Federal Register / Vol. 62, No. 63 / Wednesday, April 2, 1997 / Notices 15715

person to petition, under section 515(g)

of the act, for administrative review of

CDRH’s decision to approve this

application. A petitioner may request

either a formal hearing under 21 CFR

part 12 of FDA’s administrative

practices and procedures regulations or

a review of the application and CDRH’s

action by an independent advisory

committee of experts. A petition is to be

in the form of a petition for

reconsideration under 21 CFR 10.33(b).

A petitioner shall identify the form of

review requested (hearing or

independent advisory committee) and

shall submit with the petition

supporting data and information

showing that there is a genuine and

substantial issue of material fact for

resolution through administrative

review. After reviewing the petition,

FDA will decide whether to grant or

deny the petition and will publish a

notice of its decision in the Federal

Register. If FDA grants the petition, the

notice will state the issue to be

reviewed, the form of review to be used,

the persons who may participate in the

review, the time and place where the

review will occur, and other details.

Petitioners may, at any time on or

before May 2, 1997 file with the Dockets

Management Branch (address above)

two copies of each petition and

supporting data and information,

identified with the name of the device

and the docket number found in

brackets in the heading of this

document. Received petitions may be

seen in the office above between 9 a.m.

and 4 p.m., Monday through Friday.

This notice is issued under the

Federal Food, Drug, and Cosmetic Act

(secs. 515(d), 520(h) (21 U.S.C. 360e(d),

360j(h))) and under authority delegated

to the Commissioner of Food and Drugs

(21 CFR 5.10) and redelegated to the

Director, Center for Devices and

Radiological Health (21 CFR 5.53).

Dated: March 4, 1997.

Joseph A. Levitt,

Deputy Director for Regulations Policy, Center

for Devices and Radiological Health.

[FR Doc. 97–8273 Filed 4–1–97; 8:45 am]

BILLING CODE 4160–01–F

[Docket No. 94D–0017]

International Conference on

Harmonisation; Draft Guideline on

Dose Selection for Carcinogenicity

Studies of Pharmaceuticals:

Addendum on the Limit Dose;

Availability

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug

Administration (FDA) is publishing a

draft guideline entitled ‘‘Dose Selection

for Carcinogenicity Studies of

Pharmaceuticals: Addendum on the

Limit Dose.’’ The draft guideline was

prepared under the auspices of the

International Conference on

Harmonisation of Technical

Requirements for Registration of

Pharmaceuticals for Human Use (ICH).

The draft guideline is intended to define

the conditions under which it would be

considered acceptable to use a ‘‘limit

dose’’ for the high dose selection of

nongenotoxic pharmaceuticals in longterm carcinogenicity studies. The draft

guideline is an addendum to an earlier

ICH guideline on criteria for

establishing uniformity among

international regulatory agencies for

dose selection for carcinogenicity

studies of human pharmaceuticals.

DATES: Written comments by June 2,

1997.

ADDRESSES: Submit written comments

on the draft guideline to the Dockets

Management Branch (HFA–305), Food

and Drug Administration, 12420

Parklawn Dr., rm. 1–23, Rockville, MD

20857. Copies of the draft guideline are

available from the Drug Information

Branch (HFD–210), Center for Drug

Evaluation and Research, Food and

Drug Administration, 5600 Fishers

Lane, Rockville, MD 20857, 301–827–

5473.

FOR FURTHER INFORMATION CONTACT:

Regarding the guideline: Joseph J.

DeGeorge, Center for Drug

Evaluation and Research (HFD–24),

Food and Drug Administration,

5600 Fishers Lane, Rockville, MD

20857, 301–594–6758.

Regarding the ICH: Janet J. Showalter,

Office of Health Affairs FY–20),

Food and Drug Administration,

5600 Fishers Lane, Rockville, MD

20857, 301–827–0864.

SUPPLEMENTARY INFORMATION: In recent

years, many important initiatives have

been undertaken by regulatory

authorities and industry associations to

promote international harmonization of

regulatory requirements. FDA has

participated in many meetings designed

to enhance harmonization and is

committed to seeking scientifically

based harmonized technical procedures

for pharmaceutical development. One of

the goals of harmonization is to identify

and then reduce differences in technical

requirements for drug development

among regulatory agencies.

ICH was organized to provide an

opportunity for tripartite harmonization

initiatives to be developed with input

from both regulatory and industry

representatives. FDA also seeks input

from consumer representatives and

others. ICH is concerned with

harmonization of technical

requirements for the registration of

pharmaceutical products among three

regions: The European Union, Japan,

and the United States. The six ICH

sponsors are the European Commission,

the European Federation of

Pharmaceutical Industries Associations,

the Japanese Ministry of Health and

Welfare, the Japanese Pharmaceutical

Manufacturers Association, the Centers

for Drug Evaluation and Research and

Biologics Evaluation and Research,

FDA, and the Pharmaceutical Research

and Manufacturers of America. The ICH

Secretariat, which coordinates the

preparation of documentation, is

provided by the International

Federation of Pharmaceutical

Manufacturers Associations (IFPMA).

