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

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 concentrationtime 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 § 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 § 10.90(b).

Therefore, this guideline is not being

issued under the authority of § 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:
Federal Register / Vol. 60, No. 40 / Wednesday, March 1, 1995 / Notices 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) Toxicitybased 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
11280 Federal Register / Vol. 60, No. 40 / Wednesday, March 1, 1995 / Notices

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 pharmacokineticallydefined 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 pharmacodynamicpharmacokinetic- 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.
Federal Register / Vol. 60, No. 40 / Wednesday, March 1, 1995 / Notices 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