[Federal Register Volume 62, Number 65 (Friday, April 4, 1997)]
[Notices]
[Pages 16438-16442]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-8620]



[[Page 16437]]

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Part V





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



_______________________________________________________________________



International Conference on Harmonisation; Draft Guidline for the 
Preclinical Testing of Biotechnology-Derived Pharmaceuticals; 
Availability; Notice

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

[[Page 16438]]



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 Biotechnology-Derived 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 biotechnology-derived 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

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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

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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 biotechnology-derived 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 dose-
response 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

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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 biotechnology-derived 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., 
<ls-thn-eq> 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

[[Page 16442]]

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