junction with the IRB(s) that initially approved the trial and (for larger studies) a study-specific data safety monitoring board associated with the trial. If questions or concerns of safety arise during a clinical trial, FDA can put the study on “clinical hold” until the questions are satisfactorily addressed.

In parallel with the clinical-development path, the manufacturers develop processes to move from preparation of pilot vaccine lots to large-scale manufacture of lots that are consistent in characterization and immunogenicity. The large-scale manufacturing process is generally in final form before Phase 3 trials begin. Defined manufacturing methods and well-described tests to control the vaccine at critical steps in the manufacturing process are fundamental to ensure the safety and purity of vaccines and to achieve consistency in manufacture. FDA regulations related to the manufacture, product quality, and clinical testing of vaccines are found in Title 21 of the Code of Federal Regulations (CFR).1 To supplement information contained in the CFR, FDA periodically makes available guidance documents that address various aspects of and issues related to vaccine safety.2

If the results of the Phase 1, 2, and 3 clinical trials support the safety, immunogenicity, and efficacy of the vaccine, the manufacturing facility is adequate, and the product of manufacture is consistent, the sponsor can submit a BLA to FDA. After consideration of the data, FDA, with advice from VRBPAC, can license the vaccine. VRBPAC includes public members and non-FDA scientists, clinicians, biostatisticians, and epidemiologists (FDA, 2002).

Postmarket Surveillance of Vaccine Safety

FDA continues to play an important role after licensure by making periodic inspections of the manufacturing facility. It can request results of


Some examples of relevant sections of the CFR are: 21 CFR 25, Environmental impact considerations; 21 CFR 50, Protection of human subjects; 21 CFR 56, Institutional Review Boards; 21 CFR 58, Good Laboratory Practice for non-clinical laboratory studies; 21 CFR 201, Labeling; 21 CFR 210, Current Good Manufacturing Practice (GMP) in manufacturing, processing packing or holding of drugs (general); 21 CFR 211, GMP practice for finished pharmaceuticals; 21 CFR 312, Investigational New Drug application; 21 CFR 314.126, Adequate and well-controlled clinical trials; 21 CFR 600, Biological products (general); 21 CFR 601, Licensing; and 21 CFR 610, General biological products standards.


In 21 CFR 600, safety is defined as “the relative freedom from harmful effect to persons affected directly or indirectly, by a product when prudently administered, taking into consideration the characteristics of the product in relation to the condition of the recipient at the time.”

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