[Federal Register Volume 61, Number 163 (Wednesday, August 21, 1996)]
[Notices]
[Pages 43298-43300]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-21230]


      

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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; Draft Guideline on Testing 
for Carcinogenicity of Pharmaceuticals; Notice

  Federal Register / Vol. 61, No. 163 / Wednesday, August 21, 1996 / 
Notices  

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

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


International Conference on Harmonisation; Draft Guideline 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 draft 
guideline entitled ``Testing for Carcinogenicity of Pharmaceuticals.'' 
This 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 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: Written comments by October 21, 1996.

ADDRESSES: Submit written comments on the draft guideline entitled 
``Testing for Carcinogenicity of Pharmaceuticals'' 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, 
7500 Standish Pl., Rockville, MD 20855, 301-594-1012; written requests 
for single copies of the ICH documents can be submitted to the 
Manufacturers Assistance and Communication Staff (HFM-42), Center for 
Biologics Evaluation and Research, Food and Drug Administration, 1401 
Rockville Pike, Rockville, MD 20852-1448. Send one self-addressed 
adhesive label to assist that office in processing your requests. The 
document may also be obtained by mail or FAX by calling the Center for 
Biologics Evaluation and Research Voice Information System at 1-800-
835-4709.
    Persons with access to the INTERNET may obtain the document in 
several ways.
     Users of ``Web Browser'' software, such as Mosaic, Netscape, or 
Microsoft Internet Explorer may obtain this document via the World Wide 
Web by using the following Uniform Resource Locators (URL's):
    http://www.fda.gov/cber/cberftp.html
    ftp://ftp.fda.gov/CBER/
 The document may also be obtained via File Transfer Protocol (FTP). 
Requesters should connect to the FDA FTP Server, FTP.FDA.GOV 
(192.73.61.21). The Center for Biologics Evaluation and Research's 
(CBER's) documents are maintained in a subdirectory called ``CBER'' on 
the server. Logins with the user name of anonymous are permitted, and 
the user's e-mail address should be sent as the password.
    The ``READ.ME'' file in that subdirectory describes the available 
documents which may be available as an ASCII text file (*.TXT), or a 
WordPerfect 5.1 or 6.x document (*.w51,wp6), or both.
    The document can be obtained by ``bounce-back e-mail.'' A message 
should be sent to: ICH[email protected].
    Finally, an electronic version of this guideline is available via 
the U.S. Government Printing Office's ``GPO Access.'' Internet users 
can access the database through the World Wide Web; the Superintendent 
of Documents home page address is http://www.access.gpo.gov/su--
docs/

FOR FURTHER INFORMATION CONTACT:
    Regarding the guideline: Joseph Contrera, Center for Drug 
Evaluation and Research (HFD-900), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-443-4750.
    Regarding 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 it 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 April 30, 1996, the ICH Steering Committee 
agreed that a draft guideline entitled ``Testing for Carcinogenicity of 
Pharmaceuticals'' should be made available for public comment. The 
draft guideline is the product of the Safety Expert Working Group of 
ICH. Comments are requested on this draft and will be considered by FDA 
and the Safety Expert Working Group. Ultimately, FDA intends to adopt 
the ICH Steering Committee's 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 draft guideline 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.
    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).

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Although this guideline does not create or confer any rights for or on 
any person and does not operate to bind FDA, it does represent the 
agency's current thinking on methods for evaluating the carcinogenic 
activity of pharmaceuticals.
    Although not required, FDA would normally provide at least a 75-day 
comment period and preferably a 90-day comment period to provide 
interested persons with ample time to review and comment upon this type 
of action. However, the comment period for this draft guideline has 
been shortened to 60 days so that comments and scientific data can be 
received by FDA in time to be discussed at an upcoming ICH meeting 
involving this guideline.
    Interested persons may, on or before October 21, 1996, 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.
    The text of the draft guideline follows:

Testing for Carcinogenicity of Pharmaceuticals

1. Objective

    This document provides guidance on methods for evaluating the 
carcinogenic activity of pharmaceuticals.

