedule: Adverse Reactions following statement must appear at the
(1) For products for which an NDA, Drug Interactions end of Contents: ‘‘* Sections or
BLA, or efficacy supplement is Use in Specific Populations subsections omitted from the full
submitted for approval on or after June Full Prescribing Information: Contents prescribing information are not listed.’’
30, 2006, proposed conforming labeling (5) Any risk information that is
Full Prescribing Information
must be submitted as part of the required under § 201.57(c)(9)(iv) is
Boxed Warning
application. considered ‘‘appropriate pediatric
1 Indications and Usage
(2) For products for which an NDA, contraindications, warnings, or
2 Dosage and Administration
BLA, or efficacy supplement is pending precautions’’ within the meaning of
3 Dosage Forms and Strengths
on June 30, 2006, or that has been section 505A(l)(2) of the Federal Food,
4 Contraindications
approved any time from June 30, 2005, Drug, and Cosmetic Act (the act) (21
5 Warnings and Precautions
up to and including June 30, 2006, a U.S.C. 355A(l)(2)), whether such
6 Adverse Reactions
supplement with proposed conforming information appears in the
7 Drug Interactions
labeling must be submitted no later than 8 Use in Specific Populations ‘‘Contraindications,’’ ‘‘Warnings and
June 30, 2009. 8.1 Pregnancy Precautions,’’ or ‘‘Use in Specific
(3) For products for which an NDA, 8.2 Labor and delivery Populations’’ section of labeling.
BLA, or efficacy supplement has been (e) Labeling requirements for older
8.3 Nursing mothers
approved anytime from June 30, 2004, 8.4 Pediatric use prescription drug products. This
up to and including June 29, 2005, a 8.5 Geriatric use paragraph applies only to approved
supplement with proposed conforming 9 Drug Abuse and Dependence prescription drug products not
labeling must be submitted no later than 9.1 Controlled substance described in paragraph (b)(1) of this
June 30, 2010. 9.2 Abuse section.
(4) For products for which an NDA, 9.3 Dependence (1) Prescription drug labeling
BLA, or efficacy supplement has been 10 Overdosage described in § 201.100(d) must contain
approved anytime from June 30, 2003, 11 Description the specific information required under
up to and including June 29, 2004, a 12 Clinical Pharmacology § 201.80 under the following section
supplement with proposed conforming 12.1 Mechanism of action headings and in the following order:
labeling must be submitted no later than 12.2 Pharmacodynamics Description
June 30, 2011. Clinical Pharmacology
12.3 Pharmacokinetics
(5) For products for which an NDA, Indications and Usage
13 Nonclinical Toxicology
Contraindications
BLA, or efficacy supplement has been 13.1 Carcinogenesis, mutagenesis, Warnings
approved anytime from June 30, 2002, impairment of fertility Precautions
up to and including June 29, 2003, a 13.2 Animal toxicology and/or Adverse Reactions
supplement with proposed conforming pharmacology Drug Abuse and Dependence
labeling must be submitted no later than 14 Clinical Studies Overdosage
June 30, 2012. 15 References Dosage and Administration
(6) For products for which an NDA, 16 How Supplied/Storage and How Supplied
BLA, or efficacy supplement has been Handling (2) The labeling may contain the
approved anytime from June 30, 2001, 17 Patient Counseling Information following additional section headings if
up to and including June 29, 2002, a (2) Additional nonstandard appropriate and if in compliance with
supplement with proposed conforming subheadings that are used to enhance § 201.80(l) and (m):
labeling must be submitted no later than labeling organization, presentation, or Animal Pharmacology and/or Animal
June 30, 2013. ease of use (e.g., for individual warnings Toxicology
(d) Labeling requirements for new and or precautions, or for each drug Clinical Studies
more recently approved prescription interaction) must be assigned a decimal References
drug products. This paragraph applies number that corresponds to their (3) Omit clearly inapplicable sections,
only to prescription drug products placement in labeling. The decimal subsections, or specific information.
described in paragraph (b)(1) of this numbers must be consistent with the (4) The labeling may contain a
section and must be implemented standardized identifying numbers listed ‘‘Product Title’’ section preceding the
according to the schedule specified in in paragraph (d)(1) of this section (e.g., ‘‘Description’’ section and containing
paragraph (c) of this section. subheadings added to the ‘‘Warnings only the information required by
(1) Prescription drug labeling and Precautions’’ section must be § 201.80(a)(1)(i), (a)(1)(ii), (a)(1)(iii), and
described in § 201.100(d) must contain numbered 5.1, 5.2, and so on). (a)(1)(iv) and § 201.100(e). The
the specific information required under (3) Any reference in Highlights to information required by § 201.80(a)(1)(i)
§ 201.57(a), (b), and (c) under the information appearing in the full through (a)(1)(iv) must appear in the
‘‘Description’’ section of the labeling, statement must be placed on the line significant clinical pharmacologic
whether or not it also appears in a immediately beneath the established information.
‘‘Product Title.’’ name or, for biological products, proper (8) Dosage forms and strengths. A
(5) The labeling must contain the date name of the product. concise summary of the information
of the most recent revision of the (4) Boxed warning. A concise required under paragraph (c)(4) of this
labeling, identified as such, placed summary of any boxed warning required section, with any appropriate
prominently immediately after the last by paragraph (c)(1) of this section, not subheadings (e.g., tablets, capsules,
section of the labeling. to exceed a length of 20 lines. The injectable, suspension), including the
(6) The requirement in § 201.80(f)(2) summary must be preceded by a strength or potency of the dosage form
to reprint any FDA-approved patient heading, in upper-case letters, in metric system (e.g., 10-milligram
labeling at the end of prescription drug containing the word ‘‘WARNING’’ and tablets) and whether the product is
labeling or accompany the prescription other words that are appropriate to scored.
drug labeling must be implemented no identify the subject of the warning. The (9) Contraindications. A concise
later than June 30, 2007. heading and the summary must be statement of each of the product’s
■ 3. Section 201.57 is redesignated as contained within a box and bolded. The contraindications, as required under
§ 201.80 and new § 201.57 is added to following verbatim statement must be paragraph (c)(5) of this section, with any
read as follows: placed immediately following the appropriate subheadings.
heading of the boxed warning: ‘‘See full (10) Warnings and precautions. A
§ 201.57 Specific requirements on content prescribing information for complete
and format of labeling for human
concise summary of the most clinically
boxed warning.’’ significant information required under
prescription drug and biological products (5) Recent major changes. A list of the
described in § 201.56(b)(1). paragraph (c)(6) of this section, with any
section(s) of the full prescribing appropriate subheadings, including
The requirements in this section information, limited to the labeling
apply only to prescription drug information that would affect decisions
sections described in paragraphs (c)(1),
products described in § 201.56(b)(1) and about whether to prescribe a drug,
(c)(2), (c)(3), (c)(5), and (c)(6) of this
must be implemented according to the recommendations for patient monitoring
section, that contain(s) substantive
schedule specified in § 201.56(c), except that are critical to safe use of the drug,
labeling changes that have been
for the requirement in paragraph (c)(18) and measures that can be taken to
approved by FDA or authorized under
of this section to reprint any FDA- prevent or mitigate harm.
§ 314.70(c)(6) or (d)(2), or § 601.12(f)(1)
approved patient labeling at the end of (11) Adverse reactions. (i) A list of the
through (f)(3) of this chapter. The
prescription drug labeling or accompany heading(s) and, if appropriate, the most frequently occurring adverse
the prescription drug labeling, which subheading(s) of the labeling section(s) reactions, as described in paragraph
must be implemented no later than June affected by the change must be listed (c)(7) of this section, along with the
30, 2007. together with each section’s identifying criteria used to determine inclusion
(a) Highlights of prescribing number and the date (month/year) on (e.g., incidence rate). Adverse reactions
information. The following information which the change was incorporated in important for other reasons (e.g.,
must appear in all prescription drug labeling. These labeling sections must because they are serious or frequently
labeling: be listed in the order in which they lead to discontinuation or dosage
(1) Highlights limitation statement. appear in the full prescribing adjustment) must not be repeated under
The verbatim statement ‘‘These information. A changed section must be this heading in Highlights if they are
highlights do not include all the listed under this heading in Highlights included elsewhere in Highlights (e.g.,
information needed to use (insert name for at least 1 year after the date of the Warnings and Precautions,
of drug product) safely and effectively. labeling change and must be removed at Contraindications).
