preclinical safety evaluation of biotechnology-derived pharmaceuticals

Guidance for Industry S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals July 1997 ICH Guidance for Industry S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals Additional copies are available from: the Drug Information Branch (HFD-210), Center for Drug Evaluation and Research (CDER), 5600 Fishers Lane, Rockville, MD 20857 (Tel) 301-827-4573 http://www.fda.gov/cder/guidance/index.htm or Office of Communication, Training, and Manufacturers Assistance (HFM-40) Center for Biologics Evaluation and Research (CBER) 1401 Rockville Pike, Rockville, MD 20852-1448, http://www.fda.gov/cber/guidelines.htm (Fax) 888-CBERFAX or 301-827-3844 (Voice Information) 800-835-4709 or 301-827-1800 U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) July 1997 ICH i Table of Contents I. INTRODUCTION (1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 A. Background (1.1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 B. Objectives (1.2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 C. Scope (1.3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 II. SPECIFICATION OF THE TEST MATERIAL (2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 III. PRECLINICAL SAFETY TESTING (3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 A. General Principles (3.1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 B. Biological Activity/Pharmacodynamics (3.2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 C. Animal Species/Model Selection (3.3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 D. Number/Gender of Animals (3.4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 E. Administration/Dose Selection (3.5) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 F. Immunogenicity (3.6) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 IV. SPECIFIC CONSIDERATIONS (4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 A. Safety Pharmacology (4.1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 B. Exposure Assessment (4.2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 C. Single Dose Toxicity Studies (4.3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 D. Repeated Dose Toxicity Studies (4.4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 E. Immunotoxicity Studies (4.5) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 F. Reproductive Performance and Developmental Toxicity Studies (4.6) . . . . . . . . . 9 G. Genotoxicity Studies (4.7) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 H. Carcinogenicity Studies (4.8) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 I. Local Tolerance Studies (4.9) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 This guidance was developed within the Expert Working Group (Safety) of the International Conference on1 Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been subject to consultation by the regulatory parties, in accordance with the ICH process. This document has been endorsed by the ICH Steering Committee at Step 4 of the ICH process, July 1997. At Step 4 of the process, the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan and the United States. This guidance was published in the Federal Register on November 18, 1997 (62 FR 61515), and is applicable to drug and biological products. This guidance represents the Agency’s current thinking on preclinical safety evaulation 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. GUIDANCE FOR INDUSTRY1 S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals I. INTRODUCTION (1) A. Background (1.1) 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. B. Objectives (1.2) 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 2 quality and consistency of the preclinical safety data supporting the development of biopharmaceuticals. C. Scope (1.3) 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 deoxyribonucleic 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. II. SPECIFICATION OF THE TEST MATERIAL (2) 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 3 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. III. PRECLINICAL SAFETY TESTING (3) A. General Principles (3.1) 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. B. Biological Activity/Pharmacodynamics (3.2) 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 4 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 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. C. Animal Species/Model Selection (3.3) 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 5 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. D. Number/Gender of Animals (3.4) 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. E. Administration/Dose Selection (3.5) 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. 6 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). F. Immunogenicity (3.6) 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.