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li U.S. FOOD & DRUG

ADMINISTRAT I ON

Stephen Sherman
Insys Therapeutics, Inc.
1333 South Spectrum Blvd., Suite 100
Chandler, AZ 85286

RE: Docket No. FDA-2017-P-6411 APR 0 6 ?Q~P

Dear Mr. Sherman:

This letter responds to your citizen petition received on November 8, 2017 (Petition). In that
Petition, you request that the Food and Drug Administration (FDA or the Agency):

(1) Decline to receive or approve any [abbreviated new drug application (ANDA)] for
generic dronabinol oral solution that relies on SYNDROS as the Reference Listed
Drug ("RLD" ) if the ANDA relies on a waiver in lieu of establi shing in vivo
bioequivalence to SYNDROS;

(2) Require that ANDA applicants for generic versions of SYNDROS include fed and
fasted state bioequivalence studies.

Petition at I.

FDA has considered the information submitted in the Petition, the comments submitted to the
docket, 1 and other relevant data. Based on our review of this information and for the reasons
described below, the Petition is denied.

I. BACKGROUND

A. Syndros

FDA approved new drug application (NDA) 205525 for Syndros (dronabinol) oral solution, 5
milligrams per milliliter, on March 23, 2017. The Syndros NDA, held by Insys Development
Company, Inc., was submitted through the pathway described in section 505(b)(2) of the Federal
Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(b)(2)). NDA 205525 relied upon
FDA's finding of safety and effectiveness for Marino! (dronabinol) capsules, for oral use, NDA
018651.

Syndros is approved for use in adults for the treatment of (1) anorexia associated with weight

1
E.g., December 8, 2017, Comment to Docket No. FDA-2017-P-64 11 , submitted by Latham & Watkins LLP on
behalf of Par Pharmaceutical, Inc.

U.S. Food & Drug Adrrinis tration

10903 New Harrpshire Avenue
Silver Spring, MD 20993
w ww.fda.gov
Docket No. FDA-2017-P-6411
Page2

loss in patients with Acquired Immune Deficiency Syndrome (AIDS), and (2) nausea and
vomiting associated with cancer chemotherapy in patients who have failed to respond adequately
to conventional antiemetic treatments. The Syndros labeling directs that the first dose be
administered at least 30 minutes prior to eating.2

Syndros is the first approved oral solution formulation of dronabinol, a synthetic delta-9-
tetrahydrocannabinol (delta-9-THC). Delta-9-tetrahydrocannabinol is a naturally occuning
component of Cannabis sativa L. (marijuana). Syndros is classified as a Schedule II drug under
the Controlled Substances Act (21 U.S.C. 812).

Dronabinol is insoluble in water. Unlike Marinol ( dronabinol) capsules, for oral use, which is
formulated in sesame oil, Syndros (dronabinol) oral solution is formulated in an aqueous
cosolvent system. Syndros is systemically absorbed. Its labeling states the following:
"Dronabinol (delta-9-THC) is almost completely absorbed (90 to 95%) after single oral doses.
Due to the combined effects of first pass hepatic metabolism and high lipid solubility, only 10 to
20% of the administered dose reaches the systemic circulation." The Syndros labeling also
explains that "Dronabinol undergoes extensive first-pass hepatic metabolism, primarily by
hydroxylation, yielding both active and inactive metabolites. The major metabolite (11-hydroxy-
delta-9-THC) is pharmacologically active."

B. Applicable Statutory and Regulatory Framework

1. ANDAs

The Drug Price Competition and Patent Tenn Restoration Act of 1984 (Public Law 98-417) (the
Hatch-Waxman Amendments) amended the FD&C Act to, among other things, add section
505G), which established an abbreviated approval pathway for generic drugs. 3 To obtain
approval, an ANDA applicant is not required to provide independent evidence of the safety and
effectiveness of the proposed generic drug product. Instead, the applicant relies on FDA' s
previous finding that the RLD is safe and effective. 4 The ANDA applicant must identify the
listed drug on which it seeks to rely, and with limited exceptions, a drug product described in an
ANDA must contain the same active ingredient, route of administration, dosage form, strength,
and (with certain permissible differences) labeling as the RLD. 5

