Accelerated Approval

Accelerated approval, 21 CFR 601.40, may be granted for certain biological products that have been studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit over existing treatments. Accelerated approval may reduce the development time for a new vaccine. Such an approval is based on adequate and well-controlled clinical trials establishing that the product has an effect on a surrogate endpoint that is based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit. Currently, the use of surrogate endpoints for evaluating vaccine effectiveness is subject to the requirement that the sponsor study the biological product further, to verify and describe its clinical benefit. Recently, the option to pursue an accelerated approval pathway for trivalent inactivated influenza vaccines became available if a shortage of influenza vaccine exists for the US market at the time the new vaccine is approved. In this case, the FDA interprets the regulation as allowing accelerated approval of an influenza vaccine during a shortage because influenza is a serious and sometimes life-threatening illness. The agency has licensed two seasonal influenza vaccines using this regulatory mechanism. Any endpoint considered appropriate to support approval, whether a surrogate or a clinical endpoint, must be supported by substantial evidence of effectiveness. The accelerated approval regulations give the FDA flexibility with respect to the types of endpoints that support marketing approval, but do not affect the quantity or quality of evidence needed to demonstrate substantial evidence of effectiveness or safety.

Priority Review

General Considerations for Vaccine Trials

The general considerations for clinical studies to license a vaccine include demonstration of safety, immunogenicity, efficacy (immunogenicity may be sufficient in some cases), and evaluation of simultaneous administration with other licensed vaccines. Efficacy should be demonstrated ideally in randomized, double-blind well-controlled trials. The endpoints will be product-specific, and may be clinical disease or immune response endpoints, if efficacy against clinical disease has been previously established.

Safety evaluation is the other component in the clinical evaluation of vaccines. Safety is one of the most important considerations when evaluating new vaccines and modifications to currently licensed vaccines. The initial responsibility for determining vaccine safety starts with clinical investigators and vaccine manufacturers. The NRA is responsible for ensuring that clinical trials are carried out under good clinical practices—a requirement essential for evaluating safety data. In general, when evaluating safety, one must compare the risk of the vaccine-preventable disease with the risk of the adverse event(s) possibly associated with the vaccine, and these may change over time.

Regulatory Evaluation of Influenza Vaccines

Seasonal Influenza Vaccines

Currently, all influenza vaccines licensed in the US are derived from viruses grown in chicken eggs, and contain 15 μg of hemagglutinin antigen from each of the three strains selected for that year's vaccine—two influenza A strains (H1N1 and H3N2) and one influenza B strain. For each year's seasonal influenza vaccines, any of the previous three influenza strains in the trivalent vaccine may be replaced with a new strain. Strain changes are based on evaluation of circulating wild-type strains. Public health experts from national influenza surveillance centers, the FDA, and the World Health Organization (WHO) annually evaluate world-wide epidemiological data to determine the virus strains that manufacturers will use to make the vaccines administered in the fall. The process of selecting the strains and manufacturing the final vaccine is a lengthy process that extends from 6 to 8 months. For these strain changes that occur every year, manufacturers must submit a prior approval manufacturing supplement to an existing BLA. FDA does not require clinical data, however, for approval of these annual supplements for licensed manufacturers of inactivated influenza vaccine.