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PGx Highlights – A PGx Focus Group Newsletter, AAPS Volume 4; Issue 1, March 2012 Highlight 1

Regulatory Affairs: New FDA Draft Guidance -2011: Clinical Pharmacogenomics:
Premarketing Evaluation in Early Phase Clinical Studies
E. Jane Mitchell, PhD, RAC
Regulatory Operations, Optum Insight
E-mail: Jane.Mitchell@optum.com
In February 2011, FDA published a new Draft
1. “Identify populations that should receive lower or higher doses of a drug because of excretory Pharmacogenomics: Premarketing Evaluation in or metabolic differences. The latter are Early Phase Clinical Trials [1]. This draft guidance generally identified by genetic abnormalities attempts to provide a deeper and more consolidated defining metabolic status for enzymes with approach to the current thinking than provided in pharmacogenomics (PGx) [2-5]. The comment 2. “Identify responder populations based on period for this draft guidance has passed, however, phenotype, receptor, or genetic characteristics, and FDA will no doubt reflect further and revise it a critical element in treatment individualization before implementation. The focus is intended to be that has been used primarily in the oncologic on general principles of study design, data setting. Predicted differences in response can collection and data analysis mainly for Phase 1 and lead to enrichment strategies based on such 2 exploratory and observational studies. It does not address statistical considerations for Phase 3 randomized trials. There is no explicit specific 3. “Help define the dose range for later trials by mention of voluntary exploratory data submissions identifying the dose-response for pertinent (VXDS) or joint meetings between sponsors and biomarker and/or early effectiveness and more FDA as these have been outlined previously [2, 4] common adverse effects. In many cases, the phase 3 trials would evaluate several doses to Background Section
define benefit and risk further. It would be of FDA outlines definitions, terminology, and particular interest to identify subsets with describes the current state of understanding of PGx different dose-response relationships. However, in relation to biomarkers, disease states, drug the study of several doses is not common in response and PGx studies. Drug exposure (E) refers phase 3 oncology trials of cell and gene therapy pharmacokinetic (PK) profiles. Drug response (R) refers to pharmacodynamics (PD) and all of the 4. “Identify high risk groups. Although the ability various physiological and pathological processes to cause serious adverse effects will not be affected. Genetic variations influence the generally acceptable in most settings, even if relationship between drug exposure and response by they can be predicted, it is possible that such altering the E/R curve and the maximum drug effects could be linked to factors (metabolic, genetic) that could be managed in later trials, The contributions of Phase 1 and 2 results and support approval of drugs with particular toward the design of randomized controlled Phase 3 value. To date, the most likely use of such studies in terms of providing specific PGx data on information would be to identify poor PK and PD are outlined early in the guidance, as metabolizers or ultra-rapid metabolizes (e.g., CYP2D6) whose blood levels of parent or PGx Highlights – A PGx Focus Group Newsletter, AAPS Volume 4; Issue 1, March 2012 relevant metabolites could be markedly bleeding events. VKORC1 (1639GA) decreases affected; in trials they could be excluded or gene expressions and increases responsiveness to their doses modified to account for genetic warfarin so patients require a lower dose. In 2010, the label was updated with a DOSING TABLE to be used for initial dosing based on CYP2C9 and The value of PGx is discussed in the draft guidance by means of an overview of case histories for These examples, where PGx information are already incorporated into labels, guide physicians to For Abacavir, hypersensitivity occurred with better predict benefits and risks for their patients 5-8 % of patients. In 3-4 years after approval, new and are part of what is referred to as the new term PGx findings indicated the HLA-B*5701 allele was “regulatory science”. Whether a label includes a associated with these hypersensitivity reactions. PREDICT-1 was a 6-week prospective randomized BOX WARNING, based on predictable genetic controlled trial designed to assess the marker for effects, the Pharma industry will be required to add clinical utility in HLA-B*5701 allele screening more thought, time and money throughout its drug prior to treatment. The Positive Predictive Value of development pipelines, as an attempt to identify the PREDICT-1 was 47.9 % i.e., about 50 % of positive major genetic effects. While this may initially be HLA-B*5701-tested patients developed hypersen- perceived to increase approval timelines, the risks to sitivity and none with a negative test did (Net the Pharma industry associated with withdrawing a drug from market and/or dealing with lawsuits Clopidogrel is a pro-drug that is metabolized would hopefully be reduced with the concomitant in a 2-step process involving CYP2C19. Studies better safety outcomes to patients. Drug indicated that a loss of function (LOF) allele development expectations will change such that resulted in reduced exposure to the active companies will be required to have gained a deeper metabolite and less inhibition of platelet understanding of the major predictable genetic aggregation. The TRITON-TIMI 38 study of effects, impacting both efficacy and safety, when genotyped LOF CYP2C19 alleles indicated that these patients had a higher rate of death, nonfatal myocardial infarction or nonfatal stroke as DNA Sampling
