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GUIDANCE FOR INDUSTRY
Dose Selection for Carcinogenicity Studies of Pharmaceuticals ICH Topic S1C
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Published by authority of the Minister of Health
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1994
Health Products and Food Branch Guidance Document
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© Minister of Public Works and Government Services Canada 1994
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Également disponible en français sous le titre: Sélection
des doses pour les études de carcinogénicité des produits pharmaceutiques
FOREWORD
This guidance has been developed by the appropriate ICH Expert Working
Group and has been subject to consultation by the regulatory parties,
in accordance with the ICH Process. The ICH Steering Committee has endorsed
the final draft and recommended its adoption by the regulatory bodies
of the European Union, Japan and USA.
In adopting this ICH guidance, Health Canada endorses the principles
and practices described therein. This document should be read in conjunction
with the accompanying notice and the relevant sections of other applicable
guidances.
Guidance documents are meant to provide assistance to industry and health
care professionals on how to comply with the policies and governing
statutes and regulations. They also serve to provide review and compliance
guidance to staff, thereby ensuring that mandates are implemented in a
fair, consistent and effective manner.
Guidance documents are administrative instruments not having force of
law and, as such, allow for flexibility in approach. Alternate approaches
to the principles and practices described in this document may be
acceptable provided they are supported by adequate scientific justification.
Alternate approaches should be discussed in advance with the relevant
program area to avoid the possible finding that applicable statutory or
regulatory requirements have not been met.
As a corollary to the above, it is equally important to note that Health
Canada reserves the right to request information or material, or define
conditions not specifically described in this guidance, in order to allow
the Department to adequately assess the safety, efficacy or quality of
a therapeutic product. Health Canada is committed to ensuring that such
requests are justifiable and that decisions are clearly documented.
TABLE OF CONTENTS
1. INTRODUCTION
2. GENERAL CONSIDERATIONS FOR THE CONDUCT OF DOSE-RANGING
STUDIES
3. TOXICITY ENDPOINTS IN HIGH DOSE SELECTION
4. PHARMACOKINETIC ENDPOINTS IN HIGH DOSE SELECTION
5. CRITERIA FOR COMPARISONS OF AUC IN ANIMALS AND MAN
FOR USE IN HIGH DOSE SELECTION
6. SATURATION OF ABSORPTION IN HIGH DOSE SELECTION
7. PHARMACODYNAMIC ENDPOINTS IN HIGH DOSE SELECTION
8. MAXIMUM FEASIBLE DOSE
9. ADDITIONAL ENDPOINTS IN HIGH DOSE SELECTION
10. SELECTION OF MIDDLE AND LOW DOSES IN CARCINOGENICITY
STUDIES
11. SUMMARY
1. 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 (100x on a 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.
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 non-genotoxic agents (Note 2). For non-genotoxic 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 non-genotoxic pharmaceuticals
should provide an exposure 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 focus broadly on the properties of the agent and the suitability
of the animal (4) and permit data interpretation in the context of clinical
use.
In order to achieve international harmonisation 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
guidances. 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 non-genotoxic 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) toxicity-based endpoints; 2) pharmacokinetic endpoints;
3) saturation of absorption; 4) pharmacodynamic endpoints; 5) maximum
feasible dose; 6) additional endpoints.
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 recognised
that the fundamental mechanisms of carcinogenesis are only poorly understood
at the present time. Further, it is also recognised 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 guidance document is therefore intended to serve as guidance
in this difficult and complex area, recognising the importance of updating
the specific provisions outlined below as new data become available.
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2. 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 utilised.
- In practice, carcinogenicity studies are carried out in a limited
number of rat and mouse strains for which there are reasonable information
on spontaneous tumour incidence. Ideally, rodent species/strains with
metabolic profiles as similar as possible to humans should be studied
(Note 3).
- Dose-ranging studies should be conducted for both males and females
for all strains and species to be tested in the carcinogenicity bioassay.