2
The labeling for Syndros is available at
https://www.accessdata.fda.gov/drugsatfda_ docs/label/20 17/205 525s003lbl. pdf.
3For purposes of this response, the term generic drug refers to a new drug product for which approval is sought in
an ANDA submitted under section 505(j) of the FD&C Act.
4
An RLD is "the listed drug identified by FDA as the drug product upon which an appl icant relies in seeking
approval of its ANDA" (2 1 CFR 314.3). RLDs are identified in FDA ' s Approved.Drug Products With Therapeutic
Equivalence Evaluation (the Orange Book).
5 Section 505(j)(2)(A), (j)(2)(C), and (j)(4) of the FD&C Act; see also 21 CFR 314.94(a).
Docket No. FDA-2017-P-6411
Page 3

2. The Bioequivalence Requirement

An ANDA applicant must also demonstrate that its proposed generic drug is bioequivalent to the
RLD.6 Section 505(j)(8)(B)(i) of the FD&C Act states that a generic drug is bioequivalent to the
listed drug if:

the rate and extent of absorption of the drug do not show a significant difference from the
rate and extent of absorption of the listed drug when administered at the same molar dose
of the therapeutic ingredient under similar experimental conditions in either a single dose
or multiple doses ....7

A showing that the active ingredient in the proposed generic drug reaches the site of drug action
at a rate and to an extent not significantly different from that of the RLD, along with other
information required for approval, permits FDA to conclude that the proposed generic drug can
be expected to perfonn the same way in the body as the RLD. Bioequivalence testing
determines whether differences in formulation (e.g., differences in inactive ingredients) between
a proposed generic drug and the RLD have an effect on the rate and extent to which the active
ingredient becomes available at the site of action.

As discussed further below, the statute, regulations, and case law give FDA considerable
flexibility in determining how the bioequivalence requirement is met. The testing methods may
include in vivo data (data from a study on human subjects), in vitro data (data from laboratory
studies), or a combination of in vivo and in vitro data. 8 This flexibility is reflected in FDA ' s
regulations, which describe these types of evidence that may be used to establish bioequivalence:

FDA may require in vivo or in vitro testing, or both, to measure the bioavailability of a
drug product or establish the bioequivalence of specific drug products .... The selection
of the method used to meet an in vivo or in vitro testing requirement depends upon the
purpose of the study, the analytical methods available, and the nature of the drug product.
Applicants shall conduct bioavailability and bioequivalence testing using the most
accurate, sensitive, and reproducible approach available among those set forth in
paragraph (b) of this section. The method used must be capable of measuring

6See, e.g., section 505(j)(2)(A)(iv) of the FD&C Act (requiring "infonnation to show that the new drug is
bioequivalent to the listed drug"); § 314.94(a)(7) (requiring that an ANDA contain infonnation to show that the
drug product is bioequivalent to the RLD); and 21 CFR 314.127(a)(6)(i) (stating that FDA will refuse to
approve an ANDA if information submitted is insufficient to show that the drug product is bioequivalent to the
RLD referred to in the ANDA).
7
See also 2 1 CFR 314.3(b) and 320.23(b).
8
See section 505(j)(7)(A)(i)(III) of the FD&C Act; see also Schering C01p. v. FDA, 51 F.3d 390, 398 (3d Cir.
1995) (noting that this provision "vests the FDA with the discretion to determine whether in vitro or in vivo
[bioequivalence] studies, or both, will be required for the approval of generic drugs under the abbreviated
application processes").
Docket No. FDA-20 17-P-6411
Page4

bioavailability or establishing bioequivalence, as appropriate, for the product being

tested. 9

Section 320.24(b) (21 CFR 320.24(b)) of FDA' s regulations describes preferred methods for
demonstrating bioequivalence in general descending order of accuracy, sensitivity, and
reproducibility. The bioequivalence test methods include: (1) in vivo PK studies in whole blood,
plasma, serum, or other appropriate biological fluid or an in vitro test that has been correlated
with and is predictive of in vivo bioavailability data; (2) in vivo studies in which urinary
excretion of the active moiety and, when appropriate, its active metabolite(s) are measured; (3) in
vivo pharmacodynamic (PO) effect studies; (4) clinical endpoint studies; and (5) other in vitro
studies acceptable to FDA that ensure human in vivo bioavailability. 10 In addition, consistent
with section 505(j)(8)(C) of the FD&C Act, § 320.24(b)(6) ofthe regulations states that FDA has
the authority to use "[a]ny other approach deemed adequate by FDA to ... establish
bioequivalence." 11

