[Federal Register Volume 59, Number 40 (Tuesday, March 1, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-4566]
[[Page Unknown]]
[Federal Register: March 1, 1994]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
[Docket No. 94D-0017]
International Conference on Harmonisation; Draft Guideline on
Dose Selection for 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 draft
guideline on dose selection for carcinogenicity studies of
pharmaceuticals. This draft guideline examines criteria for
establishing uniformity among international regulatory agencies for
high dose selection for carcinogenicity studies of human
pharmaceuticals. This draft guideline was prepared by the Expert
Working Group on Safety of the International Conference on
Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH), and it is intended to help ensure
that dose selection for carcinogenicity studies of pharmaceuticals to
support drug registration is carried out according to sound scientific
principles.
DATES: Written comments by May 16, 1994.
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.
FOR FURTHER INFORMATION CONTACT:
Regarding the draft guideline: Alan Taylor, Center for Drug
Evaluation and Research (HFD-502), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-443-2544.
Regarding ICH: Janet Showalter, Office of Health Affairs (HFY-50),
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.
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 other interested parties. Through notices
such as this, FDA invites public comment on ICH initiatives that have
reached the draft guideline stage. 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 Industry Associations, the Japanese
Ministry of Health and Welfare, the Japanese Pharmaceutical
Manufacturers Association, FDA, and the U.S. Pharmaceutical
Manufacturers Association. 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 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 from October 27 through 29, 1993, the ICH
Steering Committee agreed that the draft tripartite guideline entitled
``Dose Selection for Carcinogenicity Studies of Pharmaceuticals''
should be made available for public comment. The draft guideline will
be made available for comment by the European Commission and Japanese
Ministry of Health and Welfare, as well as by FDA, in accordance with
their respective consultation procedures. After analyzing the comments
and revising the guideline, if appropriate, FDA will determine whether
it will adopt and issue the guideline. The draft guideline discusses
criteria for high dose selection for carcinogenicity studies of
pharmaceuticals. Five generally acceptable criteria are dose limiting
pharmacodynamic effects, maximum tolerated dose, a minimum of a 25-fold
area under the concentration-time curve (AUC) ratio (rodent:human),
saturation of absorption, and maximum feasible dose. The draft
guideline also considers other pharmacodynamic-, pharmacokinetic-, or
toxicity-based endpoints in study design based on scientific rationale
and individual merits.
Guidelines are generally issued under Secs. 10.85(d) and 10.90(b)
(21 CFR 10.85(d) and 10.90(b)), which provide for the use of guidelines
to establish procedures or standards of general applicability that are
not legal requirements but that are acceptable to FDA. The agency is
now in the process of considering whether to revise Secs. 10.85(d) and
10.90(b). Therefore, if the agency issues the guideline in final form,
the guideline would not be issued under the authority of Secs. 10.85(d)
and 10.90(b), and would not create or confer any rights, privileges, or
benefits for or on any person, nor would it operate to bind FDA in any
way.
Interested persons may, on or before May 16, 1994, 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 single copies. 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:
Dose Selection for Carcinogenicity Studies of Pharmaceuticals
Introduction
Traditionally, carcinogenicity studies for chemical agents have
relied upon the maximally tolerated dose (MTD) as the standard
method for high dose selection (Note 1). The MTD is generally chosen
based on data derived from toxicity studies of 3 months' duration.
In the past, the criteria for high dose selection for
carcinogenicity studies of human pharmaceuticals have not been
uniform among international regulatory agencies. In Europe and
Japan, dose selection based on toxicity endpoints or attaining high
multiples of the maximum recommended human daily dose (greater than
100 times on a milligram per kilogram (mg/kg) basis) have been
accepted. However, in the United States, dose selection based on the
MTD has traditionally been the only acceptable practice. All regions
have used a maximum feasible dose as an acceptable endpoint (Note
2).
For pharmaceuticals with low rodent toxicity, use of the MTD
may result in the administration of very large doses in
carcinogenicity studies, often representing high multiples of the
clinical dose. The usefulness of an approach developed for genotoxic
substances or radiation exposure where a threshold carcinogenic dose
is not necessarily definable may not be appropriate for nongenotoxic
agents. For nongenotoxic substances where thresholds may exist and
carcinogenicity may result from alterations in normal physiology,
linear extrapolations from high dose effects have been questioned.