- Dose selection is generally determined from 90-day studies using
the route and method of administration that will be used in the bioassay.
- Selection of an appropriate dosing schedule and regimen should be
based on clinical use and exposure patterns, pharmacokinetics, and practical
considerations.
- Ideally, both the toxicity profile and any dose-limiting toxicity
should be characterised. Consideration should also be given to general
toxicity, the occurrence of preneoplastic lesions and/or tissue-specific
proliferative effects, and disturbances in endocrine homeostasis.
- Changes in metabolite profile or alterations in metabolising enzyme
activities (induction or inhibition) over time, should be understood
to allow for appropriate interpretation of studies.
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3. 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 the use of toxicity endpoints other than
the MTD. Therefore, the ICH Expert Working Group on Safety has agreed
to continue use of the MTD as an acceptable toxicity-based endpoint for
high dose selection for carcinogenicity studies.
The following definition of the MTD is considered consistent with those
published previously by international regulatory authorities (Note 1):
The top dose or maximum tolerated dose is that which is predicted to produce
a minimum toxic effect over the course of the carcinogenicity study. Such
an effect may be predicted from a 90-day dose range-finding study in which
minimal toxicity is observed. Factors to consider are alterations in physiological
function which would be predicted to alter the animal's normal life span
or interfere with interpretation of the study. Such factors include: no
more than 10% decrease in body weight gain relative to controls; target
organ toxicity; significant alterations in clinical pathological parameters.
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4. 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 pharmaceuticals
(Note 2) which have similar metabolic profiles in humans and rodent 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 exposure to provide reassurance of an adequate test of carcinogenicity.
It is recognised 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
a 25-fold ratio of rodent to human plasma AUC of parent compound and/or
metabolites is considered pragmatic (Note 4).
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5. 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.
- 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).
- 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.
- Documentation is provided on the similarity of metabolism between
rodents and humans (Note 8).
- In assessing exposure, scientific judgement 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.
- Interspecies differences in protein binding are taken into consideration
when estimating relative exposure (Note 9).
- Human pharmacokinetic data are derived from studies encompassing
the maximum recommended human daily dose (Note 10).
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6. 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.
7. PHARMACODYNAMIC ENDPOINTS IN HIGH DOSE SELECTION
The utility and safety of many pharmaceuticals 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. The high dose selected should produce
a pharmacodynamic response in dosed animals of such magnitude as would
preclude further dose escalation. However, the dose should not produce
disturbances of physiology or homeostasis which would compromise the validity
of the study. Examples include hypotension and inhibition of blood clotting
(because of the risk of spontaneous bleeding).
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8. MAXIMUM FEASIBLE DOSE
Currently, the maximum feasible dose by dietary administration is considered
5% of diet. International regulatory authorities are re-evaluating this
standard. It is believed that the use of pharmacokinetic endpoints (AUC
ratio) for dose selection of low toxicity pharmaceuticals, discussed in
this guidance document, should significantly decrease the need to select
high doses based on feasibility criteria.
When routes other than dietary administration are appropriate, the high
dose will be limited based on considerations including practicality and
local tolerance.
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9. ADDITIONAL ENDPOINTS IN HIGH DOSE SELECTION
It is recognised that there may be merit in the use of alternative endpoints
not specifically defined in this guidance on high dose selection for rodent
carcinogenicity studies. Use of these additional endpoints in individual
study designs must be based on scientific rationale. Such designs are
evaluated based on their individual merits. (Note 11)
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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:
- Linearity of pharmacokinetics and saturation of metabolic pathways.
- Human exposure and therapeutic dose.
- Pharmacodynamic response in rodents.
- Alterations in normal rodent physiology.
- Mechanistic information and potential for threshold effects.
- The unpredictability of the progression of toxicity observed in short-term
studies.