The FD&C Act and FDA' s implementing regulations do not require in vivo studies for all
ANDAs in the first instance. If FDA determines that in vivo data is the appropriate means of
demonstrating bioequivalence for a product or product class, however, 21 CFR 320.21 (f)
provides that applicants may apply for a waiver of the in vivo requirement consistent with
§ 320.22 (21 CFR 320.22). 12 Section 320.22 in turn directs that FDA " shall" waive the in vivo
requirement upon a subsequent showing that the individual applicant's product meets certain
additional criteria. 13 Relevant for this discussion, FDA will "waive the requirement for the
submission of evidence obtained in vivo measuring the bioavailability or demonstrating the
bioequivalence" of the drug product if the product: (I) is an oral solution; (2) contains an active
drug ingredient in the same concentration and dosage form as the RLD; and (3) contains no
inactive ingredient or other change in formulation from the RLD "that may significantly affect
absorption of the active drug ingredient or active moiety for products that are systemically
absorbed, or that may significantly affect systemic or local availability for products intended to

9§ 320.24(a) (emphasis added). In the preamble to the final rule setting forth FDA 's reg ulations for ANDAs, the
Agency explained that, depending upon the drug, it would determine the appropriate bioequivalence methodology
on a case-by-case basis:
Bioequivalence can be established by pharmacodynamic measurement as well as by in vitro
techniques and bioequivalence studies with clinical endpoints. The preferred method for
establishment ofbioequivalence .. . is determined on a case-by-case basis, depending on the drug
under study.
"Abbreviated New Drug Application Regulations, Final Rule" (57 FR 17950 at 17972; Apr 28, 1992) (emphasis
added).
10
§ 320.24. Whereas a PK study measures the rate and the extent to which the drug is delivered to biological fluids
(generally the bloodstream), a PD study measures effects associated with the delivery of the active ingredient to the
site of action.
II§ 320.24(b)(6).
12
§ 320.2 1(f) (" Information to permit FDA to waive the submission of evidence measuring the in vivo
bioavailability or demonstrating the in vivo bioequivalence shall meet the criteria set forth in 320.22.").
13 § 320.22(a).
Docket No. FDA-2017-P-6411
Page 5

act locally." 14 Even in instances in which such additional criteria are met, however, FDA may,
for good cause, require in vivo data if the Agency determines that any differences between the
drug product and the RLD may affect the bioequivalence or bioavailability of the drug product. 15
Section 320.22 also provides that FDA "may" waive any Agency-imposed in vivo
bioequivalence data requirement for a particular product "for good cause ... if waiver is
compatible with the protection of the public health," underscoring FDA's discretion to determine
the most appropriate bioequivalence methodology for each product. 16

The Agency's authority to make bioequivalence determinations on a case-by-case basis using in

vivo, in vitro, or both types of data enables FDA to effectuate several long-recognized policies
that protect the public health: ( 1) refraining from unnecessary human research when other
methods of demonstrating bioequivalence meet the statutory and regulatory standards for
approval; 17 (2) permitting the Agency to use the latest scientific advances in approving drug
products; 18 (3) protecting the public by ensuring only safe and effective generic drugs are
approved for marketing; 19 and (4) making more safe and effective generic drugs available. 20

3. Receiving an ANDA

As described in our regulations, the Agency conducts an initial review of a submitted ANDA to
determine whether, as a threshold matter, it will "receive" the application for review. 21
"Receipt" is a term of art, and the Agency's receipt of an ANDA "means that FDA has made a
threshold determination that the abbreviated application is sufficiently complete to permit a

