[Federal Register: March 1, 1996 (Volume 61, Number 42)]
[Notices]
[Page 8153-8156]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]

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Part III

Department of Health and Human Services

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Food and Drug Administration

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International Conference on Harmonisation; Notice

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 95D-0217]

International Conference on Harmonisation; Final Guideline on the
Need for Long-Term Rodent Carcinogenicity Studies of Pharmaceuticals;
Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is publishing a final
guideline entitled ``Guideline on the Need for Long-Term Rodent
Carcinogenicity Studies of Pharmaceuticals.'' The guideline was
prepared under the auspices of the International Conference on
Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH). The 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: Effective March 1, 1996. Submit written comments at any time.

ADDRESSES: Submit written comments on the guideline to the Dockets
Management Branch (HFA-305), Food and Drug Administration, 12420
Parklawn Dr., rm. 1-23, Rockville, MD 20857. Copies of the guideline
are available from the Division of Communications Management (HFD-210),
Center for Drug Evaluation and Research, Food and Drug Administration,
7500 Standish Pl., Rockville, MD 20855, 301-594-1012. An electronic
version of this guideline is also available via Internet by connecting
to the CDER file transfer protocol (FTP) server (CDVS2.CDER.FDA.GOV).

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 ICH: Janet Showalter, Office of Health Affairs (HFY-1),
Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857,
301-443-1382.

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 August 21, 1995 (60 FR 43498), FDA
published a draft tripartite guideline entitled ``Conditions Which
Require Carcinogenicity Studies for Pharmaceuticals.'' The notice gave
interested persons an opportunity to submit comments by October 5,
1995.
    After consideration of the comments received and revisions to the
guideline, a final draft of the guideline was submitted to the ICH
Steering Committee and endorsed by the three participating regulatory
agencies at the ICH meeting held on November 29, 1995.
    The 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. 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 the maximum duration of
patient treatment and any perceived cause for concern arising from
other investigations. Other factors may also be considered such as the
intended patient population, prior assessment of carcinogenic
potential, the extent of systemic exposure, the (dis)similarity to
endogenous substances, the appropriate study design, or the timing of
study performance relative to clinical development.
    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). Although this
guideline does not create or confer any rights on or for any person and
does not operate to bind FDA in any way, it does represent the agency's
current thinking on long-term rodent carcinogenicity studies of
pharmaceuticals.
    As with all of FDA's guidelines, the public is encouraged to submit
written comments with new data or other new information pertinent to
this guideline. The comments in the docket will be periodically
reviewed, and, where appropriate, the guideline 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
final 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 guideline and
received comments may be seen in the office above between 9 a.m. and 4
p.m., Monday through Friday.
    The text of the guideline follows:

-Guideline on the Need for Long-Term Rodent Carcinogenicity Studies of
Pharmaceuticals

 1. Introduction

    The objectives of carcinogenicity studies are to identify a
tumorigenic potential in

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animals and to assess the relevant 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 be
performed only when human exposure warrants the need for information
from life-time studies in animals in order to assess carcinogenic
potential.

 2. Historical Background

    In Japan, according to the 1990 ``Guidelines for Toxicity
Studies of Drugs Manual,'' carcinogenicity studies were needed if
the clinical use was expected to be continuously for 6 months or
longer. If there was cause for concern, pharmaceuticals generally
used continuously for less than 6 months may have needed
carcinogenicity studies. In the United States, most pharmaceuticals
were tested in animals for their carcinogenic potential before
widespread use in humans. According to the U.S. Food and Drug
Administration, pharmaceuticals generally used for 3 months or more
necessitated carcinogenicity studies. In Europe, the Rules Governing
Medicinal Products in the European Community defined the
circumstances when carcinogenicity studies were required. These
circumstances included 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 was
similar.

3. Objective of the Guideline-

    The objective of this guideline is to define the conditions
under which carcinogenicity studies should be conducted 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 the maximum duration of patient
treatment and any perceived cause for concern arising from other
investigations. Other factors may also be considered such as the
intended patient population, prior assessment of carcinogenic
potential, the extent of systemic exposure, the (dis)similarity to
endogenous substances, the appropriate study design, or the timing
of study performance relative to clinical development.

