[Federal Register Volume 60, Number 40 (Wednesday, March 1, 1995)]
[Notices]
[Pages 11278-11281]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-4960]




[[Page 11277]]

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Part XII





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



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International Conference on Harmonisation; Guideline on Dose Selection 
for Carcinogenicity Studies of Pharmaceuticals; Availability; Notice

Federal Register / Vol. 60, No. 40 / Wednesday, March 1, 1995 / 
Notices 
[[Page 11278]] 

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 94D-0017]


International Conference on Harmonisation; Guideline on Dose 
Selection for Carcinogenicity Studies of Pharmaceuticals; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is publishing a final 
guideline entitled ``Dose Selection for Carcinogenicity Studies of 
Pharmaceuticals.'' This guideline was prepared under the auspices of 
the International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use (ICH). The guideline 
examines criteria for establishing uniformity among international 
regulatory agencies for dose selection for carcinogenicity studies of 
human pharmaceuticals. The guideline 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: Effective (insert date of publication in the Federal Register). 
Submit written comments at any time.

ADDRESSES: Submit written comments on the guideline to the Dockets 
Management Branch (HFA-305), Food and Drug Administration, rm. 1-23, 
12420 Parklawn Dr., Rockville, MD 20857. Copies of the guideline are 
available from CDER Executive Secretariat Staff (HFD-8), Center for 
Drug Evaluation and Research, Food and Drug Administration, 7500 
Standish Pl., Rockville, MD 20855.

FOR FURTHER INFORMATION CONTACT:
    Regarding the guideline: Roger L. Williams, Center for Drug 
Evaluation and Research (HFD-4), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-594-6740.
    Regarding the ICH: Janet J. Showalter, Office of Health Affairs 
(HFY-20), 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 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 Industry 
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 Association (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.
    Harmonization of dose selection for carcinogenicity studies of 
pharmaceuticals was selected as a priority topic during the early 
stages of the ICH initiative. In the Federal Register of March 1, 1994 
(59 FR 9752), FDA published a draft tripartite guideline entitled, 
``Dose Selection for Carcinogenicity Studies of Pharmaceuticals.'' The 
notice gave interested persons an opportunity to submit comments by May 
16, 1994.
    After consideration of the comments received and revisions to the 
guideline, a final draft of the guideline was submitted to the ICH 
Steering Committee and endorsed by the three participating regulatory 
agencies at the ICH meeting held in October 1994.
    The 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 guideline also considers other pharmacodynamic-, 
pharmacokinetic-, or toxicity-based endpoints in study design based on 
scientific rationale and individual merits.
    FDA offers consultation and concurrence on carcinogenicity study 
designs and dose selection upon request. Regulatory consultation may be 
valuable when using any endpoint discussed in the guideline. However, 
it is considered especially important for sponsors to consult with FDA 
when planning carcinogenicity studies using pharmacodynamic endpoints 
and other product-specific designs to ensure their acceptability.
    The guideline discusses a new pharmacokinetic endpoint, the 25X AUC 
ratio, developed specifically for carcinogenicity studies of 
nongenotoxic pharmaceuticals. The metabolism of the pharmaceutical 
should be qualitatively similar between humans and rodents to use the 
AUC ratio approach. Adequate data on comparative systemic exposure, 
metabolism and protein binding should be provided.
    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). Therefore, this 
guideline is not being issued under the authority of Sec. 10.90(b), and 
it does not create or confer any rights, privileges, or benefits for or 
on any person, nor does it operate to bind FDA in any way.
    As with all of FDA's guidelines, the public is encouraged to submit 
written comments with new data or other new information pertinent to 
this guideline. The comments in the docket will be periodically 
reviewed, and, where appropriate, the guideline will be amended. The 
public will be notified of any such amendments through a notice in the 
Federal Register.
    Interested persons may, at any time, submit written comments on the 
final 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 final 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 guideline follows: [[Page 11279]] 

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 (>lOOX 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.
    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 
(NOTE 2). 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 an exposure to the agent 
that (1) allows an adequate margin of safety over the human 
therapeutic exposure, (2) is tolerated without significant chronic 
physiological dysfunction and are compatible with good survival, (3) 
is 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, and (4) permits 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) 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 
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 guideline 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.

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 of 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 percent decrease in body weight gain 
relative to controls; target organ toxicity; significant alterations 
in clinical pathological parameters.

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 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 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 [[Page 11280]] concentrations in animals and 
humans for the assessment of carcinogenic risk to humans. However, 
for the present, and based on an analysis of a data base 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).

Criteria for Comparisons of AUC in Animals and Humans 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 metabolism 
between rodents and humans (NOTE 8).
    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 9).
    6. Human pharmacokinetic data are derived from studies 
encompassing the maximum recommended human daily dose (NOTE 10).

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.

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).

Maximum Feasible Dose

    Currently, the maximum feasible dose by dietary administration 
is considered 5 percent of diet. International regulatory 
authorities are reevaluating this standard. It is believed that the 
use of pharmacokinetic endpoints (AUC ratio) for dose selection of 
low toxicity pharmaceuticals, discussed in this guideline, 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.

Additional Endpoints in High Dose Selection

    It is recognized 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).

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 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 
optimizing the design of carcinogenicity studies for therapeutic 
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.'' (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, p. 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 recognized that standard test batteries may not 
examine all potential genotoxic mechanisms, for the purposes of this 
guideline, a pharmaceutical is considered nongenotoxic 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. [[Page 11281]] 

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 were adequate pharmacokinetic data in rats and humans, 
approximately, l/3 had a relative systemic exposure ratio less than 
or equal to 1, another l/3 had ratios between l and 10.
    An analysis of the correlation between the relative systemic 
exposure ratio, the relative dose ratio (rat mg/kg MTD: 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 above 
described data base 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 data base 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 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 the International Agency for Research on 
Cancer (IARC) class l and 2A pharmaceuticals with positive rat 
findings. For phenacetin, sufficient rat and human pharmacokinetic 
data are 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 percent of compounds tested in the FDA 
data base, is high enough to detect known or probable (IARC 1, 2A) 
human carcinogenic drugs and represent 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 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, 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 characterized 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).

    Dated: February 23, 1995.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 95-4960 Filed 2-28-95; 8:45 am]
BILLING CODE 4160-01-F