Federal Register / Vol. 62, No. 222 / Tuesday, November 18, 1997 / Notices 61515

In a number of cases there were findings

observed by 12 months, but not by 6 months.

It was concluded that these would, or could,

have been detected in a study of 9 months

duration. Varying degrees of concern for the

differences in findings detected between the

studies of different durations were expressed.

An agreement on the clinical relevance of

these findings could not be reached.

Studies of 12 months duration are usually

not necessary and studies of shorter than 9

months duration may be sufficient.

In the European Union, studies of 6

months duration in nonrodents are

acceptable according to Council Directive 75/

318/EEC, as amended. To avoid duplication,

where studies with a longer duration have

been conducted, it would not be necessary to

conduct a study of 6 months.

Guidance on duration of chronic toxicity

testing for tripartite development plan:

Arising from the extensive analysis and

review of the above mentioned data in

nonrodents and based upon the

achievements of ICH 1 for testing in rodents,

and so as to avoid duplication and to follow

a single development plan for chronic

toxicity testing of new medicinal products,

the following studies are considered

acceptable for submission in the three

regions:

(1) Rodents: a study of 6 months duration;

(2) Nonrodents: a study of 9 months

duration.

Dated: November 12, 1997.

William K. Hubbard,

Associate Commissioner for Policy

Coordination.

[FR Doc. 97–30273 Filed 11–17–97; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

[Docket No. 97D–0113]

International Conference on

Harmonisation; Guidance on

Preclinical Safety Evaluation of

Biotechnology-Derived

Pharmaceuticals; Availability

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug

Administration (FDA) is publishing a

guidance entitled ‘‘S6 Preclinical Safety

Evaluation of Biotechnology-Derived

Pharmaceuticals.’’ The guidance was

prepared under the auspices of the

International Conference on

Harmonisation of Technical

Requirements for Registration of

Pharmaceuticals for Human Use (ICH).

The guidance is intended to provide

general principles for designing

scientifically acceptable preclinical

safety evaluation programs for

biopharmaceuticals.

DATES: Effective November 18, 1997.

Submit written comments at any time.

ADDRESSES: Submit written comments

on the guidance to the Dockets

Management Branch (HFA–305), Food

and Drug Administration, 12420

Parklawn Dr., rm. 1–23, Rockville, MD

20857. Copies of the guidance 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 guidance

may be obtained by mail from the Office

of Communication, Training and

Manufacturers Assistance (HFM–40),

Center for Biologics Evaluation and

Research (CBER), 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 guidance: 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.

In the Federal Register of April 4,

1997 (62 FR 16438), FDA published a

draft tripartite guideline entitled

‘‘Preclinical Testing of BiotechnologyDerived Pharmaceuticals’’ (S6). The

notice gave interested persons an

opportunity to submit comments by

June 3, 1997.

After consideration of the comments

received and revisions to the guidance,

a final draft of the guidance was

submitted to the ICH Steering

Committee and endorsed by the three

participating regulatory agencies on July

16, 1997.

In accordance with FDA’s Good

Guidance Practices (62 FR 8961,

February 27, 1997), this document has

been designated a guidance, rather than

a guideline.

The guidance recommends a basic

framework for the preclinical safety

evaluation of biotechnology-derived

pharmaceuticals. Adherence to the

principles presented in the guidance

will allow for improvement in the

quality and consistency of preclinical

safety data supporting the development

of biopharmaceuticals.

This guidance represents the agency’s

current thinking on preclinical safety

evaluation 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.

As with all of FDA’s guidances, the

public is encouraged to submit written

comments with new data or other new

information pertinent to this guidance.

The comments in the docket will be

periodically reviewed, and, where

appropriate, the guidance will be

amended. The public will be notified of

any such amendments through a notice

in the Federal Register.
61516 Federal Register / Vol. 62, No. 222 / Tuesday, November 18, 1997 / Notices

1This guidance represents the agency’s current

thinking on preclinical safety evaluation 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 of such approach

satisfies the requirements of the applicable statute,

regulations, or both.

