[Federal Register Volume 63, Number 35 (Monday, February 23, 1998)]
[Notices]
[Pages 8983-8986]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-4373]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 96D-0235]


International Conference on Harmonisation; Guidance on Testing 
for Carcinogenicity of Pharmaceuticals

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is publishing a 
guidance entitled ``S1B Testing for Carcinogenicity of 
Pharmaceuticals.'' 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 
outlines experimental approaches to evaluating the carcinogenic 
potential of pharmaceuticals to humans that may obviate the necessity 
for the routine conduct of two long-term rodent carcinogenicity 
studies.

DATES: Effective February 23, 1998. 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. Single copies of the draft 
guidance may be obtained by mail from the Office of Communication, 
Training and Manufacturers Assistance (HFM-40), Center for Biologics 
Evaluation and Research (CBER), or by calling the CBER Voice 
Information System at 1-800-835-4709 or 301-827-1800. Copies may be 
obtained from CBER's FAX Information System at 1-888-CBER-FAX or 301-
827-3844.

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 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

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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, 1996 (61 FR 43298), FDA 
published a draft tripartite guideline entitled ``Testing for 
Carcinogenicity of Pharmaceuticals'' (S1B). The notice gave interested 
persons an opportunity to submit comments by October 21, 1996.
    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.
    Long-term rodent carcinogenicity studies for assessing the 
carcinogenic potential of pharmaceuticals to humans are currently 
receiving critical examination. Many investigations have shown that it 
is possible to provoke a carcinogenic response in rodents by a 
diversity of experimental procedures, some of which are now considered 
to have little or no relevance for human risk assessment. It is in 
keeping with the mission of ICH to examine whether the need for 
carcinogenicity studies in two species could be reduced without 
compromising human safety. This guidance outlines experimental 
approaches to the evaluation of carcinogenic potential that may obviate 
the necessity for the routine conduct of two long-term rodent 
carcinogenicity studies for those pharmaceuticals that need such 
evaluation.
    This guidance represents the agency's current thinking on methods 
for evaluating the carcinogenic activity 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.
    As with all of FDA's guidances, 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 at ``http://www.fda.gov/cder/
guidance.index.htm'' or at CBER's World Wide Web site at ``http://
www.fda.gov/cber/cberftp.html''.
    The text of the guidance follows:

S1B Testing for Carcinogenicity of Pharmaceuticals\1\
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    \1\ This guidance represents the agency's current thinking on 
methods for evaluating the carcinogenic activity 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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1. Objective

    This document provides guidance on approaches for evaluating the 
carcinogenic potential of pharmaceuticals.

2. Background

    Historically, the regulatory requirements for the assessment of 
the carcinogenic potential of pharmaceuticals in the three regions 
(EU, Japan, the United States) provided for the conduct of long-term 
carcinogenicity studies in two rodent species, usually the rat and 
the mouse. Given the cost of these studies and their extensive use 
of animals, it is in keeping with the mission of ICH to examine 
whether this practice requiring long-term carcinogenicity studies in 
two species could be reduced without compromising human safety.
    This guidance should be read in conjunction with other 
guidances, especially:
    S1A The Need for Carcinogenicity Studies of Pharmaceuticals.
    S1C Dose Selection for Carcinogenicity Studies of 
Pharmaceuticals.
    Long-term rodent carcinogenicity studies for assessing the 
carcinogenic potential of chemicals (including pharmaceuticals) to 
humans are currently receiving critical examination. Since the early 
1970's, many investigations have shown that it is possible to 
provoke a carcinogenic response in rodents by a diversity of 
experimental procedures, some of which are now considered to have 
little or no relevance for human risk assessment. This guidance 
outlines experimental approaches to the evaluation of carcinogenic 
potential that may obviate the necessity for the routine conduct of 
two long-term rodent carcinogenicity studies for those 
pharmaceuticals that need such evaluation. The relative individual 
contribution of rat and mouse carcinogenicity studies and whether 
the use of rats or mice alone would result in a significant loss of 
information on carcinogenicity relevant to human risk assessment has 
been addressed by six surveys of the data for human pharmaceuticals. 
The surveys were those of the International Agency for Research on 
Cancer (IARC), the U.S. Food and Drug Administration (FDA), the U.S. 
Physicians' Desk Reference (PDR), the Japanese Pharmaceutical 
Manufacturers' Association (JPMA), the EU Committee for Proprietary 
Medicinal Products (CPMP), and the UK Centre for Medicines Research 
(CMR). The dimensions of these surveys and the principal conclusions 
of the analyses can be found in the Proceedings of the Third 
International Conference (1995) on Harmonisation.
    Positive results in long-term carcinogenicity studies that are 
not relevant to the therapeutic use of a pharmaceutical present a 
dilemma to all parties: Regulatory reviewers, companies developing 
drugs, and the public at large. The conduct of one long-term 
carcinogenicity study (rather than two long-term studies) would, in 
part, allow resources to be diverted to other approaches to uncover 
potential carcinogenicity relevant to humans. A ``weight of 
evidence'' approach, that is use of scientific judgment in 
evaluation of the totality of the data

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derived from one long-term carcinogenicity study along with other 
appropriate experimental investigations, enhances the assessment of 
carcinogenic risk to humans.