2. Background

    The current regulatory requirements for the assessment of the 
carcinogenic potential of pharmaceuticals in the three regions 
(E.U., Japan, U.S.) provide for the conduct of long-term 
carcinogenicity studies in two rodent species, usually the rat and 
the mouse. Given the cost of bioassays and their extensive use of 
animals, 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 guideline should be read in conjunction with other 
guidelines, especially:
    S1.A: Guideline on the Need for Carcinogenicity Studies of 
Pharmaceuticals.
    S1.C: 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 guideline 
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 question of whether 
the use of rats or mice alone would result in the loss of 
information on carcinogenicity relevant to human risk assessment has 
been addressed by a survey of six pharmaceutical data bases. The 
data bases 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 European Medicines 
Evaluation Agency (Committee for Proprietary Medicinal Products) 
(CPMP), and the UK Centre for Medicines Research (CMR). The 
dimensions of these data bases and the principal conclusions of the 
analyses can be found in the Proceedings of the Third International 
Conference (1995) on Harmonization.
    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 and companies 
developing drugs. The conduct of only one long-term carcinogenicity 
study (rather than two) would, in part, allow resources to be 
diverted towards other currently evolving experimental approaches. 
The totality of the data derived from one long-term study and other 
appropriate experimental investigations contribute to a ``weight of 
evidence'' approach that should improve the assessment of 
carcinogenic risk to humans.

3. Scope of the Guideline

    The guideline embraces all pharmaceutical agents, including 
biotechnology-derived pharmaceuticals, that need carcinogenic 
testing as indicated by Guidelines S1A and S6.

4. The Guideline

4.1 Preamble.

    The decision to conduct a long-term carcinogenicity study of a 
pharmaceutical is made only after the acquisition of certain key 
units of information, including the results of genetic toxicology 
(Guidelines S2A and S2B), intended patient population, clinical 
dosage regimen (Guideline S1A), pharmacodynamics, in animals and in 
humans (selectivity, dose-response) (Guideline S1C), and repeated-
dose toxicology in two species. Repeated-dose toxicology studies in 
any species (including nonrodents) may indicate that the test 
compound possesses immunosuppressant properties or hormonal activity 
known 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 activity.

    Flexibility and judgment should be exercised in the choice of 
approach. It 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 accurately the carcinogenic potential of a chemical in 
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 
(see Note 2).

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

    The species selected should be the most appropriate one, based 
on considerations that may include the following comparative studies 
in two or more rodent species:
    (a) Pharmacology.
    (b) Repeated-dose toxicology studies.
    (c) Metabolism (see also Guidelines S1C and S3A).
    (d) Toxicokinetics (see also Guidelines 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 tests for carcinogenic activity in vivo.

    (a) Short or medium-term rodent test systems.
    Possibilities include the use of models providing insight into 
carcinogenic endpoints in vivo. These may include models of 
initiation-promotion in rodents, or transgenic rodents, or new-born 
rodents (Note 3).
    (b) A long-term carcinogenicity study in a second rodent 
species.
    It is still acceptable to conduct a long-term carcinogenicity 
study in a second rodent species.

5. Mechanistic Studies

    Mechanistic studies are often useful for the interpretation of 
tumor findings in a carcinogenicity study, and to provide a 
perspective on their relevance to human risk assessment. The choice 
of investigative study will be dictated by the particular properties 
of the drug and/or the specific results from carcinogenicity 
testing. 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, or 
changes in intercellular communication.

5.2. Biochemical measurements.

    Depending on the putative mode of action, investigations could 
involve measurements of and dose-dependency of such areas as 
circulating prolactin, thyroid stimulating hormone, luteinizing 
hormone, 17-estradiol, gastrin, cholecystokinin, binding to 
2-globulin, and growth factors.
    In some situations, it may be possible to test a hypothesis of, 
for example, a hormone imbalance with another study in which the

[[Page 43300]]

imbalance has been, at least in part, compensated.