14
§ 320.22(b)(3). See, generally,§ 320.22(b)-(d) (providing additional categories of products for which waivers of
an in vivo data requirement may be sought).
15
§ 320.22(f).
16
§ 320.22(e).
17
21 CFR 320.25(a) (stating that a "guiding principle" for the conduct of an in vivo bioavailability study is "that no
unnecessary human research should be done"); " Abbreviated New Drug Application Regulations, Proposed Rule"
(54 FR 28872 at 28883; Jul I 0, 1989) (stating, in a discussion of§ 320.22, that "the [A]gency does not believe
Congress intended that unnecessary human research be conducted .. . if the [A]gency concludes that bioequivalence
can be demonstrated by in vitro tests, the [A]gency proposes to require only such tests rather than in vivo studies").
18
"Bioavailability and Bioequivalence Requirements: Procedures for Establishing a Bioequivalence Requirement"
( 42 FR 1624 at 1629; Jan 7, 1977) ("As with all new regulations relating to an evolving science, the
Commissioner reserves the right to consider other factors that may indicate the need to establish a
[bioeq u ivalence] requirement.").
19
Schering Corp. v. Sullivan, 782 F. Supp. 645, 650 (D.D.C. 1992) (noting that one underlying policy of the
Hatch-Waxman Amendments is to "ensure the safety of these drugs before they are substituted for their name-
brand counterparts").
20
Id. (stating that the purposes of the Hatch-Waxman Amendments are "to make more inexpensive generic drugs
available" and "to ensure the safety of these drugs"); Fisons Corp. v. Shalala, 860 F. Supp. 859, 866-67 (D.D.C.
1994) (concluding that the bioequivalence waiver provision "comports with the structure and broader policy
objectives of the Hatch-Waxman Act," including making safe and affordable generic drugs available).
21
See 21 CFR 314.10 l (b)(l).
 Docket No. FDA-2017-P-6411
Page 6

substantive review."22 This initial review focuses, in part, on whether the ANDA contains the
information required under section 505(j)(2)(A) of the FD&C Act. 23

The reasons for which FDA may in certain cases, and will in others, refuse to receive an ANDA
are generally set forth in § 314.1 Ol(d)-(e) of the Agency ' s regulations.24 If none of these reasons
applies, FDA generally will receive the application and notify the applicant in writing. 25 Receipt
of an ANDA is the first step in a complex, multi-disciplinary review of the application that
involves many rigorous scientific evaluations of the applicant's bioequivalence testing methods
and data, chemistry information, proposed product labeling, and manufacturing processes and
infonnation, among other things.

C. General Principles of Bioequivalence

For systemically acting drug products, the rate and extent of systemic absorption of the drug is
usually the most sensitive, accurate, and reliable indicator of the rate and extent to which the
active ingredient becomes available at the site of drug action. The determination of
bioequivalence of drug products whose primary mechanism of action depends on systemic
absorption generally rests on a comparison of drug and/or metabolite concentrations in an
accessible biological fluid, such as blood, after administration of a single dose or multiple doses
of each drug product to healthy volunteers.26

The choice of appropriate bioequivalence study design is based on the ability of the study to
compare the drug delivered by the two products at the particular site of action of the drug, and
Congress assigned this decision to FDA. Congress intended to grant FDA wide discretion to
establish bioequivalence standards on a drug-by-drug basis when it enacted the Hatch-Waxman
Amendments, and courts have recognized FDA's discretion to determine how the bioequivalence
requirement should be met for a product or class of products, as long as its determination is not
contrary to the governing statute and regulations and is based on a " reasonable and scientifically
supported criterion. " 27

22 ld.
23See section 505(j)(5)(B)(iv)(Il)(cc) of the FD&C Act (stating that an ANDA is "substantially complete" if, on its
face, it "is sufficientl y complete to permit a substantive review and contains all the information required by
paragraph (2)(A)").
24FDA "may" refuse to receive an ANDA if any of the deficiencies under § 3 14.10 l (d) apply. In contrast, the
Agency "will" refuse to receive an ANDA if any of the deficiencies under § 3 14. 10 1(e) apply. See § 314.101(d)-(e).
25 § 3 14.10l(b)(2).
26
Section 505(j)(8)(B) of the FD&C Act; see generally FDA guidance for industry Bioequivalence Studies with
Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA , available on the FDA Drugs guidance web page
at http:. www. fda.go' Drugs GuidanceComphance Regulatorylnfonnatio n Guidances default.htm.