3. Scope of the Guidance

    The guidance embraces all pharmaceutical agents that need 
carcinogenicity testing as indicated in ICH guidance S1A. For 
biotechnology-derived pharmaceuticals, refer to ICH guidance ``S6 
Preclinical Safety Evaluation of Biotechnology-Derived 
Pharmaceuticals.''

4. The Guidance

4.1 Preamble.

    The strategy for testing the carcinogenic potential of a 
pharmaceutical is developed only after the acquisition of certain 
key units of information, including the results of genetic 
toxicology (ICH guidances ``S2A Guidance on Specific Aspects of 
Regulatory Genotoxicity Tests for Pharmaceuticals'' and ``S2B 
Genotoxicity: A Standard Battery for Genotoxicity Testing of 
Pharmaceuticals''), intended patient population, clinical dosage 
regimen (ICH guidance S1A), pharmacodynamics in animals and in 
humans (selectivity, dose-response) (ICH guidance S1C), and 
repeated-dose toxicology studies. Repeated-dose toxicology studies 
in any species (including nonrodents) may indicate that the test 
compound possesses immunosuppressant properties, hormonal activity, 
or other activity considered to be a risk factor for humans, and 
this information should be considered in the design of any further 
studies for the assessment of carcinogenic potential (see also Note 
1).

4.2 Experimental approaches to testing for carcinogenic potential.

    Flexibility and judgment should be exercised in the choice of an 
approach, which should be influenced by the information cited in the 
above preamble. Given the complexity of the process of 
carcinogenesis, no single experimental approach can be expected to 
predict the carcinogenic potential of all pharmaceuticals for 
humans.
    The basic principle:
    The basic scheme comprises one long-term rodent carcinogenicity 
study, plus one other study of the type mentioned in section 4.2.2 
that supplements the long-term carcinogenicity study and provides 
additional information that is not readily available from the long-
term assay.

4.2.1 Choice of species for a long-term carcinogenicity study.

    The species selected should be appropriate, based on 
considerations that include the following:
    (a) Pharmacology.
    (b) Repeated-dose toxicology.
    (c) Metabolism (see also ICH guidances S1C and ``S3A 
Toxicokinetics: The Assessment of Systemic Exposure in Toxicity 
Studies'').
    (d) Toxicokinetics (see also ICH guidances S1C, S3A, and S3B).
    (e) Route of administration (e.g., less common routes such as 
dermal and inhalation).
    In the absence of clear evidence favoring one species, it is 
recommended that the rat be selected. This view is based on the 
factors discussed in section 6.

4.2.2 Additional in vivo tests for carcinogenicity.

    Additional tests may be either (a) or (b) (see Note 2).
    (a) Short- or medium-term in vivo rodent test systems.
    Possibilities should focus on the use of in vivo models 
providing insight into carcinogenic endpoints. These may include 
models of initiation-promotion in rodents or models of 
carcinogenesis using transgenic or neonatal rodents (Note 3).
    (b) A long-term carcinogenicity study in a second rodent species 
is still considered acceptable (see section 4.2.1 for 
considerations).

4.2.3 Considerations in the choice of short- or medium-term tests for 
carcinogenicity.

    Emphasis should be placed on selection of a test method that can 
contribute information valuable to the overall ``weight of 
evidence'' for the assessment of carcinogenic potential. The 
rationale for this choice should be documented and based on 
information available at the time of method selection about the 
pharmaceutical, such as pharmacodynamics and exposure compared to 
human or any other information that may be relevant. This rationale 
should include a scientific discussion of the strengths and 
weaknesses of the method selected for the pharmaceutical (see Note 
4).

5. Mechanistic Studies

    Mechanistic studies are often useful for the interpretation of 
tumor findings in a carcinogenicity study and can provide a 
perspective on their relevance to human risk assessment. The need 
for or the design of an investigative study will be dictated by the 
particular properties of the drug and/or the specific results from 
the carcinogenicity testing. Dose dependency and the relationship to 
carcinogenicity study conditions should be evaluated in these 
investigational studies. Suggestions include:

5.1 Cellular changes.

    Relevant tissues may be examined for changes at the cellular 
level using morphological, histochemical, or functional criteria. As 
appropriate, attention may be directed to such changes as the dose-
relationships for apoptosis, cell proliferation, liver foci of 
cellular alteration, or changes in intercellular communication.

