Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Notices 2167

selecting patient representatives, and (2)

a plan for soliciting nominations.

A. Qualifications for Patient

Representatives

The agency has decided that patient

representatives on FDA advisory

committees that review and consider

cancer therapies will be voting

members. Patient representatives will be

subject to the same conflict of interest

requirements as other committee

members as set out in § 14.80 (21 CFR

14.80) and must serve as special

Government employees. Section 14.80

defines the qualifications for voting

members of advisory committees. FDA

recognizes that in some cases the

composition of an advisory committee is

mandated by statute or regulation. The

agency will make a determination to

add a voting patient representative on a

case-by-case basis when: (1) Meetings

are planned; (2) FDA determines it is

allowable within the statutes and

regulations; and (3) it is feasible and

beneficial to a committee’s deliberation.

The primary role of the patient

representative would be to provide to

the advisory committee the perspective

of the patients with the disease for

which the therapeutic agent is being

considered. Currently, many of the FDA

advisory committees, including those

that provide advice on cancer-related

issues, include a representative who is

broadly identified with consumer

interests and who has been nominated

and recommended by a consumeroriented organization. However, because

there are so many different cancers, the

number of appropriate perspectives is

larger than a single consumer can

represent. To more specifically

represent the interests of the patients,

the FDA believes that a patient

representative who understands issues

specific to the cancer for which a drug,

device, or biologic approval is being

sought would bring valuable insights to

the FDA advisory committee process.

Multiple factors are important to

determine the ability of a person to be

an effective patient representative. In

addition to the qualifications described

under § 14.80, the following

qualifications are under consideration

for selecting patient representatives: (1)

Personal experience with an illness,

condition, or treatment; (2) experience

as a patient advocate; (3) formal

affiliation with a patient advocacy

organization; (4) ability to articulate the

perspective of the patient; (5) ability to

identify issues through communications

with patient constituencies; (6) ability to

access mechanisms to disseminate

information from an advisory committee

meeting to the affected community; and

(7) experience in technical issues before

the committee.

B. Soliciting Nominations

The agency believes that a mechanism

for soliciting nominations of qualified

patient representatives to ensure broad

representation in the nominee pool is

critical. After the qualifications for

voting patient representatives are

defined, the agency proposes to solicit

nominations by the following methods:

(1) Federal Register announcement as

set out in 21 CFR 14.82; and possibly

through Internet announcements; (2)

direct mailings of announcements and

personalized letters to patient advocacy

groups, community organizations, and

other public interest organizations; (3)

patient newsletter announcements; or

(4) display announcements at

conferences, advisory committee

meetings, workshops, etc. that FDA staff

members attend, and at other

conferences, meetings, and workshops.

Nominations may be submitted by

individuals, patient advocacy groups

and organizations. Self nominations will

also be acceptable.

III. Comments

FDA is seeking the views of the public

with regard to the proposed

qualifications that should be considered

in selecting a patient representative and

comments on the adequacy of the

methods proposed to obtain

nominations. The agency will review

and consider written comments on the

approach set forth in this notice. Any

comments received will be considered

in determining whether amendments to,

or revisions of, the approach are

warranted. Two copies of any comments

should be submitted, except that

individuals may submit one copy.

Comments are to be identified with the

docket number found in the brackets in

the heading of this document.

Comments received are available for

public examination in the Dockets

Management Branch (address above)

between 9 a.m. and 4 p.m., Monday

through Friday.

Dated: December 30, 1996.

Michael A. Friedman,

Deputy Commissioner for Operations.

[FR Doc. 97–945 Filed 1–14–97; 8:45 am]

BILLING CODE 4160–01–F

[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.

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.
2168 Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Notices

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

§ 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

§ 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
Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Notices 2169

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

Health Resources and Services

Administration

Program Announcement for Grant

Programs Administered by the

Division of Associated, Dental and

Public Health Professions, Bureau of

Health Professions for Fiscal Year

1997

Correction

In notice document 96–28112

appearing on page 56550 on the issue of

Friday, November 1, 1996 make the

following correction:

On page 56550, in the table on the

fourth line titled ‘‘Public Health Special

Projects’’ in the fourth column under

the column heading ‘‘Available for

competing awards’’, the amount should

read ‘‘$2,500,000’’.

Dated: January 7, 1997.

Ciro V. Sumaya,

Administrator.

[FR Doc. 97–943 Filed 1–14–97; 8:45 am]

BILLING CODE 4160–15–P

National Institutes of Health

National Cancer Institute; Opportunity

for a Cooperative Research and

Development Agreement (CRADA) for

the Scientific and Commercial

Development of Monoclonal

Antibodies to a Tumor-Specific Growth

Factor for the Diagnosis and

Prognosis of Premalignant Lesion and

Cancer

AGENCY: National Institutes of Health,

DHHS.

ACTION: Notice.

SUMMARY: The National Cancer Institute

(NCI) seeks a pharmaceutical or

biotechnology company that can

effectively pursue the scientific and

commercial generation and

development of a panel of monoclonal

antibodies against an epidermal growth

factor (EGF)-related peptide, cripto-1

(CR–1) and its novel receptor. The

project is of scientific importance

because CR–1 is a protein that exhibits

structural homology to the

EGF / transforming growth factor α

(TGFα) gene family of peptides. As

such, CR–1 might function as a growth

or survival factor. Therefore, CR–1 may

be important as an autocrine or

paracrine modulator in such processes a

tumor cell growth, wound repair,

neovascularization, inflammation, and

apoptosis.

NCI has successfully isolated and

cloned the gene that encodes CR–1, an

EGF-related peptide growth factor that

does not bind to the EGF receptor or

other type 1 receptor tyrosine kinases.

The NCI has also obtained a rabbit antipeptide polyclonal antibody that can

detect the expression of CR–1 in

formalin-fixed, paraffin-embedded

human tissue sections. CR–1 has been

shown to be preferentially and

differentially expressed in several

different human premalignant lesions

and cancers. The selected sponsor will

purify a recombinant CR–1 protein and

use this material as an immunogen to

generate anti-CR–1 monoclonal

antibodies for use in the diagnosis and

prognosis of human cancers.

ADDRESSES: Inquiries and proposals

regarding this opportunity should be

sent to Richard I. Kohn, J.D., M.S.,

Office of Technology Development,

National Cancer Institute, as follows: (a)

by U.S. Mail to: Executive Plaza South,

Room 450, 6120 Executive Blvd., MSC

7182, Bethesda MD 20892–7182; (b) By

messengers and express delivery to:

6120 Executive Blvd, Suite 450,

Rockville, MD 20852; (c) by telephone at

(301) 496–0477; (d) by fax at (301) 402–

2117.