Regulatory overview of biological therapeutic products

The FDA's Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) are responsible for ensuring the safety, efficacy, and purity of biological products. The types of biological products regulated within


Regulated products in FDA/CDER vs. FDA/CBER

cber cder

Gene and cell therapy Allergen patch tests

Venoms and antivenoms and antitoxins Vaccines

Blood and blood products

Monoclonal antibodies for in vivo use Cytokines, enzymes, growth factors, and thrombolytics Peptide hormones

Extracted proteins these two centers are shown in Table 6.1. This section will focus on the products regulated by FDA/CDER. Examples of these products are shown in Table 6.2. FDA/ CDER is subdivided into a number of different offices, with the Office of New Drugs (OND) being responsible for ensuring the safety of new drugs, including the biological products defined above. CDER/OND is further divided into divisions based on indication, as presented in Table 6.3.

All drug products must undergo a thorough safety evaluation before being marketed in the United States and other countries. The safety evaluation process includes conducting pharmacology and toxicology studies in laboratory animals and in vitro systems; conducting clinical trials in the intended patient population to evaluate safety and efficacy; and thoroughly evaluating the manufacturing process to ensure that quality drug products can be consistently produced. Entities that initiate clinical trials in human subjects and assume responsibility for the trials are referred to as sponsors. Although the majority of sponsors of new drug products are pharmaceutical and biopharmaceutical companies, other entities, such as government agencies, academic institutions, and private organizations, can also serve as sponsors. In order to lawfully conduct clinical trials with drug products in the United States, sponsors must submit an Investigational New Drug (IND) Application to FDA/CDER for review. Federal regulations (21 CFR 312)22 specify the general content of INDs. The contents include a general investigational plan; protocol(s) for clinical trials; chemistry, manufacturing, and control information; and pharmacology and toxicology information. After receiving an IND application from a sponsor, the FDA has


Examples of approved Biologicals product Name

Herceptin® (trastuzumab) Intron A® (interferon-alpha) Rebif® (interferon-beta) Remicade® (infliximab) TNKase® (tenecteplase)

product type

Monoclonal antibody



Monoclonal antibody Thrombolytic enzyme


Metastatic breast cancer


Multiple sclerosis

Rheumatoid arthritis Crohn's disease Acute myocardial infarction


Divisions of FDA/CDER

Goer Review divisions

Anti-Infective and Ophthalmic Products Anesthesia, Analgesia, and Rheumatology

Products Oncology Drug Products Biologic Oncology Products Neurology Products Psychiatry Products Cardio-Renal products Pulmonary Products

Metabolic and Endocrine Products Gastrointestinal and Coagulation Products Reproductive and Urologic Products Medical Imaging and

Radiopharmaceutical Products Dermatologic and Dental Products Anti-Viral Products

Special Pathogen and Immunologic Drug Products

30 days to review the application to ensure that it is reasonably safe for the sponsor to begin evaluating the product in humans. Sponsors cannot lawfully initiate clinical trials until the IND is in effect, which can occur after the 30-day review period or after the sponsor has satisfactorily addressed any concerns on the part of the FDA.

Clinical trials are divided into three phases, Phases 1 through 3. Human subjects, either patients or healthy volunteers, are first introduced to a new product during Phase 1 trials. Phase 1 trials are closely monitored and focus on safety and pharmacokinetics of the new product. Although it might be possible to obtain early evidence of efficacy, the primary objective of Phase 1 trials is to evaluate the safety of the new product. Generally, 20 to 80 subjects are included in Phase 1 trials. Phase 2 trials are conducted in the intended patient population and are designed to evaluate safety and efficacy. Phase 2 trials typically involve no more than several hundred patients. Phase 3 trials are conducted after preliminary evidence of efficacy has been obtained. They are intended to evaluate safety and efficacy in the target patient population and usually include several hundred to several thousand patients (21 CFR 312.23).22 If, after completing the Phase 3 trials, sponsors believe that their product is safe and effective in the target patient population and that they have met all of the other requirements, they submit a Biologics Licensing Application (BLA) to the FDA for review. If the FDA concurs that the product is safe and effective, the sponsor is granted a license to market the product.

Before even initiating clinical trials, sponsors conduct pharmacology and toxicology studies in laboratory animals and in vitro systems to support the safety of clinical trials. Collectively, these studies are referred to as nonclinical or preclinical studies to distinguish them from the clinical trials conducted in human subjects. During the course of the drug development process, additional nonclinical studies are needed to support the safety of clinical trials and, ultimately, product approval. FDA/CDER has defined the types of nonclinical studies needed to support clinical trials and approval in a series of guidance documents. The primary guidance documents were generated under a process referred to as the International Conference on Harmonization (ICH). The ICH is an international organization comprising scientists from regulatory agencies and the regulated industry in the United States, Europe, and Japan that was formed in 1990 to delineate a common pathway for the development of drugs and biologicals. The ICH has published guidance documents on clinical safety and efficacy, chemistry, and nonclinical pharmacology and toxicology. These documents provide the regulated industry in the United States, Europe, and Japan with an acceptable path forward for development of drugs and biologicals. By clearly defining an acceptable path forward, these documents have allowed for more economical use of human, animal, and material resources and have significantly limited unnecessary delay in the development of new medicines. The FDA has adopted the ICH documents. The ICH documents relating to nonclinical pharmacology and toxicology are shown in Table 6.4.

