Pharmacogenomic-Guided Drug Development LJ Lesko and J Woodcock 21

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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 regulatory 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 pharmacogenetic 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- compared to a placebo or to an have been filtered from the discovery ment process, the major issues, over- accepted standard therapy. and development pipeline because arching principles and final rec- The FDA believes that a drug can be their hepatic metabolism requires ommendations of SACGT can be determined to be effective and safe CYP-450 enzymes subject to genetic extrapolated to issues and questions only when the relationship of ben- polymorphism. Several experts in the related to PGx/PGt tests used in drug eficial and adverse effects to a defined science of drug development perceive development. The final report of exposure (eg, dose or plasma the increasing costs, and recent SACGT, issued in July 2000, is publicly concentrations) is known. Exposure- decreasing return on investment, as a available on the Internet (http://www4. response relationships define the significant threat to the viability of the od.nih.gov/oba/gtdocuments.html). drug’s safety margin as well as its dose- pharmaceutical industry in the next Traditionally, drug development is or plasma level-limiting side effects. It 10 years. divided into the discovery phase, pre- is well known that in drug develop- Conventional wisdom suggests that clinical phase and three clinical phases ment clinical trials, traditional medical PGx-guided clinical trials would shift (I, II and III). In the past 10 years, the histories and the usual demographic the drug development paradigm most dramatic changes in drug devel- factors often fail to explain the inter- toward a more efficient and informa- opment have occurred in drug dis- individual variation in exposure- tive process, resulting in a lower covery due to the technological response relationships. The Agency is attrition rate of new drug candidates, advancements in combinatorial chem- very interested in understanding the and an overall lower development cost istry, high throughput screening and intrinsic (eg, age, disease state, to the sponsor, albeit in the long-run. molecular targeting. Animal studies genetics) and extrinsic (eg, drugs, diet, Furthermore, many believe that drug

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therapy based on the genetic profile of information as reported by the spon- approval for the PGx/PGt diagnostic individuals could provide public sors was as follows: (1) to define test at the time of approving the health benefits such as better manage- patients subgroups in either early drug? ment of post-approval risks, and a phase PK studies and/or late phase ¼ What are the performance and stat- decreased incidence of drug-induced efficacy trials using sparse sample istical requirements for the PGx/PGt morbidity and mortality. PGx could analysis and population PK method- diagnostic that would be used for also reduce the incidence of drug pro- ologies to assess the significance of this purpose? duct market withdrawals due to seri- geno-/phenotype as a co-variate; (2) to ¼ What use would the Agency allow ous or fatal adverse events by allowing provide a post hoc explanation for the for a post hoc subset analysis based pre-selection, in advance of prescrib- variability in drug exposure (and on a PGx/PGt diagnostic test in a ing the drug, those patients who will response) in some subjects and/or clinical trial that failed to demon- be predisposed to toxicity. That the patients (eg, outliers where plasma lev- strate efficacy or had an unac- pharmaceutical industry is investing els were too high or low) as a basis to ceptably high rate of adverse events? in this promise is no more evident exclude such subjects from an analy- ¼ What information would be than by the high level of interest and sis; (3) to measure the impact of CYP expected in those patient subgroups cooperation within the SNP (single enzyme polymorphism on plasma excluded from the pivotal clinical nucleotide polymorphisms) Consor- drug clearance in subject subgroups trials based on a PGx/PGt test? tium, a collaboration of pharmaceut- defined by PGt; and (4) to use the ¼ What PGx/PGt testing might be ical companies, bioinformatic results of PGx/PGt as an entrance or required for drugs currently enterprises and academia established exclusion criteria for subjects in drug approved and in the marketplace as to explore SNPs as a drug development interaction studies. While providing new genetic/genomic information tool. SNPs are single-base differences insight into the inter-individual varia- is discovered? in the DNA sequence that can be dis- bility in the dose-plasma drug