Drug Information Journal

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Product Selection, Bioequivalence, and Therapeutic Equivalence: The Generic Drug

Market
Jerome A. Halperin
Drug Information Journal 1983 17: 73
DOI: 10.1177/009286158301700204

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Drug Information Journal, Vol. 17, pp. 13-16, 1983 0092-8615/83 $3.00 + .OO
Printed in the USA. All rights reserved. Q 1983 Drug Information Association Inc.

PRODUCT SELECTION,
BIOEQUIVALENCE, AND THERAPEUTIC
EQUIVALENCE: THE GENERIC
DRUG MARKET
JEROMEA. HALPERIN
Vice President, Technology
ClBA Consumer Pharmaceuticals
Raritan Center
Edison. New Jersey

Pharmacists are continually faced with drug product selection decisions. When is a
generic drug product equivalent to the innovator product and, thus, a suitable candi-
date for generic substitution? The FDA policy has been that only drug products that
are therapeutic equivalents are candidatesfor product selection decisions. This paper
outlines the regulatory and scientific framework f o r the FDA’s policies and require-
ments for generic drug products. The history and current status of the Drug Efficacy
Study Implementation (DESI,) project is described. Originally begun in 1966 as a review
of about 3.400 drug products, the review in mid-1983 is more than 90% complete,
but its impact has already affected more than 7,000 marketed drug products. The
therapeutic equivalence policy and the manner in which decisions on therapeutic
equivalence are communicated are reviewed. Regulatory policies for the approval of
generic drug products are reviewed and specific litigation challenging the rights of
generic drug manufacturers to produce generic “look-alikes”and challenging the FDA 3
policy that a generic drug product is a new drug requiring an approved New Drug
Application for marketing is discussed. The conclusion reached is that the evaluation
of regulatory requirements and science is leading to a point where all generic drug
products will be known to be safe, effective and therapeutically equivalent, andphar-
macists can be optimistic about the quality of products in the generic drug market.