6.2.1 ICH S6: Preclinical SAfETY Evaluation of Biotechnology-Derived Pharmaceuticals

ICH S6, Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals, which was finalized in 1997, is the primary nonclinical guidance document for biologicals. The document applies to products derived from characterized cells through the use of a variety of expression systems. The principles in the document can also be applied to recombinant protein vaccines, chemically synthesized peptides, plasma-derived products, endogenous proteins extracted from human tissue, and oligonucle-otide drugs. The document provides information on two general areas: (1) general principles that can be applied to virtually all nonclinical studies, and (2) types of


Relevant International Conference on Harmonization (ICH) Documents

ICH S1A, Guideline on the Need for Carcinogenicity Studies of Pharmaceuticals23 ICH S1B, Testing for Carcinogenicity of Pharmaceuticals24 ICH SIC, Dose Selection for Carcinogenicity Studies of Pharmaceuticals25

ICH S2A, Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals26 ICH S2B,

Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals27 ICH S3A, Note for Guidance on Toxicokinetics: The Assessment of Systemic Exposure in Toxicity Studies28 ICH S3B, Pharmacokinetics: Guidance for Repeated Dose Tissue Distribution Studies29 ICH S4, Duration of Chronic Toxicity Testing in Animals (Rodent and Nonrodent Toxicity Testing)30 ICH S5A, Detection of Toxicity to Reproduction for Medicinal Products31 ICH 5B(M), Toxicity to Male Fertility, An Addendum to the ICH Tripartite Guideline on Detection of Toxicity to Reproduction for Medicinal Products32 ICH S6, Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals33 ICH S7A, Safety Pharmacology Studies for Human Pharmaceuticals34 ICH S7B (draft), The Non-Clinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals35 ICH S8 (2006), Immunotoxicology Studies for Human Pharmaceuticals36

ICH M3(M), Maintenance of the ICH Guideline on Non-Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals37

pharmacology and toxicology studies applicable to biologicals. These areas are discussed in detail below. General principles addressed in ICH S6 include selection of a relevant animal model, dosing (route, frequency, and dosage levels), nature of the test material, and GLP compliance.

6.2.2 Relevant Animal Model

Because of the high degree of species specificity of many biologicals, toxicology studies intended to support the safety of these products should be conducted in pharmacologically relevant species. ICH S6 defines a pharmacologically relevant species as "one in which the test material is pharmacologically active due to expression of the receptor or an epitope (in the case of monoclonal antibodies)." Immunochemical studies to evaluate the binding of the product to the human and animal receptor and functional assays demonstrating pharmacological activity of the product in human and animal cells can be used to identify a relevant species.

For example, the cytokine IL-4 has many effects, including stimulating proliferation of T lymphocytes. In order to identify a relevant species for toxicology studies intended to support the safety of a monoclonal antibody directed against human IL-4, Hart and coworkers38 used an in vitro IL-4-dependent T-cell proliferation assay. The results of the assay showed that the anti-human IL-4 antibody inhibited monkey T-cell responses to recombinant cynomolgus monkey (Macaca fascilularis) IL-4.38 In contrast, the anti-human IL-4 antibody showed no reactivity with mouse or rat IL-4. The goal of toxicology studies conducted with an anti-human IL-4 antibody would be to identify any adverse effects associated with blocking the activity of IL-4. The most direct way to achieve this goal is to conduct the toxicology studies in a species in which the anti-human IL-4 antibody is active. Based on the results of their in vitro T-cell proliferation assay, Hart et al. selected the cynomolgus monkey as the relevant species for toxicology studies. Because many biologicals are highly specific for human targets, the only relevant species is frequently a nonhuman primate. It is not unusual, therefore, for entire nonclinical safety programs to be conducted in a single species of nonhuman primate. Although safety evaluation programs should ideally include two species, in certain cases, such as when only one relevant species can be identified or the biological activity of the product is well understood, one species can suffice.

