16438 Federal Register / Vol. 62, No. 65 / Friday, April 4, 1997 / Notices

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

[Docket No. 97D–0113]

International Conference on

Harmonisation; Draft Guideline for the

Preclinical Testing of BiotechnologyDerived Pharmaceuticals; Availability

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug

Administration (FDA) is publishing a

draft guideline entitled ‘‘Guideline for

the Preclinical Testing of

Biotechnology-Derived

Pharmaceuticals.’’ The draft guideline

was prepared under the auspices of the

International Conference on

Harmonisation of Technical

Requirements for Registration of

Pharmaceuticals for Human Use (ICH).

The draft guideline is intended to

provide general principles for the design

of internationally acceptable preclinical

safety evaluation programs for

biopharmaceuticals.

DATES: Written comments by June 3,

1997.

ADDRESSES: Submit written comments

on the draft guideline to the Dockets

Management Branch (HFA–305), Food

and Drug Administration, 12420

Parklawn Dr., rm. 1–23, Rockville, MD

20857. Copies of the draft guideline are

available from the Drug Information

Branch (HFD–210), Center for Drug

Evaluation and Research, Food and

Drug Administration, 5600 Fishers

Lane, Rockville, MD 20857, 301–827–

4573. Single copies of the draft

guideline may be obtained by mail from

the Office of Communication, Training

and Manufacturers Assistance (HFM–

40), Center for Biologics Evaluation and

Research, or by calling the CBER Voice

Information System at 1–800–835–4709

or 301–827–1800. Copies may be

obtained from CBER’s FAX Information

System at 1–888–CBER–FAX or 301–

827–3844.

FOR FURTHER INFORMATION CONTACT:

Regarding the guideline: Joy A.

Cavagnaro, Center for Biologics

Evaluation and Research (HFM–5),

Food and Drug Administration,

1401 Rockville Pike, Rockville, MD

20852, 301–827–0379.

Regarding the ICH: Janet J. Showalter,

Office of Health Affairs (HFY–20),

Food and Drug Administration,

5600 Fishers Lane, Rockville, MD

20857, 301–827–0864.

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 Industries 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 Associations (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.

At a meeting held on November 7,

1996, the ICH Steering Committee

agreed that a draft guideline entitled

‘‘Guideline for the Preclinical Testing of

Biotechnology-Derived

Pharmaceuticals’’ should be made

available for public comment. The draft

guideline is the product of the Safety

Expert Working Group of the ICH.

Comments on this draft will be

considered by FDA and the Safety

Expert Working Group.

The draft guideline recommends a

basic framework for the preclinical

safety testing of biotechnology-derived

pharmaceutical products. Adherence to

the preclinical safety testing principles

presented in the guideline will allow for

continual improvement in the quality

and consistency of data supporting the

development of biopharmaceuticals.

Although not required, FDA has in

the past provided a 75- or 90-day

comment period for draft ICH

guidelines. However, the comment

period for this guideline has been

shortened to 60 days so that comments

may be received by FDA in time to be

reviewed and then discussed at a July

1997 ICH meeting involving this

guideline.

This guideline represents the agency’s

current thinking on preclinical testing of

biotechnology-derived pharmaceuticals.

It does not create or confer any rights for

or on any person and does not operate

to bind FDA or the public. An

alternative approach may be used if

such approach satisfies the

requirements of the applicable statute,

regulations, or both.

Interested persons may, on or before

June 3, 1997, submit to the Dockets

Management Branch (address above)

written comments on the draft

guideline. 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 draft

guideline and received comments may

be seen in the office above between 9

a.m. and 4 p.m., Monday through

Friday. An electronic version of this

guideline is available via Internet by

using the World Wide Web (WWW). To

connect to the CDER home page, type

http://www.fda.gov/cder and go to the

‘‘Regulatory Guidance’’ section. To

connect to CBER’s WWW site, type

http://www.fda.gov/cber/cberftp.html.