The ICH Steering Committee includes

representatives from each of the ICH

sponsors and the IFPMA, as well as

observers from the World Health

Organization, the Canadian Health

Protection Branch, and the European

Free Trade Area.

At a meeting held on November 6,

1996, the ICH Steering Committee

agreed that a draft guideline entitled

‘‘Dose Selection for Carcinogenicity

Studies of Pharmaceuticals: Addendum

on the Limit Dose’’ should be made

available for public comment. The draft

guideline is the product of the Safety

Expert Working Group of the ICH.

Comments about this draft will be

considered by FDA and the Safety

Expert Working Group.

The draft guideline is an addendum to

an ICH final guideline published in the

Federal Register of March 1, 1995 (60

FR 11278), entitled ‘‘Guideline on Dose

Selection for Carcinogenicity Studies of

Pharmaceuticals.’’ The draft guideline is

intended to define the conditions under

which it would be considered

acceptable to use a ‘‘limit dose’’ for the

high dose selection of nongenotoxic

pharmaceuticals in long-term

carcinogenicity studies.

Although not required, FDA has in

the past provided a 75- or 90-day

comment period for draft ICH

guidelines. However, the comment

period for this draft guideline has been

shortened to 60 days so that comments

may be received by FDA in time to be

reviewed and then discussed at a July

1997 ICH meeting involving this

guideline.

This draft guideline represents the

agency’s current thinking on dose

selection for carcinogenicity studies of
15716 Federal Register / Vol. 62, No. 63 / Wednesday, April 2, 1997 / Notices

pharmaceuticals. It does not create or

confer any rights for or on any person

and does not operate to bind FDA or the

public. An alternative approach may be

used if such approach satisfies the

requirements of the applicable statute,

regulations, or both.

Interested persons may, on or before

June 2, 1997, submit written comments

on the draft guideline to the Dockets

Management Branch (address above).

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. The draft guideline and

received comments may be seen in the

office above between 9 a.m. and 4 p.m.,

Monday through Friday. An electronic

version of this draft guideline is

available via the Internet using the

World Wide Web (WWW). To connect

to the CDER home page, type http://

www.fda.gov/cder and go to the

‘‘Regulatory Guidance’’ section.

The text of the draft guideline follows:

Addendum to ‘‘Dose Selection for

Carcinogenicity Studies of Pharmaceuticals’’

Limit Dose

Under a defined set of conditions, it would

be considered acceptable to limit the high

dose administered for nongenotoxic

pharmaceuticals in long-term carcinogenicity

testing to a maximum, e.g., 1000 mg/kg/day

in rats. This approach is only considered

appropriate where the other accepted

methods of dose selection have been

evaluated and each has been considered not

applicable based on scientific justification.

Use of this alternative is considered

appropriate when:

1. Neither a toxicity-based endpoint (MTD)

nor a pharmacodynamic-based dose selection

endpoint can be achieved; and

2. Determination of pharmacokinetic

parameters needed to apply pharmacokinetic

endpoints (the 25-fold ratio of rodent to

human AUC or saturation of absorption) is

not feasible or is inappropriate due to

scientific or technical limitations.

Under such circumstances, it would be

considered acceptable to use the maximum

feasible dose (e.g., 5 percent of diet) for

selection of the high dose. However, if in

addition to meeting the criteria 1. and 2.

above, the dose of the pharmaceutical for use

in humans is 50 mg/day, a ‘‘limit dose’’ of

1000 mg/kg/day is considered acceptable for

high dose selection (see NOTE). This

endpoint is consistent with the principles set

forth in the paragraphs on pharmacokinetic

endpoints, achieving approximately the same

margin of safety as specified there based on

a mg/m2 basis. For those pharmaceuticals

used at maximum daily human doses higher

or lower than 50 mg/day it is considered

acceptable to limit the top dose in a rat

carcinogenicity study proportionally.

NOTE

The dose of 50 mg/day in humans (leading

to 1 mg/kg on an assumed human weight of

50 kg) is an approximate calculation based

upon the following: A conversion from mg/

kg to mg/m2, the AUC ratio of 25, and a

multiplication factor of 6 to account for the

variance (approximately 95 percent

confidence interval) for estimation of the

AUC ratio from mg/m2 ratio (rodent to

human) (see, for the data, Contrera, et al.,

Journal of the American College of

Toxicology, 14:1–10, 1995). A similar

rationale and calculation can be applied for

other rodent species.

