[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