5.2 Biochemical measurements.

    Depending on the putative mode of tumorigenic action, 
investigations could involve measurements of:
     plasma hormone levels, e.g. T3/T4, TSH, prolactin;
     growth factors;
     binding to proteins such as 2-
globulin;
     tissue enzyme activity, etc.
    In some situations, it may be possible to test a hypothesis of, 
for example, a hormone imbalance with another study in which the 
imbalance has been, at least in part, compensated.

5.3 Considerations for additional genotoxicity testing (see ICH 
guidances S2A and S2B).

    Additional genotoxicity testing in appropriate models may be 
invoked for compounds that were negative in the standard test 
battery but that have shown effects in a carcinogenicity test with 
no clear evidence for an epigenetic mechanism. Additional testing 
can include modified conditions for metabolic activation in in vitro 
tests or can include in vivo tests measuring genotoxic damage in 
target organs of tumor induction (e.g., DNA damage and repair tests, 
32P-postlabeling, mutation induction in transgenes).

5.4 Modified protocols.

    Modified protocols may be helpful to clarify the mode of 
tumorigenic action of the test substance. Such protocols might 
include groups of animals to explore, for example, the consequence 
of interrupted dosage regimens, or the reversibility of cellular 
changes after cessation of dosing.

6. General Considerations in the Choice of an Appropriate Species for 
Long-Term Carcinogenicity Testing

    There are several general considerations that, in the absence of 
other clear indications, suggest that the rat will normally be the 
species of choice for a long-term carcinogenicity study.

6.1 Information from surveys on pharmaceuticals.

    In the six analyses, attention was given to data on genetic 
toxicology, tumor incidence, strain of animal, route and dosage 
regimen, pharmacological or therapeutic activity, development and/or 
regulatory status, and, if relevant, reason for termination of 
development. Inevitably, there was considerable overlap of the data, 
but that is not necessarily an impediment to drawing valid 
conclusions.
    The main overall conclusions from the analysis were:
    a. Although very few instances have been identified of mouse 
tumors being the sole reason for regulatory action concerning a 
pharmaceutical, data from this species may have contributed to a 
``weight of evidence'' decision and to identifying agents that 
caused tumors in two rodent species.
    b. Of the compounds displaying carcinogenic activity in only one 
species, the number of ``rat-only'' compounds was about double the 
number of ``mouse-only'' compounds, implying in a simplistic sense 
that the rat is more ``sensitive'' than the mouse.
    c. As with other surveys accessible in the literature, the data 
for pharmaceuticals were dominated by the high incidence of rodent 
liver tumors. The high susceptibility of mouse liver to nongenotoxic 
chemicals has been the subject of many symposia and workshops. These 
have concluded that these tumors may not always have relevance to 
carcinogenic risk in humans and can potentially be misleading.

6.2 Potential to study mechanisms.

    The carcinogenic activity of nongenotoxic chemicals in rodents 
is characterized by a

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high degree of species, strain, and target organ specificity and by 
the existence of thresholds in the dose-response relationship. 
Mechanistic studies in recent years have permitted the distinction 
between effects that are specific to the rodent model and those that 
are likely to have relevance for humans. Progress has often been 
associated with increased understanding of species and tissue 
specificity. For example, receptor-mediated carcinogenesis is being 
recognized as of growing importance. Most of these advances are 
being made in the rat, and only rarely in the mouse.

6.3 Metabolic disposition.

    Neither rats nor mice would seem, on metabolic grounds, to be a 
priori generally more suitable for the conduct of long-term 
carcinogenicity studies. However, much attention is now being given 
to pharmacokinetic-pharmacodynamic relationships and rapid progress 
is occurring in knowledge of the P-450 isozymes that mediate the 
biotransformation of drugs. Most of this research activity is 
confined to rats and humans. Therefore, in the near future at least, 
where specific information on the P-450 isozymes involved in 
biotransformation is critical for the evaluation, it appears that 
mice would be less likely to provide this mechanistic information.

6.4 Practicality.

    Pertinent to the above two topics is the question of feasibility 
of investigative studies. Size considerations alone put the mouse at 
a severe disadvantage when it comes to the taking of serial blood 
samples, microsurgery/catheterization, and the weighing of organs. 
Blood sampling often requires the sacrifice of the animals, with the 
result that many extra animals may be needed when mice are subject 
to such investigations.