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11. SUMMARY
This guidance document outlines four generally acceptable criteria for
selection of the high dose for carcinogenicity studies of therapeutics:
maximum tolerated dose, 25-fold AUC ratio (rodent:human), dose-limiting
pharmacodynamic effects, saturation of absorption, and 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 optimising the design of
carcinogenicity studies for therapeutic agents.
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Note 1
The following are considered equivalent definitions of the toxicity based
endpoint describing the maximum tolerated dose:
The US 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 haematologic, urinary, and
clinical chemistry measurements can be useful in conjunction with the
usually more definitive toxic, pathologic or histopathologic endpoints."
(Environmental Health Perspectives, Vol. 67, pp. 201-281, 1986)
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." (Toxicity
test guideline for pharmaceuticals, Chapter 5, pg. 127, 1985)
The Committee on Proprietary Medicinal Products of the European Community
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." (Rules
Governing Medicinal Products in the European Community, Vol. III,
1987)
Note 2
While it is recognised that standard test batteries may not examine all
potential genotoxic mechanisms, for the purposes of this guidance document,
a pharmaceutical is considered non-genotoxic with respect to the use of
pharmacokinetic endpoints for dose selection, if it is negative in the
standard battery of assays required for pharmaceutical registration.
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 carcinogenicity studies
of therapeutics conducted at the MTD for which there was sufficient human
and rodent pharmacokinetic data for comparison of AUC values.
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 less than or equal to 1, another
1/3 had ratios between 1 and 10.
An analysis of the correlation between the relative systemic exposure
ratio, the relative dose ratio (rat mg/kg: human mg/kg MRD) and the dose
ratio adjusted for body surface area (rat mg/M2 MTD:human mg/M2 MRD),
performed in conjunction with the abovedescribed database analysis indicates
that the relative systemic exposure corresponds better with dose ratios
expressed in terms of body surface area rather than body weight. When
123 compounds in the expanded FDA database were analysed 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 represent an adequate margin of safety, would detect known
or probable human carcinogens, and could be attained by a reasonable proportion
of compounds.
To address the issue of detection of known or probable human carcinogenic
pharmaceuticals, an analysis of exposure and/or dose ratios was performed
on IARC class 1 and 2A pharmaceuticals 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
analysis. 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 the rodent
corresponding to body surface area ratios of 10 or more would identify
the carcinogenic potential of these pharmaceuticals.
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% of compounds
tested in the FDA database, is high enough to detect known or probable
(IARC 1, 2A) human carcinogenic drugs and represents an adequate margin
of safety. Those pharmaceuticals tested using a 25 fold or greater AUC
ratio for the high dose will have exposure ratios greater than 75% of
pharmaceuticals tested previously in carcinogenicity studies performed
at the MTD.
Note 5
The rodent AUCs and metabolite profiles may be determined from separate
steadystate 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, 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 pharmaceuticals in rodents
and humans.
Note 8
It is recommended that in vivo metabolism be characterised in humans
and rodents, if possible. However, in the absence of appropriate in
vivo metabolism data, in vitro metabolism data (e.g. from liver
slices, uninduced microsomal preparations) may provide adequate support
for the similarity of metabolism across species.
Note 9
While in vivo determinations of unbound drug may be the best approach,
in vitro determinations of protein binding using parent and/or metabolites
as appropriate (over the range of concentrations achieved in vivo in rodents
and humans) may be used in the estimation of AUC unbound. 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 humans,
the comparison of total plasma concentration of drug is acceptable. When
protein binding is high and the unbound fraction is greater in humans
than in rodents, the ratio of the unbound concentrations should be used.
Note 10
Human systemic exposure data may be derived from pharmacokinetic monitoring
in normal volunteers and/or patients. The possibility of extensive inter-individual
variation in exposure should be taken into consideration. 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 11
Additional pharmaceutical-specific endpoints to select an appropriate high dose are currently under discussion (e.g. additional pharmacodynamic, pharmacokinetic and toxicity endpoints as well as alternatives to a maximum feasible dose).
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