The text of the draft guideline follows:

Preclinical Testing of Biotechnology-Derived

Pharmaceuticals

1. Introduction

1.1 Objectives

Regulatory standards for biotechnologyderived pharmaceutical products/

biopharmaceuticals have generally been

comparable among the United States, Europe,

and Japan. All regions appear to have a

flexible, case-by-case, science-based

approach to preclinical safety evaluation

needed to support clinical development and

marketing authorization. For a case-by-case

philosophy to succeed in a harmonized way,

there is a need for a common understanding

among the regions.

Biotechnology-derived pharmaceutical

products were initially developed in the

early 1980’s. The first marketing

authorizations were granted later in the

decade, followed soon after by the adoption

of the first pharmacopeial monographs. Since

this time considerable experience has been

gathered. Critical review of this experience

has been the basis for development of this

guidance which is intended to help provide

the general principles for design of

internationally acceptable preclinical safety
Federal Register / Vol. 62, No. 65 / Friday, April 4, 1997 / Notices 16439

evaluation programs for biopharmaceuticals.

The principles in this guidance should be

implemented in a flexible way.

The primary goals of preclinical safety

evaluation are: (1) To identify an initial safe

starting dose and subsequent dose escalation

scheme in humans; (2) to identify potential

target organs for toxicity and possible

reversibility; and (3) to identify parameters

for clinical monitoring. Adherence to the

principles presented in this document will

allow for continual improvement in the

quality and consistency of the data

supporting the development of

biopharmaceuticals.

1.2 Background

Several guidelines and points-to-consider

documents are available from the various

regulatory agencies regarding the assessment

of biotechnology-derived pharmaceutical

products. Review of such documents may

provide useful background data in

developing new products.

1.3 Scope

This guideline recommends a basic

framework for the preclinical safety testing of

biotechnology-derived pharmaceutical

products. It applies to products derived from

characterized cells through the use of a

variety of expression systems including

bacteria, yeast, insect, plant, and mammalian

cells. The intended indications may include

in vivo diagnostic, therapeutic, or

prophylactic uses. The active substances

include proteins and peptides, their

derivatives and products of which they are

components; they could be derived from cell

cultures or produced using recombinant DNA

technology. Examples include but are not

limited to: Cytokines, plasminogen

activators, recombinant blood plasma factors,

growth factors, hormones, and monoclonal

antibodies.

Some of the following guidance may also

be applicable to recombinant DNA protein

vaccines, chemically synthesized peptides,

blood plasma extracted factors, endogenous

proteins extracted from human tissue, and

oligonucleotide drugs.

This document does not cover antibiotics,

allergenic extracts, heparin, vitamins,

cellular blood components, conventional

bacterial or viral vaccines, DNA vaccines,

and cellular and gene therapies.

2. Safety and specification of the test

material

Biotechnology-derived pharmaceutical

products may have potential risks associated

with host cell contaminants from bacteria,

yeast, insect, plant, and mammalian cell

sources. The presence of cellular host

contaminants can result in allergic reactions

and other immunopathological effects. The

adverse effects associated with nucleic acid

contaminants are theoretical and include

potential integration into the host genome.

For products derived from insect, plant, or

mammalian cells or transgenic animals, there

may be the additional risk of viral infections.

These issues are not covered in this

document but they are addressed elsewhere

(Note 1). Safety concerns may arise from the

presence of impurities or contaminants. It is

preferable to rely on purification processes to

remove impurities and contaminants rather

than to establish a preclinical testing program

for their qualification. In all cases, the

product should be sufficiently characterized

to allow an appropriate design of preclinical

studies.

In general, the product used in the

definitive pharmacology, toxicology,

absorption, distribution, metabolism, and

excretion (ADME) studies should be

comparable to the product proposed for the

initial clinical studies. However, it is

appreciated that during the course of

development programs, changes normally

occur in the manufacturing process in order

to improve product quality and yields. The

potential impact of such changes for

extrapolation of the animal findings to

humans should be considered.