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

    Additional genotoxicity testing in appropriate models may be 
invoked for compounds that were negative in the standard 3-test 
battery but which 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., liver UDS test, 32P-
postlabeling, mutation induction in transgenes).

5.4. Modified protocols.

    Sponsors are encouraged to develop modified protocols that may 
clarify the mode of 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 the Most Appropriate Species

    There are several general considerations which, in the absence 
of other clear indications, suggest that the rat will normally be 
the species of choice for a bioassay.

6.1. Information from pharmaceutical data bases.

    In the analysis of the six data bases, 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 between the data bases, 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 in 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 data bases accessible in the literature, the 
pharmaceutical data bases were dominated by the high incidence of 
rodent liver tumors. The high susceptibility of rodent 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 frequently make 
the use of the rodent for this purpose misleading.

6.2. Potential to study mechanisms.

    The carcinogenic activity of nongenotoxic chemicals in rodents 
is characterized by a 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 of receptors and receptor sub-types. 
Receptor-mediated carcinogenesis is of growing importance. Nearly 
all 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 bioassays. 
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. Nearly all of this research activity is confined to rats 
and humans. Therefore, in the near future at least, it appears that 
mice would be less likely to provide metabolic information useful in 
mechanistic studies.

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 required when mice are subject 
to such investigations.

6.5. Exceptions.

    Despite the above considerations, there may be circumstances 
when the mouse or another rodent species could be justified on 
mechanistic, metabolic, or other grounds as being a more appropriate 
species than the rat for human risk assessment.

Notes

    Note 1. Data from cell transformation assays can be useful at 
the compound selection stage. Data exist in the literature for over 
200 agents including rodent carcinogens and noncarcinogens that have 
been tested in both cell transformation assays and in long-term 
rodent carcinogenicity tests.
    Note 2. If the findings of a long-term carcinogenicity study and 
of genotoxicity tests and other data indicate that a pharmaceutical 
poses a carcinogenic hazard to humans, a second carcinogenicity 
study would not be necessary.
    Note 3. Several experimental methods are currently under 
investigation but, thus far, relatively few pharmaceutical agents 
have been evaluated. During the ICH Step 2 to Step 3 process, i.e., 
during the open comment period, interested parties are invited to 
submit information on in vivo models for which there is currently 
sufficient experience available for human risk assessment. The 
evaluation will include consideration of animal numbers and welfare. 
The following list of approaches may be revised in the light of 
further information.
    (a) One rat initiator-promoter model for the detection of 
hepatocarcinogens (and modifiers of hepatocarcinogenicity) employs 
an initiator, followed by several weeks' exposure to the test 
substance. Another multi-organ model employs up to five initiators 
followed by several months' exposure to the test substance.
    (b) Several transgenic mouse assays are currently under 
evaluation. These include the p53 deficient model, the TG.AC model, 
the ras H2 model, the E-pim-1 model, the TGF- 
model, the XPA deficient model, etc.
    (c) Neonatal rodents have been studied since the 1960's. The 
chemicals tested are mostly genotoxic. A number of nongenotoxic 
pharmaceutical agents are currently being evaluated.

Other ICH Guidelines Cited

    Guideline S2A: Notes for Guidance on Specific Aspects of 
Regulatory Genotoxicity Tests.
    Guideline S2B: A Standard Battery of Genotoxicity Testing of 
Pharmaceuticals.
    Guideline S3A: Notes for Guidance on Toxicokinetics. The 
Assessment of Systemic Exposure in Toxicity Studies.
    Guideline S3B: Guidance on Repeat-Dose Tissue Distribution 
Studies.
    Guideline S6: Preclinical Testing of Biotechnology-derived 
Pharmaceuticals.

    Dated: August 13, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-21230 Filed 8-20-96; 8:45 am]
BILLING CODE 4160-01-F