The CBER, FDA, Rockville, MD is responsible for regulating vaccines and other biologics in the United States. In addition to meeting the general standards before public release (Table 7), each vaccine and adjuvant are tested for safety on a case by case basis, preferably with the help and guidance of the CBER as noted before. Such guidance, informal in nature but quite helpful, was published in 1993 in response to the needs of HIV-1 vaccine development (52). The principles laid down by that publication can be adapted to the needs of other vaccines. It is recommended that as a general principle, all novel (nonaluminum) vaccine/adjuvant formulations be discussed earlier rather than later in preclinical development with the staff of the CBER. The principles are summarized in the next few paragraphs. These and other preclinical and clinical trial study design issues have been discussed in some detail (52,53).
1. Extensive experience with aluminum compounds have shown them to be safe. Therefore, for vaccines with aluminum adjuvants, postinjection observation of the animal and injection site is generally adequate for preclinical safety without the need for formal toxicology study of the combined product, unless there is some special concern about the antigen.
2. For other adjuvants, additional tests are necessary. These include reactogenicity and toxicology tests of the adjuvant alone and the antigen-adjuvant combination in a manner that is relevant to the intended clinical use, including route of administration, injection volume, and clinical formulation. A standard safety assessment protocol in rabbits should be utilized, but only if the rabbit is thought to be sensitive to the biological effects of the vaccine. This standard safety assessment protocol provides a bridging study that links preclinical and clinical development.
3. Early in clinical development, the FDA recommends inclusion of a control group of volunteers given antigen alone and/or antigen adsorbed to aluminum as comparison groups. Results of the immunological assessments obtained from such early phase 1 studies should be combined with the safety profile to help define the risk/benefit of proceeding to further clinical studies.
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