This has led to the concern that exposures in rodents greatly in
excess of the intended human exposures may not be relevant to human
risk, because they so greatly alter the physiology of the test
species, the findings may not reflect what would occur following
human exposure.
Ideally, the doses selected for rodent bioassays for
nongenotoxic pharmaceuticals should provide exposures to the agent
that: (1) Allow an adequate margin of safety over the human
therapeutic exposure, (2) are tolerated without significant chronic
physiological dysfunction and are compatible with good survival, (3)
are guided by a comprehensive set of animal and human data that
focuses broadly on the properties of the agent and the suitability
of the animal, and (4) permit data interpretation in the context of
clinical use.
In order to achieve international harmonization of requirements
for high dose selection for carcinogenicity studies of
pharmaceuticals, and to establish a rational basis for high dose
selection, the ICH Expert Working Group on Safety initiated a
process to arrive at mutually acceptable and scientifically based
criteria for high dose selection. Several features of pharmaceutical
agents distinguish them from other environmental chemicals and can
justify a guideline which may differ in some respects from other
guidelines. This should enhance the relevance of the carcinogenicity
study for pharmaceuticals. Thus, much knowledge may be available on
the pharmacology, pharmacokinetics, and metabolic disposition in
humans. In addition, there will usually be information on the
patient population, the expected use pattern, the range of exposure,
and the toxicity and/or side effects that cannot be tolerated in
humans. Diversity of the chemical and pharmacological nature of the
substances developed as pharmaceuticals, plus the diversity of
nongenotoxic mechanisms of carcinogenesis calls for a flexible
approach to dose selection. This document proposes that any one of
several approaches may be appropriate and acceptable for dose
selection, and should provide for a more rational approach to dose
selection for carcinogenicity studies for pharmaceuticals. These
include:
1. Pharmacodynamic endpoints,
2. Toxicity-based endpoints,
3. Pharmacokinetic endpoints,
4. Saturation of absorption,
5. Maximum feasible dose.
Consideration of all relevant animal data and integration with
available human data is paramount in determining the most
appropriate endpoint for selecting the high dose for the
carcinogenicity study. Relevant pharmacokinetic, pharmacodynamic and
toxicity data should always be considered in the selection of doses
for the carcinogenicity study regardless of the primary endpoint
used for high dose selection.
In the process of defining such a flexible approach, it is
recognized that the fundamental mechanisms of carcinogenesis are
only poorly understood at the present time. Further, it is also
recognized that the use of the rodent to predict human carcinogenic
risk has inherent limitations although this approach is the best
available option at this time. Thus, while the use of plasma levels
of drug-derived substances represents an important attempt at
improving the design of the rodent bioassay, progress in this field
will necessitate continuing examination of the best method to detect
human risk. This document is therefore intended to serve as guidance
in this difficult and complex area recognizing the importance of
updating the specific provisions outlined below as new data become
available.
General Considerations for the Conduct of Dose-Ranging Studies
The considerations involved when undertaking dose-ranging
studies to select the high dose for carcinogenicity studies are the
same regardless of the final endpoint utilized.
1. In practice, carcinogenicity studies are carried out in a limited
number of rat and mouse strains for which there are reasonable
information on spontaneous tumor incidence. Ideally, rodent species/
strains with metabolic profiles as similar as possible to humans should
be studied (Note 3).
2. Dose-ranging studies should be conducted for both males and females
for all strains and species to be tested in the carcinogenicity
bioassay.
3. Dose selection is generally determined from 90-day studies using
the route and method of administration that will be used in the
bioassay.
4. Selection of an appropriate dosing schedule and regimen should be
based on clinical use and exposure patterns, pharmacokinetics, and
practical considerations.
5. Ideally, both the toxicity profile and any dose-limiting toxicity
should be characterized. Consideration should also be given to general
toxicity, the occurrence of preneoplastic lesions and/or tissue-
specific proliferative effects, and disturbances in endocrine
homeostasis.
6. Changes in metabolite profile or alterations in metabolizing enzyme
activities (induction or inhibition) over time, should be understood to
allow for appropriate interpretation of studies.
