Safety Assessment of Biotechnology-Derived Pharmaceuticals:

Transcription

1 Safety Assessment of Biotechnology-Derived Pharmaceuticals: ICH and Beyond* MERCEDES A. SERABIAN AND ANNE M. PILARO U. S. Food and Drug Administration, Center for Biologics Office of Therapeutics Research and Review, Rockville, Maryland Evaluation and Research, ABSTRACT Many scientific discussions, especially in the past 8 yr, have focused on definition of criteria for the optimal assessment of the preclinical toxicity of pharmaceuticals. With the current overlap of responsibility among centers within the Food and Drug Administration (FDA), uniformity of testing standards, when appropriate, would be desirable. These discussions have extended beyond the boundaries of the FDA and have culminated in the acceptance of formalized, internationally recognized guidances. The work of the International Committee on Harmonisation (ICH) and the initiatives developed by the FDA are important because they (a) represent a consensus scientific opinion, (b) promote consistency, (c) improve the quality of the studies performed, (d) assist the public sector in determining what may be generally acceptable to prepare product development plans, and (e) provide guidance for the sponsors in the design of preclinical toxicity studies. Disadvantages associated with such initiatives include (a) the establishment of a historical database that is difficult to relinquish, (b) the promotion of a check-the-box approach, i.e., a tendancy to perform only the minimum evaluation required by the guidelines, (c) the creation of a disincentive for industry to develop and validate new models, and (d) the creation of state-of-the-art guidances that may not allow for appropriate evaluation of novel therapies. The introduction of biotechnology-derived pharmaceuticals for clinical use has often required the application of unique approaches to assessing their safety in preclinical studies. There is much diversity among these products, which include the gene and cellular therapies, monoclonal antibodies, human-derived recombinant regulatory proteins, blood products, and vaccines. For many of the biological therapies, there will be unique product issues that may require specific modifications to protocol design and may raise additional safety concerns (e.g., immunogenicity). Guidances concerning the design of preclinical studies for such therapies are generally based on the clinical indication. Risk versus benefit decisions are made with an understanding of the nature of the patient population, the severity of disease, and the availability of alternative therapies. Key components of protocol design for preclinical studies addressing the risks of these agents include (a) a safe starting dose in humans, (b) identification of potential target organs, (c) identification of clinical parameters that should be monitored in humans, and (d) identification of at-risk populations. One of the distinct aspects of the safety evaluation of biotechnology-derived pharmaceuticals is the use of relevant and often nontraditional species and the use of animal models of disease in preclinical safety evaluation. Extensive contributions were made by the Center for Biologics Evaluation and Research to the ICH document on the safety of biotherapeutics, which is intended to provide worldwide guidance for a framework approach to the design and review of preclinical programs. Rational, scientifically sound study design and early identification of the potential safety concerns that may be anticipated in the clinical trial can result in preclinical data that facilitate use of these novel therapies for use of animals. use in humans without duplication of effort or the unnecessary Keywords. Preclinical trials; toxicity testing; biotherapeutics; S6 document OVERVIEW OF SAFETY EVALUATIONS As clinical development of a pharmaceutical agent moves from phase I to phase II and phase III trials, product and preclinical development should also move forward in advance of the human studies. The seemingly logical progression for achieving licensure of a pharmaceutical agent begins with drug discovery, followed by preclinical assessment of the product, and ending with definitive clinical trials; however, the preclinical evaluation of a drug is actually directed in the opposite direction (Fig. 1). Prior to initiating preclinical studies, it is important to identify any pertinent information such as the clinical indication, route of administration, and dosing regimen that will aid in the design and interpretation of preclinical studies intended to support the introduction of the pharmaceutical agent into human trials. The primary goals of performing preclinical studies for * Address correspondence to: Mercedes A. Serabian, FDA/CBER/ OTRR/DCTDA, Woodmont