64260 Federal Register / Vol. 62, No. 233 / Thursday, December 4, 19977 / Notices

1This guidance represents the agency’s current

thinking on dose selection for carcinogenicity

studies of 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.

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

[Docket No. 94D–0017]

International Conference on

Harmonisation; Guidance on Dose

Selection for Carcinogenicity Studies

of Pharmaceuticals: Addendum on a

Limit Dose and Related Notes;

Availability

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug

Administration (FDA) is publishing a

guidance entitled ‘‘S1C(R) Addendum to

‘Dose Selection for Carcinogenicity

Studies of Pharmaceuticals’: Addition of

a Limit Dose and Related Notes.’’ The

guidance was prepared under the

auspices of the International Conference

on Harmonisation of Technical

Requirements for Registration of

Pharmaceuticals for Human Use (ICH).

The guidance 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, and is an

addendum to an earlier ICH guidance on

criteria for establishing uniformity

among international regulatory agencies

for dose selection for carcinogenicity

studies of human pharmaceuticals.

DATES: Effective December 4, 1997.

Submit written comments at any time.

ADDRESSES: Submit written comments

on the guidance to the Dockets

Management Branch (HFA–305), Food

and Drug Administration, 12420

Parklawn Dr., rm. 1–23, Rockville, MD

20857. Copies of the guidance 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–

4573.

FOR FURTHER INFORMATION CONTACT:

Regarding the guidance: 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 ICH: Janet J. Showalter,

Office of Health Affairs (HFY–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.

In the Federal Register of April 2,

1997 (62 FR 15715), FDA published a

draft tripartite guideline entitled ‘‘Dose

Selection for Carcinogenicity Studies of

Pharmaceuticals: Addendum on the

Limit Dose’’ (S1C(R)). The notice gave

interested persons an opportunity to

submit comments by June 2, 1997.

After consideration of the comments

received and revisions to the guidance,

a final draft of the guidance was

submitted to the ICH Steering

Committee and endorsed by the three

participating regulatory agencies on July

17, 1997.

In accordance with FDA’s Good

Guidance Practices (62 FR 8961,

February 27, 1997), this document has

been designated a guidance, rather than

a guideline.

The guidance is an addendum to an

ICH final guidance published in the

Federal Register of March 1, 1995 (60

FR 11278), entitled ‘‘Dose Selection for

Carcinogenicity Studies of

Pharmaceuticals.’’ The guidance 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.

This guidance represents the agency’s

current thinking on dose selection for

carcinogenicity studies of

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.

The public is encouraged to submit

written comments with new data or

other new information pertinent to this

guidance. The comments in the docket

will be periodically reviewed, and,

where appropriate, the guidance will be

amended. The public will be notified of

any such amendments through a notice

in the Federal Register.

Interested persons may, at any time,

submit written comments on the

guidance 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 guidance 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 guidance is available on

the Internet (http://www.fda.gov/cder/

guidance.htm).

The text of the guidance follows:

‘‘S1C(R) Addendum to ‘Dose Selection for

Carcinogenicity Studies of Pharmaceuticals’:

Addition of a Limit Dose and Related

Notes’’1

Limit Dose

In determining the high dose for

carcinogenicity studies using the approaches

outlined in this guidance, it may not be

necessary to exceed a dose of 1500

milligrams (mg)/kilograms (kg)/day (Note 1).

This limit dose applies only in cases where

there is no evidence of genotoxicity and

where the maximum recommended human

dose does not exceed 500 mg/day (Note 2).

Data should be provided comparing

exposure of rodents and humans to drug and
Federal Register / Vol. 62, No. 233 / Thursday, December 4, 19977 / Notices 64261

metabolites primarily to support dose

selection for and interpretation of the

carcinogenicity study. Based on such

information, there may be cases where the

limit of 1500 mg/kg/day is not acceptable

because it cannot be assured that animal

exposure after 1500 mg/kg/day is sufficiently

high compared to the exposure achieved in

humans. The rodent systemic exposure at

1500 mg/kg/day should be greater by at least

an order of magnitude than human exposure

measured at the intended human therapeutic

dose. [If this is not the case, efforts should

be made to increase the rodent exposure or

to reconsider the animal model in a case-bycase approach.] If the human dose exceeds

500 mg/day, the high dose may be increased

up to the maximum feasible dose.

Note 1

Review of the FDA carcinogenicity

database of nearly 900 carcinogenicity tests

indicated that about 20 tests had been

conducted that used doses of 1000 mg/kg or

greater as the highest dose tested. About 10

of these tests were considered as having

demonstrated a carcinogenic response. Seven

of these were positive only at or above 1000

mg/kg, including two that were positive in

two species (in neither case were doses above

1000 mg/kg necessary to detect the

carcinogenic response in both species, but

rather in only one of the two species was a

dose greater than 1000 mg/kg necessary).

Some of the one species positives were also

only positive at doses greater than 1000 mg/

kg. In one case where the drug was

considered as demonstrating a significant

tumor response only above 1000 mg/kg, it

was positive in several nonstandard

genotoxicity assays but not in standard

genotoxicity studies. Regulatory action has

resulted from some of these cases. Based on

these results, the limit dose for

carcinogenicity testing should be 1500 mg/kg

rather than 1000 mg/kg to eliminate the risk

that a genotoxic carcinogen will not be able

to be identified as a result of adoption of a

limit dose of 1000 mg/kg.

Note 2

It has been agreed that if a nongenotoxic

drug is only positive in rodents at doses

above those producing a 25-fold exposure

over humans, such finding would not be

considered likely to pose a relevant risk to

humans.

It has been shown that systemic exposure

comparisons between rodents and humans

are better estimated by dose using mg/square

meters (m2) than using mg/kg (Note 4 of the

S1C document ‘‘Dose Selection for

Carcinogenicity Studies of

Pharmaceuticals’’). Therefore, the human

dose should be at least 25-fold lower on a

mg/m2 basis than the high dose in the

carcinogenicity study. The factor, 6–7 (6.5),

is used to convert rat doses from mg/kg to

mg/m2 and 40 is used to convert human

doses from mg/kg to mg/m2 . Thus, the

estimated systemic exposure ratio of 25-fold

rodent to human is equal to about a 25-fold

mg/m2 ratio or a 150-fold mg/kg ratio (150 ≈

25 x 40/6.5). Therefore, a human dose below

10 mg/kg/day (about 500 mg/day or less)

could be tested in rats at 1500 mg/kg as the

high dose.

Dated: November 24, 1997.

William K. Hubbard,

Associate Commissioner for Policy

Coordination.

[FR Doc. 97–31780 Filed 12–4–97; 8:45 am]

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