[Federal Register Volume 62, Number 222 (Tuesday, November 18, 1997)]
[Notices]
[Pages 61515-61519]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-30274]


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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.

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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 Single copies of the draft 
guidance may be obtained by mail from the Office of Communication, 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 Biotechnology-Derived 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.

[[Page 61516]]

    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\
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    \1\ 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 of such approach satisfies the 
requirements of the applicable statute, regulations, or both.
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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 points-to-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 biotechnology-derived 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

[[Page 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 cross-reactivity 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 cross-reactivity 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 long-term 
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.

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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 immune-mediated 
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 dose-response 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.

[[Page 61519]]

4.8 Carcinogenicity Studies

    Standard carcinogenicity bioassays are generally inappropriate 
for biotechnology-derived pharmaceuticals. However, product-specific 
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