level- ¼ When is it appropriate to prescreen cerned between individuals in a popu- response relationship, differences in, or out, subjects for bioavail- lation. SNPs are the most frequent type thought to be related to PGx/PGt sub- ability, bioequivalence, drug inter- of variation in the human genome and groups were not used as a basis for any action and other clinical pharma- are attractive as biomarkers for the specific dosing recommendations for cology studies? drug discovery and development pro- these subgroups in the product labels. cess. The challenge will be to identify It is hoped that more extensive use In addition to these general ques- correctly those SNPs that influence or of PGx/PGt information will be util- tions, there are further uncertainties change pharmacokinetics, pharmaco- ized in future clinical trials. However, based on new genetic information, dynamics and/or clinical endpoints. there are many unanswered questions which have not been addressed for- However, pharmaceutical compa- about the FDA’s regulation of clinical mally to our knowledge. For example, nies appear to be moving forward cau- development programs using various it is well known that there are demo- tiously in integrating PGx/PGt in their elements of PGx/PGt. The following graphic factors (eg, race) which influ- drug development programs. As a issues and questions, which need ence the response to drugs in several result, FDA has limited experience further discussion, are among the pharmacological classes such as beta- with clinical pharmacology and clini- major concerns of the industry with blockers and ACE inhibitors.1,2 More cal efficacy and/or safety studies in regard to drug development: recently, it has been reported that which sponsors have prescreened sub- patients with high cholesterol who jects using PGx/PGt tests. To increase ¼ What are the regulatory impli- have the B1B1 variant of the CETP our awareness, the Office of Clinical cations of genetic profile screening gene will have greater reductions in Pharmacology and Biopharmaceutics of patients during investigational blood lipid levels when treated with conducted a survey of recent Investi- drug therapy? certain lipid-lowering ‘statins’.3 Simi- gational New Drug (INDs) and New ¼ Is it acceptable to the FDA to stratify larly, subsets of women with breast Drug Applications (NDAs) to identify patients entering into a clinical trial cancer defined by mutations in BRCA1 the extent to which PGx/PGt was used a priori based on a PGx/PGt test? and BRCA2 susceptibility genes may in clinical studies. The survey, still ¼ What are the statistical ramifications be more or less responsive to tamox- being analyzed, found over 15 appli- when using PGx/PGt to define ifen chemoprevention.4 What if these cations in which PGx/PGt tests were patient subsets? types of drugs were currently under reported with all but one test related ¼ If a PGx/PGt test is used to enrich development? Would the Agency to pharmacogenetic variability in CYP a patient cohort receiving a certain expect that PGx/PGt testing be done enzymes. The tests were used to either dose and dosing interval during a to determine the cause of these varia- phenotype or genotype CYP 2D6 in clinical trial, will the label for that bilities in response? Would such tests seven submissions, 2C19 in five sub- drug require a PGx/PGt diagnostic be part of the drug approval process? missions and CYP 2C9, 3A4 or other test? These are only a few examples of the metabolizing enzymes respectively in ¼ Would the Agency require the drug many issues and questions, which may one submission each. The use of this sponsor to submit an application for either be decided on a case-by-case, or

The Pharmacogenomics Journal Pharmacogenomic-guided drug development LJ Lesko and J Woodcock 23

lead us to further discussion and the that is an important determinant of press the protein, HER2, in large development of an over-arching set of exposure. It has been shown that clini- amounts. This patient subset rep- principles to be used in drug develop- cal outcomes are related to the meta- resents up to 30% of all women with ment and regulatory decision-making. bolic genotypes for drugs such as ome- breast cancer. The FDA has also Successful use of PGX/PGt-cus- prazole (a 2C19 substrate) in the approved one prognostic PGt assay tomized medicines will require phys- treatment of H. pylori. In addition, a and two PGx immunohistochemical icians to: (1) select patients for drug subset of patients are unable to con- assays to measure HER2 neu protein therapy before writing a prescription; vert drugs to metabolites (eg, poor overexpression to be used in patient (2) exclude patients from drug therapy metabolizers of CYP 2C9 or 2D6) and selection before prescribing trastu- before writing a prescription (based on are prone to either