Interested persons may, at any time,

submit written comments on the

guidance 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 guidance 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 guidance is available on

the Internet at ‘‘http://www.fda.gov/

cder/guidance.htm’’ or at CBER’s World

Wide Web site at ‘‘http://www.fda.gov/

cber/publications.htm’’.

The text of the guidance follows:

S6 Preclinical Safety Evaluation of

Biotechnology-Derived Pharmaceuticals 1

1. Introduction

1.1. Background

Biotechnology-derived pharmaceuticals

(biopharmaceuticals) were initially

developed in the early 1980’s. The first

marketing authorizations were granted later

in the decade. Several guidelines and pointsto-consider documents have been issued by

various regulatory agencies regarding safety

assessment of these products. Review of such

documents, which are available from

regulatory authorities, may provide useful

background in developing new

biopharmaceuticals.

Considerable experience has now been

gathered with submission of applications for

biopharmaceuticals. Critical review of this

experience has been the basis for

development of this guidance, which is

intended to provide general principles for

designing scientifically acceptable preclinical

safety evaluation programs.

1.2 Objectives

Regulatory standards for biotechnologyderived pharmaceuticals have generally been

comparable among the European Union,

Japan, and the United States. All three

regions have adopted a flexible, case-by-case,

science-based approach to preclinical safety

evaluation needed to support clinical

development and marketing authorization. In

this rapidly evolving scientific area, there is

a need for common understanding and

continuing dialogue among the regions.

The primary goals of preclinical safety

evaluation are: (1) To identify an initial safe

dose and subsequent dose escalation schemes

in humans; (2) to identify potential target

organs for toxicity and for the study of

whether such toxicity is reversible; and (3) to

identify safety parameters for clinical

monitoring. Adherence to the principles

presented in this document should improve

the quality and consistency of the preclinical

safety data supporting the development of

biopharmaceuticals.

1.3 Scope

This guidance is intended primarily to

recommend a basic framework for the

preclinical safety evaluation of

biotechnology-derived pharmaceuticals. 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

deoxyrebonucleic acid (DNA) technology,

including production by transgenic plants

and animals. Examples include but are not

limited to: Cytokines, plasminogen

activators, recombinant plasma factors,

growth factors, fusion proteins, enzymes,

receptors, hormones, and monoclonal

antibodies.

The principles outlined in this guidance

may also be applicable to recombinant DNA

protein vaccines, chemically synthesized

peptides, plasma derived products,

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, or

cellular and gene therapies.

2. Specification of the Test Material

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

safety studies.

There are potential risks associated with

host cell contaminants derived from bacteria,

yeast, insect, plants, and mammalian cells.

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 but include

potential integration into the host genome.

For products derived from insect, plant, and

mammalian cells, or transgenic plants and

animals, there may be an additional risk of

viral infections.

In general, the product that is used in the

definitive pharmacology and toxicology

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.

The comparability of the test material

during a development program should be

demonstrated when a new or modified

manufacturing process is developed or other

significant changes in the product or

formulation are made in an ongoing

development program. Comparability can be

evaluated on the basis of biochemical and

biological characterization (i.e., identity,

purity, stability, and potency). In some cases,

additional studies may be needed (i.e.,

pharmacokinetics, pharmacodynamics and/

or safety). The scientific rationale for the

approach taken should be provided.

3. Preclinical Safety Testing

3.1 General Principles

The objectives of the preclinical safety

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 that are

structurally and pharmacologically

comparable to a product for which there is

wide experience in clinical practice may

need less extensive toxicity testing.

Preclinical safety testing should consider:

(1) Selection of the relevant animal species;

(2) age; (3) physiological state; (4) the manner

of delivery, including dose, route of

administration, and treatment regimen; and

(5) stability of the test material under the

conditions of use.

Toxicity studies are expected to be

performed in compliance with Good

Laboratory Practice (GLP); however, it is

recognized that some studies employing

specialized test systems, which are often

needed for biopharmaceuticals, may not be

able to comply fully with GLP. Areas of

noncompliance should be identified and

their significance evaluated relative to the

overall safety assessment. In some cases, lack

of full 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 that 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 which effects of

the product may be 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

pharmaceuticals, it is important to select

relevant animal species for toxicity testing. In

vitro cell lines derived from mammalian cells

can be used to predict specific aspects of in

vivo activity and to assess quantitatively the

relative sensitivity of various species

(including human) to the biopharmaceutical.

