[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]
BILLING CODE 4160-01-F