[Federal Register Volume 60, Number 161 (Monday, August 21, 1995)]
[Notices]
[Pages 43498-43500]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-20610]
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[Docket No. 95D-0217]
International Conference on Harmonisation; Draft Guideline on
Conditions Which Require Carcinogenicity Studies for Pharmaceuticals;
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 ``Conditions Which Require Carcinogenicity Studies
for Pharmaceuticals.'' This 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 for which
carcinogenicity studies should be conducted, to provide guidance to
avoid the unnecessary use of animals in testing, and to provide
consistency in worldwide regulatory assessments of applications.
DATES: Written comments by October 5, 1995.
ADDRESSES: Submit written comments on the draft guideline to the
Dockets Management Branch (HFA-305), Food and Drug Administration, rm.
1-23, 12420 Parklawn Dr., Rockville, MD 20857. Copies of the draft
guideline are available from the CDER Executive Secretariat Staff (HFD-
8), Center for Drug Evaluation and Research, Food and Drug
Administration, 7500 Standish Pl., Rockville, MD 20855.
FOR FURTHER INFORMATION CONTACT:
Regarding the guideline: Joy A. Cavagnaro, Center for Biologics
Evaluation and Research (HFM-500), Food and Drug Administration, 1401
Rockville Pike, Rockville, MD 20852, 301-827-0379.
Regarding the 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.
At a meeting held on March 29, 1995, the ICH Steering Committee
agreed that a draft guideline entitled ``Conditions Which Require
Carcinogenicity Studies for Pharmaceuticals'' 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 Expert Working Group. Ultimately, FDA intends
to adopt the ICH Steering Committee's final guideline.
The draft guideline is intended to define the conditions which
require carcinogenicity studies, to provide guidance in order to avoid
the unnecessary use of animals in testing, and to provide consistency
in worldwide regulatory assessments of applications. The objectives of
carcinogenicity studies are to identify a tumorigenic potential in
animals and to understand the potential for such risk in humans. Any
cause for concern derived from laboratory investigations, animal
toxicity studies, and data in humans may lead to a need for
carcinogenicity studies. The fundamental considerations in assessing
the need for carcinogenicity studies are any perceived cause for
concern arising from other investigations and the maximum duration of
patient treatment. Other factors may also be considered such as the
appropriate study design, the timing of study performance relative to
clinical development, the intended patient population, prior assessment
of carcinogenic potential, the extent of systemic exposure, or the
(dis)similarity to endogenous substances.
In the past, guidelines have generally been issued under
Sec. 10.90(b) (21 CFR 10.90(b)), which provides for the use of
guidelines to state procedures or standards of general applicability
that are not legal requirements but are acceptable to FDA. The agency
is now in the process of revising Sec. 10.90(b). Therefore, this
guideline is not being issued under the authority of Sec. 10.90(b), and
it does not create or confer any rights, privileges, or benefits for or
on any person, nor does it operate to bind FDA in any way.
Interested persons may, on or before October 5, 1995, submit to the
Dockets Management Branch (address above) written comments on the draft
guideline. 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
[[Page 43499]]
a.m. and 4 p.m., Monday through Friday.
The text of the draft guideline follows:
Conditions Which Require Carcinogenicity Studies for Pharmaceuticals
Purpose
The objectives of carcinogenicity studies are to identify a
tumorigenic potential in animals and to understand the potential for
such risk in humans. Any cause for concern derived from laboratory
investigations, animal toxicology studies, and data in humans may
lead to a need for carcinogenicity studies. The practice of
requiring carcinogenicity studies in rodents was instituted for
pharmaceuticals that were expected to be administered regularly over
a substantial part of a patient's lifetime. The design and
interpretation of the results from these studies preceded much of
the available current technology to test for genotoxic potential and
the more recent advances in technologies to assess systemic
exposure. These studies also preceded our current understanding of
tumorigenesis with nongenotoxic agents. Results from genotoxicity
studies, toxicokinetics, and mechanistic studies can now be
routinely applied in preclinical safety assessment. These additional
data are important not only in considering whether to perform
carcinogenicity studies but for interpreting study outcomes with
respect to relevance for human safety. Since carcinogenicity studies
are time consuming and resource intensive they should only be
performed when human exposure warrants the need for information from
life-time studies in animals in order to assess carcinogenic
potential.