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
Federal Register / Vol. 62, No. 222 / Tuesday, November 18, 1997 / Notices 61517

pharmacology and toxicology studies. The

combined results from in vitro and in vivo

studies 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 use of

the 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. Such crossreactivity studies should be carried out by

appropriate immunohistochemical

procedures using a range of human tissues.

3.3 Animal Species/Model Selection

The biological activity together with

species and/or tissue specificity of many

biotechnology-derived pharmaceuticals often

preclude standard toxicity testing designs in

commonly used species (e.g., rats and dogs).

Safety evaluation programs should include

the use of relevant species. A relevant species

is one in which the test material is

pharmacologically active due to the

expression of the receptor or an epitope (in

the case of monoclonal antibodies). A variety

of techniques (e.g., immunochemical or

functional tests) can be used to identify a

relevant species. Knowledge of receptor/

epitope distribution can provide greater

understanding of potential in vivo toxicity.

Relevant animal species for testing of

monoclonal antibodies are those that express

the desired epitope and demonstrate a

similar tissue cross-reactivity profile as for

human tissues. This would optimize the

ability to evaluate toxicity arising from the

binding to the epitope and any unintentional

tissue cross-reactivity. An animal species that

does not express the desired epitope may still

be of some relevance for assessing toxicity if

comparable unintentional tissue crossreactivity to humans is demonstrated.

Safety evaluation programs should

normally include two relevant species.

However, in certain justified cases one

relevant species may suffice (e.g., when only

one relevant species can be identified or

where the biological activity of the

biopharmaceutical is well understood). In

addition, even where two species may be

necessary to characterize toxicity in short

term studies, it may be possible to justify the

use of only one species for subsequent longterm toxicity studies (e.g., if the toxicity

profile in the two species is comparable in

the short term).

Toxicity studies in nonrelevant species

may be misleading and are discouraged.

When no relevant species exists, the use of

relevant transgenic animals expressing the

human receptor or the use of homologous

proteins should be considered. The

information gained from use of a transgenic

animal model expressing the human receptor

is optimized when the interaction of the

product and the humanized receptor has

similar physiological consequences 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. Where

it is not possible to use transgenic animal

models or homologous proteins, 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 that

includes an evaluation of important

functional endpoints (e.g., cardiovascular

and respiratory).

In recent years, there has been much

progress in the development of animal

models that are thought to be similar to the

human disease. These animal models include

induced and spontaneous models of disease,

gene knockout(s), and transgenic animals.

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

performed in animal models of disease may

be used as an acceptable alternative to

toxicity studies in normal animals (Note 1).

The scientific justification for the use of these

animal models of disease to support safety

should be provided.

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

failure to observe toxic events due to

observed frequency alone regardless of

severity. The limitations that are 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 that

proposed for clinical use. Consideration

should be given to pharmacokinetics and

bioavailability of the product in the species

being used and to the volume which can be

safely and humanely 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 exposure of the test

animal relative to the clinical exposure

should be defined. Consideration should also

be given to the effects of volume,

concentration, formulation, and site of

administration. 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 to size/physiology of the

animal species.

Dosage levels should be selected to provide

information on a dose-response relationship,

including 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 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 to or

potency in the cells of the selected species

than in human cells, testing of higher doses

may be important. The multiples of the

human dose that are needed to determine

adequate safety margins may vary with each

class of biotechnology-derived

pharmaceutical and its clinical indication(s).

3.6 Immunogenicity

Many biotechnology-derived

pharmaceuticals intended for humans are

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., titer, number of responding animals,

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 parameters, incidence

and/or severity of adverse effects,

complement activation, or the emergence of

new toxic effects should be considered when

interpreting the data. Attention should also

be paid to the evaluation of possible

pathological changes related to immune

complex formation and deposition.