See full prescribing information for the first printing subsequent to the 1 (ii) For drug products other than
(insert name of drug product).’’ year period. vaccines, the verbatim statement ‘‘To
(2) Drug names, dosage form, route of (6) Indications and usage. A concise report SUSPECTED ADVERSE
administration, and controlled statement of each of the product’s REACTIONS, contact (insert name of
substance symbol. The proprietary name indications, as required under manufacturer) at (insert manufacturer’s
and the established name of the drug, if paragraph (c)(2) of this section, with any phone number) or FDA at (insert current
any, as defined in section 502(e)(3) of appropriate subheadings. Major FDA phone number and Web address
the Federal Food, Drug, and Cosmetic limitations of use (e.g., lack of effect in for voluntary reporting of adverse
Act (the act) or, for biological products, particular subsets of the population, or reactions).’’
the proper name (as defined in § 600.3 second line therapy status) must be (iii) For vaccines, the verbatim
of this chapter) including any briefly noted. If the product is a member statement ‘‘To report SUSPECTED
appropriate descriptors. This of an established pharmacologic class, ADVERSE REACTIONS, contact (insert
information must be followed by the the concise statement under this name of manufacturer) at (insert
drug’s dosage form and route of heading in Highlights must identify the manufacturer’s phone number) or
administration. For controlled class in the following manner: ‘‘(Drug) VAERS at (insert the current VAERS
substances, the controlled substance is a (name of class) indicated for phone number and Web address for
symbol designating the schedule in (indication(s)).’’ voluntary reporting of adverse
which the controlled substance is listed (7) Dosage and administration. A reactions).’’
must be included as required by concise summary of the information (iv) For manufacturers with a Web site
§ 1302.04 of this chapter. required under paragraph (c)(3) of this for voluntary reporting of adverse
(3) Initial U.S. approval. The verbatim section, with any appropriate reactions, the Web address of the direct
statement ‘‘Initial U.S. Approval’’ subheadings, including the link to the site.
followed by the four-digit year in which recommended dosage regimen, starting (12) Drug interactions. A concise
FDA initially approved a new molecular dose, dose range, critical differences summary of the information required
entity, new biological product, or new among population subsets, monitoring under paragraph (c)(8) of this section,
combination of active ingredients. The recommendations, and other clinically with any appropriate subheadings.
(13) Use in specific populations. A recognized disease or condition, or of a evidence that the drug is effective or
concise summary of the information manifestation of a recognized disease or safe for that use or condition.
required under paragraph (c)(9) of this condition, or for the relief of symptoms (iii) Any statements comparing the
section, with any appropriate associated with a recognized disease or safety or effectiveness of the drug with
subheadings. condition. other agents for the same indication
(14) Patient counseling information (i) This section must include the must, except for biological products, be
statement. The verbatim statement ‘‘See following information when the supported by substantial evidence
17 for Patient Counseling Information’’ conditions listed are applicable: derived from adequate and well-
or, if the product has FDA-approved (A) If the drug is used for an controlled studies as defined in
patient labeling, the verbatim statement indication only in conjunction with a § 314.126(b) of this chapter unless this
‘‘See 17 for Patient Counseling primary mode of therapy (e.g., diet, requirement is waived under § 201.58 or
Information and (insert either FDA- surgery, behavior changes, or some § 314.126(c) of this chapter. For
approved patient labeling or Medication other drug), a statement that the drug is biological products, such statements
Guide).’’ indicated as an adjunct to that mode of must be supported by substantial
(15) Revision date. The date of the therapy. evidence.
most recent revision of the labeling, (B) If evidence is available to support (iv) For drug products other than
identified as such, placed at the end of the safety and effectiveness of the drug biological products, all indications
Highlights. or biological product only in selected listed in this section must be supported
(b) Full prescribing information: subgroups of the larger population (e.g., by substantial evidence of effectiveness
Contents. Contents must contain a list of patients with mild disease or patients in based on adequate and well-controlled
each heading and subheading required a special age group), or if the indication studies as defined in § 314.126(b) of this
in the full prescribing information is approved based on a surrogate chapter unless the requirement is
under § 201.56(d)(1), if not omitted endpoint under § 314.510 or § 601.41 of waived under § 201.58 or § 314.126(c) of
under § 201.56(d)(4), preceded by the this chapter, a succinct description of this chapter. Indications or uses must
identifying number required under the limitations of usefulness of the drug not be implied or suggested in other
§ 201.56(d)(1). Contents must also and any uncertainty about anticipated sections of the labeling if not included
contain any additional subheading(s) clinical benefits, with reference to the in this section.
included in the full prescribing ‘‘Clinical Studies’’ section for a (v) For biological products, all
information preceded by the identifying discussion of the available evidence. indications listed in this section must be
number assigned in accordance with (C) If specific tests are necessary for supported by substantial evidence of
§ 201.56(d)(2). selection or monitoring of the patients effectiveness. Indications or uses must
(c) Full prescribing information. The who need the drug (e.g., microbe not be implied or suggested in other
full prescribing information must susceptibility tests), the identity of such sections of the labeling if not included
contain the information in the order tests. in this section.
required under paragraphs (c)(1) (D) If information on limitations of (3) 2 Dosage and administration. (i)
through (c)(18) of this section, together use or uncertainty about anticipated This section must state the
with the headings, subheadings, and clinical benefits is relevant to the recommended dose and, as appropriate:
identifying numbers required under recommended intervals between doses, (A) The dosage range,
§ 201.56(d)(1), unless omitted under to the appropriate duration of treatment (B) An upper limit beyond which
§ 201.56(d)(4). If additional subheadings when such treatment should be limited, safety and effectiveness have not been
are used within a labeling section, they or to any modification of dosage, a established, or beyond which increasing
must be preceded by the identifying concise description of the information the dose does not result in increasing
number assigned in accordance with with reference to the more detailed effectiveness,
§ 201.56(d)(2). information in the ‘‘Dosage and (C) Dosages for each indication and
(1) Boxed warning. Certain Administration’’ section. subpopulation,
contraindications or serious warnings, (E) If safety considerations are such (D) The intervals recommended
particularly those that may lead to death that the drug should be reserved for between doses,
or serious injury, may be required by the specific situations (e.g., cases refractory (E) The optimal method of titrating
FDA to be presented in a box. The to other drugs), a statement of the dosage,
boxed warning ordinarily must be based information. (F) The usual duration of treatment
on clinical data, but serious animal (F) If there are specific conditions that when treatment duration should be
toxicity may also be the basis of a boxed should be met before the drug is used limited,
warning in the absence of clinical data. on a long term basis (e.g., demonstration (G) Dosing recommendations based on
The box must contain, in uppercase of responsiveness to the drug in a short clinical pharmacologic data (e.g.,
letters, a heading inside the box that term trial in a given patient), a statement clinically significant food effects),
includes the word ‘‘WARNING’’ and of the conditions; or, if the indications (H) Modification of dosage needed
conveys the general focus of the for long term use are different from because of drug interactions or in
information in the box. The box must those for short term use, a statement of special patient populations (e.g., in
briefly explain the risk and refer to more the specific indications for each use. children, in geriatric age groups, in
detailed information in the (ii) If there is a common belief that the groups defined by genetic
‘‘Contraindications’’ or ‘‘Warnings and drug may be effective for a certain use characteristics, or in patients with renal
Precautions’’ section, accompanied by or if there is a common use of the drug or hepatic disease),
the identifying number for the section or for a condition, but the preponderance (I) Important considerations
subsection containing the detailed of evidence related to the use or concerning compliance with the dosage
information. condition shows that the drug is regimen,