27
Fisons Corp. , 860 F. Supp.at 865 (quoting Schering Corp., 782 F. Supp. at 65 1) ; see also Fisons Corp., 860 F.
Supp. at 866-67 ("[T]he factual determ ination of how bioequi valence is determined properly rests within the FDA 's
discretion.") ; Schering Co1p., 51 F.3d 390, 397-400 (3d Cir. 1995).
 Docket No. FDA-2017-P-6411
Page 7

D. Product Specific Recommendations

Our guidance for industry on Bioequivalence Recommendations for Specific Products 28 (Specific
Product Guidance) describes FDA's process for making available to the public FDA guidance on
the design ofbioequivalence studies for specific drug products. Prior to establishing the product-
specific guidance mechanism outlined in the Specific Product Guidance, the Agency provided
recommendations on the design ofbioequivalence studies for specific products on an individual
basis to parties who expressly requested such information, as is its practice in cases in which
product-specific guidances have not been published.

Currently, the Agency periodically publishes notices in the Federal Register announcing the
availability of draft, revised draft, and final versions of product-specific guidances. These
notices identify a comment period for the draft product-specific guidances. The draft and final
product-specific guidances are available on FDA's web site.

The Agency considers comments received on product-specific guidances in developing its final
guidances. As with Agency guidance in general, these product-specific guidances describe the
Agency's current thinking and should be viewed only as recommendations unless specific
regulatory or statutory requirements are cited. Applicants following our product-specific
guidances have an expectation that FDA will agree that their approach to establishing
bioequivalence is appropriate. However, applicants may confer with the Agency on use of
different approaches for establishing bioequivalence. Recommendations made in a draft or final
guidance do not bind the Agency or the public. Further, even in the absence of a product-
specific guidance, FDA has the authority to approve a product supported by bioequivalence data
that meet the statutory and regulatory requirements.

FDA has published a draft product-specific guidance on dronabinol oral capsules, first
recommended in February 2010 with a revised draft published in February 20 14 (Draft Guidance
on Dronabinol). 29 That draft guidance recommends that ANDA applicants seeking to establish
bioequivalence to dronabinol capsules conduct two in vivo studies, one under fasted conditions
and the other under fed conditions. In the field for "Analytes to measure," the draft guidance
lists dronabinol and its active metabolite, 11-hydroxy-delta-9-THC. FDA has not published a
draft or final product-specific guidance on dronabinol oral solution.

II. DISCUSSION

As stated above, the Petition asks FDA to decline to receive or approve any ANDA that relies
upon a waiver rather than establishing in vivo bioequivalence to Syndros, and that FDA require
ANDA applicants to Syndros to conduct fasted and fed bioequivalence studies. You argue that
such studies are required because of the complexity of the drug product and directions for use of
the product with food. You further assert that a waiver is inappropriate because metabolite
equivalence should be measured in addition to parent drug equivalence. You request that FDA

28 Available at
https://www.fda.gov/d ownloads/drugs/guidancecomplianceregulat oryinformation/guida nces/ucm072872.pdf.
29 Available
at
https:// www. fda. gov/ downloads/drugs/guidancecompliancere gulatoryinformati on/guidances/ ucm 199636.pdf.
 Docket No. FDA-2017-P-6411
Page 8

exercise its authority under 21 CFR 320.22(f) to require evidence of bioequivalence for ANDAs
that rely upon Syndros. We address each of these points below.

A. Complex Structure and Profile of Dronabinol

The Petition first asserts that a waiver ofbioequivale nce studies is not appropriate under
§ 320.22 because the complex structure and profile of Syndros require any formulation changes
to be supported by in vivo studies. Petition at 4. The Petition states that because the absorption
and bioavailability profile ofSyndros can vary, "changes to the formulation of the product risks
bioequivalence differences." Id. You cite an Advisory Committee transcript and two scientific
articles in support of this view. Id.

The Petition also notes that certain excipients " are known to alter drug metabolism and/or
transporter activities," and could influence exposure to, properties of, or onset of action of the
drug. Id. at 5. The Petition points to literature about the effects of certain excipients on
dronabinol and discusses the particulars of excipients proposed by a particular ANDA applicant.
Id. at 5-6.

