[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]
[[Page 43297]]
_______________________________________________________________________
Part III
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
International Conference on Harmonisation; Draft Guideline on Testing
for Carcinogenicity of Pharmaceuticals; Notice
Federal Register / Vol. 61, No. 163 / Wednesday, August 21, 1996 /
Notices
[[Page 43298]]
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.
-----------------------------------------------------------------------
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).
[[Page 43299]]
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