In order to allow the timely use of the

product made by a new or modified

manufacturing process in an ongoing

development program, the comparability of

the test material should be demonstrated

throughout development on the basis of

biochemical and biological characterization

(i.e., identity, purity, stability, and potency).

In some cases additional studies may be

needed to assure product comparability (e.g.,

pharmacokinetics). The scientific rationale

for the approach taken should be provided.

3. Preclinical testing

3.1 General principles

The objectives of the preclinical studies are

to define pharmacological and toxicological

effects not only prior to initiation of human

studies but throughout clinical development.

Both in vitro and in vivo studies can

contribute to this characterization.

Biopharmaceuticals structurally and

pharmacologically comparable to a product

for which there is wide experience in clinical

practice may, under certain conditions, need

less extensive toxicity testing, especially if a

similar kinetic profile has been

demonstrated.

Preclinical models should consider: (1)

Selection of the animal species and

physiological state and (2) the manner of

delivery, including dose, route of

administration, and treatment regimen.

Pivotal toxicology studies are expected to

be performed in compliance with Good

Laboratory Practices (GLP’s). However, it is

recognized that some specialized test systems

often needed for biopharmaceuticals may not

be able to comply fully. Areas of

noncompliance should be identified and

their significance evaluated relative to the

overall safety assessment. In some cases, a

lack of overall GLP compliance does not

necessarily mean that the data from these

studies cannot be used to support clinical

trials and marketing authorizations.

Conventional approaches to toxicity testing

of pharmaceuticals may not be appropriate

for biopharmaceuticals due to the unique and

diverse structural and biological properties of

the latter which may include species

specificity, immunogenicity, and

unpredicted pleiotropic activities.

3.2 Biological activity/pharmacodynamics

Biological activity may be evaluated using

in vitro assays to determine effects of the

product which are related to clinical activity.

The use of cell lines and/or primary cell

cultures can be useful to examine the direct

effects on cellular phenotype and

proliferation. Due to the species specificity of

many biotechnology-derived pharmaceutical

products, it is important to select an

appropriate animal species for toxicity

testing. In vitro cell lines from mammalian

cells can be used to predict specific aspects

of in vivo activity. Such studies may be

designed to determine for example, receptor

occupancy, receptor affinity, and/or

pharmacological effects, and to assist in the

selection of an appropriate animal species for

further in vivo pharmacology and toxicology

studies. The combined results from in vitro

and in vivo studies will assist in the

extrapolation of the findings to humans. In

vivo studies to assess pharmacological

activity, including defining mechanism(s) of

action, are often used to support the rationale

of the proposed product in clinical studies.

For monoclonal antibodies, the

immunological properties of the antibody

should be described in detail, including its

antigenic specificity, complement binding,

and any unintentional reactivity and/or

cytotoxicity towards human tissues distinct

from the intended target. Testing to include

such cross-reactivity should be carried out by

appropriate immunohistochemical

procedures using a range of human tissues.

3.3 Animal species/model selection

The pharmacological activity together with

species and/or tissue specificity of many

biotechnology-derived pharmaceutical

products often preclude standard toxicology

testing designs in commonly used species

(e.g., rats and dogs). Safety evaluation

programs will normally include two relevant

species. In certain situations one relevant

species may suffice. In these cases the

rationale should be provided.

Toxicology studies in pharmacologically

nonrelevant species are not needed and are

discouraged. However, if in vitro preclinical

studies have not identified a relevant animal

species, due to the unique species restriction

to human cells, it may still be prudent to

assess some aspects of potential toxicity in a

limited toxicity evaluation in a single species

(e.g., a repeated dose toxicity study of < 14

days duration) including the evaluation of

important functional endpoints (e.g.,

cardiovascular, respiratory).

Alternative approaches, when no relevant

species exist, may include the use of

transgenic animals expressing the human

receptor or the use of homologous proteins.

