As discussed in Chapter 1 and throughout the report, FDA has initiated or is initiating many changes related to drug safety in its internal procedures and organization. Some of the changes may supersede the descriptions in this chapter. Also on the horizon is FDA’s Critical Path Initiative, announced in 2004, which is intended to stimulate the development and use of new scientific tools to better assess the safety and effectiveness of drugs under study (FDA, 2004a; DHHS/FDA, 2006).

Investigational New Drug Submission and Review

The vast majority of chemical molecules and candidate drugs screened for therapeutic potential and toxicity never show sufficient promise to enter human trials (PhRMA, 2006). But when preclinical data indicate that a compound is reasonably safe for initial testing in humans, shows promising pharmacologic activity, and has commercial prospects, the sponsor submits an Investigational New Drug (IND) Application to FDA, and the agency’s oversight begins (FDA, 2006c).

IND sponsors can be companies, research institutions, or individual investigators. Often the sponsor has been in frequent contact with FDA throughout the development process prior to submission of the IND, and has participated in FDA’s pre-IND consultation program (FDA, 2006c). FDA produces numerous guidance documents to steer sponsors through the regulatory process. Those documents are prepared and updated continually. Some are very specific, for example, describing appropriate methods for a specific type of study; others provide more general guidance about preparing submissions to the agency (FDA and CDER, 2006b). Some reflect international harmonization efforts among European, Japanese, and US regulators.

The average new commercial IND submission totals about 28 volumes of about 500 pages each—about 14,000 pages (Henderson, 2006). It contains manufacturing and chemical information about the drug and the results of animal tests, toxicology studies, and other preclinical tests. The IND also contains protocols for small phase 1 human studies intended to document the drug’s metabolism and excretion, determine a safe dose, and identify acute side effects (FDA and CDER, 2006b). Local institutional review boards (IRBs) must review the protocols to ensure protection of human subjects. If a sponsor has already begun human trials outside the United States, it also includes their results.

By law, FDA has 30 days from the date an IND is received to place a hold on the proposed human trials (FD&C Act, SEC. 505(i)(2)) if it deems it to be necessary. CDER can take up to about 2 weeks of that period to process the IND, assign it to a review division within OND on the basis of

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