[Federal Register Volume 62, Number 10 (Wednesday, January 15, 1997)]
[Notices]
[Pages 2167-2169]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-944]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
[Docket No. 97N-0002]
Policy on Period of Marketing Exclusivity for Newly Approved Drug
Products With Enantiomer Active Ingredients; Request for Comments
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is reevaluating its
policy on the appropriate period of marketing exclusivity for newly
approved drug products whose active ingredient is a single enantiomer
of a previously approved racemate. This action is being taken to assess
incentives for the development of new enantiomer drug products that may
represent significant pharmaceutic advances. The agency is requesting
comments on this issue and intends to publish a notice in Federal
Register at a later date announcing its policy.
DATES: Written comments by March 17, 1997.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,
Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: Wayne H. Mitchell, Center for Drug
Evaluation and Research (HFD-7), Food and Drug Administration, 7500
Standish Pl., Rockville, MD 20855, 301-594-1049.
SUPPLEMENTARY INFORMATION: FDA is requesting comments on the agency's
policy on marketing exclusivity for drug products whose active
ingredient is a single enantiomer of a previously approved racemate.
I. Enantiomers and Racemates
Stereoisomers are molecules that have the same constitution (i.e.,
molecular formula and chemical connectivity), but differ in the spatial
orientation of the atoms. When two stereoisomers are mirror images, but
are not superimposable upon each other (like left and right hands),
they are referred to as enantiomers. Enantiomeric molecules are
identical in all physical and chemical properties, except in an
environment which is also chiral (characterized by handedness).
Polarized light is such an environment, and pairs of enantiomers rotate
the plane of polarization by equal amounts in opposite directions.
Enantiomers may be either right-handed (dextro-rotary) S(+)-isomers or
left-handed (levo-rotary) R(-)-isomers. Racemates are equimolar
mixtures of enantiomers of the same molecule.
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Frequently, both enantiomers found in a racemate will have similar
desirable pharmacological activity. In other cases, one member of a
pair of enantiomers is pharmacologically active and the other inactive
or nearly inactive, as in baclofen where the R(-)-isomer is a muscle
relaxant and antispastic, and the S(+)-isomer is essentially inactive.
In other racemates, the enantiomers show significantly different
pharmacological activity. For example, both isomers of sotalol have
similar antiarrhythmic effects, but only the R(-)-isomer has
significant beta-blocking activity. There are also instances where only
one member of a pair of enantiomers has shown significant toxicity; an
example of this may be found with thalidomide, where it is generally
believed that most, if not all, of the teratogenicity associated with
the drug is attributable to the R(-)-isomer.
In the past, the usual practice in the pharmaceutical industry has
been to develop either a racemate or an enantiomer without fully
characterizing or studying its respective properties. When separation
of enantiomers was difficult, the question of which stereoisomeric form
should be developed was largely an academic question. However, in many
cases, current technology permits production of pure enantiomers on a
commercial scale. Improved pharmacologic study of enantiomers has been
permitted by developments in analytical technology that frequently
enable detection of one enantiomer in the presence of the other at
concentrations found in biological fluids.
The increased feasibility of such efforts led the agency to issue
on May 1, 1992,``FDA's Policy Statement on the Development of New
Stereoisomeric Drugs'' (Stereoisomeric Drug Policy). (See the Federal
Register of May 27, 1992 (57 FR 22249).) The Stereoisomeric Drug Policy
provides general recommendations for conducting and reviewing studies
of the safety and effectiveness of drug products whose active
ingredient is an enantiomer, a racemate, or a nonracemic mixture of
enantiomers. Although the Stereoisomeric Drug Policy does not address
issues of marketing exclusivity, it does contain the agency's thinking
on the approval of stereoisomeric drug products. As such, it may be of
interest to anyone commenting on marketing exclusivity for drug
products whose active ingredient is a single enantiomer of an approved
racemate.
II. Marketing Exclusivity
A. The 1984 Amendments
The 1984 amendments amended the Federal Food, Drug, and Cosmetic
Act (the act) to establish two new types of marketing applications:
Abbreviated new drug applications (ANDA's), established under section
505(j) of the act (21 U.S.C. 355(j)); and 505(b)(2) applications,
established under section 505(b)(2) of the act. The 1984 amendments
also provide for the granting of nonpatent marketing exclusivity to
certain drug products. Marketing exclusivity gives qualified drug
products periods free of competition from drugs approved under ANDA's
and 505(b)(2) applications.
Marketing exclusivity is provided for in section 505(c)(3)(D) of
the act, which limits approval of competing 505(b)(2) applications, and
section 505(j)(4)(D) of the act, which limits approval of competing
ANDA's.
Section 505(c)(3)(D)(ii) and (j)(4)(D)(ii) of the act provides that
if an NDA is approved for a drug, no active ingredient of which has
been approved in a previous NDA, no 505(b)(2) application or ANDA for a
drug product with the same active ingredient as the previously approved
NDA drug product may be submitted until 5 years after the date of
approval of the first drug product.
Section 505(c)(3)(D)(iii) and (j)(4)(D)(iii) of the act provides 3
years of exclusivity to a drug product that includes a previously
approved active ingredient, where the NDA for the drug product contains
reports of new clinical investigations (other than bioavailability
studies), conducted or sponsored by the applicant, that are essential
to the approval of the NDA. (Section 505(c)(3)(D) and (j)(4)(D) of the
act has other marketing exclusivity provisions which are not relevant
to this notice.)
