BOX 48 Continued

additional staff members to increase efficiency in the NDA and BLA review process.

• FDA Modernization Act (1997). This act contains some of the most sweeping changes to the Food, Drug and Cosmetic Act. The act contains changes in how user fees are assessed and collected. For example, fees are waived for the first application for small businesses, orphan products, and pediatric supplements. The act codifies FDA's accelerated approval regulations and requires guidance on fast-track policies and procedures. In addition the agency must issue guidance for NDA and BLA reviewers.

drug is absolutely safe ... there is always some risk of an adverse reaction. However, when a proposed drug's benefits outweigh known risks, the FDA . . . considers it safe enough to approve." While rules and regulations governing the review and final approval by the FDA continue to evolve, what remains constant, according to the FDA position, is "Safety and effectiveness and benefit vs. risk remain the pivotal issues in drug review" (Benefit vs. Risk. How CDER approves new drugs, 2000).

NDA and BLA submissions are assigned to a team of FDA staff members that include expert chemists, pharmacologists, physicians, pharmacokineticists, statisticians, and microbiologists (see Box 4.9 for additional explanation). FDA staff critically evaluate the submitted data guided by the key question, "Does this drug work for the proposed use?" They will study how the drug is manufactured, processed, and packaged; the results of animal studies; the disposition of the drug—what happens after administration and how the body distributes and clears the drug, and what happened during the clinical studies. A number of statistical methods are used to evaluate clinical data to determine whether they demonstrate effectiveness for intended use and whether the benefit-to-risk relationship is favorable.

The pharmaceutical company must also provide a sample of the drug and proposed professional labeling. The FDA plays a major role in shaping the final approved labeling. The label serves as a way for the FDA to control the risks that the drug product carries, by distributing it to physicians and pharmacists who then become the risk-managers for the product. The information contained in the drug's approved labeling—how the drug should be used—is part of the drug package.

As a matter of course, biotechnology companies recognize the need to discuss with FDA staff the overall plan for drug development before the IND is submitted. To avoid delays and perhaps failure, the company must understand what the FDA expects with respect to study design, the conduct of studies, and data analysis. The FDA has field reviewers available to assist drug companies with these issues as well as with issues related to regulations relevant to manufacturing and packaging facilities.

In the final analysis, approval of a BLA or NDA comes down to two key questions: Do the results of well-controlled studies provide substantial evidence of effectiveness? and Do the results show the product to be safe under the conditions of use in the proposed labeling? Safe, in this context, means that the benefits of the drug appear to outweigh its risks. On completion of the review, CDER or CBER sends a letter to the applicant sponsor stating that the drug is approved for marketing; is approvable,

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