 4. Factors to Consider for Carcinogenicity Testing

 4.1 Duration and Exposure

     Carcinogenicity studies should be performed for any
pharmaceutical whose expected clinical use is continuous for at
least 6 months (see Note 1).
     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 a clinically relevant treatment
period 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. 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 duration of exposure (e.g., anesthetics and radiolabeled
imaging agents) do not need carcinogenicity studies unless there is
cause for concern.

 4.2 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) Previous demonstration of carcinogenic potential in the
product class that is considered relevant to humans; (2) structure-
activity relationship suggesting carcinogenic risk; (3) evidence of
preneoplastic lesions in repeated dose toxicity studies; and (4)
long-term tissue retention of parent compound or metabolite(s)
resulting in local tissue reactions or other pathophysiological
responses.

 4.3 Genotoxicity

     Unequivocally genotoxic compounds, in the absence of other
data, are presumed to be transspecies carcinogens, implying a hazard
to humans. Such compounds need not be subjected to long-term
carcinogenicity studies. However, if such a drug is intended to be
administered chronically to humans, a chronic toxicity study (up to
1 year) may be necessary to detect early tumorigenic effects.
     Assessment of the genotoxic potential of a compound should 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 single positive result in any assay for
genotoxicity does not necessarily mean that the test compound poses
a genotoxic hazard to humans (see the ICH Guideline on Specific
Aspects of Regulatory Genotoxicity Tests).

 4.4 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 serious
diseases, carcinogenicity testing need not be conducted before
market approval although these studies should be conducted post-
approval. This speeds the availability of pharmaceuticals for life-
threatening or severely debilitating diseases, especially where no
satisfactory alternative therapy exists.
     In instances where the life-expectancy in the indicated
population is short (i.e., less than 2 to 3 years), no long-term
carcinogenicity studies may be required. 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.

 4.5 Route of Exposure

     The route of exposure in animals should be the same as the
intended clinical route when feasible (see the ICH Guideline on Dose
Selection for Carcinogenicity Studies of Pharmaceuticals). If
similar metabolism and systemic exposure can be demonstrated by
differing routes of administration, carcinogenicity studies should
only be conducted by a single route, recognizing that it is
important that relevant organs for the clinical route (e.g., lung
for inhalational agents) be adequately exposed to the test material.
Evidence of adequate exposure may be derived from pharmacokinetic
data (see the ICH Guideline on Repeated Dose Tissue Distribution
Studies).

 4.6 Extent of Systemic Exposure

     Pharmaceuticals applied topically (e.g., dermal and ocular
routes of administration) may need carcinogenicity studies.
Pharmaceuticals showing poor systemic exposure from topical routes
in humans may not need studies by the oral route to assess the
carcinogenic potential to internal organs. Where there is cause for
concern for photocarcinogenic potential, carcinogenicity studies by
dermal application (generally in mice) may be needed.
Pharmaceuticals administered by the ocular route may not need
carcinogenicity studies unless there is cause for concern or unless
there is significant systemic exposure.
     For different salts, acids, or bases of the same therapeutic
moiety, where prior carcinogenicity studies are available, evidence
should be provided that there are

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no significant changes in pharmacokinetics, pharmacodynamics, or
toxicity. When changes in exposure and consequent toxicity are
noted, additional bridging studies may be used 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.

 4.7 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 (e.g., animal insulins, pituitary-
derived growth hormone, and calcitonin).
     Although not usually necessary, long-term carcinogenicity
studies in rodent species should be considered for the other
biotechnology products noted above if indicated by the treatment
duration, clinical indication, or patient population (provided
neutralizing antibodies are not elicited to such an extent in
repeated dose studies as to invalidate the results). Conduct of
carcinogenicity studies may be important 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).

 5. 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. Mechanistic studies are
useful to evaluate the relevance of tumor findings in animals for
human safety.
    Supplementary Note-
    Note 1: It is expected that most pharmaceuticals indicated for
3-months treatment would also likely be used for 6 months. In an
inquiry to a number of pharmaceutical research and regulatory
groups, no cases were identified in which a pharmaceutical would be
used only for 3 months.

    Dated: February 23, 1996
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-4791 Filed 2-29-96; 8:45 am]
BILLING CODE 4160-01-F