(2) 1 Indications and usage. This ineffective or that the therapeutic (J) Efficacious or toxic concentration
section must state that the drug is benefits of the product do not generally ranges and therapeutic concentration
indicated for the treatment, prevention, outweigh its risks, FDA may require that windows of the drug or its metabolites,
mitigation, cure, or diagnosis of a this section state that there is a lack of if established and clinically significant.
Information on therapeutic drug hypersensitivity to the drug has not (7) 6 Adverse reactions. This section
concentration monitoring (TDM) must been demonstrated, it should not be must describe the overall adverse
also be included in this section when listed as a contraindication). If no reaction profile of the drug based on the
TDM is necessary. contraindications are known, this entire safety database. For purposes of
(ii) Dosing regimens must not be section must state ‘‘None.’’ prescription drug labeling, an adverse
implied or suggested in other sections of (6) 5 Warnings and precautions. (i) reaction is an undesirable effect,
the labeling if not included in this General. This section must describe reasonably associated with use of a
section. clinically significant adverse reactions drug, that may occur as part of the
(iii) Radiation dosimetry information (including any that are potentially fatal, pharmacological action of the drug or
must be stated for both the patient are serious even if infrequent, or can be may be unpredictable in its occurrence.
receiving a radioactive drug and the prevented or mitigated through This definition does not include all
person administering it. appropriate use of the drug), other adverse events observed during use of a
(iv) This section must also contain potential safety hazards (including those drug, only those adverse events for
specific direction on dilution, that are expected for the which there is some basis to believe
preparation (including the strength of pharmacological class or those resulting there is a causal relationship between
the final dosage solution, when from drug/drug interactions), limitations the drug and the occurrence of the
prepared according to instructions, in in use imposed by them (e.g., avoiding adverse event.
terms of milligrams of active ingredient certain concomitant therapy), and steps (i) Listing of adverse reactions. This
per milliliter of reconstituted solution, that should be taken if they occur (e.g., section must list the adverse reactions
unless another measure of the strength dosage modification). The frequency of that occur with the drug and with drugs
is more appropriate), and administration all clinically significant adverse in the same pharmacologically active
of the dosage form, if needed (e.g., the reactions and the approximate mortality and chemically related class, if
rate of administration of parenteral drug and morbidity rates for patients applicable. The list or lists must be
in milligrams per minute; storage experiencing the reaction, if known and preceded by the information necessary
conditions for stability of the necessary for the safe and effective use to interpret the adverse reactions (e.g.,
reconstituted drug, when important; of the drug, must be expressed as for clinical trials, total number exposed,
essential information on drug provided under paragraph (c)(7) of this extent and nature of exposure).
incompatibilities if the drug is mixed in section. In accordance with §§ 314.70 (ii) Categorization of adverse
vitro with other drugs or diluents; and and 601.12 of this chapter, the labeling reactions. Within a listing, adverse
the following verbatim statement for must be revised to include a warning reactions must be categorized by body
parenterals: ‘‘Parenteral drug products about a clinically significant hazard as system, by severity of the reaction, or in
should be inspected visually for soon as there is reasonable evidence of order of decreasing frequency, or by a
particulate matter and discoloration a causal association with a drug; a combination of these, as appropriate.
prior to administration, whenever causal relationship need not have been Within a category, adverse reactions
solution and container permit.’’) definitely established. A specific must be listed in decreasing order of
(4) 3 Dosage forms and strengths. This warning relating to a use not provided frequency. If frequency information
section must contain information on the for under the ‘‘Indications and Usage’’ cannot be reliably determined, adverse
available dosage forms to which the section may be required by FDA in reactions must be listed in decreasing
labeling applies and for which the accordance with sections 201(n) and order of severity.
manufacturer or distributor is 502(a) of the act if the drug is commonly (A) Clinical trials experience. This
responsible, including: prescribed for a disease or condition section must list the adverse reactions
(i) The strength or potency of the and such usage is associated with a identified in clinical trials that occurred
dosage form in metric system (e.g., 10 clinically significant risk or hazard. at or above a specified rate appropriate
milligram tablets), and, if the apothecary (ii) Other special care precautions. to the safety database. The rate of
system is used, a statement of the This section must contain information occurrence of an adverse reaction for the
strength in parentheses after the metric regarding any special care to be drug and comparators (e.g., placebo)
designation; and exercised by the practitioner for safe must be presented, unless such data
(ii) A description of the identifying and effective use of the drug (e.g., cannot be determined or presentation of
characteristics of the dosage forms, precautions not required under any comparator rates would be misleading.
including shape, color, coating, scoring, other specific section or subsection). If adverse reactions that occurred below
and imprinting, when applicable. The (iii) Monitoring: Laboratory tests. This the specified rate are included, they
National Drug Code number(s) for the section must identify any laboratory must be included in a separate listing.
drug product must not be included in tests helpful in following the patient’s If comparative rates of occurrence
this section. response or in identifying possible cannot be reliably determined (e.g.,
(5) 4 Contraindications. This section adverse reactions. If appropriate, adverse reactions were observed only in
must describe any situations in which information must be provided on such the uncontrolled trial portion of the
the drug should not be used because the factors as the range of normal and overall safety database), adverse
risk of use (e.g., certain potentially fatal abnormal values expected in the reactions must be grouped within
adverse reactions) clearly outweighs any particular situation and the specified frequency ranges as
possible therapeutic benefit. Those recommended frequency with which appropriate to the safety database for the
situations include use of the drug in tests should be performed before, drug (e.g., adverse reactions occurring at
patients who, because of their particular during, and after therapy. a rate of less than 1/100, adverse
age, sex, concomitant therapy, disease (iv) Interference with laboratory tests. reactions occurring at a rate of less than
state, or other condition, have a This section must briefly note 1/500) or descriptively identified, if
substantial risk of being harmed by the information on any known interference frequency ranges cannot be determined.
drug and for whom no potential benefit by the product with laboratory tests and For adverse reactions with significant
makes the risk acceptable. Known reference the section where the detailed clinical implications, the listings must
hazards and not theoretical possibilities information is presented (e.g., ‘‘Drug be supplemented with additional detail
must be listed (e.g., if severe Interactions’’ section). about the nature, frequency, and
severity of the adverse reaction and the (1) Pregnancy category A. If adequate appear that the possibility of fetal harm
relationship of the adverse reaction to and well-controlled studies in pregnant is remote, if the drug is used during
drug dose and demographic women have failed to demonstrate a risk pregnancy. Nevertheless, because the
characteristics, if data are available and to the fetus in the first trimester of studies in humans cannot rule out the
important. pregnancy (and there is no evidence of possibility of harm, (name of drug)
(B) Postmarketing experience. This a risk in later trimesters), the labeling should be used during pregnancy only
section of the labeling must list the must state: ‘‘Pregnancy Category A. if clearly needed.’’ The labeling must
adverse reactions, as defined in Studies in pregnant women have not also contain a description of the human
paragraph (c)(7) of this section, that are shown that (name of drug) increases the studies and a description of available
identified from domestic and foreign risk of fetal abnormalities if data on the effect of the drug on the later
spontaneous reports. This listing must administered during the first (second, growth, development, and functional
be separate from the listing of adverse third, or all) trimester(s) of pregnancy. If maturation of the child.
reactions identified in clinical trials. this drug is used during pregnancy, the (3) Pregnancy category C. If animal
(iii) Comparisons of adverse reactions possibility of fetal harm appears remote. reproduction studies have shown an
between drugs. For drug products other Because studies cannot rule out the adverse effect on the fetus, if there are
than biological products, any claim possibility of harm, however, (name of no adequate and well-controlled studies
comparing the drug to which the drug) should be used during pregnancy in humans, and if the benefits from the
labeling applies with other drugs in only if clearly needed.’’ The labeling use of the drug in pregnant women may
terms of frequency, severity, or must also contain a description of the be acceptable despite its potential risks,
character of adverse reactions must be human studies. If animal reproduction the labeling must state: ‘‘Pregnancy
based on adequate and well-controlled studies are also available and they fail Category C. (Name of drug) has been
studies as defined in § 314.126(b) of this to demonstrate a risk to the fetus, the shown to be teratogenic (or to have an
chapter unless this requirement is labeling must also state: ‘‘Reproduction embryocidal effect or other adverse
waived under § 201.58 or § 314.126(c) of studies have been performed in (kinds effect) in (name(s) of species) when
this chapter. For biological products, of animal(s)) at doses up to (x) times the given in doses (x) times the human
any such claim must be based on human dose and have revealed no dose. There are no adequate and well-
substantial evidence. evidence of impaired fertility or harm to controlled studies in pregnant women.
(8) 7 Drug interactions. (i) This the fetus due to (name of drug).’’ The (Name of drug) should be used during
section must contain a description of labeling must also contain a description pregnancy only if the potential benefit
of available data on the effect of the justifies the potential risk to the fetus.’’
clinically significant interactions, either
drug on the later growth, development, The labeling must contain a description
observed or predicted, with other
and functional maturation of the child. of the animal studies. If there are no
prescription or over-the-counter drugs,
animal reproduction studies and no
classes of drugs, or foods (e.g., dietary (2) Pregnancy category B. If animal adequate and well-controlled studies in
supplements, grapefruit juice), and reproduction studies have failed to humans, the labeling must state:
specific practical instructions for demonstrate a risk to the fetus and there ‘‘Pregnancy Category C. Animal
preventing or managing them. The are no adequate and well-controlled reproduction studies have not been
mechanism(s) of the interaction, if studies in pregnant women, the labeling conducted with (name of drug). It is also
known, must be briefly described. must state: ‘‘Pregnancy Category B. not known whether (name of drug) can
Interactions that are described in the Reproduction studies have been cause fetal harm when administered to
‘‘Contraindications’’ or ‘‘Warnings and performed in (kind(s) of animal(s)) at a pregnant woman or can affect
Precautions’’ sections must be discussed doses up to (x) times the human dose reproduction capacity. (Name of drug)
in more detail under this section. and have revealed no evidence of should be given to a pregnant woman
