Pharmacogenetics to Improve the Safety and Efficacy of Drug in Development

One of the main ways by which pharmacogenetics may have an impact on drug development is in the design and analysis of clinical trials, with a number of authors claiming that this will lead to smaller, smarter, and cheaper trials (15,16). Others have suggested that drugs causing adverse drug reactions (ADRs) in particular genomic groups could be "rescued" in late stage trials. A third possibility would be to target drug development at patients most likely to respond to a therapy. These two latter applications would most likely be used in a stepwise manner when there is a clear need to ensure a return on the very heavy costs of late stage drug development.

Preclinical Testing and the Redesign of Early Clinical Trials

In early, preclinical studies or prospectively in Phase I trials, genotyping might be used either to exclude or to include particular genomically defined groups in order to increase the chances of a drug being shown to be safe (17). However, this type of prescreening is likely to meet significant opposition from regulatory authorities, due to the risk of missing serious ADRs. It seems more likely that companies will actually use pharmacogenetics to ensure that sample populations are representative of the general population for particular alleles associated with drug metabolism (e.g., CYP2D6). This could greatly help to minimize the risk of trial bias, or reduce the risk of a drug failing at a later stage of development as a result of bias, and to improve the safety profile of the final product.

"Rescue" of Products in Late Stage Trials Due to ADRs

In later stage Phase II and III trials, pharmacogenetics may be used retrospectively to identify particular genomically defined groups who are at higher risk of ADRs. This might be particularly important in "rescuing" a therapy that was highly effective but was associated with a small number of serious genetically based ADRs. These groups could be identified and excluded from subsequent pivotal trials. A drug developed in this way would only be licensed for use in specific subpopulations and would need careful monitoring, because of the risk of it being given to the wrong patient group.

Consequently, it would have to be used in conjunction with a test for pre-prescription geno-typing and have a restricted market. Regulators might license such a product solely for use in specialist secondary and tertiary settings, due to the higher risk of off label prescribing in primary care.

The Creation of New Drugs for Particular Subpopulations of "Good Responders" In later stages of Phase II and III trials pharmacogenetics might be used in two ways to improve efficacy. First, prospective studies could test new drugs in subpopulations of patients believed to be good responders. This might significantly increase the chance of a drug reaching the market. Second, where the overall benefit of a drug across the whole population is shown to be marginal, pharmacogenetics might be used retrospectively to identify a genomic subgroup who are particularly good responders to the therapy. These groups could be specifically included in subsequent pivotal trials. In both cases this would lead to the development of new drugs licensed purely for use in a specific genomic group. The breast cancer therapy herceptin (trastuzumab) is an example of a very successful product developed for a genetically defined group of patients whose tumors overexpress the HER-2 gene product. Although this drug is largely safe in all patients, it is only effective in this subpopulation.

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