I, HFM-579, 1401 Rockville Pike, Rockville, Maryland phase I/II trials should be (a) to recommend an initial safe starting dose and dose escalation scheme in humans, (b) to determine an acceptable risk : benefit ratio in humans, (c) to identify potential target organs of toxicity and/or activity (i.e., surrogate endpoints), (d) to identify parameters for clinical monitoring, (e) to delineate patient inclusion/exclusion criteria, and (f) to support eventual labeling claims (5). DEVELOPMENT OF HARMONIZED GUIDANCES The principal mechanism that the Center for Biologics Evaluation and Research (CBER) uses to ensure that the appropriate evaluations are completed is through contact with the sponsor prior to filing the application for an Investigational New Drug (IND). Such contact can be in the form of teleconferences or face-to-face meetings. However, with the broadening overlap of regulatory responsibility among the centers within the FDA, mainly as a function of the increasing complexity of the products themselves, there is awareness that uniformity of testing standards is desirable. In an attempt to integrate and co-

2 28 FIG. 2.-The international generation of the ICH guidance document for biotechnology-derived pharmaceuticals. FIG. The progression to licensure for a pharmaceutical agent. ordinate the regulatory process on a global scale, CBER and the Center for Drug Evaluation and Research (CDER) have participated extensively in discussions under the auspices of the International Conference on Harmonisation (ICH). Numerous exchanges over the past 7 yr have culminated in the acceptance of formalized, internationally harmonized guidances (Fig. 2). There are both advantages and disadvantages to the development of regulatory guidances. Advantages may include (a) the formalization of a consensus scientific opinion, (b) the promotion of consistency of review, (c) the improvement of the quality of the studies performed, especially in those cases where there may not be sufficient in-house expertise to design or evaluate such studies, and (d) the guidance given to the public sector in determining what may be generally acceptable for a successful product development plan. Some disadvantages to the establishment of guidances may include (a) the temporal nature of guidances, in that they may be state-ofthe-art at the time of issuance and therefore may become evaluation of outdated, thus not allowing for appropriate new and evolving technologies, (b) the lack of comfort in using a check-the-box approach to regulatory toxicology studies, which may lead to conducting only the minimum tests stipulated by the guidance, (c) the performance of fewer studies than are scientifically justified, and (d) the potential for creating a disincentive for industry to develop and validate new models because of lack of experience or expertise in interpreting unknown or unexpected results (2). Despite these potential disadvantages, the regulatory agencies, industry, and academia concurred that generation of a harmonization document would be beneficial to the overall progression of a biotechnology-derived pharmaceutical agent to clinical trials. The ICH document generated via this internationally coordinated scientific and regulatory effort that is considered the most applicable to the regulation of biologic products is entitled &dquo;preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals&dquo; (hereinafter referred to as the S6 document). This document provides a flexible, rational, science-based framework for the preclinical safety evaluation of biotechnology-derived pharmaceuticals (1). The S6 document was written with the intent of addressing the general concepts and principles related to preclinical assessment of these products while allowing modifications to the general test designs. Thus, if the need arises, a regulatory region is then able to generate additional specific guidances to address a particular issue. In keeping with its flexible, data-driven approach to the preclinical safety evaluation of biologics, CBER has applied the principles of the S6 document to other FDA guidances (e.g., the Points to Consider documents, available from the FDA/CBER, 5600 Fishers Lane, Rockville, MD 20857). OVERVIEW OF PRECLINICAL STUDY DESIGN AND EVALUATION The duration and design of preclinical studies for pharmaceutical agents are generally based on the clinical indication, i.e., the requirements for studies are linked to the route, duration, and risk: benefit ratio associated with to obtain human the particular agent (4). The opportunity data in well controlled clinical studies is critical to validating or assessing the predictive value of the preclinical studies (in addition to obtaining safety data in the clinical setting). Risk versus benefit decisions are made with an