Details of drug interaction impaired fertility or harm to the fetus only if clearly needed.’’ The labeling
pharmacokinetic studies that are due to (name of drug). There are, must contain a description of any
included in the ‘‘Clinical however, no adequate and well- available data on the effect of the drug
Pharmacology’’ section that are controlled studies in pregnant women. on the later growth, development, and
pertinent to clinical use of the drug Because animal reproduction studies are functional maturation of the child.
must not be repeated in this section. not always predictive of human (4) Pregnancy category D. If there is
(ii) This section must also contain response, this drug should be used positive evidence of human fetal risk
practical guidance on known during pregnancy only if clearly based on adverse reaction data from
interference of the drug with laboratory needed.’’ If animal reproduction studies investigational or marketing experience
tests. have shown an adverse effect (other or studies in humans, but the potential
(9) 8 Use in specific populations. This than decrease in fertility), but adequate benefits from the use of the drug in
section must contain the following and well-controlled studies in pregnant pregnant women may be acceptable
subsections: women have failed to demonstrate a risk despite its potential risks (for example,
(i) 8.1 Pregnancy. This subsection to the fetus during the first trimester of if the drug is needed in a life-
may be omitted only if the drug is not pregnancy (and there is no evidence of threatening situation or serious disease
absorbed systemically and the drug is a risk in later trimesters), the labeling for which safer drugs cannot be used or
not known to have a potential for must state: ‘‘Pregnancy Category B. are ineffective), the labeling must state:
indirect harm to the fetus. For all other Reproduction studies in (kind(s) of ‘‘Pregnancy Category D. See ‘Warnings
drugs, this subsection must contain the animal(s)) have shown (describe and Precautions’ section.’’ Under the
following information: findings) at (x) times the human dose. ‘‘Warnings and Precautions’’ section,
(A) Teratogenic effects. Under this Studies in pregnant women, however, the labeling must state: ‘‘(Name of drug)
subheading, the labeling must identify have not shown that (name of drug) can cause fetal harm when administered
one of the following categories that increases the risk of abnormalities when to a pregnant woman. (Describe the
applies to the drug, and the labeling administered during the first (second, human data and any pertinent animal
must bear the statement required under third, or all) trimester(s) of pregnancy. data.) If this drug is used during
the category: Despite the animal findings, it would pregnancy, or if the patient becomes
pregnant while taking this drug, the (B) If a drug is absorbed systemically pediatric dosage information must be
patient should be apprised of the and is known to be excreted in human given under the ‘‘Dosage and
potential hazard to a fetus.’’ milk, this subsection must contain one Administration’’ section. The ‘‘Pediatric
(5) Pregnancy category X. If studies in of the following statements, as use’’ subsection must cite any
animals or humans have demonstrated appropriate. If the drug is associated limitations on the pediatric indication,
fetal abnormalities or if there is positive with serious adverse reactions or if the need for specific monitoring, specific
evidence of fetal risk based on adverse drug has a known tumorigenic potential, hazards associated with use of the drug
reaction reports from investigational or the labeling must state: ‘‘Because of the in any subsets of the pediatric
marketing experience, or both, and the potential for serious adverse reactions in population (e.g., neonates), differences
risk of the use of the drug in a pregnant nursing infants from (name of drug) (or, between pediatric and adult responses
woman clearly outweighs any possible ‘‘Because of the potential for to the drug, and other information
benefit (for example, safer drugs or other tumorigenicity shown for (name of related to the safe and effective pediatric
forms of therapy are available), the drug) in (animal or human) studies), a use of the drug. Data summarized in this
labeling must state: ‘‘Pregnancy decision should be made whether to subsection should be discussed in more
Category X. See ‘Contraindications’ discontinue nursing or to discontinue detail, if appropriate, under the
section.’’ Under ‘‘Contraindications,’’ the drug, taking into account the ‘‘Clinical Pharmacology’’ or ‘‘Clinical
the labeling must state: ‘‘(Name of drug) importance of the drug to the mother.’’ Studies’’ section. As appropriate, this
may (can) cause fetal harm when If the drug is not associated with serious information must also be contained in
administered to a pregnant woman. adverse reactions and does not have a the ‘‘Contraindications’’ and/or
(Describe the human data and any known tumorigenic potential, the ‘‘Warnings and Precautions’’ section(s).
pertinent animal data.) (Name of drug) labeling must state: ‘‘Caution should be (C) If there are specific statements on
is contraindicated in women who are or exercised when (name of drug) is pediatric use of the drug for an
may become pregnant. If this drug is administered to a nursing woman.’’ indication also approved for adults that
used during pregnancy, or if the patient (C) If a drug is absorbed systemically are based on adequate and well-
becomes pregnant while taking this and information on excretion in human controlled studies in the pediatric
drug, the patient should be apprised of milk is unknown, this subsection must population, they must be summarized in
the potential hazard to a fetus.’’ contain one of the following statements, the ‘‘Pediatric use’’ subsection and
(B) Nonteratogenic effects. Under this as appropriate. If the drug is associated discussed in more detail, if appropriate,
with serious adverse reactions or has a under the ‘‘Clinical Pharmacology’’ and
subheading the labeling must contain
known tumorigenic potential, the ‘‘Clinical Studies’’ sections. Appropriate
other information on the drug’s effects
labeling must state: ‘‘It is not known pediatric dosage must be given under
on reproduction and the drug’s use
whether this drug is excreted in human the ‘‘Dosage and Administration’’
during pregnancy that is not required
milk. Because many drugs are excreted section. The ‘‘Pediatric use’’ subsection
specifically by one of the pregnancy
in human milk and because of the of the labeling must also cite any
categories, if the information is relevant
potential for serious adverse reactions in limitations on the pediatric use
to the safe and effective use of the drug.
nursing infants from (name of drug) (or, statement, need for specific monitoring,
Information required under this heading
‘‘Because of the potential for specific hazards associated with use of
must include nonteratogenic effects in
tumorigenicity shown for (name of the drug in any subsets of the pediatric
the fetus or newborn infant (for drug) in (animal or human) studies), a
example, withdrawal symptoms or population (e.g., neonates), differences
decision should be made whether to between pediatric and adult responses
hypoglycemia) that may occur because discontinue nursing or to discontinue
of a pregnant woman’s chronic use of to the drug, and other information
the drug, taking into account the related to the safe and effective pediatric
the drug for a preexisting condition or importance of the drug to the mother.’’
disease. use of the drug. As appropriate, this
If the drug is not associated with serious information must also be contained in
(ii) 8.2 Labor and delivery. If the drug adverse reactions and does not have a
has a recognized use during labor or the ‘‘Contraindications’’ and/or
known tumorigenic potential, the ‘‘Warnings and Precautions’’ section(s).
delivery (vaginal or abdominal labeling must state: ‘‘It is not known
delivery), whether or not the use is (D)(1) When a drug is approved for
whether this drug is excreted in human pediatric use based on adequate and
stated in the Indications and Usage milk. Because many drugs are excreted
section, this subsection must describe well-controlled studies in adults with
in human milk, caution should be other information supporting pediatric
the available information about the exercised when (name of drug) is
effect of the drug on the mother and the use, the ‘‘Pediatric use’’ subsection of
administered to a nursing woman.’’ the labeling must contain either the
fetus, on the duration of labor or (iv) 8.4 Pediatric use. (A) Pediatric
delivery, on the possibility that forceps following statement or a reasonable
population(s)/pediatric patient(s): For alternative:
delivery or other intervention or the purposes of paragraphs (c)(9)(iv)(B) The safety and effectiveness of (drug name)
resuscitation of the newborn will be through (c)(9)(iv)(H) of this section, the have been established in the age groups ___
necessary, and the effect of the drug on terms pediatric population(s) and to ___ (note any limitations, e.g., no data for
the later growth, development, and pediatric patient(s) are defined as the pediatric patients under 2, or only applicable
functional maturation of the child. If pediatric age group, from birth to 16 to certain indications approved in adults).
any information required under this years, including age groups often called Use of (drug name) in these age groups is
subsection is unknown, it must state neonates, infants, children, and supported by evidence from adequate and
that the information is unknown. well-controlled studies of (drug name) in
adolescents. adults with additional data (insert wording
(iii) 8.3 Nursing mothers. (A) If a drug (B) If there is a specific pediatric that accurately describes the data submitted
is absorbed systemically, this subsection indication different from those to support a finding of substantial evidence
must contain, if known, information approved for adults that is supported by of effectiveness in the pediatric population).
about excretion of the drug in human adequate and well-controlled studies in (2) Data summarized in the preceding
milk and effects on the nursing infant. the pediatric population, it must be prescribed statement in this subsection
Pertinent adverse effects observed in described under the ‘‘Indications and must be discussed in more detail, if
animal offspring must be described. Usage’’ section, and appropriate appropriate, under the ‘‘Clinical
Pharmacology’’ or the ‘‘Clinical an increased risk of toxic effects to such differences, the ‘‘Geriatric use’’
Studies’’ section. For example, pediatric neonates or other pediatric subgroups, a subsection must include the following
pharmacokinetic or pharmacodynamic special note of this risk must be made, statement:
studies and dose response information generally in the ‘‘Contraindications’’ or Clinical studies of (name of drug) did
should be described in the ‘‘Clinical ‘‘Warnings and Precautions’’ section. not include sufficient numbers of
Pharmacology’’ section. Pediatric dosing (v) 8.5 Geriatric use. (A) A specific subjects aged 65 and over to determine
instructions must be included in the geriatric indication, if any, that is whether they respond differently from
‘‘Dosage and Administration’’ section. supported by adequate and well- younger subjects. Other reported
Any differences between pediatric and controlled studies in the geriatric clinical experience has not identified
adult responses, need for specific population must be described under the differences in responses between the
monitoring, dosing adjustments, and ‘‘Indications and Usage’’ section, and elderly and younger patients. In general,
any other information related to safe appropriate geriatric dosage must be dose selection for an elderly patient
and effective use of the drug in pediatric stated under the ‘‘Dosage and should be cautious, usually starting at
patients must be cited briefly in the Administration’’ section. The ‘‘Geriatric the low end of the dosing range,
‘‘Pediatric use’’ subsection and, as use’’ subsection must cite any reflecting the greater frequency of
appropriate, in the ‘‘Contraindications,’’ limitations on the geriatric indication, decreased hepatic, renal, or cardiac
‘‘Warnings and Precautions,’’ and need for specific monitoring, specific function, and of concomitant disease or
‘‘Dosage and Administration’’ sections. hazards associated with the geriatric other drug therapy.
(E) If the requirements for a finding of indication, and other information (2) If clinical studies (including
substantial evidence to support a related to the safe and effective use of studies that are part of marketing
pediatric indication or a pediatric use the drug in the geriatric population. applications and other relevant studies