The information gained from use of a

transgenic species expressing the human

receptor is optimized when the interaction of

the product and the humanized receptor has

physiological consequences similar to those

expected in humans. While useful

information may also be gained from the use

of homologous proteins, it should be noted

that the production process, range of

impurities/contaminants, pharmacokinetics,

and exact pharmacological mechanism(s)

may differ between the homologous form and

the product intended for clinical use.

In recent years, there has been much

progress in the development of animal

models that are thought to be similar to the
16440 Federal Register / Vol. 62, No. 65 / Friday, April 4, 1997 / Notices

disease to be treated in humans. These

animal models include spontaneous disease

models or spontaneous models of disease.

These models may provide further insight,

not only in determining the pharmacological

action of the product, pharmacokinetics, and

dosimetry, but may also be useful in the

determination of safety (e.g., evaluation of

undesirable promotion of disease

progression). In certain cases, studies in

animal models of disease may be used as an

acceptable alternative to toxicology studies in

normal animals. The scientific justification

for the use of these animal models of disease

to support safety should be provided (Note

2).

3.4 Number/gender of animals

The number of animals used per dose has

a direct bearing on the ability to detect

toxicity. A small sample size may lead to a

failure to observe toxic events due to

observed frequency alone regardless of

severity. The limitations imposed by sample

size, as often is the case for nonhuman

primate studies, may be in part compensated

by increasing the frequency and duration of

monitoring. Both genders should generally be

used or justification given for specific

omissions.

3.5 Administration/dose selection

The route and frequency of administration

should be as close as possible to the

proposed clinical use and should also take

into account the pharmacokinetics and

bioavailability of the product in the species

being used, and the volume which can safely

and humanely be administered to the test

animals. For example, the frequency of

administration in laboratory animals may be

increased compared to the proposed

schedule for the human clinical studies in

order to compensate for faster clearance rates

or low solubility of the active ingredient. In

these cases, the level of test animal exposure

relative to the clinical exposure should be

presented. Considerations should be given to

the effects of volume of the administered

dose, size of the animal species, and muscle

mass, on the absorption of products into the

systemic circulation. The use of routes of

administration other than those used

clinically may be acceptable if the route must

be modified due to limited bioavailability,

limitations due to the route of

administration, or size/physiology of the

animal species.

Ideally, dose levels should be selected to

provide information on a dose-response

relationship, a toxic dose, and a no observed

adverse effect level (NOAEL). For some

classes of products with little to no toxicity

it may not be possible to define a specific

maximum dose. In these cases, a strong

scientific justification of the rationale for the

dose selection and projected multiples of

human exposure should be provided. To

justify high dose selection, consideration

should be given to the expected

pharmacological/physiological effects,

availability of suitable test material, and the

intended clinical use. Where a product has

a lower affinity or potency in the cells of the

target species than in human cells, testing of

higher doses may be important. The

multiples of the human dose necessary to

determine adequate safety margins may vary

with each class of biotechnology-derived

pharmaceutical product and its clinical

indication(s).

3.6 Immunogenicity

It is likely that many biotechnologyderived pharmaceutical products will be

immunogenic in animals. Therefore,

measurement of antibodies associated with

administration of these types of products

should be performed when conducting

repeated dose toxicity studies in order to aid

in the interpretation of these studies.

Antibody responses should be characterized

(e.g., neutralizing or non-neutralizing), and

their appearance should be correlated with

any pharmacological and/or toxicological

changes. Specifically, the effects of antibody

formation on pharmacokinetic/

pharmacodynamic characteristics, incidence

and/or severity of adverse effects, or the

emergence of new toxic effects, should be

considered when interpreting the data.