Pharmacodynamic Endpoints in High Dose Selection
The utility and safety of many therapeutics depend on their
pharmacodynamic receptor selectivity. Pharmacodynamic endpoints for
high dose selection will be highly compound-specific and are
considered for individual study designs based on scientific merits
(Note 10). The high dose selected should not produce disturbances of
physiology or homeostasis but should produce a pharmacodynamic
response in dosed animals which would preclude further dose
escalation and compromise the validity of the study.
Toxicity Endpoints in High Dose Selection
ICH 1 agreed to evaluate endpoints other than the MTD for the
selection of the high dose in carcinogenicity studies. These were to
be based on the pharmacological properties and toxicological profile
of the test compound. There is no scientific consensus for the use
of toxicity endpoints other than the MTD. Therefore, the ICH Expert
Working Group on Safety has currently agreed to continue use of the
MTD as an acceptable toxicity-based endpoint for high dose selection
for carcinogenicity studies (Note 1).
Pharmacokinetic Endpoints in High Dose Selection
A systemic exposure representing a large multiple of the human
AUC (at the maximum recommended daily dose) may be an appropriate
endpoint for dose selection for carcinogenicity studies for
nongenotoxic therapeutic agents which have similar metabolic
profiles in humans and rodents and low organ toxicity in rodents
(high doses are well tolerated in rodents). The level of animal
systemic exposure should be sufficiently great, compared to human
exposure, to provide reassurance of an adequate test of
carcinogenicity.
It is recognized that the doses administered to different
species may not correspond to tissue concentrations because of
different metabolic and excretory patterns. Comparability of
systemic exposure is better assessed by blood concentrations of
parent drug and metabolites than by administered dose. The unbound
drug in plasma is thought to be the most relevant indirect measure
of tissue concentrations of unbound drug. The AUC is considered the
most comprehensive pharmacokinetic endpoint since it takes into
account the plasma concentration of the compound and residence time
in vivo.
There is as yet, no validated scientific basis for use of
comparative drug plasma concentrations in animals and humans for the
assessment of carcinogenic risk to humans. However, for the present,
and based on an analysis of a database of carcinogenicity studies
performed at the MTD, the selection of a high dose for
carcinogenicity studies which represents at a minimum a 25-fold
ratio of rodent to human plasma AUC of parent compound and/or
metabolites is considered pragmatic (Note 4).
Criteria for comparisons of AUC in animals and man for use in high
dose selection
The following criteria are especially applicable for use of a
pharmacokinetically-defined exposure for high dose selection.
1. Rodent pharmacokinetic data are derived from the strains used for
the carcinogenicity studies using the route of compound administration
and dose ranges planned for the carcinogenicity study (Notes 5, 6, and
7).
2. Pharmacokinetic data are derived from studies of sufficient
duration to take into account potential time-dependent changes in
pharmacokinetic parameters which may occur during the dose ranging
studies.
3. Documentation is provided on the similarity of exposure to parent
compound and metabolites between rodents and humans.
4. In assessing exposure, scientific judgment is used to determine
whether the AUC comparison is based on data for the parent, parent and
metabolite(s) or metabolite(s). The justification for this decision is
provided.
5. Interspecies differences in protein binding are taken into
consideration when estimating relative exposure (Note 8).
6. Human pharmacokinetic data are derived from studies encompassing
the maximum recommended human daily dose (Note 9).
Saturation of Absorption in High Dose Selection
High dose selection based on saturation of absorption measured
by systemic availability of drug-related substances is acceptable.
The mid and low doses selected for the carcinogenicity study should
take into account saturation of metabolic and elimination pathways.
Additional Endpoints in High Dose Selection
It is recognized that there may be merit in the use of
alternative pharmacokinetic (e.g. Cmax) and toxicity endpoints, not
specifically defined in this guidance on high dose selection for
rodent carcinogenicity studies. Use of these additional endpoints in
individual study designs should be justified. Such designs are
evaluated based on their individual merits (Note 10).