Dated: March 25, 1997.

William B. Schultz,

Deputy Commissioner for Policy.

[FR Doc. 97–8353 Filed 4–1–97; 8:45 am]

BILLING CODE 4160–01–F

National Institutes of Health

National Center for Research

Resources; Closed Meetings

Pursuant to Section 10(d) of the

Federal Advisory Committee Act, as

amended (5 U.S.C. Appendix 2), notice

is hereby given of the following

National Center for Research Resources

Special Emphasis Panel (SEP) meetings:

Name of SEP: General Clinical Research

Centers.

Date: May 13–14, 1997.

Time: 8 a.m.

Place: Holiday Inn Iowa City, Johnson 1 &

2 Conference Room, 210 South Dubuque

Street, Iowa City, IA 52240, (319) 337–4058.

Contact Person: Dr. Bela Gulyas, Scientific

Review Administrator, 6705 Rockledge Drive,

MSC 7965, Room 6018, Bethesda, MD 20892–

7965, (301) 435–0811.

Name of SEP: Biomedical Research

Technology.

Date: May 27–29, 1997.

Time: 8 a.m.

Place: Doubletree Hotel, Conference

Rooms—Twinbrook, Montrose, and

Parklawn, 1750 Rockville Pike, Rockville,

MD 20852, (301) 468–1100.

Contact Person: Dr. Sharon Moss,

Scientific Review Administrator, 6705

Rockledge Drive, MSC 7965, Room 6018,

Bethesda, MD 20892–7965, (301) 435–0811.

Purpose/Agenda: To evaluate and review

grant applications.

The meetings will be closed in accordance

with the provisions set forth in sections

552b(c)(4) and 552b(c)(6), Title 5, U.S.C.

Applications and/or proposals and the

discussions could reveal confidential trade

secrets or commercial property such as

patentable material and personal information

concerning individuals associated with the

applications and/or proposals, the disclosure

of which would constitute a clearly

unwarranted invasion of personal privacy.

(Catalog of Federal Domestic Assistance

Program No. 93.371, Biomedical Research

Technology; 93.333, Clinical Research,

National Institutes of Health, HHS)

Dated: March 27, 1997.

LaVerne Y. Stringfield,

Committee Management Officer, National

Institutes of Health.

[FR Doc. 97–8294 Filed 4–1–97; 8:45 am]

BILLING CODE 4140–01–M

National Center for Research

Resources; Closed Meeting

Pursuant to Section 10(d) of the

Federal Advisory Committee Act, as

amended (5 U.S.C. Appendix 2), notice

is hereby given of the following

meeting:

Name of Committee: Scientific and

Technical Review Board on Biomedical and

Behavioral Research Facilities.

Dates of Meeting: May 28–30, 1997.

Time: 8 a.m.–until adjournment.

Place of Meeting: Doubletree Hotel,

Halpine Room, 1750 Rockville Pike,

Rockville, MD 20892, Tel: (301) 468–1100.

Scientific Review Administrator: Dr. D. G.

Patel, National Institutes of Health, 1

Rockledge Center, Room 6018, 6705

Rockledge Drive, MSC 7965, Bethesda, MD

20892–7965, Telephone: (301) 435–0822.

Purpose/Agenda: To review and evaluate

grant applications. The meeting will be

closed in accordance with the provisions set

forth in sections 552b(c)(4) and 552b(c)(6),

Title 5, U.S.C. Applications and/or proposals

and the discussions could reveal confidential

trade secrets or commercial property such as

patentable material and personal information

concerning individuals associated with the

applications and/or proposals, the disclosure

of which would constitute a clearly

unwarranted invasion of personal privacy.

(Catalog of Federal Domestic Assistance

Program No. 93.167 Research Facilities

Improvement Program, National Institutes of

Health, HHS)

Dated: March 27, 1997.

LaVerne Y. Stringfield,

Committee Management Officer, National

Institutes of Health.

[FR Doc. 97–8297 Filed 4–1–97; 8:45 am]

BILLING CODE 4140–01–M

National Institute of Mental Health;

Closed Meetings

Pursuant to Section 10(d) of the

Federal Advisory Committee Act, as

amended (5 U.S.C. Appendix 2), notice

is hereby given of the following

meetings of the National Institute of

Mental Health Special Emphasis Panel:

Agenda/Purpose: To review and evaluate

grant applications.

Committee Name: National Institute of

Mental Health Special Emphasis Panel.

Date: April 3, 1997.

Time: 3 p.m.

Place: Parklawn, Room 9C–26, 5600

Fishers Lane, Rockville, MD 20857.

Contact Person: Phyllis D. Artis, Parklawn,

Room 9C–26, 5600 Fishers Lane, Rockville,

MD 20857, Telephone: 301, 443–6470.