The detection of antibodies should not be

the sole criterion for the early termination of

a preclinical study or modification in the

duration of the study design unless the

immune response neutralizes the

pharmacological and/or toxicological effect

in a large proportion of the animals. In most

cases, the immune response to recombinant

proteins is variable, like that observed in

humans. Specific attention should be paid to

the evaluation of possible pathological

changes related to immune complex

formation and deposition. If the

interpretation of the data from the safety

study is not compromised by these issues,

then no special significance should be

ascribed to the antibody response.

The significance of antibody formation in

animals to the potential for antibody

formation in humans is often questionable.

Humans develop serum antibodies even

against humanized proteins, and frequently

the therapeutic response persists in their

presence. The occurrence of severe

anaphylactic responses to recombinant

proteins is rare in humans. In this regard, the

results of guinea pig anaphylaxis tests, which

are generally positive for protein products,

are not predictive for humans. Therefore,

such studies are considered of little value for

these types of products.

4. Specific considerations

4.1 Safety pharmacology

It is important to investigate the potential

for undesirable pharmacological activity in

appropriate animal models and, where

necessary, to incorporate particular

monitoring for this activity in the toxicity

studies and/or clinical studies. Safety

pharmacology studies provide functional

indices of toxicity. These functional indices

may be investigated in separate studies or

incorporated into the design of the toxicology

studies. The aim of the safety pharmacology

studies should be to establish the functional

effects on the major physiological systems.

Investigations may include use of isolated

organs or other test systems not involving

intact animals. The evaluation of function of

specific organ systems (e.g., cardiovascular,

respiratory, CNS, and autonomic nervous

systems, and the renal system) depends on

the pharmacological properties of the

product. Such studies should allow for a

mechanistically-based explanation of specific

organ toxicities which should be considered

carefully with respect to human use and

indication(s).

4.2 Toxicokinetics and pharmacokinetics

(Absorption, Distribution, Metabolism,

Excretion—ADME)

Toxicokinetics and pharmacokinetics

should follow relevant ICH guidelines (Note

1). It is difficult to establish uniform

guidelines for ADME studies for

biotechnology-derived pharmaceutical

products. Single dose pharmacokinetics and

tissue distribution studies are often useful;

however, routine studies that attempt to

assess mass balance, accumulation, and

excretion are not useful. Differences in

ADME among animal species may have

significant impact on the predictiveness of

animal studies or on the assessment of doseresponse relationships in toxicology studies.

Alterations in the pharmacokinetic profile

due to immune-mediated clearance

mechanisms may affect the ADME profiles

and the interpretation of the toxicity data.

ADME studies should, whenever possible,

utilize test material that is representative of

that intended for clinical use using a route

of administration relevant to the anticipated

clinical studies.

4.2.1 Assays

The use of one or more assay methods

should be addressed on a case-by-case basis

and the scientific rationale should be

provided. One validated assay method is

usually considered sufficient. For example,

quantitation of TCA-precipitable

radioactivity following administration of a

radiolabeled protein may provide adequate

information, but a specific assay for the

analyte is preferred. It is important to show

that the radiolabeled test material

administered maintains equivalent activity

and biological properties to the unlabeled

compound. Ideally the assay methods should

be the same for animals and humans. The

possible influence of plasma binding proteins

and/or antibodies on the assay performance

should be determined.

4.2.2 Animal species selection

Relevant animal species should be selected

to retain comparability of the data with data

obtained from pharmacology and toxicology

studies.

4.2.3 Absorption

Absorption and/or bioavailability should

be characterized in relation to the proposed

route of clinical administration. Absorption

studies may be performed in conjunction

with toxicology studies. Patterns of

absorption may be influenced by formulation

and/or volume. Some information on

disposition in relevant animal models should

be available prior to clinical studies in order

to project expected margins of safety based

upon exposure and dose.

