Clinical studies intended to evaluate the safety and efficacy of new drugs in development generally involve large number of patients and are critical to the evaluation and approval of a new drug. The role of pharmacogenetics in late clinical development (Phase III trials) is to focus on either the further exploration of genetically defined populations or the confirmation of pharmacogenetic data from these populations to support efficacy, safety, and the labeling of the drug. When subsets of patients respond to a drug differently, clinical trials can be designed to take advantage of these differences. For instance, trials could be limited to individuals who are more likely to receive a clinical benefit or less likely to suffer an adverse response. However, in so doing, the trials may not adequately determine the safety and efficacy of the drug in all individuals who might be exposed to it. Approaches to having the study power for genotypes need to be reconciled to take into account the need for a thorough assessment of the beneficial and harmful effects of the drug once it is in clinical practice.

In another potential use of pharmacogenetics, drugs that have not been shown to be adequately safe and effective in a clinical trial on an entire population may achieve that goal in a genetically defined subset of the population. Because genotypes do not change in an individual, it should be possible to detect a group who will derive a clear clinical benefit by reanalyzing the data from a previously completed trial through genetic stratification. In this way, a drug that is otherwise unregisterable might be approved for the genetically defined group. However, this use of pharmacogenetics poses a number of questions for which there are no definitive answers at present:

• Are there conditions under which such a retrospective study would be acceptable for drug registration?

• To what extent do these studies need to be replicated?

• Can the data from such studies, not specifically designed as a pharmacogenetic study or even from investigative studies with no genetic hypothesis, be used for registration?

• What constitutes acceptable data in such studies?

• How do these data apply from one racial or ethnic group to another when there may be significant differences in allele frequencies between groups?

To date, there appears to have been relatively little application of pharmacogenetics in Phase III studies and subsequently in regulatory decision-making. Few examples exist that can be used to assess various models for pharmacogenetic trials. The workshop focused discussion on the types of trials that might be conducted and to estimate the likely reception that such trials might receive. In practice, any such trial, especially those with novel pharmacogenetic approaches, should be discussed in detail between the sponsors and the regulatory authorities and would likely be evaluated on a case-by-case basis. Only after numerous examples exist will it be possible to develop a general guidance for industry that will provide recommendations to direct the conduct of these trials.

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