Historical Background
In Japan, according to the 1990 ``Guidelines for Toxicity
Studies of Drugs Manual,'' carcinogenicity studies are needed if the
clinical use is expected to be continuously for 6 months or longer.
If there is cause for concern, pharmaceuticals generally used
continuously for less than 6 months may need carcinogenicity
studies. In the United States, most pharmaceuticals are tested in
animals for their carcinogenic potential before widespread use in
humans. According to the U.S. Food and Drug Administration,
pharmaceuticals generally used 3 months or more require
carcinogenicity studies. In Europe, the Rules Governing Medicinal
Products in the European Community define the circumstances when
carcinogenicity studies are required. These circumstances include
administration over a substantial period of life, i.e., continuously
during a minimum period of 6 months or frequently in an intermittent
manner so that the total exposure is similar.
Introduction
The objective of this guideline is to define the conditions that
require carcinogenicity studies, to provide the appropriate guidance
to avoid the unnecessary use of animals in testing, and to provide
consistency in worldwide regulatory assessments of applications. It
is expected that these studies will be performed in a manner that
reflects currently accepted scientific standards.
The fundamental considerations in assessing the need for
carcinogenicity studies are any perceived cause for concern arising
from other investigations and the maximum duration of patient
treatment. Other factors may also be considered such as the
appropriate study design, the timing of study performance relative
to clinical development, the intended patient population, prior
assessment of carcinogenic potential, the extent of systemic
exposure, or the (dis)similarity to endogenous substances.
For novel compounds, for which the pharmacologic profile or
spectrum of biological effects is poorly understood, mechanistic
studies may be particularly appropriate. Important research
initiatives over the next decade will include optimization of study
designs, modifications in diet, and development of new animal
models, such as the newborn mouse, partially hepatectomized rats,
and transgenic animals.
Cause for Concern
Carcinogenicity studies may be recommended for some
pharmaceuticals if there is concern about their carcinogenic
potential. Criteria for defining these cases should be very
carefully considered because this is the most important reason to
conduct carcinogenicity studies for most categories of
pharmaceuticals. Several factors which could be considered may
include: (1) Findings in genotoxicity studies (Note 1); (2) previous
demonstration of carcinogenic potential in the product class that is
considered relevant to humans; (3) structure-activity relationship
suggesting genotoxic or carcinogenic risk; (4) evidence of
preneoplastic toxicity in repeated dose toxicity studies; and (5)
long-term tissue retention of parent compound or metabolite(s)
resulting in local tissue reactions or other pathophysiological
responses.
Duration and Exposure
Carcinogenicity studies should be performed for any
pharmaceutical whose expected clinical use is continuous for at
least 6 months. It is expected that most pharmaceuticals indicated
for 3-months treatment would also likely be used for 6 months.
Certain classes of compounds may not be used continuously over a
minimum of 6 months but may be expected to be used repeatedly in an
intermittent manner. It is difficult to determine and to justify
scientifically what time represents clinically relevant treatment
periods for frequent use with regard to carcinogenic potential,
especially for discontinuous treatment periods. For pharmaceuticals
used frequently in an intermittent manner in the treatment of
chronic or recurrent conditions, carcinogenicity studies are
generally needed. Some examples of such conditions include allergic
rhinitis, depression, and anxiety. Carcinogenicity studies may also
need to be considered for certain delivery systems which may result
in prolonged exposures. Pharmaceuticals administered infrequently or
for short durations of exposure (e.g., anesthetics and radiolabeled
imaging agents) do not need carcinogenicity studies unless there is
cause for concern.
Indication and Patient Population
When carcinogenicity studies are required they usually need to
be completed before application for marketing approval. However,
completed rodent carcinogenicity studies are not needed in advance
of the conduct of large scale clinical trials, unless there is
special concern for the patient population.