understanding of the nature of the patient population, the severity of disease, and the availability of alternative therapies. For the low-molecular-weight synthetic pharmaceuticals, precedent has been set and historical databases developed for preclinical toxicity studies. These databases have been primarily developed using animals in which pharmacologic and toxic effects are independent of species restrictions, with both rodents (i.e., mice and rats) and nonrodents (i.e., dogs). However, the species-specific nature of many of the biotechnology-derived products has required the use of pharmacologically relevant (and often nontraditional) animal species, the use of homologous products, and/or applicable animal models of disease in preclinical safety evaluations. For example, interferons were initially studied in rats and rabbits, but because of the extreme species specificity of this class of recombinant proteins no toxicity was observed until a nontraditional but pharmacologically relevant species (i.e., a nonhuman primate model) was used. Adequate study designs for biopharmaceuticals have relied on the use of concurrent controls (positive and negative) and extensive baseline data for interpretation of any toxicologic findings (5). SAFETY EVALUATION OF BIOTECHNOLOGY-DERIVED PRODUCTS Because of the diversity of biotechnology-derived products and in keeping with the philosophy of the S6

3 29 document, CBER encourages the use of flexible preclinical study designs. The determination of what preclinical studies are performed should be based on considerations such as (a) establishment of a rationale, (b) identification of a clinical indication, (c) selection of an appropriate animal model, (d) pharmacokinetic/pharmacodynamic parameters, and (e) characterization of the general and specific toxicities (i.e., neurotoxicity, developmental toxicity) of the agent. ESTABLISHMENT OF RATIONALE Demonstration of biologic activity supportive of the rationale for the selection of species, the route of administration, the dose administered, and the clinical indication can be performed with in vitro and/or in vivo studies (e.g., patient-derived tissues/cells or use of animal models of disease). At this stage, initiation of potency assays for product activity and the evaluation of receptor characteristics across species should begin. Results of previous studies can also be helpful for some agents in establishing justification for clinical use, although much confidential information remains unpublished. The animal model(s) used to establish rationale can also be used to help discern any potential toxicities of the agent of interest. Many times information concerning activity/toxicity can be obtained from the same preclinical study. APPLICATION TO THE CLINICAL INDICATION The risk: benefit ratio is assessed based on the human population of interest (i.e., normal individuals vs patients with a non-life-threatening illness vs patients with a lifethreatening illness). Information gathered in the preclinical studies is pertinent to the evalaution of this ratio and to the final design of the clinical trial. For example, if anaphylactoid reactions have been observed in animals, then humans should be closely monitored for similar re- to avoid sponses or perhaps premedicated in an attempt the adverse effect. All potential target tissues identified by the preclinical data should be properly monitored in humans via acceptable and available clinical procedures. For example, renal toxicity has been reported in several animal species exposed to basic fibroblast growth factor; therefore, patients should be monitored for proteinuria and renal functional changes as part of the clinical evaluation (3). The preclinical data will also help to delineate the inclusion/exclusion criteria for the patient population (e.g., the exclusion of patients with certain malignancies when administering mitogenic growth factors). SPECIES SELECTION A critical element in the successful interpretation of preclinical study data is the selection of the appropriate animal species. Considerations such as (a) the presence of the target receptor, (b) the affinity of the biologic for the receptor, (c) the metabolic profile of the animal, and (d) the pharmacologic profile of the animal play a role in the determination of a relevant species for use in the toxicology studies. Another considerations for animal selection is the intended human route of administration (ROA), where the size of the animal may play a significant role. Use of alternative models, such as knockout animals or transgenic animals expressing a human receptor, is also an option when assessing activity of agents with a high degree of species specificity. In some cases, animal models of disease may be used as an acceptable alternative to traditional