Pharmacogenetics in the evaluation of new drugs: A multiregional regulatory perspective

1] Medicines Evaluation Board, Utrecht and Radboud University Nijmegen Medical Center, PO Box 8275, 3503 RG Utrecht, The Netherlands. [2].
Nature Reviews Drug Discovery (Impact Factor: 41.91). 02/2013; 12(2):103-115. DOI: 10.1038/nrd3931
Source: PubMed


Pharmacogenetics, one of the cornerstones of personalized medicine, has the potential to change the way in which health care is offered by stratifying patients into various pretreatment categories, such as likely responders, likely non-responders or likely to experience adverse drug reactions. In order to advance drug development and regulatory science, regulatory agencies globally have promulgated guidelines on pharmacogenetics for nearly a decade. The aim of this article is to provide an overview of new guidelines for the implementation of pharmacogenetics in drug development from a multiregional regulatory perspective - encompassing Europe, the United States and Japan - with an emphasis on clinical pharmacokinetics.

17 Reads
  • Source
    • "PLK1 is an important oncogene and drug target in many cancer entities. Genetic variability of such proteins can have an impact upon the risk and the outcome of different cancer types as well as the response of an individual to drug treatments [27,28]. Until now, only very limited information about functionally relevant genetic variations of the PLK1 gene is available. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Polo-like Kinase 1 (PLK1) protein regulates cell cycle progression and is overexpressed in many malignant tissues. Overexpression is associated with poor prognosis in several cancer entities, whereby expression of PLK1 shows high inter-individual variability. Although PLK1 is extensively studied, not much is known about the genetic variability of the PLK1 gene. The function of PLK1 and the expression of the corresponding gene could be influenced by genomic variations. Hence, we investigated the gene for functional polymorphisms. Such polymorphisms could be useful to investigate whether PLK1 alters the risk for and the course of cancer and they could have an impact on the response to PLK1 inhibitors. The coding region, the 5[prime] and 3[prime]UTRs and the regulatory regions of PLK1 were systematically sequenced. We determined the allele frequencies and genotype distributions of putatively functional SNPs in 120 Caucasians and analyzed the linkage and haplotype structure using Haploview. The functional analysis included electrophoretic mobility shift assay (EMSA) for detected variants of the silencer and promoter regions and reporter assays for a 3[prime]UTR polymorphism. Four putatively functional polymorphisms were detected and further analyzed, one in the silencer region (rs57973275), one in the core promoter region (rs16972787), one in intron 3 (rs40076) and one polymorphism in the 3[prime]untranslated region (3[prime]UTR) of PLK1 (rs27770). Alleles of rs27770 display different secondary mRNA structures and showed a distinct allele-dependent difference in mRNA stability with a significantly higher reporter activity of the A allele (p < 0.01). The present study provides evidence that at least one genomic variant of PLK1 has functional properties and influences expression of PLK1. This suggests polymorphisms of the PLK1 gene as an interesting target for further studies that might affect cancer risk, tumor progression as well as the response to PLK1 inhibitors.
    Molecular Cancer 04/2014; 13(1):87. DOI:10.1186/1476-4598-13-87 · 4.26 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pharmacogenomics (PGx) or biomarker (BM) has the potential to facilitate the development of safer and more effective drugs in terms of their benefit/risk profiles by stratifying population into categories such as responders/non-responders and high-/low-risks to drug-induced serious adverse reactions. In the past decade, practical use of PGx or BM has advanced the field of anti-cancer drug development. To identify the characteristics of the PGx/BM-guided clinical trials for regulatory approval of anti-cancer drugs in Japan, we collected information on design features of 'key trials' in the review reports of anti-cancer drugs that were approved after the implementation of the 'Revised Guideline for the Clinical Evaluation of Anti-cancer drugs' in April 2006. On the basis of the information available on the regulatory review data for the newly approved anti-cancer drugs in Japan, this article aims to explain the limitations and points to consider in the study design of PGx/BM-guided clinical trials.Journal of Human Genetics advance online publication, 9 May 2013; doi:10.1038/jhg.2013.36.
    Journal of Human Genetics 05/2013; 58(6). DOI:10.1038/jhg.2013.36 · 2.46 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The FDA emphasizes the role of regulatory science in the fulfillment of its mission to promote and protect public health and foster innovation. With respect to the evaluation of drug effects in the real world, regulatory science plays an important role in drug risk assessment and management. This paper discusses opportunities and challenges with population-based drug risk assessment as well as related regulatory science knowledge gaps in the following areas: (1) population-based data sources and methods to evaluate drug safety issues; (2) evidence-based thresholds to account for uncertainty in postmarket data; (3) approaches to optimize the integration and interpretation of evidence from different sources; and (4) approaches to evaluate real world impact of regulatory decisions. Regulators should continue the ongoing dialogue with multiple stakeholders to strengthen regulatory safety science and address these and other critical knowledge gaps.Clinical Pharmacology & Therapeutics (2013); accepted article preview online 5 June 2013; doi:10.1038/clpt.2013.118.
    Clinical Pharmacology &#38 Therapeutics 06/2013; 94(3). DOI:10.1038/clpt.2013.118 · 7.90 Impact Factor
Show more