The detection of antibodies should not be

the sole criterion for the early termination of

a preclinical safety study or modification in

the duration of the study design unless the

immune response neutralizes the

pharmacological and/or toxicological effects

of the biopharmaceutical in a large

proportion of the animals. In most cases, the

immune response to biopharmaceuticals is

variable, like that observed in humans. 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 induction of antibody formation in

animals is not predictive of a potential for

antibody formation in humans. Humans may

develop serum antibodies 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 reactions in humans; therefore,

such studies are considered of little value for

the routine evaluation of these types of

products.
61518 Federal Register / Vol. 62, No. 222 / Tuesday, November 18, 1997 / Notices

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 these activities in the toxicity

studies and/or clinical studies. Safety

pharmacology studies measure functional

indices of potential toxicity. These functional

indices may be investigated in separate

studies or incorporated in the design of

toxicity studies. The aim of the safety

pharmacology studies should be to reveal any

functional effects on the major physiological

systems (e.g., cardiovascular, respiratory,

renal, and central nervous systems).

Investigations may also include the use of

isolated organs or other test systems not

involving intact animals. All of these studies

may 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 Exposure assessment

4.2.1 Pharmacokinetics and Toxicokinetics

It is difficult to establish uniform

guidances for pharmacokinetic studies for

biotechnology-derived pharmaceuticals.

Single and multiple dose pharmacokinetics,

toxicokinetics, and tissue distribution studies

in relevant species are useful; however,

routine studies that attempt to assess mass

balance are not useful. Differences in

pharmacokinetics among animal species may

have a significant impact on the

predictiveness of animal studies or on the

assessment of dose-response relationships in

toxicity studies. Alterations in the

pharmacokinetic profile due to immunemediated clearance mechanisms may affect

the kinetic profiles and the interpretation of

the toxicity data. For some products, there

may also be inherent, significant delays in

the expression of pharmacodynamic effects

relative to the pharmacokinetic profile (e.g.,

cytokines) or there may be prolonged

expression of pharmacodynamic effects

relative to plasma levels.

Pharmacokinetic studies should, whenever

possible, utilize preparations that are

representative of those intended for toxicity

testing and clinical use and employ a route

of administration that is relevant to the

anticipated clinical studies. Patterns of

absorption may be influenced by

formulation, concentration, site, and/or

volume. Whenever possible, systemic

exposure should be monitored during the

toxicity studies.

When using radiolabeled proteins, it is

important to show that the radiolabeled test

material maintains activity and biological

properties equivalent to that of the unlabeled

material. Tissue concentrations of

radioactivity and/or autoradiography data

using radiolabeled proteins may be difficult

to interpret due to rapid in vivo metabolism

or unstable radiolabeled linkage. Care should

be taken in the interpretation of studies using

radioactive tracers incorporated into specific

amino acids because of recycling of amino

acids into nondrug related proteins/peptides.

Some information on absorption,

disposition, and clearance in relevant animal

models should be available prior to clinical

studies in order to predict margins of safety

based upon exposure and dose.

4.2.2 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 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. Ideally, the assay

methods should be the same for animals and

humans. The possible influence of plasma

binding proteins and/or antibodies in

plasma/serum on the assay performance

should be determined.

4.2.3 Metabolism

The expected consequence of metabolism

of biotechnology-derived pharmaceuticals is

the degradation to small peptides and

individual amino acids. Therefore, the

metabolic pathways are generally

understood. Classical biotransformation

studies as performed for pharmaceuticals are

not needed.

Understanding the behavior of the

biopharmaceutical in the biologic matrix

(e.g., plasma, serum, cerebral spinal fluid)

and the possible influence of binding

proteins is important for understanding the

pharmacodynamic effect.

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

toxicity studies. Information on doseresponse relationships may be gathered

through the conduct of a single dose toxicity

study or as a component of pharmacology or

animal model efficacy studies. The

incorporation of safety pharmacology

parameters in the design of these studies

should be considered.

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 the

reversal or potential worsening of

pharmacological/toxicological effects, and/or

potential delayed toxic effects. For

biopharmaceuticals that induce prolonged

pharmacological/toxicological effects,

recovery group animals should be monitored

until reversibility is demonstrated. The

duration of repeated dose studies should be

based on the intended duration of clinical

exposure and disease indication. This

duration of animal dosing has generally been

1-3 months for most biotechnology-derived

pharmaceuticals. For biopharmaceuticals

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 biopharmaceuticals

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. For

biopharmaceuticals intended for chronic use,

the duration of long-term toxicity studies

should be scientifically justified.