statement have not been met for a Unless otherwise noted, information available to the sponsor that have not
particular pediatric population, the contained in the ‘‘Geriatric use’’ been submitted in the sponsor’s
‘‘Pediatric use’’ subsection must contain subsection must pertain to use of the applications) included enough elderly
an appropriate statement such as drug in persons 65 years of age and subjects to make it likely that
‘‘Safety and effectiveness in pediatric older. Data summarized in this differences in safety or effectiveness
patients below the age of (__) have not subsection must be discussed in more between elderly and younger subjects
been established.’’ If use of the drug in detail, if appropriate, under ‘‘Clinical would have been detected, but no such
this pediatric population is associated Pharmacology’’ or the ‘‘Clinical differences (in safety or effectiveness)
with a specific hazard, the hazard must Studies’’ section. As appropriate, this were observed, and other reported
be described in this subsection, or, if information must also be contained in clinical experience has not identified
appropriate, the hazard must be stated the ‘‘Warnings and Precautions’’ and/or such differences, the ‘‘Geriatric use’’
in the ‘‘Contraindications’’ or ‘‘Contraindications’’ section(s). subsection must contain the following
‘‘Warnings and Precautions’’ section (B) Specific statements on geriatric statement:
and this subsection must refer to it. use of the drug for an indication Of the total number of subjects in clinical
(F) If the requirements for a finding of approved for adults generally, as studies of (name of drug), __ percent were 65
substantial evidence to support a distinguished from a specific geriatric and over, while __ percent were 75 and over.
pediatric indication or a pediatric use indication, must be contained in the (Alternatively, the labeling may state the total
statement have not been met for any ‘‘Geriatric use’’ subsection and must number of subjects included in the studies
pediatric population, this subsection reflect all information available to the who were 65 and over and 75 and over.) No
overall differences in safety or effectiveness
must contain the following statement: sponsor that is relevant to the
were observed between these subjects and
‘‘Safety and effectiveness in pediatric appropriate use of the drug in elderly younger subjects, and other reported clinical
patients have not been established.’’ If patients. This information includes experience has not identified differences in
use of the drug in premature or neonatal detailed results from controlled studies responses between the elderly and younger
infants, or other pediatric subgroups, is that are available to the sponsor and patients, but greater sensitivity of some older
associated with a specific hazard, the pertinent information from well- individuals cannot be ruled out.
hazard must be described in this documented studies obtained from a (3) If evidence from clinical studies
subsection, or, if appropriate, the hazard literature search. Controlled studies and other reported clinical experience
must be stated in the include those that are part of the available to the sponsor indicates that
‘‘Contraindications’’ or ‘‘Warnings and marketing application and other use of the drug in elderly patients is
Precautions’’ section and this subsection relevant studies available to the sponsor associated with differences in safety or
must refer to it. that have not been previously submitted effectiveness, or requires specific
(G) If the sponsor believes that none in the investigational new drug monitoring or dosage adjustment, the
of the statements described in application, new drug application, ‘‘Geriatric use’’ subsection must contain
paragraphs (c)(9)(iv)(B) through biologics license application, or a a brief description of observed
(c)(9)(iv)(F) of this section are supplement or amendment to one of differences or specific monitoring or
appropriate or relevant to the labeling of these applications (e.g., postmarketing dosage requirements and, as
a particular drug, the sponsor must studies or adverse drug reaction appropriate, must refer to more detailed
provide reasons for omission of the reports). The ‘‘Geriatric use’’ subsection discussions in the ‘‘Contraindications,’’
statements and may propose alternative must contain the following statement(s) ‘‘Warnings and Precautions,’’ ‘‘Dosage
statement(s). FDA may permit use of an or reasonable alternative, as applicable, and Administration,’’ or other sections.
alternative statement if FDA determines taking into account available (C)(1) If specific pharmacokinetic or
that no statement described in those information: pharmacodynamic studies have been
paragraphs is appropriate or relevant to (1) If clinical studies did not include carried out in the elderly, they must be
the drug’s labeling and that the sufficient numbers of subjects aged 65 described briefly in the ‘‘Geriatric use’’
alternative statement is accurate and and over to determine whether elderly subsection and in detail under the
appropriate. subjects respond differently from ‘‘Clinical Pharmacology’’ section. The
(H) If the drug product contains one younger subjects, and other reported ‘‘Clinical Pharmacology’’ and ‘‘Drug
or more inactive ingredients that present clinical experience has not identified Interactions’’ sections ordinarily contain
information on drug/disease and drug/ (ii) 9.2 Abuse. This subsection must or, for biological products, the proper
drug interactions that is particularly state the types of abuse that can occur name (as defined in § 600.3 of this
relevant to the elderly, who are more with the drug and the adverse reactions chapter) and any appropriate
likely to have concomitant illness and to pertinent to them, and must identify descriptors;
use concomitant drugs. particularly susceptible patient (B) The type of dosage form(s) and the
(2) If a drug is known to be populations. This subsection must be route(s) of administration to which the
substantially excreted by the kidney, the based primarily on human data and labeling applies;
‘‘Geriatric use’’ subsection must include human experience, but pertinent animal (C) The same qualitative and/or
the statement: data may also be used. quantitative ingredient information as
This drug is known to be substantially (iii) 9.3 Dependence. This subsection required under § 201.100(b) for drug
excreted by the kidney, and the risk of must describe characteristic effects labels or §§ 610.60 and 610.61 of this
adverse reactions to this drug may be greater resulting from both psychological and chapter for biological product labels;
in patients with impaired renal function. physical dependence that occur with (D) If the product is sterile, a
Because elderly patients are more likely to the drug and must identify the quantity statement of that fact;
have decreased renal function, care should be (E) The pharmacological or
taken in dose selection, and it may be useful
of the drug over a period of time that
may lead to tolerance or dependence, or therapeutic class of the drug;
to monitor renal function. (F) For drug products other than
(D) If use of the drug in the elderly both. Details must be provided on the
adverse effects of chronic abuse and the biological products, the chemical name
appears to cause a specific hazard, the and structural formula of the drug; and
hazard must be described in the effects of abrupt withdrawal. Procedures
necessary to diagnose the dependent (G) If the product is radioactive, a
‘‘Geriatric use’’ subsection, or, if statement of the important nuclear
appropriate, the hazard must be stated state and the principles of treating the
effects of abrupt withdrawal must be physical characteristics, such as the
in the ‘‘Contraindications’’ or principal radiation emission data,
‘‘Warnings and Precautions’’ section, described.
(11) 10 Overdosage. This section must external radiation, and physical decay
and the ‘‘Geriatric use’’ subsection must characteristics.
be based on human data. If human data
refer to those sections. (ii) If appropriate, other important
are unavailable, appropriate animal and
(E) Labeling under paragraphs chemical or physical information, such
in vitro data may be used. The following
(c)(9)(v)(A) through (c)(9)(v)(C) of this as physical constants or pH, must be
specific information must be provided:
section may include statements, if they (i) Signs, symptoms, and laboratory stated.
are necessary for safe and effective use findings associated with an overdosage (13) 12 Clinical pharmacology. (i)
of the drug, and reflect good clinical of the drug; This section must contain information
practice or past experience in a (ii) Complications that can occur with relating to the human clinical
particular situation, e.g., for a sedating the drug (for example, organ toxicity or pharmacology and actions of the drug in
drug, it could be stated that: delayed acidosis); humans. Pharmacologic information
Sedating drugs may cause confusion and (iii) Concentrations of the drug in based on in vitro data using human
over-sedation in the elderly; elderly patients biomaterials or pharmacologic animal
biologic fluids associated with toxicity
generally should be started on low doses of models, or relevant details about in vivo
(name of drug) and observed closely. or death; physiologic variables
influencing excretion of the drug, such study designs or results (e.g., drug
(F) If the sponsor believes that none interaction studies), may be included in
of the requirements described in as urine pH; and factors that influence
the dose response relationship of the this section if essential to understand
paragraphs (c)(9)(v)(A) through dosing or drug interaction information
(c)(9)(v)(E) of this section are drug, such as tolerance. The
pharmacokinetic data given in the presented in other sections of the
appropriate or relevant to the labeling of labeling. This section must include the
a particular drug, the sponsor must ‘‘Clinical Pharmacology’’ section also
may be referenced here, if applicable to following subsections:
provide reasons for omission of the (A) 12.1 Mechanism of action. This
statements and may propose an overdoses;
(iv) The amount of the drug in a single subsection must summarize what is
alternative statement. FDA may permit known about the established
dose that is ordinarily associated with
omission of the statements if FDA mechanism(s) of the drug’s action in
symptoms of overdosage and the
determines that no statement described humans at various levels (e.g., receptor,
amount of the drug in a single dose that
in those paragraphs is appropriate or membrane, tissue, organ, whole body). If
is likely to be life threatening;
relevant to the drug’s labeling. FDA may (v) Whether the drug is dialyzable; the mechanism of action is not known,
permit use of an alternative statement if and this subsection must contain a statement
the agency determines that such (vi) Recommended general treatment about the lack of information.
statement is accurate and appropriate. procedures and specific measures for (B) 12.2 Pharmacodynamics. This
(vi) Additional subsections. support of vital functions (e.g., proven subsection must include a description of
Additional subsections may be antidotes, gastric lavage, forced diuresis, any biochemical or physiologic
included, as appropriate, if sufficient or as per Poison Control Center). Such pharmacologic effects of the drug or
data are available concerning the use of recommendations must be based on data active metabolites related to the drug’s
the drug in other specified available for the specific drug or clinical effect in preventing, diagnosing,
subpopulations (e.g., renal or hepatic experience with pharmacologically mitigating, curing, or treating disease, or
impairment). related drugs. Unqualified those related to adverse effects or
(10) 9 Drug abuse and dependence. recommendations for which data are toxicity. Exposure-response
This section must contain the following lacking for the specific drug or class of relationships (e.g., concentration-
information, as appropriate: drugs must not be stated. response, dose-response) and time
(i) 9.1 Controlled substance. If the (12) 11 Description. (i) This section course of pharmacodynamic response
drug is controlled by the Drug must contain: (including short-term clinical response)
Enforcement Administration, the (A) The proprietary name and the must be included if known. If this
schedule in which it is controlled must established name, if any, as defined in information is unknown, this subsection
be stated. section 502(e)(2) of the act, of the drug must contain a statement about the lack
of information. Detailed dosing or shown by adequate and well-controlled well-controlled as described in

