Vaccine Pre-clinical Toxicology Testing

Pre-IND and IND Submissions

The Pre-IND meeting materials should contain background and justification of efficacy and/or immunogenicity of the proposed candidate vaccine in relevant animal models as well as summaries of the manufacturing and controls process (including flowcharts), the proposed pre-clinical safety testing, and the proposed Phase I clinical trial(s). The Pre-IND meeting request and the meeting materials should contain specific questions you would like FDA to address (such as questions about the design of your pre-clinical toxicology study). Extensive (and understandable) advice on how to prepare for a Pre-IND meeting and what is needed for pre-IND meeting materials may be obtained in the article "The HIV/AIDS vaccine researchers Orientation to the Process of Preparing a U.S. FDA application for an Investigational New Drug (IND): what it is all about and how you start by preparing for your Pre-IND meeting" published in Vaccine [Stuart Shapiro, Vaccine 2001, Oct 18, 20(2002):1261-1280; http://www.niaid.nih.gov/aidsvaccine/talkstaff.htm]. Further guidance on the IND process, including pre-IND meetings, may be obtained from the following chapters: "IND Submissions for Vaccines: Perspectives of IND Reviewers" by Chandler, McVittie, & Novak in Vaccines from Concept to Clinic: A guide to the development and clinical testing of vaccines for human use, edited by Paoletti & McInnes, published by CRC Press, 1998; "The IND for Biological Products" by Novak, Barrett, McVittie, & Chandler in Global Biotechnology Product Registration: EU, US, and Japan, edited by Struck, Mathieu, and Okabe, published by Parexel International Corp., 1997; and "The Biological IND" by Novak, Barrett, McVittie, & Chandler in Biologics Development: A Regulatory Overview," edited by Mathieu, published by Parexel International Corp., 1997 [the latter two documents are quite similar, but one may be easier for you to obtain than the other, so both are listed here].

The IND Application submitted to CBER pulls together all the components in the development of the candidate vaccine. The details of the required content and format are described in detail in 21 CFR § 312 . Briefly, the application contains ALL known information on the vaccine. This includes:

• the background and discovery of the vaccine;
• the chemistry, manufacturing, and controls (CMC) of the drug substance and final product formulation information including the production and characterization of the Master and Working Cell Banks, characterization of the end-of-production cell cultures, adventitious agent testing, identity, purity, sterility or bioburden, and the general safety test;
• documentation of controlled and validated¹¹ assay results supporting the product safety, consistency, stability, potency, and lot release criteria¹² for the vaccine;
• the results of the pre-clinical pharmacology, toxicology and immunogenicity studies to verify that there are no known safety concerns in animal studies;
• any known human experience, either with the candidate vaccine or similar products;
• planned clinical study protocol(s) including details of the management of the trials and patient recruitment;
• an investigators' brochure; and
• any additional information or references necessary to facilitate FDA review and evaluation.