4.5 Immunotoxicity Studies

One aspect of immunotoxicological

evaluation includes assessment of potential

immunogenicity (see section 3.6). Many

biotechnology-derived pharmaceuticals are

intended to stimulate or suppress the

immune system and, therefore, may affect not

only humoral but also cell-mediated

immunity. Inflammatory reactions at the

injection site may be indicative of a

stimulatory response. It is important,

however, to recognize that simple injection

trauma and/or specific toxic effects caused by

the formulation vehicle may also result in

toxic changes at the injection site. In

addition, the expression of surface antigens

on target cells may be altered, which has

implications for autoimmune potential.

Immunotoxicological testing strategies may

require screening studies followed by

mechanistic studies to clarify such issues.

Routine tiered testing approaches or standard

testing batteries, however, are not

recommended for biotechnology-derived

pharmaceuticals.

4.6 Reproductive Performance and

Developmental Toxicity Studies

The need for reproductive/developmental

toxicity studies is dependent upon the

product, clinical indication and intended

patient population (Note 2). The specific

study design and dosing schedule may be

modified based on issues related to species

specificity, immunogenicity, biological

activity, and/or a long elimination half-life.

For example, concerns regarding potential

developmental immunotoxicity, which may

apply particularly to certain monoclonal

antibodies with prolonged immunological

effects, could be addressed in a study design

modified to assess immune function of the

neonate.

4.7 Genotoxicity Studies

The range and type of genotoxicity studies

routinely conducted for pharmaceuticals are

not applicable to biotechnology-derived

pharmaceuticals and therefore are not

needed. Moreover, the administration of large

quantities of peptides/proteins may yield

uninterpretable results. It is not expected that

these substances would interact directly with

DNA or other chromosomal material (Note 3).

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 (e.g.,

because of the presence of an organic linker

molecule in a conjugated protein product).

The use of standard genotoxicity studies for

assessing the genotoxic potential of process

contaminants is not considered appropriate.

If performed for this purpose, however, the

rationale should be provided.
Federal Register / Vol. 62, No. 222 / Tuesday, November 18, 1997 / Notices 61519

4.8 Carcinogenicity Studies

Standard carcinogenicity bioassays are

generally inappropriate for biotechnologyderived pharmaceuticals. However, productspecific assessment of carcinogenic potential

may still be needed depending upon duration

of clinical dosing, patient population, and/or

biological activity of the product (e.g., growth

factors, immunosuppressive agents, etc.).

When there is a concern about carcinogenic

potential, a variety of approaches may be

considered to evaluate risk.

Products that may have the potential to

support or induce proliferation of

transformed cells and clonal expansion

possibly leading to neoplasia should be

evaluated with respect to 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 normal or

malignant cells expressing the receptor

should be determined. When in vitro data

give cause for concern about carcinogenic

potential, further studies in relevant animal

models may be needed. Incorporation of

sensitive indices of cellular proliferation in

long-term repeated dose toxicity studies may

provide useful information.

In those cases where the product is

biologically active and nonimmunogenic in

rodents and other studies have not provided

sufficient information to allow an assessment

of carcinogenic potential, then the utility of

a single rodent species should be considered.

Careful consideration should be given to the

selection of doses. The use of a combination

of pharmacokinetic and pharmacodynamic

endpoints with consideration of comparative

receptor characteristics and intended human

exposures represents the most scientifically

based 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. The

formulation intended for marketing should

be tested; however, in certain justified cases,

the testing of representative formulations

may be acceptable. In some cases, the

potential adverse effects of the product can

be evaluated in single or repeated dose

toxicity studies, thus obviating the need for

separate local tolerance studies.

Notes

Note 1

Animal models of disease may be useful in

defining toxicity endpoints, selection of

clinical indications, and determination of

appropriate formulations, route of

administration, and treatment regimen. 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 2

There may be extensive public information

available regarding potential reproductive

and/or developmental effects of a particular

class of compounds (e.g., interferons) where

the only relevant species is the nonhuman

primate. In such cases, 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 3

With some biopharmaceuticals, there is a

potential concern about accumulation of

spontaneously mutated cells (e.g., via

facilitating a selective advantage of

proliferation) leading to carcinogenicity. The

standard battery of genotoxicity tests is not

designed to detect these conditions.

