NOTICE
Adoption of ICH1 Guidance
Health Canada is pleased to announce the adoption of this
ICH guidance: S6: Preclinical Safety Evaluation of Biotechnology-Derived
Pharmaceuticals
This guidance has been developed by the appropriate ICH
Expert Working Group and has been subject to consultation by the regulatory
parties, in accordance with the ICH Process. The ICH Steering Committee
has endorsed the final draft and recommended its adoption by the regulatory
bodies of the European Union, Japan and USA.
In adopting this ICH guidance, Health Canada endorses the
principles and practices described therein. This document should be read
in conjunction with this accompanying notice and with the relevant sections
of other applicable Health Canada guidances.
This and other Guidance documents are available on the Therapeutic
Products Directorate / Biologics and Genetic Therapies Directorate Website
(s)
(http://www.hc-sc.gc.ca/dhp-mps/prodpharma/index_e.html). The availability of printed copies of guidance documents
may be confirmed by consulting the Guidelines and Publications Order Forms
(available on the TPD/BGTD Website) or by contacting the Publications
Coordinator2.
Should you have any questions regarding the content of the
guidance, please contact:
Director
Biologicals & Radiopharmaceuticals Evaluation Centre
Biologics and Genetic Therapies Directorate
Health Canada
Building #6, A.L. 0603C3
Tunney's Pasture
Ottawa, Ontario
K1A 0L2
Internet: Director, Biologics and Radiopharmaceuticals Evaluation Centre
c/o:
Susanne_Geertsen@hc-sc.gc.ca
Phone: (613) 957-8064
Fax: (613) 957-6302
1 International Conference on Harmonisation of Technical Requirements
for the Registration of Pharmaceuticals for Human Use.
2 Tel: (613) 954-6466; E-mail: publications_coordinator@hc-sc.gc.ca
GUIDANCE FOR INDUSTRY
Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals ICH Topic S6
Published by authority of the
Minister of Health
| Date Adopted |
2003/02/10 |
| Effective Date |
2003/02/10 |
Health Products and Food Branch
Guidance Document
|
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their health.
Health Canada
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© Minister of Public Works and Government Services Canada 2003
Available in Canada through
Health Canada - Publications
Brooke Claxton Building, A.L. #0913A
Tunney's Pasture
Ottawa, Ontario
K1A 0K9
Tel: (613) 954-5995
Fax: (613) 941-5366
Également disponible en français sous le titre: Évaluation au stade
préclinique de la sécurité des produits pharmaceutiques issus de la biotechnologie
Catalogue No. H49/-173/2003E
ISBN 0-662-33370-5
FOREWORD
This guidance has been developed by the appropriate ICH Expert Working
Group and has been subject to consultation by the regulatory parties,
in accordance with the ICH Process. The ICH Steering Committee has endorsed
the final draft and recommended its adoption by the regulatory bodies
of the European Union, Japan and USA.
In adopting this ICH guidance, Health Canada endorses the principles
and practices described therein. This document should be read in conjunction
with the accompanying notice and the relevant sections of other applicable
guidances.
Guidance documents are meant to provide assistance to industry and health
care professionals on how to comply with the policies
and governing statutes and regulations. They also serve to provide review
and compliance guidance to staff, thereby ensuring that mandates are implemented
in a fair, consistent and effective manner.
Guidance documents are administrative instruments not having force of
law and, as such, allow for flexibility in approach. Alternate approaches
to the principles and practices described in this document may
be acceptable provided they are supported by adequate scientific
justification. Alternate approaches should be discussed in advance with
the relevant program area to avoid the possible finding that applicable
statutory or regulatory requirements have not been met.
As a corollary to the above, it is equally important to note that Health
Canada reserves the right to request information or material, or define
conditions not specifically described in this guidance, in order to allow
the Department to adequately assess the safety, efficacy or quality of
a therapeutic product. Health Canada is committed to ensuring that such
requests are justifiable and that decisions are clearly documented.
TABLE OF CONTENTS
1. INTRODUCTION
1.1 Background
1.2 Objectives
1.3 Scope
2. SPECIFICATION OF THE TEST MATERIAL
3. PRECLINICAL SAFETY TESTING
3.1 General Principles
3.2 Biological Activity/Pharmacodynamics
3.3 Animal Species/Model Selection
3.4 Number/ Gender of Animals
3.5 Administration/Dose Selection
3.6 Immunogenicity
4. SPECIFIC CONSIDERATIONS
4.1 Safety Pharmacology
4.2 Exposure Assessment
4.2.1 Pharmacokinetics and Toxicokinetics
4.2.2 Assays
4.2.3 Metabolism
4.3 Single Dose Toxicity Studies
4.4 Repeated Dose Toxicity Studies
4.5 Immunotoxicity Studies
4.6 Reproductive Performance and Developmental Toxicity Studies
4.7 Genotoxicity Studies
4.8 Carcinogenicity Studies
4.9 Local Tolerance Studies
NOTES
1. INTRODUCTION
1.1 Background
Biotechnology-derived pharmaceuticals (biopharmaceuticals)
were initially developed in the early 1980s. The first marketing authorisations
were granted later in the decade. Several guidances 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 that 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 United
States. All regions have adopted a flexible, case-by-case, science-based
approach to preclinical safety evaluation needed to support clinical development
and marketing authorisation. 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 is intended to improve the quality and consistency of
the preclinical safety data supporting the development of biopharmaceuticals.
1.3 Scope
This guidance document is intended primarily to recommend
a basic framework for thepreclinical safety evaluation of biotechnology-derived
pharmaceuticals. It applies to products derived from characterised 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 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 document may also
be applicable to recombinant DNA protein vaccines, chemically synthesised
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
characterised 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 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 characterisation (i.e., identity, purity, stability, and
potency). In some cases additional studies may be needed (i.e., charmacokinetics,
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 characterisation. 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:
- selection of the relevant animal species;
- age;
- physiological state;
- the manner of delivery, including dose, route of administration, and
treatment regimen; and
- 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 recognised that some studies
employing specialised test systems which are often needed for biopharmaceuticals,
may not be able to comply fully with GLP. Areas of non-compliance 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 authorisations.
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 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 mechanisms)
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 optimise the ability to evaluate toxicity
arising from the binding to the epitope and any unintentional tissue cross-reactivity.
An animal species which 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 characterise 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 non-relevant 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 optimised when the interaction
of the product and the humanised 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
non-human 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 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 human 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 characterised (e.g., titre, number of responding
animals, neutralising or non-neutralising), 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 neutralises 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 humanised 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.
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 forbiotechnology-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, utilise
preparations that arerepresentative of that 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 non-drug 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, quantization
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 behaviour of the biopharmaceutical in the biologic matrix,
(e.g., plasma, serum, cerebral spinal fluid) and the possible influence of inding
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, 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 lifethreatening diseases, repeated dose studies
up to two weeks duration have been considered adequate to support clinical
studies as well as marketing authorisation. 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 authorisations. 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 recognise 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.
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 non-immunogenic
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 optimise 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 non-human 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.
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