Finally, the Petition notes that Syndros fonns a turbid nanoemulsion in both fed and fasted states,
and that the nanoemulsion ranges in particle size. Id. at 6. The Petition argues that any changes
to formulation could affect the formation of the nanoemulsion and, in turn, the absorption
profile, particle size, and bioequivalence. Id. For these reasons, you request that FDA require
ANDA applicants to conduct in vivo bioequivalence studies.

As stated above, FDA has considerable flexibility in determining how the bioequivalence
requirement is met. Under§ 320.22(b)(3), bioequivalence may be "self-evident," and the
Agency shall waive the requirement for bioequivalenc e studies for proposed generic versions of
oral solutions that contain an active drug ingredient in the same concentration and dosage fonn
as the RLD if the applicant provides an acceptable justification showing that any change in
formulation (such as difference in inactive ingredient type or amount) between its proposed
generic product and the RLD would not significantly affect absorption of the active drug
ingredient or active moiety.

As explained in section I.A., Syndros is a systemically absorbed oral solution, and therefore,
under § 320.22(b)(3), an ANDA applicant may be eligible for a waiver of in vivo bioequivalence
studies if the listed criteria are met. Whether a generic drug product application provides an
acceptable justification in support of a waiver is a matter decided on a case-by-case basis and
would be assessed during the normal course of the ANDA review. 30

We disagree with your assertions that the complex structure and profile of dronabinol makes a
waiver of bioequivalence studies under§ 320.22 inappropriate in all cases. We have reviewed
the materials cited in the Petition in support of these arguments and found no evidence therein
supporting your view that a waiver ofbioequivale nce studies under § 320.22 should not be
available here. In particular, the literature cited in the Petition discusses scenarios that are

30
Your petition discusses particular pending ANDAs. We note that FDA does not generally comment on pending
applications, including whether a given ANDA has been submitted. See 21 CFR 314.430(b).
 Docket No. FDA-2017-P-6411
Page 9

distinguishable from those that would be presented by an ANDA application that relies upon
Syndros as the RLD. For example, the conclusions in Midha KK, et al. , "The bioequivalence of
highly variable drugs and drug products," Int J Clin Pharmacol Ther. 2005;43(1 0):485-498,
related to discussing tablet to tablet variability in dronabinol tablets. Here, dronabinol oral
solution is homogenous, meaning the mixture has the same uniform appearance and composition
throughout as long as it remains in a solution, and, therefore, the dissolution data discussed in
this article are not relevant because a tablet to tablet variability issue would not be a concern with
oral solutions. Similarly, in Davit BM, et al., "Highly Variable Drugs: Observations from
Bioequivalence data submitted to the FDA for new generic drug applications," AAPS J.
2008; 10(1 ): 148-156, the discussion pertained to a dissolution profile analysis; here, the drug is
already dissolved in a solution. Likewise, in Fagerberg JH, et al. , "Concomitant intake of
alcohol may increase the absorption of poorly soluble drugs," Eur J ofPharm Sci. 2015;67:12-
20, the authors discussed the effect of alcohol intake on solubility. Here, the drug is already
dissolved in a solution.

As stated above, you assert that Syndros forms a turbid nanoemulsion that ranges in particle size,
and that therefore any changes to fonnulation could affect the formation of the nanoemulsion and
the rate and extent of drug absorption. Petition at 6. You have provided no evidence that
Syndros forms a nanoemulsion in vivo or that there is an effect on drug absorption. Under
§ 320.22(b)(3), we consider whether a product is an oral solution at the time of administration.
However, during the review process, we would, among other things, evaluate whether
differences in formulation between the ANDA and RLD would lead to differences in drug
precipitation (e.g. , forming a nanoemulsion or crystal drug precipitants with different sizes) in
vivo that could significantly affect drug absorption. As stated above, whether a generic drug
product application provides an acceptable justification in support of a waiver is a matter decided
on a case-by-case basis and would be assessed during the nonnal course of the ANDA review.

Overall, applications for generic versions of Syndros should consider dronabinol 's
characteristics, including its absorption mechanism, and how any excipients proposed for
inclusion in a generic version ofSyndros may affect such mechanism. The effect of any
differences of excipients between the products on drug absorption, and whether in vivo studies
should be undertaken to demonstrate bioequivalence in light of those differences, would be
considered during the ANDA review in evaluating an applicant' s request for a waiver. Based on
the evidence you provided, we do not find it necessary for FDA to exercise its authority under 21
CFR 320.22(£) to require evidence of in vivo bioequivalence for all AND As that rely upon
Syndros.