Alternative in vitro or in vivo models to

address such concerns may have to be

developed and evaluated.

Dated: November 12, 1997.

William K. Hubbard,

Associate Commissioner for Policy

Coordination.

[FR Doc. 97–30274 Filed 11–17–97; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

National Institutes of Health

National Institute of Arthritis and

Musculoskeletal and Skin Diseases;

Notice of Closed Meeting

Pursuant to Section 10(d) of the

Federal Advisory Committee Act, as

amended (5 U.S.C. Appendix 2), notice

is hereby given of the following

National Institute of Arthritis and

Musculoskeletal and Skin Diseases

Special Emphasis Panel (SEP) meeting:

Name of SEP: Mechano Transduction in

Bone.

Date: December 18, 1997.

Time: 8:00 a.m.–5:00 p.m.

Place: Holiday Inn Bethesda, 8120

Wisconsin Avenue, Bethesda, Maryland

20814.

Contact Person: Tommy L. Broadwater,

Ph.D., Scientific Review Administrator,

Natcher Building, 45 Center Drive, Rm

5AS25U, Bethesda, Maryland 20892–6500,

Telephone: 301–594–4952.

Purpose/Agenda: To evaluate and review a

research grant application.

This meeting will be closed in accordance

with the provisions set forth in sections

552b(c)(4) and 552b(c)(6), Title 5 U.S.C. The

discussion of this application could reveal

confidential trade secrets or commercial

property such as patentable material and

personal information concerning individual

associated with the application, the

disclosure of which would constitute a

clearly unwarranted invasion of personal

privacy.

(Catalog of Federal Domestic Assistance

Program Nos. [93.846, Project Grants in

Arthritis, Musculoskeletal and Skin Disease

Research], National Institutes of Health,

HHS)

Dated: November 10, 1997.

LaVerne Y. Stringfield,

Committee Management Officer, NIH.

[FR Doc. 97–30204 Filed 11–17–97; 8:45 am]

BILLING CODE 4140–01–M

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

National Institutes of Health

Prospective Grant of Exclusive

License: Immunodampening

Technology

AGENCY: National Institutes of Health,

Public Health Service, DHHS.

ACTION: Notice.

SUMMARY: This is notice in accordance

with 35 U.S.C. 209(c)(1) and 37 CFR

404.7(a)(1)(i) that the National Institutes

of Health (NIH), Department of Health

and Human Services, ins contemplating

the grant of an exclusive world-wide

license to practice the invention

embodied in U.S. Patent Number

5,585,250 and pending U.S. Patent

Application Serial No. 08/764.575 both

entitled ‘‘Dampening of an

Immunodominant Epitope of an Antigen

for Use in Plant, Animal and Human

Compositions and Immunotherapies’’

and related foreign patent applications

to Biological Memetics, Inc., of

Frederick, Maryland. The patent rights

in this invention have been assigned to

the United States of America.

It is anticipated that this license will

be limited to the field of vaccines for the

treatment and prevention of infectious

diseases in animals and humans.

DATES: Only written comments and/or

applications for a license which are

received by NIH on or before February

17, 1998 will be considered.

ADDRESSES: Requests for a copy of the

patent and/or patent application,

inquires, comments and other materials

relating to the contemplated license

should be directed to: Robert Benson,

Patent Advisor, Office of Technology

Transfer, National Institutes of Health,

6011 Executive Blvd., Suite 325,

Rockville, MD 20852–3804; Telephone:

(301) 496–7056, x267; Facsimile: (301)

402–0220.

SUPPLEMENTARY INFORMATION: The patent

and pending patent application describe

a broadly applicable method of

redirecting the immune response to an

antigen from an immunodominant

epitope to another epitope by altering

the immunogenicity of the

immunodominant epitope. The method

is most useful for those pathogens with

a highly variable immunodominant

epitope, such as HIV, HCV or gonorrhea.