monitoring recommendations based on studies, as defined in § 314.126(b) of § 314.126(b) of this chapter and must
pharmacodynamic information that this chapter, to be necessary for the safe not imply or suggest indications or uses
appear in other sections (e.g., ‘‘Warnings and effective use may be included in or dosing regimens not stated in the
and Precautions’’ or ‘‘Dosage and this section only if a waiver is granted ‘‘Indications and Usage’’ or ‘‘Dosage and
Administration’’) must not be repeated under § 201.58 or § 314.126(c) of this Administration’’ section. For biological
in this subsection, but the location of chapter. products, any clinical study that is
such recommendations must be (14) 13 Nonclinical toxicology. This discussed that relates to an indication
referenced. section must contain the following for or use of the biological product must
(C) 12.3 Pharmacokinetics. This subsections as appropriate: constitute or contribute to substantial
subsection must describe the clinically (i) 13.1 Carcinogenesis, mutagenesis, evidence and must not imply or suggest
significant pharmacokinetics of a drug impairment of fertility. This subsection indications or uses or dosing regimens
or active metabolites, (i.e., pertinent must state whether long term studies in not stated in the ‘‘Indications and
absorption, distribution, metabolism, animals have been performed to Usage’’ or ‘‘Dosage and Administration’’
and excretion parameters). Information evaluate carcinogenic potential and, if section.
regarding bioavailability, the effect of so, the species and results. If results (ii) Any discussion of a clinical study
food, minimum concentration (Cmin), from reproduction studies or other data that relates to a risk from the use of the
maximum concentration (Cmax), time to in animals raise concern about drug must also refer to the other
maximum concentration (Tmax), area mutagenesis or impairment of fertility in sections of the labeling where the risk
under the curve (AUC), pertinent half- either males or females, this must be is identified or discussed.
lives (t1/2), time to reach steady state, described. Any precautionary statement (16) 15 References. When prescription
extent of accumulation, route(s) of on these topics must include practical, drug labeling must summarize or
elimination, clearance (renal, hepatic, relevant advice to the prescriber on the otherwise rely on a recommendation by
total), mechanisms of clearance (e.g., significance of these animal findings. an authoritative scientific body, or on a
specific enzyme systems), drug/drug Human data suggesting that the drug standardized methodology, scale, or
and drug/food (e.g., dietary may be carcinogenic or mutagenic, or technique, because the information is
supplements, grapefruit juice) suggesting that it impairs fertility, as important to prescribing decisions, the
pharmacokinetic interactions (including described in the ‘‘Warnings and labeling may include a reference to the
inhibition, induction, and genetic Precautions’’ section, must not be source of the information.
characteristics), and volume of included in this subsection of the (17) 16 How supplied/storage and
distribution (Vd) must be presented if labeling. handling. This section must contain
clinically significant. Information (ii) 13.2 Animal toxicology and/or information on the available dosage
regarding nonlinearity in pharmacology. Significant animal data forms to which the labeling applies and
pharmacokinetic parameters, changes in necessary for safe and effective use of for which the manufacturer or
pharmacokinetics over time, and the drug in humans that is not distributor is responsible. The
binding (plasma protein, erythrocyte) incorporated in other sections of information must include, as
parameters must also be presented if labeling must be included in this appropriate:
clinically significant. This section must section (e.g., specifics about studies (i) The strength or potency of the
also include the results of used to support approval under dosage form in metric system (e.g., 10
pharmacokinetic studies (e.g., of § 314.600 or § 601.90 of this chapter, the milligram tablets) and, if the apothecary
metabolism or interaction) that establish absence of chronic animal toxicity data system is used, a statement of the
the absence of an effect, including for a drug that is administered over strength in parentheses after the metric
pertinent human studies and in vitro prolonged periods or is implanted in the designation;
data. Dosing recommendations based on body). (ii) The units in which the dosage
clinically significant factors that change (15) 14 Clinical studies. This section form is ordinarily available for
the product’s pharmacokinetics (e.g., must discuss those clinical studies that prescribing by practitioners (e.g., bottles
age, gender, race, hepatic or renal facilitate an understanding of how to of 100);
dysfunction, concomitant therapy) that use the drug safely and effectively. (iii) Appropriate information to
appear in other sections (e.g., ‘‘Warnings Ordinarily, this section will describe the facilitate identification of the dosage
and Precautions,’’ ‘‘Dosage and studies that support effectiveness for the forms, such as shape, color, coating,
Administration’’ or ‘‘Use in Specific labeled indication(s), including scoring, imprinting, and National Drug
Populations’’) must not be repeated in discussion of study design, population, Code number; and
this subsection, but the location of such endpoints, and results, but must not (iv) Special handling and storage
recommendations must be referenced. include an encyclopedic listing of all, or conditions.
(ii) Data that demonstrate activity or even most, studies performed as part of (18) 17 Patient counseling
effectiveness in in vitro or animal tests the product’s clinical development information. This section must contain
and that have not been shown by program. If a specific important clinical information necessary for patients to use
adequate and well-controlled clinical study is mentioned in any section of the the drug safely and effectively (e.g.,
studies to be pertinent to clinical use labeling required under §§ 201.56 and precautions concerning driving or the
may be included under this section only 201.57 because the study is essential to concomitant use of other substances that
under the following circumstances: an understandable presentation of the may have harmful additive effects). Any
(A) In vitro data for anti-infective information in that section of the FDA-approved patient labeling must be
drugs may be included if the data are labeling, any detailed discussion of the referenced in this section and the full
immediately preceded by the statement study must appear in this section. text of such patient labeling must be
‘‘The following in vitro data are (i) For drug products other than reprinted immediately following this
available but their clinical significance biological products, any clinical study section or, alternatively, accompany the
is unknown.’’ that is discussed in prescription drug prescription drug labeling. Any FDA-
(B) For other classes of drugs, in vitro labeling that relates to an indication for approved patient labeling printed
and animal data that have not been or use of the drug must be adequate and immediately following this section or
accompanying the labeling is subject to full prescribing information by the supported by substantial evidence of
the type size requirements in paragraph inclusion of a vertical line on the left effectiveness. Indications or uses must
(d)(6) of this section, except for a edge of the new or modified text. not be implied or suggested in other
Medication Guide to be detached and (10) For the information required by sections of labeling if not included in
distributed to patients in compliance paragraph (b) of this section, each this section.
with § 208.24 of this chapter. section heading must be in bold print. * * * * *
Medication Guides for distribution to Each subheading within a section must (f) * * *
patients are subject to the type size be indented and not bolded. (2) Information for patients. This
requirements set forth in § 208.20 of this ■ 4. Section 201.58 is revised to read as subsection must contain information
chapter. follows: necessary for patients to use the drug
(d) Format requirements. All labeling safely and effectively (e.g., precautions
information required under paragraphs § 201.58 Waiver of labeling requirements.
concerning driving or the concomitant
(a), (b), and (c) of this section must be An applicant may ask the Food and
use of other substances that may have
printed in accordance with the Drug Administration to waive any
harmful additive effects). Any FDA-
following specifications: requirement under §§ 201.56, 201.57,
approved patient labeling must be
(1) All headings and subheadings and 201.80. A waiver request must be
referenced in this section and the full
required by paragraphs (a) and (c) of this submitted in writing to the Director (or
text of such patient labeling must be
section must be highlighted by bold the Director’s designee), Center for Drug
reprinted immediately following the last
type that prominently distinguishes the Evaluation and Research, Food and
section of labeling or, alternatively,
headings and subheadings from other Drug Administration, 5600 Fishers
accompany the prescription drug
labeling information. Reverse type is not Lane, Rockville, MD 20857, or, if
labeling. The type size requirement for
permitted as a form of highlighting. applicable, the Director (or the
(2) A horizontal line must separate the the Medication Guide set forth in
Director’s designee), Center for Biologics
information required by paragraphs (a), § 208.20 of this chapter does not apply
Evaluation and Research, Food and
(b), and (c) of this section. to the Medication Guide that is
Drug Administration, 1401 Rockville
(3) The headings listed in paragraphs reprinted in or accompanying the
Pike, suite 200 North, Rockville, MD
(a)(5) through (a)(13) of this section prescription drug labeling unless such
20852–1448. The waiver must be
must be presented in the center of a Medication Guide is to be detached and
granted or denied in writing by the
horizontal line. distributed to patients in compliance
Director or the Director’s designee.
(4) If there are multiple subheadings with § 208.24 of this chapter.
listed under paragraphs (a)(4) through § 201.59 [Removed] * * * * *
(a)(13) of this section, each subheading ■ 5. Section 201.59 is removed. (j) Dosage and administration. * * *
must be preceded by a bullet point. ■ 6. Newly redesignated § 201.80 is
Dosing regimens must not be implied or
(5) The labeling information required suggested in other sections of labeling if
amended by:
by paragraphs (a)(1) through (a)(4), a. Revising the section heading; not included in this section. * * *
(a)(11)(ii) through (a)(11)(iv), and (a)(14) b. Amending paragraphs (b)(2)(ii), * * * * *
of this section must be in bold print. (c)(3)(i), (c)(3)(v), and (g)(4) by removing (m) * * *
(6) The letter height or type size for
the phrase ‘‘§ 314.126(b)’’ the second (1)(i) If the clinical study is cited in
all labeling information, headings, and
time it appears and by adding in its the labeling in place of a detailed
subheadings set forth in paragraphs (a),
place the phrase ‘‘§ 314.126(c)’’; discussion of data and information
(b), and (c) of this section must be a c. Removing the phrase ‘‘induced concerning an indication for use of the
minimum of 8 points, except for emesis,’’ in paragraph (i)(6); drug, the clinical study must constitute
labeling information that is on or within d. Revising paragraphs (c)(2), (f)(2), an adequate and well-controlled study
the package from which the drug is to and (m)(1); and as described in § 314.126(b) of this
be dispensed, which must be a e. Adding a new sentence after the chapter, except for biological products,
minimum of 6 points. first sentence of paragraph (j).
(7) The identifying numbers required and must not imply or suggest
The additions and revisions read as indications or uses or dosing regimens
by § 201.56(d) and paragraphs (c)(1) follows:
through (c)(18) of this section must be not stated in the ‘‘Indications and
presented in bold print and must Usage’’ or ‘‘Dosage and Administration’’
§ 201.80 Specific requirements on content
precede the heading or subheading by at and format of labeling for human section.
least two square em’s (i.e., two squares prescription drug and biological products; (ii) When prescription drug labeling
of the size of the letter ‘‘m’’ in 8 point older drugs not described in § 201.56(b)(1). must summarize or otherwise rely on a
type). * * * * * recommendation by an authoritative
(8) The information required by (c) * * * scientific body, or on a standardized
paragraph (a) of this section, not (2)(i) For drug products other than methodology, scale, or technique,
including the information required biological products, all indications because the information is important to
under paragraph (a)(4) of this section, listed in this section must be supported prescribing decisions, the labeling may
must be limited in length to an amount by substantial evidence of effectiveness include a reference to the source of the
that, if printed in 2 columns on a based on adequate and well-controlled information.
standard sized piece of typing paper (8 studies as defined in § 314.126(b) of this * * * * *
1/2 by 11 inches), single spaced, in 8 chapter unless the requirement is ■ 7. Section 201.100 is amended by
point type with 1/2-inch margins on all waived under § 201.58 or § 314.126(c) of revising paragraph (d)(3) to read as
sides and between columns, would fit this chapter. Indications or uses must follows:
on one-half of the page. not be implied or suggested in other