B. Directions to Use Dronabinol With Food

Second, you argue that a waiver ofbioequivalence studies is not appropriate under § 320.22
because FDA policy requires fed and fasted studies for products like Syndros. Petition at 6. The
Petition cites to FDA's guidance for industry entitled Food Effect Bioavailability and Fed
Bioequivalence Studies (the Food Effect Guidance).31 The Petition explains that the
administration of a drug product with food may affect bioequivalence. Petition at 6. The
31 Available at

https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm07024l .pdf.
 Docket No. FDA-2017-P-6411
Page 10

Petition then quotes the Food Effect Guidance ' s recommendations regarding bioequivalence
studies under fed conditions for orally administered, immediate-release drug products. ld. at 6-7.
The Petition notes that the Syndros labeling clearly suggests that food has an effect on its
absorption or administration, and asserts that, therefore, under the Food Effect Guidance's
recommendations, applicants for ANDAs to Syndros should be required to demonstrate
bioequivalence under fasted and fed conditions. The Petition also notes that Syndros is not a
BCS Class I drug, and asserts that waivers based on FDA 's draft guidance for industry entitled
" Waivers of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid
Oral Dosage Forms Based on a Biopharmaceutics Classification System" 32 would not be
appropriate here.

The Petition elaborates on the effect of food on Syndros, as demonstrated by certain studies that
supported Syndros's approval. Id. at 7-8. According to the Petition, those studies support the
view that changes in fonnulation can have a significant effect on bioavailability of the drug in
the presence or absence of food, and further demonstrate that a waiver ofbioequivalence studies
for an ANDA applicant to Syndros would be inappropriate. Id.

The Petition states that FDA has recognized the need for studies of the effect of food on
dronabinol by "explicitly requir[ing]" fasted and fed studies for dronabinol oral capsules in its
Draft Guidance on Dronabino1. 33 Id. at 8. You argue that " [n ]othing about the structure or
properties of the oral solution indicates that the same considerations" would not apply here. Id.

For the reasons set forth in subpart II.A, above, under§ 320.22(b)(3), an ANDA applicant that
relies upon Syndros as the RLD may be eligible for a waiver of in vivo bioequivalence studies if
the listed criteria are met. Whether a particular generic drug product applicant provides an
acceptable justification in support of a waiver, or alternatively, whether that applicant would be
required to conduct in vivo bioequivalence studies, either under fed conditions, fasted conditions,
or both, is a matter decided on a case-by-case basis and would be assessed during the normal
course of ANDA review.

We found no support for the argument in the Petition that because food has an effect on the
absorption or administration of Syndros, then a generic applicant must conduct bioequivalence
studies in both fasted and fed conditions. Because the bioavailability of a generic oral solution
product is generally considered self-evident if the product meets the criteria set forth in
§ 320.22(b)(3), the food effect observed with the innovator product is expected to be the same
for the generic product. Therefore, the Agency would consider a waiver under§ 320.22(b)(3) to
apply to both fasted and fed bioequivalence studies.

Regarding the Petition's discussion of the Food Effect Guidance, we note that the
recommendations contained in that guidance do not apply to applications for oral solution
products for which bioequivalence studies have been waived under § 320.22(b)(3). 34 Regarding
32 Available at https://www.fda.gov/ downloads/Drugs/Guidances/ucm070246.p df.
33 See note 22 , above.
34 Note
that FDA has published a draft guidance that, once finalized, will replace parts of the Food Effect Guidance
as to AND As. See FDA 's guidance for industry on Bioequiva/ence Studies with Pharmaco/..inetic Endpoints for
 Docket No. FDA-2017-P-6411
Page 11

the Petition's discussion of the guidance entitled " Waivers ofln Vivo Bioavailability and
Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a
Biopharmaceutics Classification System," we agree that guidance is inapplicable here as Syndros
is an oral solution. We also note that the Draft Guidance on Dronabinol is specific to oral
capsules and does not apply to dronabinol in oral solution. Therefore, that draft guidance does
not reflect FDA's current recommendations for potential ANDAs that rely upon Syndros as the
RLD.