Key Words: Generic; Innovator; Substitution; DESI; Equivalence

THOSE ENGAGED in modern pharmacy mism as to whether generic drug problems

practice must cope daily with generic drug
problems, including product selection, bio-
equivalence, therapeutic equivalence, look-
alikes, and other puzzling matters. The
complexities involved have led to pessi-
Based upon a presentation at the Association of
Military Surgeons’ Meeting, October 1982, Orlando,
Florida.
Reprint address: Jerome A. Halperin, Vice Presi-
dent, Technology, ClBA Consumer Pharmaceuticals,
Raritan Center, Edison, NJ 08837.
73
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ever will be solved or the turmoil subside.
However, legal and scientific developments
justify a more sanguine outlook.
To support this optimistic premise one
must first define the term “generic drug
product,” review some of its history, and
look at how science and law are helping to
settle generic drug marketing controversies.
For purposes of this article, a generic
drug is defined as a product manufactured
by someone other than the innovator, first
marketer, or market leader, but containing
74
the same active ingredients in the same
dosage form as the original product.
If the pharmaceutical marketplace has
always had multiple source drugs and ge-
neric copies of innovator and market lead-
er products, why have the problems emerged
only in the past decade? The answer is
rooted in law and science. Law comes first
because the most serious concerns about
generic drug products are their safety, ef-
fectiveness, and quality. The Food, Drug,
and Cosmetic Act provides the tool to as-
sure that generic drugs are safe, effective,
properly labeled, and manufactured ac-
cording to high standards of quality. The
statute when first enacted in 1938 required
that a new drug be shown to be safe before
it could be marketed; marketing required
FDA approval of a new drug application,
which contained reports of the evidence of
safety.
The Kefauver-Harris Amendments of
1962 mandated that a drug be effective for
its labeled indications as well as safe. Those
amendments required, prospectively from
1962, that all new drug products be shown
to be safe and effective before a new drug
application could be approved, and, more-
over, insisted that the FDA assess retro-
spectively the effectiveness of all the drugs
approved and marketed between 1938 and
1962. That project, which originally in-
volved about 3,400 drug products, came to
be known as the Drug Efficacy Study and
later the Drug Efficacy Study Implementa-
tion (DESI) project. Begun in 1966, the pro-
ject is more than 90% complete in mid-
1983. Hundreds of ineffective prescription
drugs have been removed from the market-
place and thousands more have been re-
labeled to reflect more accurately their real
therapeutic qualities.
The FDA expects the DESI program es-
sentially to be completed by mid-1984-a
22-year period -except for hearings re-
quired for drug products that did not
qualify in time. As of July 1982, more than
7,000 drug products had been withdrawn
from the market under DESI, including
about 1,000 that were originally part of the
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Jerome A. Halperin
DESI universe and about 6,000 similar and
related products that were in the market
without approved new drug applications. In
addition, there are 350 products with pen-
ding hearing requests. The results of the
DESI project affect not only the drug prod-
ucts named in the Federal Register an-
nouncements from the DESI project, but
also thousands of identical, similar, and re-
lated products.
The abbreviated New Drug Applica-
tion policy evolved from the DESI review,
growing out of the need to evaluate the ef-
fectiveness of literally tens of thousands of
related generic drugs products. For every
1 of the more than 3,400 drug products re-
viewed in the DESI project, about 10 were
estimated to be generic products. Abbrevi-
ated New Drug Applications (ANDA) are
available for products of drugs judged to be
effective in the DESI; the ANDA requires
only that the applicant provide evidence
that he can manufacture the product ac-
cording to applicable standards and that
the product is bioavailable and bioequiva-
lent to the innovator product where bio-
equivalence is at issue.
Science, or more properly, the sciences
of biopharmaceutics and pharmaceutical
chemistry provide the other reason for opti-
mism. Through the advances in technology
in these areas, pharmacists are learning
more about how to make phamaceutical
products -especially solid oral dosage
forms - whose bioavailability is satisfac-
tory and predictable and stable throughout
labeled shelf lives. Scientists also are be-
ginning to explore ways to draw inferences
of in vivo behavior through in vitro tests of
product dissolution so that pharmacists
have information available to determine
when generic products are equivalent to the
innovator product and to each other and
are candidates for product selection in ge-
neric substitution programs.
The FDA has long held that generic sub-
stitution is a matter of social and economic
policy and subject to the laws of states.
Thus, generic substitution programs can
and do vary according to the differences in
Product Selection: The Generic Drug Market
state legislation. Once a decision has been
made to substitute, however, the FDA’s
position has been that only products that
are therapeutic equivalents are, or should
be, candidates for product selection. Ther-
apeutically equivalent drug products are
defined as products of the same active in-
gredient in the same dosage form and
strength that are bioequivalent. Bioequiv-
alent drug products are pharmaceutical
equivalents or pharmaceutical alternatives
with rates and extents of absorption that do
not show significant differences when ad-
ministered at the same molar dose of the
therapeutic moiety under similar experi-
mental conditions, either single dose or
multiple dose. Therapeutically equivalent
products may differ in size, shape, color,
or flavor from each other. Where the ge-
neric manufacturer chooses to manufacture
a product that resembles an innovator
product in size, shape, color, etc., the ge-
neric look-alike problem arises. This issue
has been hotly contested in the courts as in-
novators strive to protect their trade dress.
The legal contests are being fought under
the Lanham Act, which is concerned with
antitrust and protection of trademarks and
trade dress-not under the Food, Drug,
and Cosmetic Act, which deals with safe-
ty, effectiveness, quality, and labeling of
drugs. Details on this aspect of generic
drugs can be studied in the Ives v Inwood