a higher risk of tox- zumab treatment. It is likely that FDA predicted toxicity or poor response); icity, or a lack of efficacy, than exten- would not have approved Hercept (3) select the optimal individual dose sive metabolizers when administered without the accompanying diagnostic and dosing regimen; and (4) evaluate the usual doses of drugs such as warfa- test. Also, the recent approval of Glee- the genetic basis for an adverse event. rin or codeine respectively. However, vec (imatinib mesylate) in May 2001 The safety and effectiveness profile of identifying these patients in advance for late phase chronic myelogenous drugs developed under PGx-guided of selecting a drug dose is an exception leukemia (CML) is another example programs may thus be predicated on rather than a rule in medical practice. that the CDER is well aware of, and successful PGx-guided prescribing. For these reasons, PGx-directed open to, individualization of drug As part of the drug review and clinical drug development programs therapy using PGx or other research approval process, the FDA will have to may need to include strategies to strategies. The discovery and develop- assess how well PGx information will evaluate the applicability of ment of imatinib, while not strictly be translated into clinical practice. genetic/genomic testing to clinical PGx-driven, is a good example of the Will physicians and other health care practice. While this may be straight- type of molecular targeting to abnor- professionals, who are reported to be forward in disciplines such as mal proteins, in this case in CML cells, prone to information overload, be able oncology, incorporating genetic/ that is possible with the help of PGx to learn about, understand and then genomic testing into more general information. In addition, the Center alter their professional practice to medical practice will undoubtedly be for Biological Evaluation and Research incorporate PGx-directed prescribing? more challenging. (CBER) has extensive experience with In some cases (eg, Hercept for breast To advance the notion that PGx/PGt gene therapy development for over 10 cancer) this has been successfully information is of value to drug devel- years and has reviewed applications accomplished. In other instances, opment and regulatory decision mak- for genetically engineered protein information important to successful ing, more prospective clinical trials in drugs for such indications as sepsis drug therapy has not penetrated medi- which this information is integrated and hemophilia. cal practice. For example, scientists into study design and data analysis The FDA has not been idle in the have known for many years that need to be planned and conducted. To face of emerging PGx and PGt techno- individual variations in genes date, established or unequivocal evi- logies but is preparing more for the (polymorphism) that encode and dence of the value of PGx/PGt is lim- predicted influx of NDAs containing determine the activity of Phase I (eg, ited with few real-life examples. Never- PGx/PGt information. We are carefully 2D6) and II drug metabolizing (eg, N- theless, the FDA is very interested in taking the following steps to assure acetyltransferase) enzymes are a major discussing or reviewing drug develop- that, as a regulatory agency, FDA is source of interindividual variability in ment program proposals that intend prepared to deal with the future influx systemic exposure from drug doses. In to use PGx/PGt in clinical studies. of PGx/PGt data in submissions from contrast to the acceptance of PGx/PGt Ideally, a regulatory agency should IND and NDA sponsors: tests to select patients for Hercept ther- be able to meet its public health man- apy in mainstream oncology, PGt- date without stifling new technology ¼ To assure that its scientific and clini- guided tests to identify gene variants that might lead to better drugs includ- cal staff are made aware of the evol- in patients that influence the activity ing the ‘customized medicines’ of the ution of the science, it has organized of cytochrome P-450 drug metaboliz- PGx/PGt era. It should be noted that expert seminar and educational ser- ing enzymes have not met with wide- the FDA went on record of supporting ies where speakers address issues spread acceptance despite the demon- the basic idea of ‘customized medi- related to PGx/PGt in drug develop- strated cost-effectiveness of such a cines’ for a patient subset, back in ment including the development of strategy. For example, it has been well 1998, as evidenced by its approval of diagnostic kits known for 30 years that phenotyping trastuzumab (Hercept). The approved ¼ It is meeting with industry PGx/PGt and genotyping for the activity of cer- indication of trastuzumab, a recombi- working groups to listen to their tain CYP enzymes (eg, CYP 2D6) can nant DNA-derived humanized mono- concerns and identify issues that be used to identify a large number of clonal antibody, was for the treatment need more information before resol- patients in the general population of only those patients with metastatic ution who carry a particular variant of a gene breast cancer whose tumors overex- ¼ It has chartered working groups to

