[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]
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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.
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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