Selection of Middle and Low Doses in Carcinogenicity Studies
Regardless of the method used for the selection of the high
dose, the selection of the mid and low doses for the carcinogenicity
study should provide information to aid in assessing the relevance
of study findings to humans. The doses should be selected following
integration of rodent and human pharmacokinetic, pharmacodynamic,
and toxicity data. The rationale for the selection of these doses
should be provided. While not all-encompassing, the following points
should be considered in selection of the middle and low doses for
rodent carcinogenicity studies:
1. Linearity of pharmacokinetics and saturation of metabolic pathways,
2. Human exposure and therapeutic dose,
3. Pharmacodynamic response in rodents,
4. Alterations in normal rodent physiology,
5. Mechanistic information and potential for threshold effects,
6. The unpredictability of the progression of toxicity observed in
short term studies.
Summary
This guidance outlines five equally acceptable criteria for
selection of the high dose for carcinogenicity studies of
pharmaceuticals: dose limiting pharmacodynamic effects, maximum
tolerated dose, a minimum of a 25-fold AUC ratio (rodent:human),
saturation of absorption, maximum feasible dose. The use of other
pharmacodynamic-, pharmacokinetic- or toxicity-based endpoints in
study design is considered based on scientific rationale and
individual merits. In all cases, appropriate dose ranging studies
need to be conducted. All relevant information should be considered
for dose and species/strain selection for the carcinogenicity study.
This information should include knowledge of human use, exposure
patterns and metabolism. The availability of multiple acceptable
criteria for dose selection will provide greater flexibility in
optimizing the design of carcinogenicity studies for pharmaceutical
agents.
Note 1
The following are considered equivalent definitions of the
toxicity based endpoint describing the maximum tolerated dose:
The U.S. Interagency Staff Group on Carcinogens has defined the
MTD as follows:
``The highest dose currently recommended is that which, when
given for the duration of the chronic study, is just high enough to
elicit signs of minimal toxicity without significantly altering the
animal's normal lifespan due to effects other than carcinogenicity.
This dose, sometimes called the maximum tolerated dose (MTD), is
determined in a subchronic study (usually 90 days duration)
primarily on the basis of mortality, toxicity and pathology
criteria. The MTD should not produce morphologic evidence of
toxicity of a severity that would interfere with the interpretation
of the study. Nor should it comprise so large a fraction of the
animal's diet that the nutritional composition of the diet is
altered, leading to nutritional imbalance.''
``The MTD was initially based on a weight gain decrement
observed in the subchronic study; i.e., the highest dose that caused
no more than a 10% weight gain decrement. More recent studies and
the evaluation of many more bioassays indicate refinement of MTD
selection on the basis of a broader range of biological information.
Alterations in body and organ weight and clinically significant
changes in hematologic, urinary, and clinical chemistry measurements
can be useful in conjunction with the usually more definitive toxic,
pathologic or histopathologic endpoints.'' (See Environmental Health
Perspectives, vol. 67:201-181, 1986.)
The Committee on Proprietary Medicinal Products of the European
Communities prescribes the following: ``The top dose should produce
a minimum toxic effect, for example a 10% weight loss or failure of
growth, or minimal target organ toxicity. Target organ toxicity will
be demonstrated by failure of physiological functions and ultimately
by pathological changes.'' (See ``Rules Governing Medicinal Products
in the European Communities,'' vol. III, 1987.)
The Ministry of Health and Welfare in Japan prescribes the
following:
``The dose in the preliminary carcinogenicity study that
inhibits body weight gain by less than 10% in comparison with the
control and causes neither death due to toxic effects nor remarkable
changes in the general signs and laboratory examination findings of
the animals is the highest dose to be used in the full-scale
carcinogenicity study.'' (See ``Toxicity Test Guideline for
Pharmaceuticals,'' chapter 5, p. 127, 1985.)
Note 2
Currently, the maximum feasible dose by dietary administration
is considered 5 percent of the diet.
Note 3
This does not imply that all possible rodent strains will be
surveyed for metabolic profile. But rather, that standard strains
used in carcinogenicity studies will be examined.
Note 4
In order to select a multiple of the human AUC that would serve
as an acceptable endpoint for dose selection for carcinogenicity
studies, a retrospective analysis was performed on data from FDA
files of carcinogenicity studies of products conducted at the MTD
for which there was sufficient human and rodent pharmacokinetic data
for comparison of AUC values. (See Contrera et al., ``Report to the
ICH Safety Working Group Task Force on Dose Selection for
Carcinogenicity Studies.'')