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frame anticipated issues and ques- Design, Data Analysis, and Rec- widespread availability of simple tions for internal (and across Cen- ommendations for Dosing and Labe- PGx/PGt tests to determine a patient’s ters in FDA) and public forum dis- ling phenotype and/or genotype with cussion, and to develop long-range ¼ ICH’s Ethnic Factors in the regard to polymorphism in drug meta- policies Acceptability of Foreign Clinical bolizing enzymes, there has been little ¼ It maintains a surveillance of INDs Data use of this information to tailor drug and NDAs to find new examples of ¼ ICH’s Common Technical Docu- doses and dosing regimens to individ- usage of PGx/PGt information, and ment for the Registration of Pharm- ual patient subgroups in clinical prac- where possible attempts to integrate aceuticals for Human Use tice before using the drug. Together, this information into reviews all of the stakeholders in PGx/PGt ¼ It is writing about PGx/PGt issues in FDA has also taken notice of the need to work on ways to assure that specific therapeutic areas, eg, anti- recent explosion in PGt and PGx infor- this does not happen with the second viral drugs, in the context of prepar- mation and realizes the need to and third generation of PGx/PGt diag- ing new FDA guidances actively engage in internal discussions, nostic tests. We conclude that the ¼ It is assessing the current expertise and in open dialogue with the pharm- bridge between the current and emerg- of regulatory reviewers to determine aceutical industry and to identify the ing PGx/PGt research in drug develop- future needs in skill sets, and new implications, questions and issues ment and regulatory review practices, ¼ It is discussing PGx/PGt issues with related to drug (and device) approvals. and related policy, needs to be built other regulatory agencies. If necessary, the FDA is prepared to systematically and on a sound scien- develop new domestic guidances or tific foundation. The gap between A search of several websites of work through ICH to develop new har- national regulatory agencies using research and the use of PGx/PGt in monized guidances with Europe and clinical practice remains very wide, but keywords such as pharmacogenetics, Japan. pharmacogenomics and genetic poly- we are encouraged with the progress The parallel developments in the that is being made to close this gap. morphism resulted in relatively few areas of PGx and PGt technology and ‘hits’. For example, in searching the bioinformatics, and the unraveling of FDA website (http://www.fda.gov/ DUALITY OF INTEREST the human genome hold much future None declared. cder/regulatory/default.htm) contain- promise for the development of drugs ing 144 180 documents there were 54, and dosing instructions that will alter 36 and 25 ‘hits’ for the terms pharma- Correspondence should be sent to individualization of therapy. But, who LJ Lesko, PhD, Director, Office of Clinical cogenetics, pharmacogenomics and will lead the way? Pharmacology and Biopharmaceutics, HFD- genetic polymorphism respectively. At present, patient genomic/genetic 850, Center for Drug Evaluation and Research, However, several guidances for indus- data from prospective clinical and Food and Drug Administration, 5600 Fishers try published by regulatory agencies as clinical pharmacology studies are Lane, Rockville, Maryland 20852, USA. + domestic guidances or as a result of the necessary to: (1) evaluate the role that Tel: 1 301 594 5690 Fax: +1 301 480 8329 International Conferences on Har- PGx can play in drug development; (2) E-mail: leskolȰcder.fda.gov monization (ICH) contain general identify issues that will trigger more concepts or principles related to PGx, urgent and extensive discussion including the following: 1 Joubert PH et al. Euro J Clin Pharmacol 1988: between the Agency and industry; (3) 34: 363–368. ¼ FDA’s Drug Metabolism/Drug Inter- focus the regulatory review on the 2 Joubert PH, Brandt HD. Euro J Clin Pharma- action Studies in the Drug Develop- important science/clinical questions col 1990: 39: 183–186. ment Process: Studies In Vitro and determine what evidence is neces- 3 Kuivenhoven JA et al. N Engl J Med 1998: ¼ 338:86–93. FDA’s In Vivo Drug Metabolism/ sary to support label claims. We con- 4 Narod SA et al. Lancet 2000: 356: 1876– Drug Interaction Studies — Study tinue to be concerned that despite the 1881.

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