testing in animals. When the pilot lots are ready for clinical testing in humans, the sponsor submits a Notice of Claimed Investigational Exemption for a New Drug; from that point on, the product is referred to as an investigational new drug (IND). A complete IND application includes (1) descriptions of the composition, source, and manufacturing process of the product; (2) quality control and the methods used to test the vaccine's safety, purity, and potency; (3) a summary of all laboratory and preclinical animal testing; (4) a detailed description of the proposed clinical study; and (5) names and qualifications of each clinical investigator. During a 30-day waiting period, the IND application is reviewed by the FDA to determine whether human subjects will be exposed to unwarranted risks (Hopps et al., 1988).
Although an establishment license (described below in more detail) is not required to begin a clinical trial, it is important that the manufacturer produces vaccine lots in a facility meeting current Good Manufacturing Practices. Plants that follow current Good Manufacturing Practices must demonstrate complete control over product components, equipment, manufacturing environment, record-keeping, and personnel. There should be no changes in the facility or manufacturing process that could alter any critical aspects of the product between the time that pivotal lots for clinical trials are prepared to establish vaccine efficacy and the time that lots are prepared for final licensing and distribution (Weber, 1991).
If the manufacturer is convinced that the vaccine is safe and effective after having performed clinical trials, an application for a license is made to CBER. The Product License Application (PLA) is an exhaustive document which includes (1) a detailed description of the manufacturing procedures, testing methods, and process controls for the product; (2) results of all laboratory tests performed on a specified number of lots (including stability testing); (3) results of clinical studies; and (4) proposed labeling (Hopps et al., 1988).
The newly created Office of Vaccines Research and Review within CBER is now responsible for the review of vaccine IND applications and PLAs. The internal review process entails a detailed examination and analysis of the submitted data for scientific content and accuracy and for compliance with applicable regulations. Individuals from other offices of CBER may also participate in the vaccine review and approval process.
The vaccine manufacturer must also submit an Establishment License Application (ELA). The ELA describes (1) the organization and personnel, (2) buildings and work areas, (3) equipment and systems, (4) control of components and containers, (5) production and process controls, (6) packaging and labeling controls, and (7) records and reports to be maintained (Hopps et al., 1988). The manufacturer must satisfy the FDA that it has complied with an extensive body of regulations termed Good Manufac-