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Designing prospective clinical pharmacogenomic (PG) trials: meeting report on drug development strategies to enhance therapeutic decision making

The Pharmacogenomics Journal volume 6, pages 89–94 (2006)Cite this article

For some drugs, measurement of expression of an obvious molecular drug target will provide a reasonably accurate basis for pharmacogenomic selection of patients. Herceptin for the treatment of breast cancer is one such example.1 For many drugs, however, there may be no such a priori measurement that results in accurate identification of the appropriate patient population. For example, immunohistochemical measurement of EGFR expression does not accurately predict response of lung tumors to Iressa.2, 3 In such cases, a pharmacogenomic profile can be used to identify patients who are either responsive to treatment or free of serious adverse events when treated. Derivation of such profiles requires a process of screening large numbers of potential markers. Identification of such marker sets can be achieved through various methodologies. Example are: a genome-wide expression profile as measured by DNA microarray analysis of the mRNA transcripts collected from diseased cells, single nucleotide polymorphisms (SNPs) in candidate genes related to metabolic processes or the mechanism of action of the drug, or indeed SNPs identified through ‘hypothesis free’ whole genome scanning.

During the development of a pharmacogenomic profile, individual markers are evaluated, and those correlated with the end point (i.e. the defined phenotype) are selected. The selected markers that are identified as having potential predictive value are then combined into a pharmacogenomic profile that is, a ‘composite biomarker’ having an association with a specified phenotype or clinical end point. It is important to note that the pharmacogenomic profile or composite biomarker may comprise one or more individual markers. For pharmacogenomic targeting with regard to a composite biomarker, it is not necessary that the individual markers be correlated with the clinical end point, but rather that the composite biomarker itself is evaluated and validated. The ultimate goal is to show that the pharmacogenomic profile can be used during clinical development to select, deselect, or stratify patients for treatment or following drug approval to manage patient treatment options in a manner which improves patient outcomes. If this cannot be accomplished, then one does not have a well-defined pharmacogenomic profile against which drug-related claims can be made.

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Authors and Affiliations

  1. Division of Molecular Medicine, Millennium Pharmaceuticals, Cambridge, MA, USA

    W L Trepicchio

  2. Regulatory Affairs, Amgen,, Thousand Oaks, CA, USA

    D Essayan

  3. US Regulatory Affairs, GlaxoSmithKline, Research Triangle Park, NC, USA

    S T Hall

  4. FDA Center for Biologics Evaluation and Research, Rockville, MD, USA

    G Schechter

  5. FDA Center for Devices and Radiological Health, Office of In Vitro Diagnostic Devices Evaluation and Safety (OIVD), Rockville, MD, USA

    Z Tezak

  6. FDA Office of Biostatistics, Office of Pharmacoepidemiology and Statistical Science, Center for Drug Evaluation and Research, Rockville, MD, USA

    S J Wang

  7. GeneLogic Inc., Gaithersburg, MD, USA

    D Weinreich

  8. Division of Cancer Treatment and Diagnosis, Biometric Research Branch, National Cancer Institute, Bethesda, MD, USA

    R Simon

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  1. W L Trepicchio
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Correspondence to W L Trepicchio.

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Trepicchio, W., Essayan, D., Hall, S. et al. Designing prospective clinical pharmacogenomic (PG) trials: meeting report on drug development strategies to enhance therapeutic decision making. Pharmacogenomics J 6, 89–94 (2006). https://doi.org/10.1038/sj.tpj.6500344

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