(9) Sections or subsections of labeling sections of labeling if not included in § 201.100 Prescription drugs for human
that are identified as containing recent this section. use.
major changes under paragraph (a)(5) of (ii) For biological products, all * * * * *
this section must be highlighted in the indications listed in this section must be (d) * * *
(3) The information required, and in (iii) Changes in the labeling, except (f) * * *
the format specified, by §§ 201.56, for changes to the information required (1) * * * An applicant cannot use
201.57, and 201.80. in § 201.57(a) of this chapter (which paragraph (f)(2) of this section to make
* * * * * must be made pursuant to paragraph any change to the information required
(b)(2)(v)(C) of this section), to in § 201.57(a) of this chapter. An
PART 314—APPLICATIONS FOR FDA accomplish any of the following: applicant may report the minor changes
APPROVAL TO MARKET A NEW DRUG * * * * * to the information specified in
(d) * * * paragraph (f)(3)(i)(D) of this section in
■ 8. The authority citation for 21 CFR (2) * * * an annual report. * * *
part 314 continues to read as follows: (x) An editorial or similar minor (2) * * *
Authority: 21 U.S.C. 321, 331, 351, 352, change in labeling, including a change (i) An applicant shall submit, at the
353, 355, 355a, 356, 356a, 356b, 356c, 371, to the information allowed by
374, 379e. time such change is made, a supplement
paragraphs (b)(2)(v)(C)(1) and (2) of this for any change in the package insert,
■ 9. Section 314.70 is amended by: section.
a. Removing from paragraph package label, or container label, except
* * * * * for changes to the package insert
(b)(2)(v)(B) the phrase ‘‘(b)(8)(iv) of this
chapter.’’ and adding in its place the required in § 201.57(a) of this chapter
PART 601—LICENSING (which must be made pursuant to
phrase ‘‘(b)(8)(iv) of this chapter; and’’;
b. Adding paragraph (b)(2)(v)(C); ■ 10. The authority cite for 21 CFR part paragraph (f)(1) of this section), to
c. Revising the introductory text of 601 continues to read as follows: accomplish any of the following:
paragraph (c)(6)(iii); and Authority: 15 U.S.C. 1451–1561; 21 U.S.C.
* * * * *
d. Revising paragraph (d)(2)(x). 321, 351, 352, 353, 355, 356b, 360, 360c– (f) * * *
The additions and revisions read as 360f, 360h–360j, 371, 374, 379e, 381; 42 (3) * * *
follows: U.S.C. 216, 241, 262, 263, 264; sec 122, Pub. (i) * * *
L. 105–115, 111 Stat. 2322 (21 U.S.C. 355
§ 314.70 Supplements and other changes note). (D) A change to the information
to an approved application. required in § 201.57(a) of this chapter as
■ 11. Section 601.12 is amended by:
* * * * * a. Adding two sentences after the follows:
(b) * * * second sentence and before the third (1) Removal of a listed section(s)
(2) * * * sentence in paragraph (f)(1); specified in § 201.57(a)(5) of this
(v) * * * b. Revising the introductory text of chapter; and
(C) Any change to the information (2) Changes to the most recent
paragraph (f)(2)(i);
required by § 201.57(a) of this chapter, c. Removing from paragraph revision date of the labeling as specified
with the following exceptions that may (f)(3)(i)(B) the word ‘‘and’’; in § 201.57(a)(15) of this chapter.
be reported in an annual report under d. Removing from paragraph
paragraph (d)(2)(x) of this section: * * * * *
(f)(3)(i)(C) the phrase ‘‘Medication
(1) Removal of a listed section(s) Guide.’’ and adding in its place the
Dated: December 7, 2005.
specified in § 201.57(a)(5) of this phrase ‘‘Medication Guide; and’’; and Andrew C. von Eschenbach,
chapter; and e. Adding paragraph (f)(3)(i)(D). Acting Commissioner of Food and Drugs.
(2) Changes to the most recent The additions and revisions read as
revision date of the labeling as specified Dated: December 7, 2005.
follows: Michael O. Leavitt,
in § 201.57(a)(15) of this chapter.
* * * * * § 601.12 Changes to an approved Secretary of Health and Human Services.
(c) * * * application. [FR Doc. 06–545 Filed 1–18–06; 10:28 am]
(6) * * * * * * * * BILLING CODE 4160–01–C

