4 | Generic Drug-Approval Process:
Hatch-Waxman Update
Mare S. Gross, Jay Lessler, S. Peter Ludwig, and Amanda L. Vaught
Darby & Darby, P.C., New York, New York, U.S.A.
OVERVIEW OF GENERIC DRUG-APPROVAL PROCESS UNDER
HATCH-WAXMAN
The regulatory scheme for approval of generic drugs changed in April 1984 with
enactment of the Drug Price Competition and Patent Term Restoration Act of 1984,
commonly known as the “Hatch-Waxman” or “Waxman-Hatch” Act (1). The act
was intended to balance the interests of consumers, the brand-name (innovator)
pharmaceutical industry, and the generic drug industry to “make available more
low cost generic drugs [and] to create a new incentive for increased expenditures
for research and development of certain products which are subject to pre-market
approval” (2). Since enactment of the statute, generic drugs have increased from
19% of prescriptions in 1984 to 67% in 2007 and, in 1998, accounted for savings to
consumers of $8 to 10 billion (3)
Breaking new ground, Title I of Hatch-Waxman authorized the marketing
of generic drugs upon approval of Abbreviated New Drug Applications (ANDAs)
(4). Under the Act, an ANDA can be approved upon submission of evidence that
the active ingredient of the generic drug is the “bioequivalent” of a drug previ-
ously approved by the Food and Drug Administration (FDA) after submission of a
full New Drug Application (NDA), without having to submit studies establishing
the safety and efficacy of the drug (5). Hatch-Waxman contains similar provisions
respecting ANDAs and so-called “505(b)(2) applications” or “paper NDAs,” which
rely on safety and /or efficacy data submitted in a prior NDA (6)
Title Il of Hatch-Waxman provided for specific extensions of patents cover-
ing drugs (and other products) subject to “regulatory review” by FDA and other
governmental agencies (7). This provision was intended to balance the benefits of
ANDA practice by providing brand-name drug companies with the restoration of
portions of the terms of their drug patents lost during the testing period required
for approval of the drugs. Patent term extensions under 35 USC §156 (Section 156
extensions), as well as patent extensions implemented 10 years after enactment of
Hatch-Waxman pursuant to the Uruguay Round of Negotiations under the Gen-
eral Agreement on Tariffs and Trade (8), authorized extended drug patent terms to
brand-name companies.
The Hatch-Waxman statutory scheme incorporates several provisions relat-
ing to the submission and approval of both ANDAs and 505(b)(2) applications
subject to certain patent and other marketing exclusivities for drugs granted to
brand-name companies. The act also specifically provides a “safe harbor” for com-
panies seeking approval of generic drugs, that is, the statute specifies that it is not
an act of patent infringement to use a patented invention “solely for uses reason-
ably related to the development and submission of information” for FDA or other
6162 Gross et al.
governmental approval (9). On the other hand, Hatch-Waxman provides that an
applicant for an ANDA or a 505(b)(2) applicant must make an appropriate certifi-
cation respecting marketing of the generic drug vis-a-vis any patents for the same
drug that are listed by the brand-name NDA holder in FDA’s list of “Approved
Drug Products With Therapeutic Equivalence Evaluations” (commonly referred to
as the “Orange Book”) (10).
Where the generic applicant certifies that there are no patents listed in the
Orange Book (a “Paragraph I Certification”) or that any listed patents have pre-
viously expired (a “Paragraph II Certification”), the drug may enter the market-
place immediately upon FDA approval. Where the applicant certifies that any listed
patent has not yet expired but will expire on a particular date and that it will not
enter the market until after that date (a “Paragraph III Certification”), FDA may
approve the ANDA and make it effective as of the patent expiration date.