C. Metabolite Equivalence

Finally, the Petition argues that metabolite bioequivalence, in addition to parent drug
bioequivalence, contributes meaningfully to the safety and/or efficacy of dronabinol , and,
therefore, under FDA guidance35 should be measured. Id. at 8. The Petition also cites to a
scientific article36 in support of this assertion. Id. Finally, the Petition points out that the Draft
Guidance on Dronabinol requires the measurement of metabolite bioequivalence, and there is no
reason that the same considerations should not be applied here. Id. at 9.

For the reasons set forth in subpart Il.A, above, under § 320.22(b)(3), an ANDA applicant that
relies upon Syndros as the RLD may be eligible for a waiver of in vivo bioequivalenc e studies if
the listed criteria are met. Whether a particular generic drug product applicant provides an
acceptable justification in support of a waiver is a matter decided on a case-by-case basis and
would be assessed during the normal course of ANDA review. We found no evidence in the
Petition or the references cited in the Petition supporting the view that metabolite equivalence
must be measured, or that a waiver under § 320.22(b)(3) would be inappropriate due to the role
of dronabinol 's metabolite in the drug's action.

If a particular ANDA applicant that relies upon Syndros as the RLD does not qualify for a
waiver under§ 320.22(b)(3), bioequivalence would be determined based on the parent drug
(dronabinol), which is a more sensitive measure of potential fonnulation differences than the
metabolite. However, as set forth in FDA' s guidances,37 FDA recommends that an ANDA
applicant submit metabolite data to provide supportive evidence of a comparable therapeutic
outcome if appropriate.

Drugs Submitted Under an ANDA (Dec. 2013), available at

https://www.fda.gov/downloads/drugs/guidances/ucm377465.pdf. Note that this change in guidance would not
change our view that the recommendations for conducting food effect studies are not applicable to oral solution
products for which bioequivalence studies have been waived.
35 See FDA guidance
for industry on Bioavailability and Bioequivalence Studies for Orally Administered Drug
Products- General Considerations (Mar. 2003), available at
https://www.fda.gov/ohrms/dockets/ac/03/briefing/3995B 1_07_ GFI-BioAvail-BioEquiv.pdf.
36See Lemberger L., et al., Comparative Phannacology of ~9 Tetrahydrocannabinol and its Metabolite, 11-0H-~9-
Tetrahydrocannabinol, 1 ofCiin Invest. 1973;52(10):2411-2417.
37
FDA draft guidance for industry on Bioequiva!ence Studies with Pharmacokinetic Endpoints for Drugs Submitted
Under an ANDA (Dec. 20 13), available at https://www.fda.gov/downloads/drugs/guidances/ucm377465.pdf. That
draft guidance, once finalized, is intended to replace in part the guidance cited in the Petition, Bioavailability and
Bioequivalence Studies for Orally Administered Drug Products-General Considerations, at 6 (Mar. 2003),
available at https://www.fda.gov/ohrms/dockets/ac/03/briefing/3995B 1_07_ GFI-BioAvaii-BioEquiv.pdf.
Docket No. FDA-2017-P-6411
Page 12

D. Request to Refuse to Receive an ANDA That Relies Upon Syndros

Regarding your request that FDA decline to receive any ANDA that relies upon a waiver rather
than establishing in vivo bioequivalence to Syndros, as noted above, during an initial review,
FDA assesses whether an application includes information required under section 505(j)(2)(A) of
the FD&C Act. During this initial assessment, FDA does not evaluate the sufficiency of specific
data or infonnation submitted by the applicant to satisfy a particular requirement for approval,
such as bioequivalence.

Here, the Petition has not asserted any basis on which, under the applicable legal and regulatory
authorities, FDA may refuse to receive an ANDA that relies upon Syndros for review. If the
ANDA includes information required under section 505(j)(2)(A) of the FD&C Act and is
sufficiently complete to permit substantive review, it can be accepted for review under
§ 314.101.

III. CONCLUSION

For the reasons described above, your Petition is denied.

Sincerely,

1ft~!u__
( / Ja?et Woodcock, M.D.
-jo, Director
Center for Drug Evaluation and Research