toxicology studies with normal animals, allowing for the generation of data regarding the intended action of the biotherapeutic agent (i.e., proof of concept) and providing some insight into potential toxicities that may result from exposure to the agent. As long as the toxicologist understands the limitations of the model and the reason for its use, the resulting data can be used in conjunction with additional in vitro and in vivo information generated from other The use of con- studies to support clinical development. current controls is especially important in this setting. EVALUATION AND USE OF ENDPOINTS Good preclinical study design allows for adequate interpretation of endpoints displayed in animals and estimation of the initial human dose. To identify potential preclinical endpoints, the demonstration of pharmacologic activity (i.e., pharmacodynamic effects) should be considered. Both primary and secondary parameters identified in preclinical studies, such as biochemical or morphologic effects, can serve as surrogate markers in the clinical trials. For example, if administration of a specific agent results in elevated transaminase levels and there is microscopic correlation indicating that the liver is a target tissue in animals, then monitoring for hepatic changes in humans is appropriate. Attempts should be made to use the same or similar reagents, test procedures, and equipment in both animals and humans to assess these crucial parameters. If new technologies are identified, they should be developed, validated, and standardized prior to routine application. DOSE SELECTION, DURATION, AND ROUTE Various dose levels and dosing regimens should be employed to fully evaluate the toxicity of the biologic agent. To select doses for general toxicity testing, consideration of the proposed human ROA and the formulation of the agent are of importance. The general dose schedule (i.e., daily versus intermittent administration) of the test agent should be defined. The dosing regimen should be based on the proposed human trial and support from in vitrolin vivo data used to generate the rationale for utilization of the biotherapeutic in the disease indication. The duration of dosing in the preclinical studies (i.e., acute versus chronic exposure) is dependent upon the proposed clinical use. The ICH S6 document cites a maximum dosing interval of up to 6 mo in the animal studies to support intended chronic exposure in humans; however, the final interpretation of this recommendation is left up to the individual regulatory agency. An important factor in the determination of the duration of the preclinical study is the development of antibodies to the biotherapeutic agent, which may result in alterations in the pharmacologic activity, the pharmacokinetic profile, and/or the toxicity observed. All repeated-dose studies should include measurements of both total and neutralizing antibodies against the biologic agent.

4 30 Regulatory &dquo;misconceptions&dquo; Focus of Preclinical Safety Evaluation More data in animals are always better. Unexplainable observations are better ignored Toxicology findings in animal models of disease are always too difficult to interpret. = Getting into clinical trials faster quicker therapeutic approval. A lack of any &dquo;significant&dquo; findings in animals gives an assurance of safety in humans FIG. 3.-Examples of regulatory misconceptions within the public sector. CHARACTERIZATION OF GENERAL AND SPECIFIC TOXICITIES Both general and specific toxicities should be identified in preclinical studies to determine the therapeutic index (effective dose/toxic dose) in humans. Single-dose and multidose toxicology studies constitute part of the toxicology package. The purposes of these studies are (a) to establish a potential dose response, (b) to determine target organs, (c) to look for reversibility for any toxicities, (d) to look for any delayed toxicities, (e) to look for any cumulative toxicities, and (f) to characterize any exaggerated pharmacologic effects. Specific preclinical studies may be needed because of unique characteristics/properties of the biotherapeutic agent or because of the desired clinical use. For example, for growth factors, additional concerns include but are not limited to developmental toxicity and carcinogenic/tumorigenic potential. Concerns to be addressed when evaluating monoclonal antibodies include the aforementioned and (a) immunotoxicity, (b) conjugate/linker toxicity, and (c) any bystander effects. SUMMARY The public sector sometimes holds the misconception that preclinical studies should not show any indication of a toxic effect. This can erroneously lead to study designs that attempt to minimize adverse findings. Examples of other such misconceptions are presented in Fig. 3. However, more