Where the applicant for generic approval intends to market the drug prior to
expiration of any patent(s) listed in the Orange Book, the applicant makes a certifica-
tion that, in its opinion, the patent(s) are not infringed or are invalid (a “Paragraph
IV Certification”), and it notifies the NDA holder and patent owner accordingly
(11). In such instance, the statute provides that the NDA holder/patent owner may
then initiate a patent infringement action against the applicant for generic approval
and FDA must suspend approval of the ANDA or 505(b)(2) application for up to
30 months (the “30-month stay”), subject to the earlier of a court determination or
the expiration of the listed patent(s) (12).
In an effort to encourage generic drug entry into the pharmaceutical mar-
ket, the Hatch-Waxman Act provides a commercial incentive to those generic com-
panies who are the first to file ANDAs incorporating Paragraph IV Certifications
challenging infringement or validity of Orange Book-listed brand-name pharmaceu-
tical patents. Thus, in the event the listed brand-name patent(s) are adjudged to be
invalid or not infringed prior to their normal expiration date(s); the first generic
filer(s) entitled to approval of their ANDAs receive a 180-day exclusivity period
during which no other ANDA can be approved for the same product (13). In such
circumstances, the first entity or entities to file an ANDA can be the only generic
marketer(s) for 180 days.
In addition, Hatch-Waxman incorporates several provisions limiting the fil-
ing or approval of ANDAs and 505(b)(2) applications in view of marketing “exclu-
sivities” previously obtained by a brand-name NDA holder. Chief among such
limitations is a 5-year bar on submitting an application for generic drug approval
following approval of an NDA on a “new chemical entity” (NCE) (14), and a 3-year
bar on obtaining approval of a generic drug application following approval of an
NDA based on new clinical investigations respecting a previously approved drug
(15). There is also a 7-year bar on obtaining approval of any drug application fol-
lowing approval of an orphan drug for the same indication (16). Finally, pediatric
exclusivity, which is granted upon completion of pediatric studies requested by
FDA, prevents generic drug approval for an additional 6 months after expiration
of any pertinent patent listed in the Orange Book. Pediatric exclusivity also extends
the 3-year, 5-year, and 7-year exclusivities by 6 months (17)
FDA's approval scheme for ANDAs containing Paragraph I, Il, II, or IV Cer-
tifications is illustrated in Figures 1 and 2 (18).
Since enactment of Hatch-Waxman, several amendments have been made to
enhance and prevent abuse of the Hatch-Waxman scheme. For instance, changesGeneric Drug-Approval Process: Hatch-Waxman Update 63
ANDA patent certification option
a Vo
| | | |
FIGURE 1 ANDA Patent Certifications.
made to Hatch-Waxman in the Medicare Prescription Drug Improvement, and
Modernization Act of 2003 (hereinafter “the 2003 Statutory Changes”) were
designed to limit brand-name companies to the opportunity to obtain a single
30-month stay of approval of ANDA or 505(b)(2) applications for the resolution
of patent infringement litigation respecting listed drug patents. More recently, the
Food and Drug Administration Amendments Act of 2007 (FDAAA) provided that
optically pure enantiomers of previously approved drugs may be considered new
chemical entities and thus receive 5 years of market exclusivity if certain conditions
are met. FDAAA also prevents delay of generic approval based on a third-party
submission of citizen petitions suggesting that generic applications should not be
approved, unless delay is necessary to protect public health.
LISTING PATENTS IN THE ORANGE BOOK
Requirements
In 1984, for the first time, Hatch-Waxman required each NDA applicant to identify
any patent which claims the drug for which the NDA was submitted or a method of
using such drug which the applicant believed could reasonably be asserted against
potential generic infringers (19). The patent information must be submitted dur-
ing the pendency of the NDA. On the other hand, if a patent eligible for listing in
the Orange Book is granted after approval of the NDA (or even after the filing of
an ANDA seeking approval of a generic equivalent of the listed product), then the
patent information must be submitted within 30 days after grant of the patent (20)
‘The information submitted during pendency of an NDA must be set forth in FDA
Form 3542a, while information for listing submitted after approval of an NDA mustGross et al.
