The Pharmacogenomics Journal (2002) 2, 20–24 2002 Nature Publishing Group All rights reserved 1470-269X/02 $25.00 www.nature.com/tpj EELS (Ethical, Economic, Legal & Social) ARTICLE response, caused by genetic differ- Pharmacogenomic-guided drug ences. The ability to predict and account for such differences could development: regulatory perspective markedly improve the therapeutic index of many drug interventions. LJ Lesko1 and J Woodcock2 Finally, it is hoped that genetically- based mechanisms of toxicity can be 1Office of Clinical Pharmacology and Biopharmaceutics, Center for Drug Evaluation and elucidated, and adverse effects avoided, Research, Food and Drug Administration, Rockville, MD, USA; 2Office of the Center by application of pharmacogenomic Director, Center for Drug Evaluation and Research, Food and Drug Administration, information. Rockville, MD, USA The explosion of interest in PGt and PGx has raised concerns that the regu- latory environment could inhibit pro- The Pharmacogenomics Journal (2002) 2, mechanism of drug actions, and the gress. While drug discovery and pre- 20–24. DOI: 10.1038/sj/tpj/ 6500046 drug–disease interaction. Taken clinical studies are not likely to be together, these techniques are significantly affected, there is concern Pharmacogenetics (PGt) and now the expected to yield major advances in about the use of PGt/PGx in clinical more global term, pharmacogenomics identifying drug candidates. trials. This article provides an overall (PGx), have come to the forefront after Genomic information will be regulatory perspective on the clinical an evolutionary period of more than increasingly used in the preclinical study issues and considerations, many 30 years. Several transforming events phases of drug development. There is of them presently unresolved, that PGt in the past 5 years, not the least of great interest in using gene expression which was the completion of the profiling to develop markers for both and PGx present to the drug develop- human genome sequence in 2001, desired pharmacologic actions and ment and regulatory decision making have created an expectation that gen- toxic effects. Batteries of markers will processes. It does not extensively dis- etic and genomic information will pro- then be used to characterize drug can- cuss the development, validation and duce sweeping changes in the practice didates and to aid in selection of those usage of diagnostic kits, although this of medicine and the prescribing of with optimal properties for further is an important issue to FDA. We drugs. The almost daily press reports of development, thus improving the acknowledge that there are also many new gene discoveries lend credence effectiveness of drug development. other stakeholders (eg, managed to the argument that personal At the clinical level, the hope is for health care agencies, insurance genetic/genomic profiles will have a true individualization of therapy, which companies) and issues (eg, privacy, tremendous impact on health by the would maximize benefit and minimize ethics) in the debate about PGt and year 2010. This vision has not been toxicity. Currently, clinicians have few PGx, but those domains will not be without naysayers; however, we tools for predicting who will respond part of this article. We hope that we believe that the central issue is not to a drug, or who will suffer ill effects. can provide a greater understanding of whether PGt- or PGx-guided drug pre- Although such differential responses the issues and an agenda of topics that scriptions will happen, but when and have long been characterized as ‘idio- will need resolution through effective how. syncratic’, clearly there are underlying communication among scientists in Genomic information has the reasons for them, and many have a academia and the industry, and those potential to revolutionize pharmaco- genetic component. It is believed then in the FDA and other regulatory logic therapies at many levels. The most chronic diseases represent a het- agencies. process of drug discovery may be erogeneous group of disorders at the We are not aware of any consensus transformed by this knowledge. Exten- molecular level. This heterogeneity is on the definition of PGt and PGx, and sive genetic data will promote under- one of the reasons that not all people in fact there are many different defi- standing of the molecular genetic con- with a disease respond to a given drug. nitions in the scientific literature. tribution to many diseases. Genes and One contribution of genomic science Occasionally, these terms are used gene products suspected of being could be to provide a much more pre- interchangeably. For the purposes of involved in disease pathogenesis will cise diagnosis, based either on under- this article, we will consider