case on cyclandelate and the American
Home Products (Ayerst) v Chelsea case on
conjugated estrogens (Premarin).
A list of drug products approved by the
Food and Drug Administration and their
bio- and therapeutic equivalence is avail-
able in Approved Prescription Drug Prod-
ucts with Therapeutic Equivalence Evalua-
tions, a publication issued annually and
updated monthly. The list is updated and
republished in October of each year and is
available from Superintendent of Docu-
ments, US Government Printing Office,
Washington, DC 20402 at a yearly sub-
scription fee of $80 ($100 for foreign sub-
scriptions) which includes new monthly
cumulative supplements. Information also
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75
is available from the National Center for
Drugs and Biologics’ Consumer and Pro-
fessional Relations Staff, which answers
hundreds of questions about these matters
each year. The June 1982 supplement of
the list contains entries for 6,203 approved
drug products from about 300 application
holders containing 832 individual mole-
cules or discrete combinations. Of these
products, 1,906 are single source and 4,297
are multi-source, and of those that are mul-
tiple source, 3,334 have been determined to
be therapeutically equivalent and 952 are
not therapeutically equivalent. The FDA’s
goal is to have all multiple source products
therapeutically equivalent. The 952 prod-
ucts that remain inequivalent contain about
50 individual drugs with continuing tech-
nical problems relating primarily to bio-
equivalence and bioavailability, including
dissolution differences, polymorphism,
particle size, coating, formulation factors
and interfering substances.
The law includes other aspects of drug
regulation. The DESI program and the
ANDA system described previously are
limited to establishing conditions for ap-
proving and marketing pre-1%2 drugs. The
ANDA system has not been available for
generic versions of drugs originally ap-
proved after 1%2. Instead generic manufac-
turers have had to conduct their own trials.
The necessity to “reprove” the safety and
efficacy through clinical trials of new prod-
ucts of drugs already known to be safe and
effective is difficult to justify on scientific
or economic grounds. Such studies are
costly and time consuming and physician-
researchers are not as interested in conduc-
ting trials of generic copies of marketed
drugs as they are of innovative products.
Moreover, the generic drug industry is
more market-oriented than research-ori-
ented. Generic manufacturers have been
anxious to find ways around the current re-
quirements for full testing because they see
the requirement for a full new drug appli-
cation as (1) anticompetitive and (2) an
unintended extension of the innovator’s
patent, which serves as a bar to developing
76
their products from post-1962 drugs with
expired patents.
However, there is a way generic drug
manufacturers can bring new, post-1962
products to market without conducting full
clinical trials to replicate what the innova-
tor was required to do. This can be accom-
plished by using the Agency’s “Paper
NDA” policy. This policy, announced in
1979, permits the statutory requirement of
full reports of studies of safety and effec-
tiveness of a drug to be satisfied by submis-
sion of reprints of medical and scientific
literature if the studies in the literature meet
the requirements for effectiveness and if
there are adequate studies of the toxicology
of the drug. This is not an easy standard to
meet. To date the FDA approved 17 Paper
NDAs for eight drugs.
Another policy change is in the offing.
The FDA is considering extension of the
ANDA process to post-1962 drugs. There
is substantial support from the generic in-
dustry and consumer groups who view the
change as increasing competition and thus
lowering the cost of drugs. Substantial op-
position may be expected from the re-
search-based pharmaceutical industry,
whose members view this proposal as anti-
innovative. However, the FDA believes that
the patent restoration bill currently await-
ing congressional action may restore to in-
novators the amount of time invested in de-
veloping their drugs and meeting FDA re-
quirements for marketing, and may thus
soften the opposition. The innovator indus-
try says extended patent life is essential to
recover research and development costs.
In the late 1970s the efforts of a few
manufacturers to market unapproved cop-
ies of post-1962 drugs resulted in a flurry
of enforcement procedures by the FDA, in-
cluding seizures, injunctions, and prosecu-
tions. Countering the enforcement actions,
several manufacturers launched court chal-
lenges, particularly in New York, New Jer-
sey and Florida, to the FDA’s authority to
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Jerome A . Halperin
require New Drug Applications (NDA) for
new products of drugs already shown to be
safe and effective.
The FDA has been largely successful in
sustaining its position that a “new drug”
means a new product requiring an approved
NDA for marketing. The Second Circuit
Court of Appeals upheld this position in
the Premo case. The Fifth (now the Elev-
enth) Circuit, however, seemed to rule just
the opposite in the Generix case, resulting
in conflicting appellate decisions for review
by the Supreme Court. Ruling in the Ge-
nerix case, the Supreme Court found for
the FDA, ruling that a generic drug prod-
uct is a “new drug” requiring premarketing
approval by FDA. Thus, pharmacists and
patients continue to have the assurance of
equivalence for product selection.
As a result of the DESI project, the
American patient more than ever before
can be assured of safe and effective drugs.
The medical and pharmaceutical communi-
ties can be more certain that they are pre-
scribing and dispensing drugs that are both
safe and capable of doing what they claim
to do, based upon evidence of effectiveness
and more reliable modern labeling infor-
mation.
Biopharmaceutical and pharmaceutical
chemistry continues to be high on the list
of scientific concerns and the FDA looks
forward to reducing the number of drugs
with bioequivalency problems. Future de-
velopments should lead to methodology
that will permit comparison of all products
of a given drug substance so pharmacists
will have knowledge of therapeutic equiva-
lence of multi-source products and freedom
of choice in filling prescriptions and recom-
mending medication.
These are the reasons for optimism that
the prospects for product selection, bio-
equivalence, and therapeutic equivalence of
generic drug products are becoming much
better for pharmacists, consumers and the
industry.