Days
64
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FIGURE 2. Paragraph IV Certifications,
be incorporated in FDA Form 3542 (21). Under Hatch—Waxman, the generic appli-
cant must make a patent certification as to each such listed patent (22), and if the
patent is not listed until after filing of the ANDA, amend its application accordingly
(23).
On the other hand, if the brand-name company fails to submit the patent infor-
mation for listing in the Orange Book within the 30-day period after the grant of
the patent, the generic applicant need not submit an amended certification and the
patent owner may not initiate an infringement suit under 35 USC §271(e)(2) (24)Generic Drug-Approval Process: Hatch-Waxman Update 65
Further, a brand-name company cannot obtain a 30-month stay of generic approval
based on the listing of a patent after the filing of the ANDA (25)
In one recent case, Eisai, the NDA holder, owned a patent which claimed the
active pharmaceutical ingredient doneprezil hydrochloride in its commercial drug
products Aricept® and Aricept ODT® (26). While Eisai properly submitted the
forms to list its patent for Aricept in 1996, Eisai failed “by ... repeated oversights”
to submit the proper forms and information to FDA for Orange Book listing of the
patent for Aricept ODT, which was approved in 2005 (27). Accordingly, FDA did not
list the patent until more than 5 months after the generic party filed its ANDA (28)
By reason of such error, which the district court characterized as “more than merely
‘clerical,’” (29) the ANDA applicant did not have to submit a Paragraph IV certifica-
tion, and Eisai was not entitled to the 30-month stay of approval of the ANDA that
the prompt commencement of suit would have achieved. Additionally, the district
court dismissed the lawsuit for lack of subject matter jurisdiction due, in part, to the
ANDA applicant's failure to submit a Paragraph IV certification.
The patents for which information must be submitted in connection with an
NDA include those directed to the drug substance (active ingredient), the drug
product (formulation or composition), and methods of use (indications) approved
for the listed drug product (30). The patents thus submitted to FDA are listed in the
Orange Book (31), and are the “listed patents” or “Orange Book patents”,
Since enactment of Hatch-Waxman, brand-name companies have submitted
patents for listing in the Orange Book directed to a wide range of subject matter,
which include different forms of an active drug substance, for example, anhydrous
or hydrated forms, salts, enantiomers or crystal forms of the active substance, dif-
ferent formulations of the drug, metabolites formed in patients after administration
of the drug, and methods of use of the drug whether or not previously approved
by FDA (32). The listing of multiple patents in the Orange Book has compelled
ANDA and 505(b)(2) applicants to make multiple patent certifications and, in some
instances, resulted in the imposition of multiple 30-month stays of generic product
approvals, with consequent delays of generic entry into the market.
EDA does not review the propriety of patents submitted by NDA holders for
listing in the Orange Book because FDA “does not have the expertise to review patent
information” (33). Rather, if the accuracy or relevance of patent information submit-
ted for listing in the Orange Book is disputed by an ANDA or 505(b)(2) applicant it
must notify FDA. The agency will then ask the NDA holder to confirm the correct-
ness of the patent information, and unless the NDA holder withdraws or amends
its patent information, FDA “will not change the patent information in the” Orange
Book (34). The agency’s failure to review patent listings in the Orange Book for possi-
ble delisting provoked criticism, and prompted proposals for reform.
In response to such criticisms, FDA implemented several rule changes in 2003
(hereafter “the 2003 Rule Changes”). Under those regulations, drug substances that
are the same active ingredients as the subject of NDAs, but in different physical
forms, that is, polymorphs (35), must be submitted for listing in the Orange Book. An
NDA holder or patent owner must, however, establish that a polymorph claimed
ina patent will “perform the same as the drug product described in the NDA with
respect to such characteristics as dissolution, solubility, and bioavailability” for list-
ing (36). To establish such “sameness” for a polymorph, the NDA holder or patent
owner must submit detailed test data in five different categories, using forms spec-
ified in the 2003 Rule Changes (37).