4.2.4 Distribution

Studies of extravascular distribution and

mechanisms of clearance may be useful in

understanding pharmacological and

toxicological properties. Tissue levels of
Federal Register / Vol. 62, No. 65 / Friday, April 4, 1997 / Notices 16441

radioactivity and/or autoradiography data

from iodinated proteins may be difficult to

interpret with rapid in vivo metabolism and

ensuing deiodination. Care should be taken

in the interpretation of studies using

radioactive tracers incorporated into specific

amino acids because of recycling of

radiolabeled amino acids into non-drug

related proteins/peptides.

4.2.5 Metabolism

Metabolic pathways for biotechnologyderived pharmaceutical products are less

complex than for conventional

pharmaceuticals and therefore major species

differences in metabolic profiles are not an

issue.

Metabolite/disposition patterns can be

discerned by a range of detection techniques

(e.g., immunochemical detection,

chromatographic separation, SDS–PAGE).

4.2.6 Excretion

Several organ systems and mechanisms

may contribute to the elimination of

biotechnology-derived pharmaceutical

products. When feasible, these studies

should characterize the rate and contribution

of the various organs to the overall

elimination process.

4.3 Single dose toxicity studies

Single dose studies may generate useful

data to describe the relationship of dose to

systemic and/or local toxicity. These data can

be used to select doses for repeated dose

toxicology studies. Data on dose-response

relationships may be gathered as a

component of pharmacology or animal model

efficacy studies or through the conduct of a

single dose toxicology study.

4.4 Repeated dose toxicity studies

For consideration of the selection of animal

species for repeated dose studies see section

3.3. The route and dosing regimen (e.g., daily

versus intermittent dosing) should reflect the

intended clinical use or exposure. When

feasible, these studies should include

toxicokinetics.

A recovery period should generally be

included in study designs to determine

reversal, potential worsening of

pharmacological/toxicological effects, and/or

potential delayed toxic effects.

The duration of repeated dose studies

should be based on the intended duration of

clinical exposure and disease indication.

This duration has generally been 1–3 months

for most biotechnology-derived products. For

products intended for short-term use (e.g., ≤

to 7 days) and for acute life-threatening

diseases, repeated dose studies up to 2 weeks

duration have been considered adequate to

support clinical studies as well as marketing

authorization. For those products intended

for chronic indications, studies of 6 months

duration have generally been appropriate

although in some cases shorter or longer

durations have supported marketing

authorizations.

4.5 Immunotoxicity

One aspect of immunotoxicological

evaluation includes assessment of potential

immunogenicity and hypersensitivity (see

section 3.6). In addition, many

biotechnology-derived pharmaceutical

products are intended to stimulate or

suppress the immune system. Inflammatory

reactions at the injection site may be

indicative of a stimulatory response. In

addition, the expression of surface antigens

on target cells may be altered with

implications for their autoimmune potential.

Immunotoxicological testing strategies

should be applied to clarify any such issues;

however, routine tiered testing approaches or

standard testing batteries are not

recommended.

4.6 Reproductive performance and

developmental toxicity

The need for reproductive/developmental

toxicity studies is dependent upon the

product, clinical indication, and intended

patient population. Reproductive and

developmental toxicity studies should follow

the relevant ICH guidelines (Note 1). The

specific study design and dosing schedule

may be modified based on issues related to

species specificity and/or antigenicity (Note

3).

4.7 Genotoxicity studies

The range and type of genotoxicity studies

routinely conducted for conventional

pharmaceuticals are not applicable to the

active components of biotechnology-derived

pharmaceutical products. The administration

of large quantities of peptides/ proteins may

yield uninterpretable results; moreover, it is

not expected that these substances would

interact directly with DNA or other

chromosomal material (Note 4).

Studies in available and relevant systems,

including newly developed systems, should

be performed in those cases where there is

cause for concern about the product (because

of the presence of an organic linker molecule

in a conjugated protein product).

4.8 Carcinogenicity studies

Product-specific assessment of

carcinogenic potential may be needed,

depending upon duration of clinical dosing

and patient population (Note 1). However,

where rodents are not the relevant species for

assessing toxicity and/or the product is

immunogenic, conventional carcinogenicity

bioassays are not appropriate. When there is

a concern about carcinogenic potential (e.g.,

growth factors) a variety of approaches

should be considered.

