[Federal Register Volume 62, Number 63 (Wednesday, April 2, 1997)]
[Notices]
[Pages 15715-15716]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-8353]


-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES
[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 long-term 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

[[Page 15716]]

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