For pharmaceuticals developed to treat certain diseases it is
not considered appropriate to require carcinogenicity testing before
market approval. For example, oncolytic agents intended for
treatment of advanced systemic disease do not generally need
carcinogenicity studies. In cases where the therapeutic agent for
cancer is generally successful and life is significantly prolonged
there may be later concerns regarding secondary cancers. When such
pharmaceuticals are intended for adjuvant therapy in tumor free
patients or for prolonged use in noncancer indications,
carcinogenicity studies are usually needed. In other cases to speed
the availability of pharmaceuticals for life-threatening or severely
debilitating diseases, especially where no satisfactory alternative
therapy exists, carcinogenicity studies may be completed
postapproval.
Route of Exposure
The route of exposure in animals should be the same as the
intended clinical route when feasible (reference ICH Safety Topic
S1C). If similar metabolism and systemic exposure can be
demonstrated by differing routes of administration, then it is only
necessary to conduct carcinogenicity studies by a single route. It
is important that relevant organs for the clinical effect be
adequately exposed to the test material. Evidence of adequate
exposure may be derived from pharmacokinetic data (reference ICH
Safety Topic S3B).
Extent of Systemic Exposure
Pharmaceuticals applied topically (e.g., dermal and ocular
routes of administration) may need carcinogenicity studies. Where
there is cause for concern for photocarcinogenic potential or if
chronic irritation occurs, carcinogenicity studies by dermal
application (generally in mice) may be needed. Pharmaceuticals
showing poor systemic exposure from topical routes may not need
studies by the oral route to assess the carcinogenic potential to
internal organs.
For different salts, acids, or bases of the same therapeutic
moiety, where prior carcinogenicity studies are available, evidence
should be provided that there are no significant changes in
pharmacokinetics, pharmacodynamics, or toxicity. When changes in
exposure and consequent toxicity are noted, then the results of
additional bridging studies may be necessary to determine whether
additional carcinogenicity studies are needed. For esters and
complex derivatives, similar data would be valuable in assessing the
need for an additional carcinogenicity study, but this should be
considered on a case-by-case basis.
[[Page 43500]]
Endogenous Peptides and Protein Substances or Their Analogs
Endogenous peptides or proteins and their analogs, produced by
chemical synthesis, by extraction/purification from an animal/human
source or by biotechnological methods such as recombinant DNA
technology may require special considerations.
Carcinogenicity studies are not generally needed for endogenous
substances given essentially as replacement therapy (i.e.,
physiological levels), particularly where there is previous clinical
experience with similar products (for example, animal insulins,
pituitary-derived growth hormone, and calcitonin).
The need for carcinogenicity studies in rodent species should be
considered if indicated by the treatment duration, clinical
indication, or patient population (providing neutralizing antibodies
are not elicited to such an extent in repeated dose studies as to
invalidate the results). Carcinogenicity studies may be needed in
the following circumstances: (1) For products where there are
significant differences in biological effects to the natural
counterpart(s); (2) for products where modifications lead to
significant changes in structure compared to the natural
counterpart; and (3) for products resulting in humans in a
significant increase over the existing local or systemic
concentration (i.e., pharmacological levels).
Need for Additional Testing
The relevance of the results obtained from animal
carcinogenicity studies for assessment of human safety are often
cause for debate. Further research may be needed, investigating the
mode of action, which may result in confirming the presence or the
lack of carcinogenic potential for humans. When it is considered
important to evaluate the relevance of tumor findings in animals for
human safety, mechanistic studies are essential.
Supplementary Notes
Note 1: Assessment of the genotoxic potential of a compound must
take into account the totality of the findings and acknowledge the
intrinsic value and limitations of both in vitro and in vivo tests.
The test battery approach of in vitro and in vivo tests is designed
to reduce the risk of false negative results for compounds with
genotoxic potential. A positive result in any assay for genotoxicity
does not necessarily mean that the test compound poses a genotoxic
hazard to humans (reference ICH Safety Topic S2A).
Dated: August 14, 1995.
William K. Hubbard,
Acting Deputy Commissioner for Policy.
[FR Doc. 95-20610 Filed 8-18-95; 8:45 am]
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