useful information about a product will be obtained from preclinical studies that are specifically designed to establish toxicity and identify adverse effect levels, providing a basis for regulatory decisions regarding the risk: benefit ratio to the patients for a particular pharmaceutical agent. In summary, the sponsor s goal is to gather sufficient relevant data needed to initiate clinical trials. Preclinical studies should be designed to answer specific questions, such as those depicted in Fig. 4. The development of biotechnology-derived pharmaceuticals has been historically directed to treatment of patients with serious or lifethreatening diseases who have few or no therapeutic options, with an emphasis on a detailed informed consent form and extensive clinical monitoring. However, as more INDs are submitted for lower risk diseases that have other therapeutic choices and for those diseases requiring more chronic exposure to a pharmaceutical agent, the risk What is the physiologic/pharmacologic profile? Are the mechanisms of action known? Are there mechanisms related to the toxicities seen? What is the relevance of the toxicities to humans? Are the effects dose-responsive? Does the route of administration/dosing regimen/dose level affect the activity/toxicity in a relevant species? What risks can be identified for the clinical trial? FIG. 4.-Examples of specific questions that preclinical studies should be designed to answer. versus benefit considerations are changing. This new clinical focus may require additional preclinical studies to assess safety and dosing rationale prior to use of these agents in humans. More conservative clinical trial designs may also be needed, especially if the existing preclinical information is limited in scope. The integrated assessment of safety obtained from product, preclinical and clinical data will allow both the sponsor and the FDA to make rational scientific decisions on whether to allow the test agent to move forward into definitive clinical trials. Based upon data generated both preclinically and clinically, additional preclinical studies that serve to (a) support changes in manufacturing, (b) address toxicities seen in animals or humans, (c) support additional clinical trials, and (d) support eventual labeling claims may also eventually be needed. The ever-increasing number of unique, as well as newly modified (i.e., second generation) biotechnology-derived pharmaceuticals being introduced for use in humans will continue to require the foresight and application of flexible approaches to fully evaluate their safety. CBER has always been a science-based agency, but the current pace of techno- demands both better access to and use logic development of the latest scientific information and resources in regulatory decision making. Efficient communication between research and review scientists at FDA and input from the scientific community and the public sector (i.e., the sponsors) should be the rule, not the exception. ACKNOWLEDGMENT We thank Dr. Joy Cavagnaro for her invaluable contributions in the writing of the ICH documents and for the initial insight concerning not defaulting to a &dquo;checkthe-box&dquo; mentality. REFERENCES 1. Food and Drug Administration (November 1997). International Conference on Harmonisation: Guidance on preclinical safety evaluation of biotechnology-derived pharmaceuticals. Fed. Register 62: Available at: 2. Henck JW, Hilbish KG, Serabian MA, Cavagnaro JA, Hendrickx AG, Agnish ND, Kung AHC, and Mordenti J (1996). Reproductive toxicity testing of therapeutic biotechnology agents. Teratology 53:

5 31 3. Mazue G, Bertolero F, Garofano L, Brughera M, and Carminati P (1992). Experience with the preclinical assessment of basic fibroblast growth factor (bfgf). Toxicol. Lett. 64/65: Siegel JP, Gerrard T, Cavagnaro JA, Keegan P, Cohen RB, and Zoon K (1995). Development of biological therapeutics for oncologic use. In: Biological Therapy of Cancer, 2nd ed., VT Devita Jr, S Hellman, and SA Rosenberg (eds). J. B. Lippincott, Philadelphia. pp Stromberg K, Chapekar MS, Goldman BA, Chambers WA, and Cavagnaro JA (1995). Regulatory concerns in the development of topical recombinant ophthalmic and cutaneous wound healing biologics. Wound Rep. Reg. 2: Workshop: Ultrastructural Pathology in Toxicologic Disease This workshop will be held June 8-10, 1999, at the College of Veterinary Medicine, Iowa State University. It will be directed by Norman Cheville, Vincent Meador, and Jane Fagerland, with experts in Veterinary Pathology from other laboratories. Emphasis will be on problem-solving interpretation of electron micrographs associated with toxic injury. For further information, contact: Norman Cheville Department of Veterinary Pathology Iowa State University Ames, IA Tel: Fax: iastate. edu