In 35 drug carcinogenicity studies carried out at the MTD for
which there was adequate pharmacokinetic data in rats and humans,
approximately 1/3 had a relative systemic exposure ratio equal to or
less than 1, and another 1/3 had a ratio greater than 1 and less
than 10 at the MTD.
An analysis of the correlation between the relative systemic
exposure ratio, the relative dose ratio (rat mg/kg MTD:human mg/kg
maximum recommended dose (MRD) and the dose ratio adjusted for body
surface area (rat mg/meter squared (M2) MTD:human mg/M2
MRD), performed in conjunction with the above described database
analysis indicates that the relative systemic exposure corresponds
better with dose ratios expressed in terms of body surface area
rather than of body weight. When 123 compounds in the expanded FDA
database were analyzed by this approach, a similar distribution of
relative systemic exposures was observed.
In the selection of a relative systemic exposure ratio (AUC
ratio) to apply in high dose selection, consideration was given to a
ratio value that would be attainable by a reasonable proportion of
compounds, that would detect known or probable human carcinogens
(International Agency for Research on Cancer (IARC) 1 or 2A) and
that represents an adequate margin of safety.
To address the issue of detection of known or probable human
carcinogenic therapeutics, an analysis of exposure and/or dose
ratios was performed on IARC class 1 and 2A therapeutics with
positive rat findings. For phenacetin, sufficient rat and human
pharmacokinetic data is available to estimate that a relative
systemic exposure ratio of at least 15 is necessary to produce
positive findings in a rat carcinogenicity study. For most of 14
IARC 1 and 2A drugs evaluated with positive carcinogenicity findings
in rats, there is a lack of adequate pharmacokinetic data. For these
compounds, the body surface area adjusted dose ratio was employed as
a surrogate for the relative systemic exposure ratio. The results of
this analysis indicated that using doses in rodents corresponding to
body surface area ratios of 20 or less would identify the
carcinogenic potential of these therapeutics.
As a result of the evaluations described above, a minimum
systemic exposure ratio of 25 is proposed as an acceptable
pharmacokinetic endpoint for high dose selection. This value was
attained by approximately 25 percent of compounds tested, is high
enough to detect known or probable (IARC 1, 2A) human carcinogenic
drugs and represents an adequate margin of safety. Those
therapeutics tested using a 25-fold or greater AUC ratio for the
high dose will have exposure ratios greater than 75 percent of
pharmaceuticals tested previously in carcinogenicity studies
performed at the MTD.
Note 5
The rodent AUC's and metabolite profiles may be determined from
separate steady state kinetic studies, as part of the subchronic
toxicity studies, or dose ranging studies.
Note 6
AUC values in rodents are usually obtainable using a small
number of animals (e.g. four or more time points with as few as four
animals each), depending on the route of administration and the
availability of data on the pharmacokinetic characteristics of the
test compound.
Note 7
Equivalent analytical methods of adequate sensitivity and
precision are used to determine plasma concentrations of
therapeutics in rodents and humans.
Note 8
For example, when protein binding is low in both humans and
rodents or when protein binding is high and the unbound fraction of
drug is greater in rodents than in man, the comparison of total
plasma concentration of drug is acceptable. When protein binding is
high and the unbound fraction is greater in man than in rodents, the
ratio of the unbound concentrations should be used.
Note 9
Human systemic exposure data may be derived from
pharmacokinetic monitoring in normal volunteers and/or patients. In
the absence of knowledge of the maximum recommended human daily
dose, at a minimum, doses producing the desired pharmacodynamic
effect in humans are used to derive the pharmacokinetic data.
Note 10
When using any new endpoint, either pharmacokinetic,
pharmacodynamic, or toxicity based for high dose selection it is
necessary to carefully consider, prior to carcinogenicity study
initiation, if the endpoint can insure the acceptability of the
carcinogenicity study. In the United States, it is considered
advisable to do this by consultation with the FDA.
Dated: February 23, 1994.
Michael R. Taylor,
Deputy Commissioner for Policy.
[FR Doc. 94-4566 Filed 2-24-94; 1:35 pm]
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