6.5 Testing in more than one species.

    Most of the currently available short- and medium-term in vivo 
models for carcinogenicity testing involve the use of mice. In order 
to allow testing in more than one species for carcinogenic potential 
when this is considered important and appropriate, the rat will 
often be used in the long-term carcinogenicity study.

6.6 Exceptions.

    Despite the above considerations, there may be circumstances 
under which the mouse or another rodent species could be justified 
on mechanistic, metabolic, or other grounds as being a more 
appropriate species for the long-term carcinogenicity study for 
human risk assessment (cf. section 4.2.1). Under such circumstances, 
it may still be acceptable to use the mouse as the short-term or 
medium-term model.

7. Evaluation of Carcinogenic Potential

    Evidence of tumorigenic effects of the drug in rodent models 
should be evaluated in light of the tumor incidence and latency, the 
pharmacokinetics of the drug in the rodent models as compared to 
humans, and data from any ancillary or mechanistic studies that are 
informative with respect to the relevance of the observed effects to 
humans.
    The results from any tests cited above should be considered as 
part of the overall ``weight of evidence,'' taking into account the 
scientific status of the test systems.
Notes
    Note 1. Data from in vitro assays, such as a cell transformation 
assay, can be useful at the compound selection stage.
    Note 2. If the findings of a short- or long-term carcinogenicity 
study and of genotoxicity tests and other data indicate that a 
pharmaceutical clearly poses a carcinogenic hazard to humans, a 
second carcinogenicity study would not usually be useful.
    Note 3. Several experimental methods are under investigation to 
assess their utility in carcinogenicity assessment. Generally, the 
methods should be based on mechanisms of carcinogenesis that are 
believed relevant to humans and applicable to human risk assessment. 
Such studies should supplement the long-term carcinogenicity study 
and provide additional information that is not readily available 
from the long-term assay. There should also be consideration given 
animal numbers, welfare, and the overall economy of the carcinogenic 
evaluation process. The following is a representative list of some 
approaches that may meet these criteria and is likely to be revised 
in the light of further information.
    (a) The initiation-promotion model in rodent. One initiation-
promotion model for the detection of hepatocarcinogens (and 
modifiers of hepatocarcinogenicity) employs an initiator, followed 
by several weeks of exposure to the test substance. Another multi-
organ carcinogenesis model employs up to five initiators followed by 
several months of exposure to the test substance.
    (b) Several transgenic mouse assays, including the p53+/- 
deficient model, the Tg.AC model, the TgHras2 model, the XPA 
deficient model, etc.
    (c) The neonatal rodent tumorigenicity model.
    Note 4. While there may be a number of approaches that will in 
general meet the criteria described in Note 3 for use as the 
additional in vivo study, not all may be equally suitable for a 
particular pharmaceutical. The following are examples of factors 
that should be considered and addressed in the rationale:
    1. Can results from the model provide new information not 
expected to be available from the long-term study that is 
informative with respect to hazard identification and/or risk 
assessment?
    2. Can results from the model address concerns related to the 
carcinogenic process arising from prior knowledge of the 
pharmaceutical or compounds with similar structures and/or 
mechanisms of action? These concerns may include genotoxic, 
mitogenic, promotional, or receptor-mediated effects, etc.
    3. Does the metabolism of the pharmaceutical shown in the animal 
model affect the evaluation of carcinogenic risk for humans?
    4. Is adequate systemic or local exposure attained in relation 
to human exposure?
    5. How extensively has the model been evaluated for its intended 
use? Prior to using any new in vivo methods in testing the 
carcinogenic potential of pharmaceuticals for humans, it is critical 
that the method be evaluated for its ability to contribute to the 
weight of evidence assessment. Many experimental studies are in 
progress (1997) to evaluate the new short or medium tests for 
carcinogenic potential. These include selected pharmaceuticals with 
known potencies and known mechanism of carcinogenic activity in 
rodents and also putative human noncarcinogens. When the results of 
these studies become available, it may be possible to offer more 
specific guidance on which of these tests have the most relevance 
for cancer assessment in humans.
Other ICH Guidances Cited
    ``S2A Guidance on Specific Aspects of Regulatory Genotoxicity 
Tests for Pharmaceuticals.''
    ``S2B Genotoxicity: A Standard Battery for Genotoxicity Testing 
of Pharmaceuticals.''
    ``S3A Toxicokinetics: The Assessment of Systemic Exposure in 
Toxicity Studies.''
    ``S3B Pharmacokinetics: Guidance for Repeated Dose Tissue 
Distribution Studies.''
    ``S6 Preclinical Safety Evaluation of Biotechnology-Derived 
Pharmaceuticals.''

    Dated: February 13, 1998.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 98-4373 Filed 2-20-98; 8:45 am]
BILLING CODE 4160-01-F