General Regulatory Issues Related to Tumor Vaccines

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Just as it is important to find novel approaches for cancer therapy, it is also important that these tumor vaccine products are developed to best reveal their therapeutic potential. The role of the product reviewer is to ensure that patients are receiving a product that is safe, pure, and potent at all stages of development. A safe, pure, and potent product is most likely to be produced if there is quality and consistency in both the testing and manufacture of the product. Although the standards outlined as Good Manufacturing Practices (GMPs) will not be achieved before licensure, many of the principles should be applied to product testing and manufacturing at all stages of product development.

2.1.1. Product Manufacture

Consistent production of tumor vaccine products, particularly multiantigen preparations, autologous tumor cell lysates, and cellular vaccines is critical in order to verify and confirm any promising activities observed at the early stages of the clinical trial. Prior to a product sponsor's submission of an Investigational New Drug (IND) application to the FDA, the product will often have already undergone pilot production/manufacturing efforts. The goal of this phase of product development is to manufacture a tumor vaccine of a quality and consistency acceptable for first use in humans in the phase I clinical trial setting. As product development continues into later stages, the quality and consistency of the tumor vaccine production should improve. Controls should be in place to ensure that the materials and methods used in manufacturing are suitable for producing a clinical-grade product. In addition, proper facilities design and maintenance as well as personnel training and oversight will contribute to the production of a safe and consistent product.

If the tumor vaccine is shipped, the shipping conditions must be shown not to have negative effects on the quality of the product. As with all biological products, a stability program for tumor vaccines must also be established, particularly if the tumor vaccine will be stored and used for repeat administration to patients. It is important to know whether the vaccine injected initially is the same as that injected during later cycles of immunization. A stability program should be initiated by phase I trials and data acquisition should continue through phase III trials to support the dating period.

2.1.2. Product Testing

In-process and lot-release testing are critical controls in the manufacturing process. Product testing should include testing for safety, identity, purity, and potency. Test methods should be chosen to allow for accurate and reproducible results. Some test methods are standard, such as the sterility testing outlined in the Code of Federal Regulations (21 CFR 610.12), whereas others are product-specific and are determined on a product-to-product basis, such as potency testing. Wherever standard tests cannot be used, alternate tests may be used if demonstrated to be of equal or greater sensitivity and specificity as the recommended methods.

Safety testing should include testing for sterility—including bacteria, fungi, and mycoplasma—and for adventitious viruses. Adventitious agent testing is especially important when allogeneic cells or cell lines are used in the manufacture or the final formulation of the tumor vaccine. Whenever cells or cell lines are cultured, the bulk harvest should be tested for mycoplasma because of the risk of contamination by fetal calf serum, other animal-derived reagents, or the individual(s) handling the cells. Additional information on cell-line testing can be found in the FDA document, "Points to Consider in the Characterization of Cell Lines Used to Produce Biologicals" (1993). Identity testing should identify and distinguish the final vaccine product from other products produced in the same facility. Purity testing should ensure that harmful substances are not introduced during the manufacturing process and includes testing for endotoxin and harmful residual solvents. Determining an appropriate assay for potency testing is one of the most difficult challenges for tumor vaccines and therefore warrants further discussion.

Potency is one of the most important measures of quality for each tumor vaccine lot and should also demonstrate manufacturing consistency between lots. The establishment of a uniform potency assay for all classes of tumor vaccines remains one of the most vexing problems and impediments to the future licensure of this class of biologics. The federal regulations are clear regarding the need for a potency assay: The definition of potency as stated in 21 CFR 600.3 is "the specific ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner intended, to affect a given result." However, defining acceptable methods to measure potency of tumor vaccines is controversial because of the uncertainty regarding appropriate laboratory tests and the inconsistent demonstration of clinical efficacy. Nevertheless, we will provide some recommendations in the sections below. There may also be assays that can be used as surrogates for potency and can be performed for lot release. For example, potency of autologous, cellular tumor vaccines could be determined by a defined process, cell viability, and the expression of phenotypic markers known to correlate with biological activity. We anticipate that advances in the field of immunology together with advances in the techniques utilized to measure tumor identity and immunological function (e.g., genomics and proteomics) will greatly improve our ability to effectively measure potency in the future.

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