Clinical studies biological products

Guidance for Industry For the Evaluation of Combination Vaccines for Preventable Diseases Production, Testing and Clinical Studies. U.S. Department of Health and Human Services, Food and Drug Administration Center for Biologies Evaluation and Research. April 1997. 

The preclinical knowledge base is initially developed by designing studies to answer fundamental questions. The development of this knowledge base is generally applicable to most pharmaceuticals as well as biopharmaceuticals, and include data to support (1) the relationship of the dose to the biological activity, (2) the relationship of the dose to the toxicity, (3) the effect of route and/or schedule on activity or toxicity and (4) identification of the potential risks for subsequent clinical studies. These questions are considered in the context of indication and/or disease state. In addition there are often unique concerns related to the specific category or product class. 

Specific (local tissue tolerance) toxicity studies may be necessary due to special characteristics of the product or the clinical indication. Adjuvanted vaccines are routinely evaluated for local (injection site) reactions, and cellular therapies are routinely screened for tumorigenic potential. Research is also needed to better predict the sensitizing potential of biological products and to determine the relevance of serum antibody levels following repeat dosing in animals and humans. 

Clinical trials, also known as clinical studies, test potential treatments in human volunteers to see whether they should be approved for wider use in the general population. A treatment could be a drug, medical device, or biologic, such as a vaccine, blood product, or gene therapy. Potential treatments, however, must be studied in laboratory animals first to determine potential toxicity before they can be tried in people. Treatments having acceptable safety profiles and showing the most promise are then moved into clinical trials. 

The type and extent of preclinical and clinical studies should be determined on a case-by-base basis. Establishing comparability among biologic products generally requires a full characterization of physico-chemical properties, identification of impurities, and quantification of biologic activity with both in-vitro and in-vivo testing. Because of the inherent variability of biologic processes, batch-to-batch consistency must also be ensured. If quality attributes (e. g., purity, potency, identity, and stability) cannot be adequately assessed with analytic studies, then preclinical and/or clinical studies will likely be needed. 

Comparative Clinical Studies. Where there are no other means, well-controlled clinical trials in humans may be useful to provide supportive evidence of BA or BE. However, the use of comparative clinical trials as an approach to demonstrate BE is generally considered insensitive and should be avoided where possible (21 CFR 320.24). The use of BE studies with clinical trial end points may be appropriate to demonstrate BE for orally administered drug products when measurement of the active ingredients or active moieties in an accessible biological fluid (pharmacokinetic approach) or pharmacodynamic approach is infeasible. 

Clinical Studies Section of Labeling for Human Prescription Drug and Biological Products—Content and Format [HTML] or [PDF] (Issued 1/18/2006 Posted 1/18/2006). Available at http //www.fda.gov/CDER/guidance/5534fnl.pdf. Accessed October 6, 2006. 

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