Products that may have the potential to

support or induce proliferation of

transformed cells and clonal expansion

leading to tumor formation should be

evaluated for receptor expression in various

malignant and normal human cells that are

potentially relevant to the patient population

under study. The ability of the product to

stimulate growth of the malignant cells

expressing the receptor or to initiate

malignant cell growth in normal cells

expressing the receptor should be

determined. When in vitro data for tumor

promotion give cause for concern, further

studies in relevant animal models may be

needed.

In those cases where the product is

biologically active and nonimmunogenic in

rodents, then an assessment of carcinogenic

potential in a single species should be

considered. Careful consideration should be

given to the selection of doses. The use of

pharmacokinetic or pharmacodynamic

endpoints with consideration of receptor

characteristics and intended exposures in

humans represents the most scientifically

valid approach for defining the appropriate

doses. The rationale for the selection of doses

should be provided.

4.9 Local tolerance studies

Local tolerance should be evaluated.

Ideally, the formulation intended for

marketing should be tested. However, in

certain cases, the testing of representative

formulations may be acceptable. In some

cases, the potential local effects of the

product can be evaluated in single or

repeated dose toxicity studies thus obviating

the need for separate local tolerance studies.

Note 1

‘‘Quality of Biotechnological Products:

Viral Safety Evaluation of Biotechnology

Products Derived from Cell Lines of Human

and Animal Origin’’ (Q5A).

‘‘Quality of Biotechnological Products:

Derivation and Characterisation of Cell

Substrates Used for Production of

Biotechnological/Biological Products’’ (Q5D).

‘‘Specifications for New Drug Substances

and Products: Biotechnolgical Products’’

(Q6B).

‘‘Guideline on the Need for Carcinogenicity

Studies of Pharmaceuticals’’ (S1A).

‘‘Carcinogenicity: Testing for

Carcinogenicity of Pharmaceuticals’’ (S1B).

‘‘Toxicokinetics: Guidance on the

Assessment of Systemic Exposure in Toxicity

Studies’’ (S3A).

‘‘Pharmacokinetics: Guidance for Repeated

Dose Tissue Distribution Studies’’ (S3B).

‘‘Detection of Toxicity to Reproduction for

Medicinal Products’’ (S5A).

‘‘Reproductive Toxicology: Toxicity to

Male Fertility’’ (S5B).

Note 2

Animal models of disease may be useful in

defining toxicity endpoints, selection of

clinical indications, and determination of

appropriate formulations. It should be noted

that with these models of disease there is

often a paucity of historical data for use as

a reference when evaluating study results.

Therefore, the collection of concurrent

control and baseline data is critical to

optimize study design.

Note 3

In cases where extensive public

information is available regarding potential

reproductive and/or developmental effects of

a particular class of compounds (e.g.,

interferons) and the only relevant species is

the nonhuman primate, mechanistic studies

indicating that similar effects are likely to be

caused by a new but related molecule may

obviate the need for formal reproductive/

developmental toxicity studies. In each case,

the scientific basis for assessing the potential

for possible effects on reproduction/

development should be provided.

Note 4

With some types of products there is a

potential concern of accumulation of

spontaneously mutated cells (e.g., via

facilitating a selective advantage of

proliferation). This could lead to concerns
16442 Federal Register / Vol. 62, No. 65 / Friday, April 4, 1997 / Notices

regarding the potential carcinogenicity of

such compounds. The standard battery of

genotoxicity tests is not designed to test for

these circumstances. Alternative responsive

in vitro or in vivo models for such conditions

may have to be developed and evaluated.

Dated: March 29, 1997.

William K. Hubbard,

Associate Commissioner for Policy

Coordination.

[FR Doc. 97–8620 Filed 4–3–97; 8:45 am]

BILLING CODE 4160–01–F