Rule: Human Drugs and Biological Products: Prescription Drug Products Labeling Requirements

Загружено:

Сведения о документе

Оригинальное название

Авторское право

Доступные форматы

Поделиться этим документом

Поделиться или встроить документ

Параметры публикации

Этот документ был вам полезен?

Это неприемлемый материал?

Авторское право:

Доступные форматы

Rule: Human Drugs and Biological Products: Prescription Drug Products Labeling Requirements

Загружено:

Авторское право:

Доступные форматы

Tuesday,

January 24, 2006

21 CFR Parts 201, 314, and 601

and thus are subject to these regulations. (See

TABLE 2.—FDA-APPROVED PATIENT LABELING WITH PRESCRIPTION DRUG LABELING

201.55, Container Labels

201.57(c)(12)(i)(D), the labeling (106 and 107)

201.56(a)(2) General Requirement

201.56(d) Product Title

201.56(d)(4) Format of Contents

201.56(d)(5) Pediatric Risk Information

201.57 and 201.80 Unsubstantiated Claims

201.57 Promotional Labeling

201.57(a)(1) Highlights Limitation Statement

201.57(a)(3) Inverted Black Triangle Symbol

201.57(a)(4) Boxed Warning

201.57(a)(5) Recent Labeling Changes

201.57(a)(6) Indications and Usage

201.57(a)(8) How Supplied

201.57(a)(11) Adverse Reactions

201.58 Waiver Provision

201.57(c)(3) Dosage and Administration

201.57(c)(4) and 201.57(c)(17) How Supplied/Storage and Handling

201.57(c)(7) Adverse Reactions

201.57(c)(9) Use in Specific Populations

201.57(c)(13)(ii) and 201.80(b)(2) In Vitro Data for Anti-infectives

201.57(c)(18) and 201.80(f)(2) Patient Counseling Information

201.57(d)(6) Font size

201.57(c)(16) and 201.80(l) References

TABLE 5.—IMPLEMENTATION PLAN

Applications submitted on or after June 30, 2006 Time of submission

Precautions (Gen- Warnings and Pre-

of such amendments unless there is a direct and

reinforce the misconception that • Clinical pharmacology (proposed section.

requirements. information, and some contains only ‘‘Patient Counseling Information’’

New Format (§ 201.57)

Any FDA-approved patient labeling except a Medication Minimum 6-point type

Medication Guide that is for distribution to patients Minimum 10-point type

Any FDA-approved patient labeling except a Medication Minimum 8-point type

Medication Guide that is for distribution to patients Minimum 10-point type

Old Format (§ 201.80)

Any FDA-approved patient labeling except a Medication No minimum requirement

Medication Guide that is for distribution to patients Minimum 10-point type

qualify as warnings compelled by description and respondent description

Annual burden associated with

Additional annual burden associ-

Total 3,349 358,343

Burden as a result of having Year 1 only 18 4.44 80 38 3,040 $400,000

Total 143,040 Up to $8.7

information based on a thorough analysis of

TABLE 9.—SUMMARY OF PROJECTED QUANTIFIABLE BENEFITS AND COSTS OVER 10 YEARS1

Total Potential Benefits 510 to 580 420 to 480 330 to 380

Total Costs 140 120 90

of the effective date of the final rule).

12 On average, physicians work 47 weeks per year

TABLE 10.—VALUE OF HEALTH CARE PRACTITIONER TIME SAVED1

Total 120 30 150 120 90

0.42 120 140 97 120

0.5 150 180 120 150

1.0 300 360 240 290

5.0 1,500 1,800 1,200 1,500

1 0.2 0.8 1.2 2.2

2 0.0 0.8 1.2 1.9