ICH S6 specifically states that toxicology studies in nonrelevant species may be misleading and are discouraged. For example, the recombinant human interferons, which are highly specific for humans and nonhuman primates, were initially studied in rats and rabbits and were deemed nontoxic. In contrast, the interferons produced toxicities when studied in nonhuman primates, which were similar to the toxicities observed in humans.18 39 The humanized monoclonal antibody Hu1D10 recognizes an HLA-DR variant expressed on normal B cells and B-cell lymphomas and leukemias. Binding of Hu1D10 to its antigen results in B-cell depletion. Hu1D10 reacts with human and rhesus monkey B cells, with the expression level of its antigen varying over a wide range among individuals. A study conducted in a mixed population of rhesus monkeys revealed that B-cell depletion occurred only in those animals expressing the antigen, which showed that Hu1D10 depletion in rhesus monkeys is antigen-specific.40

ICH S6 states that the route and frequency of administration used in the toxicology studies should be as close as possible to that intended for clinical use. Due to their protein nature, biologicals are almost always administered by intravenous, subcutaneous, or intramuscular routes. However, other routes of administration are also used. For example, Regranex® (becaplermin),41 a recombinant human platelet-derived growth factor, is applied topically for the treatment of certain diabetic neuropathic ulcers, and dnaJP1 is currently being evaluated for use as an orally administered treatment for rheumatoid arthritis.42 Furthermore, although the frequency of administration used in toxicology studies should be as close as possible to that intended for clinical use, using a different frequency might be scientifically appropriate in certain situations. For example, a more frequent administration might be used in toxicology studies to compensate for a product having a shorter half-life in laboratory animals than in humans or to overcome immunogenicity by inducing high-dose tolerance (an unresponsive state that can occur with high doses of antigens, including biologicals).

The highly targeted nature of biologicals, which generally limits the effects that they produce to the intended pharmacological effect, influences dose selection. The "typical" toxicology study defined in textbooks consists of three doses groups: low, mid, and high. The high dose should produce clear evidence of toxicity. The mid dose should produce slight toxicity. The low dose should produce no toxicity, to allow for clear definition of a no-observed-adverse-effect-level (NOAEL).43 This paradigm is applicable to biologicals that produce toxicity. It cannot, however, be readily applied to biologicals with limited or no toxicity. In these cases, ICH S6 suggests that dose selection be based upon the expected pharmacological/physiological effects of the product, availability of suitable test material, and the intended clinical use. Other factors that can influence dose selection that are not unique to biologicals include the maximum volume that can be administered to the laboratory animals and the solubility of the test material. Volumes that are considered as "good practice" are defined in a publication by Diehl et al.44 In all cases, the rationale used for dose selection should be clearly defined in the study report.

Because the pharmacological action of biological therapeutics may occur at very low doses, a no-observed-effect-level (NOEL) may not be established in the repeated-dose toxicology studies. Evaluating the biological at doses lower than the clinical range to achieve a NOEL does not add value to the program and would be an unnecessary use of animals. Under these circumstances, therefore, the goal of the safety studies is typically to identify a NOAEL rather than a NOEL. It can be difficult to determine what findings in the toxicology study are due to exaggerated pharmacological activity and when these findings become adverse and represent toxicity. An adverse effect may be considered to be a change that may impair performance and generally have a detrimental effect on growth, development, or life span, and should be an effect that would be unacceptable if it occurred in a human clinical trial.45

Several considerations can be used to determine whether these effects should be considered treatment-related, including a combined analysis of the biological and statistical effects; the presence of a dose-response relationship; whether the findings are seen in both sexes; whether the findings are outside the historical control range; and whether related histopathological correlates exist. The presence or lack of statistical significance alone is not sufficient to determine whether an effect is treatment-related or adverse. Additional considerations are the clinical indication, the reversibility of the effect and whether it can be monitored in the clinic, and the risk/benefit analysis for the patient population. In addition, because the pharmacological activity of biological therapeutics may be very different in the disease state for which the drug is being developed, as opposed to its action in the healthy animals employed in the toxicology studies, adverse findings or exaggerated pharmacological effects may not be seen in the toxicology studies. If little to no toxicity is observed, it may not be possible to define a maximum tolerated dose (MTD). In this case, conducting safety studies using reasonable multiples over the clinical doses is sufficient to demonstrate safety. What constitutes "reasonable multiples" will depend on several factors, including the clinical indication (life-threatening vs. non-life-threatening), the patient population (consideration of special populations, such as children, elderly, and women of childbearing potential), chronic vs. acute treatment, concomitant medications, and alternative therapies.

6.2.3 Nature of the Test Material

The nature of the test material that is used in safety evaluation studies is critical. ICH S6 specifically states that, 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." It is recognized, however, that changes in manufacturing to improve product quality and yield can occur during the course of drug development. Depending on the effect of manufacturing changes on the nature of the product, additional pharmacology and/or toxicology studies might be indicated.

6.2.4 FDA Compliance

The FDA established the Good Laboratory Practice (GLP) regulations (21 CFR Part 58)46 in 1978 to ensure the integrity and quality of data generated as part of the safety evaluation of products intended for human use. This regulation addresses virtually all aspects of study conduct. According to ICH S6, toxicology studies conducted to support the safety of biologicals are expected to be conducted in compliance with GLP. ICH S6 recognizes, however, that in certain cases, specialized test systems, which may not be compatible with full GLP compliance, might be needed for the safety assessment of biologicals. In such cases, the specific areas of noncompliance should be identified.

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