PGx to be become new targets for intervention, lying genotype, or on gene expression the global science of using genetic and will stimulate new drug discovery profiles. Similarly, some differences in information from an individual or programs. Conversely, gene expression drug efficacy response, and some tox- population for the purpose of: (1) profiling is being used currently to icities, are based on variability in explaining interindividual differences gain new insights into the molecular exposure or in pharmacodynamic in pharmacokinetics (PK) and pharma- Pharmacogenomic-guided drug development LJ Lesko and J Woodcock 21 codynamics (PD); (2) identifying continue to provide a fundamental smoking) factors that may alter the responders and non-responders to a understanding of the pharmacological exposure-response relationship in drug; and (3) predicting the efficacy action of drugs and represent a major patients. So-called registration studies, and/or toxicity of a drug. Also, we will preclinical effort to determine the ie, definitive PK studies in patients consider PGt to be a scientific subset feasibility of continuing with further subgroups defined by renal and/or of PGx in which there are genetic vari- development in humans. Early clinical hepatic disease, age, gender, race and ations (eg, polymorphism in cyto- studies in Phase I and Phase II drug interactions are routinely con- chrome P-450 metabolizing enzymes) (sometimes split into IIA and IIB) are ducted in today’s drug development to drug doses and dosing regimens intended to be exploratory in terms of programs. These data are reported in that result in different systemic drug estimating appropriate doses and dos- the package insert in either the clinical exposure patterns (PK) in individuals ing regimens for later trials, demon- pharmacology, precaution/warning or or populations. strating proof of therapeutic concept contraindication sections and, where PGx technologies are still evolving and making decisions to continue appropriate, dose and dosing interval but in the past 5 years there has been with further development. During adjustments are provided for these a tremendous growth rate in gene Phase III, large-scale clinical studies are patients in the dosage and adminis- databases, high-throughput DNA conducted to confirm efficacy in a tar- tration section. In the past, most of the microarray methodologies and SNP get population with a specified indi- exposure-response variability was attri- analysis tools. Methods in PGx/PGt are cation, and to confirm the relative buted to differences in PK, and as a becoming more cost-effective and safety of the drug. Concurrent with result, substantial attention has been widespread throughout the pharma- Phase III, sponsors frequently conduct focused on PGt, especially as it affects ceutical industry, and with the co- so-called registration studies (eg, drug– the activity of the CYP-450 drug meta- development of bioinformatics drug interactions) to provide the bolizing enzymes and results in inter- software and computerized decisional additional information necessary to individual variability in the dose- analysis tools, these methods are adequately label the product. Under exposure relationship. Despite this becoming much more informative as the current system, the drug develop- focus, PGt and PGx overall have not well. ment process that leads to a traditional had a major role in clinical drug devel- In 1998, the Secretary’s Advisory review and approval (ie, not opment to date. Committee on Genetic Testing accelerated) requires typically that a Over the past 5 years, many have (SACGT) was chartered to advise the sponsor conduct at least two inde- expressed the concern that human Department of Health and Human Ser- pendent, adequate and well-controlled clinical efficacy and safety trials in a vices (DHHS) on the medical, scien- clinical trials in Phase III to provide traditional drug development program tific, ethical, legal and social issues crucial evidence that a drug is effective are challenging, time-consuming and raised by the development and use of and relatively safe. Safe, in a regulatory increasingly more expensive to con- genetic tests. One of FDA’s concerns is context, means that the Agency has duct. The relatively high rate of failure to ensure the quality of PGx/PGt tests deemed the drug to have an acceptable of drug candidates entering the clini- that might be used in clinical drug risk/benefit ratio for a given indication cal phases of drug development add development, and public access to in a statistically significant number of significantly to these estimated costs. quality PGx/PGt tests. While not patients in a defined population, when More recently, new drug candidates directly bearing on the drug develop-