[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]]
_______________________________________________________________________
Part XII
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
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
