A wide variety of clinical trials intended to demonstrate safety and efficacy, which have complementary and at times overlapping goals, are required to obtain approval from the FDA or comparable government agency to use a new drug or biologi cal product. This is an expensive and lengthy process—the largest percentage of the cost of drug development is for clinical studies, about 50% of the total cost. As we have discussed, the studies have specific stages with specific requirements; have many special design features to be used; must be acceptable to not just clinicians and investigators but also to the regulatory authorities regarding medical benefits and scientific rigor; were conducted following good clinical practice guidelines for the patients, the sites, the investigators, and the company; and demonstrate real clinical differences to reasonably meet unmet clinical needs and for competitive advantage. Further, the clinical studies must meet the needs of the marketing teams to generate data and information to help convince providers to use the company's product and payors to pay for it. As stated in a recent "white paper" from the FDA [26], novel approaches to shortening the phases of clinical testing and reducing the cost are essential if the discoveries being made in the laboratory are to be translated into improvements in preventing, diagnosing, treating, and curing disease.

Failure rates of new chemical entities (NCEs) are actually series of failures at the various stages of research at a company that are to be expected and even can be a desirable outcome (Fig. 5.28). A company does not have all the resources to advance all compounds and must be selective to advance the best compounds in activity at each stage of development. In basic research, 10,000-30,000 new substances are identified, which have increased with genome screening. Then, about 100-200 molecules reach chemical synthesis and screening. At the next step, about 5-10 undergo preclinical testing in animals. Within a family of compounds (product candidates), only 2-5 enter clinical trials. Finally, 1 is approved and marketed.

Failure rates of INDs occur commonly during the clinical phases of product development (Fig. 5.29). Another way to look at this situation is to consider that of all drugs that enter phase 1 testing in humans, 1 in 3 enters phase 2 testing, 1 in r Inadequate characterization of dose-response profiles (peak response and time-course of response during dosing interval)

r Flaws in study design or drug development plan -inappropriate studies, difficult to interpret studies, studies based on unfounded assumptions r Inadequate characterization of the benefit-risk profile r Inadequate proof of improved quality of life or pharmacoeconomic benefit r Audits of study conduct or sites find major flaws Fig. 5.30. Why are drugs not approved?

4 enters phase 3 testing, and only 1 in 5 undergoes FDA review. The reasons for a company terminating the IND include safety issues (20% of the time), lack of sufficient efficacy (38%), economic reasons, that is, the product is too expensive to manufacture, or the potential sales are too low to justify the high expense and risks of further development, (34%), and others (9%). In addition, even at the terminal end of clinical research phase with reporting of all studies and filing the NDA, not all that undergo FDA review are approved.

An important question is why are drugs not approved, especially because over the past decade the regulatory authorities, especially the FDA, have worked more closely with companies at various stages in the drug development process, providing feedback on study design and data generated (Fig. 5.30). Most products that enter clinical trials are not approved because they fail to demonstrate sufficient efficacy or have substantial toxicity. Specifically, one finds inadequate characterization of dose-response profiles (peak response and time course of response during dosing interval), flaws in study design or drug development plan (e.g., inappropriate studies, difficult to interpret studies, studies based on unfounded assumptions, inappropriate dosing for the drug or disease), flaws in the conduct of the study and data collection (e.g., study sites not following exclusion criteria, too much missing data), inadequate characterization of the benefit-risk profile, inappropriate statistical analyses (e.g., insufficient statistical power with too few patients enrolled for the desired extent of change in end points), adverse events of a new product exceeding existing therapies beyond any added efficacy, and inadequate proof of quality of life or pharmacoeconomic benefit.

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