[Federal Register Volume 62, Number 233 (Thursday, December 4, 1997)]
[Notices]
[Pages 64260-64261]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-31780]



[[Page 64259]]

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Part II





Department of Health and Human Services





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Food and Drug Administration



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International Conference on Harmonisation; Guidance on Dose Selection 
for Carcinogenicity Studies of Pharmaceuticals: Addendum on a Limit 
Dose and Related Notes; Availability; Notice

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

[[Page 64260]]



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.

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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 long-term 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\
---------------------------------------------------------------------------

    \1\ 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.
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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

[[Page 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-by-case 
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]
BILLING CODE 4160-01-F