The text of the amendments and the legislative history accompanying
the amendments do not directly address how these provisions of the 1984
amendments regarding marketing exclusivity should be applied to
enantiomers.
B. Regulations
FDA's regulations implementing the marketing exclusivity provisions
of the 1984 amendments are found in Sec. 314.108 (21 CFR 314.108).
Section 314.108(b)(2) states that if a drug product that contains a
``new chemical entity'' was approved in an NDA, ``no person may submit
a 505(b)(2) application or abbreviated new drug application under
section 505(j) of the act for a drug product that contains the same
active moiety as in the new chemical entity for a period of 5 years
from the date of approval of the first approved new drug application.''
Section 314.108(b)(4) states that if an NDA is for a drug product that
contains an active moiety that has been previously approved in another
NDA, and includes reports of new clinical investigations (other than
bioavailability studies) conducted or sponsored by the applicant that
were essential to approval of the NDA, that drug product will be
entitled to 3 years of marketing exclusivity.
``New chemical entity'' is defined in Sec. 314.108(a) as ``a drug
that contains no active moiety that has been approved by FDA in any
other application submitted under section 505(b) of the act.'' ``Active
moiety'' is defined in the same section as follows:
[T]he molecule or ion, excluding those appended portions of the
molecule that cause the drug to be an ester, salt (including a salt
with hydrogen or coordination bonds), or other noncovalent
derivative (such as a complex, chelate, or clathrate) of the
molecule, responsible for the physiological or pharmacological
action of the drug substance.
The issue of marketing exclusivity for enantiomers is not addressed in
the body of the regulation.
In the Federal Register of July 10, 1989 (54 FR 28872), FDA
proposed regulations implementing the 1984 amendments. In the preamble
to the proposed rule (54 FR 28872 at 28898), FDA briefly examined the
issue of whether a single enantiomer of a previously approved racemate
is entitled to 5 years of exclusivity under section 505(c)(3)(D)(ii)
and (j)(4)(D)(ii) of the act, or 3 years of exclusivity under section
505(c)(3)(D)(iii) and (j)(4)(D)(iii) of the act. The agency stated
that:
FDA will consider whether a drug contains a previously approved
active moiety on a case-by-case basis. FDA notes that a single
enantiomer of a previously approved racemate contains a previously
approved active moiety and is therefore not considered a new
chemical entity.
FDA received one comment disagreeing with the stated policy. This
comment was received nearly 4 years after the comment period closed,
and the agency responded to it in the preamble to the final rule with a
reiteration of the statement from the proposal. (See the Federal
Register of October 3, 1994 (59 FR 50338 at 50359).)
III. Request for Comments
In light of the complexity of the scientific and regulatory issues
involved, FDA believes it is appropriate to reexamine the question of
exclusivity for enantiomers of previously approved
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racemates. The agency believes that this issue would benefit from a
more focused consideration than it was subject to in the rulemaking
process for the regulations implementing the 1984 amendments, where
there were many complicated and contentious regulatory matters under
consideration, and where this issue was raised by one comment submitted
very late in the rulemaking process. Accordingly, FDA is requesting
comments on the appropriate period of marketing exclusivity for drug
products whose active ingredient is a single enantiomer of a racemate
that is an active ingredient of a previously approved drug product.
Among the issues that the agency is interested in receiving comment on
are as follows:
(1) What period of marketing exclusivity would best effectuate the
1984 amendments' dual policy goals of increasing drug price competition
and providing incentives for the development of innovative drug
products?
(2) Would granting a 5-year period of exclusivity to enantiomers of
previously approved racemates encourage medically significant
pharmaceutical innovation?
(3) If the pharmacological action of each enantiomer is described
in the approved NDA for the racemate, should a subsequently submitted
application for an enantiomer of the racemate receive different
treatment for exclusivity purposes than if the pharmacological action
of each enantiomer is not described in the approved NDA for the
racemate drug product?
(4) If the agency were to assess requests for exclusivity for
enantiomers of previously approved racemates on a case-by-case basis,
what criteria should the agency apply?
(5) Compared with other drug products, what are the costs of and
technical barriers to obtaining safety and efficacy data for a drug
product whose active ingredient is a single enantiomer of a previously
approved racemate?
(6) How many drug products (whether approved, the subject of
pending NDA's, or in development) are likely to be affected by this
policy?
After considering comments received in response to this notice, FDA
will publish a Federal Register notice setting forth its policy on
exclusivity for a drug product whose active ingredient is an enantiomer
of a previously approved racemate.
Interested persons may, on or before March 17, 1997, submit to the
Dockets Management Branch (address above) written comments regarding
this notice. Two copies of any comments are to be submitted, except
that individuals may submit one copy. Comments are to be identified
with the docket number found in brackets in the heading of this
document. Copies of the comment on exclusivity for enantiomers
submitted to the docket for the July 10, 1989, proposed rule; FDA's
Stereoisomeric Drug Policy; and other correspondence and documents
relating to the subject matter of this notice have been placed in the
docket for this notice. Received comments and other material placed in
the docket may be seen in the office above between 9 a.m. and 4 p.m.,
Monday through Friday.
Persons considering submitting a 505(b)(2) application or an ANDA
for a drug product that may be affected by any change in FDA's policy
on marketing exclusivity for enantiomer drug products should contact
the Center for Drug Evaluation and Research's (CDER's) Office of
Generic Drugs or the appropriate review division within CDER before
submitting the application.
Dated: January 10, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-944 Filed 1-10-97; 12:29 pm]
BILLING CODE 4160-01-F