compared to non-carriers, following percutaneous FDA devotes a separate section in the draft coronary intervention. As a result of this and other studies, the label was updated in 2009 and 2010 prospective and consent should be obtained from all related to a diminished antiplatelet response and participants in trials. Sampling should be done at increased risk of cardiovascular events. enrollment to avoid bias and should be retained as Warfarin is consistently in the top ten drugs new PGx issues may arise after study completion. that cause serious adverse events, having major Samples could include a wide range of biological bleeding frequencies of 10-16 %. Dose is modified media including blood and buccal cells as well as by INR assay, but as the polymorphisms (*2 and *3 tumor cells, where somatic and acquired mutations alleles) affecting CYP2C9 result in decreased could be used in predicting drug response as well as clearance and higher blood levels of S-warfarin disease severity. FDA indicates this practice should (which is more potent than the R-enantiomer), more allow sponsors of new drugs an opportunity to than INR testing alone may be needed. Warfarin investigate the causes for lack of efficacy or toxicity acts on the Vitamin K epoxide reductase encoded in different individuals using genome-wide by VKORC1 and this polymorphism can affect association, candidate gene or targeted pathway response to warfarin to a clinically significant analysis, as appropriate. There are references on extent in some individuals, increasing an collection of biospecimens as well as storage and individual’s risk of potentially life-threatening coding of samples provided in the guideline, PGx Highlights – A PGx Focus Group Newsletter, AAPS Volume 4; Issue 1, March 2012 however there are other considerations, in particular should be taken into consideration in the design of bioethics and informed consent that are not raised. dose/response (D/R) studies in genotype-defined How, where and why the obtained samples that are subgroups. This ability to test and to identify collected “routinely” would be used needs to be genotypes that are important in predicting drug clearly addressed not only in recommended levels and drug effect are important to the guidelines but likely in new regulation and/or policies. Clarity on a number of points are required Phase 2 dose/response studies using either including: How long the samples could be retained; biomarkers or clinical end points that stratify dose could the samples be used retrospectively to groups by genotype or genotype-guided D/R should reanalyze data from only the original intended be considered. Drug plasma levels assist in clinical study or would there be later circumstances interpreting results when there are major differences where these samples could be analyzed to obtain in blood levels resulting from genomic factors and data for other purposes? If and when decisions apparent variability on D/R relationship. around the samples were to be made, would there be some kind of central ethics committee and who Clinical Study Design
would that committee be composed of? Would there The draft guidance provides mainly high level be differences in the way different classes of drugs, considerations and references to additional non-PGx estimated safety profiles, or disease states handled guidance documents. Meetings with FDA are expected during development phases, so comments are general. According to the draft guidance, study Clinical Evaluation of Pharmacogenomics
design is similar to studies of e.g., the hepatically Some of the main points in the second half of the impaired where the goal of PGx study is to compare guidance are outlined below; consult the draft genomically defined PK subgroups of healthy guidance and/or other FDA guidances for further volunteers or patients. The goal is to include results Clinical Pharmacogenomics:
biomarker may be more exploratory early in In healthy volunteers: PK and PD with prospective development where the goal is to seek genomic DNA analysis together with information on known predictors of PD effects and later in development, ADME variants may assist in evaluating outliers, or it could assist when there are concerns about Analytical validation of phenotyping and toxicity, by excluding individuals at risk, until a genotyping methods is expected to be done before greater understanding of the metabolic relevance is initiating PGx clinical studies. Regarding study populations, the exclusion of patients with certain in vitro studies suggest that a drug is genotypes may be appropriate. Multiple covariate metabolized by polymorphic pathways, then the PK considerations in drug response resulting from studies should be conducted in healthy volunteers genetic as well as non-genetic factors are to be prospectively representing various common considered as they are important in assessing the genotypes. Pro-drugs activated through impact of genetics vs other factors on PK, PD, polymorphic pathways should be characterized dosing, efficacy and safety. It is the Agency’s early and subgroups of subjects with genetic opinion that this is an area for greater exploration variants of metabolic and transporter genes should and understanding in particular drug interactions. be included. As in the case of clopidogrel, failure to Effort is needed in the area of theoretical trial form the active metabolite may have profound design to ensure the feasibility of studies that can provide interpretable results that can translate into In patients, when important variability in PK solid and meaningful regulatory decision-making of active species is shown in healthy volunteers, this when multiple factors are to be considered. PGx Highlights – A PGx Focus Group Newsletter, AAPS Volume 4; Issue 1, March 2012 Concerning statistical considerations, the draft the individual patient, but also for healthcare guidance indicates that early studies should be able communities that develop, deliver or pay for care. to demonstrate definitive differences in PK (e.g., CYP2D6 poor metabolizers), though genomic PD References
differences require further [more subjects] study. 1. Clinical Pharmacogenomics: Premarketing Evaluation in PGx study dose selection is to be at clinically Early Phase Clinical Studies Draft Guidance. Web. 18 relevant doses, with lower doses selected if the Feb. 2011. http://www.fda.gov/downloads/Drugs/GuidanceComplian subject’s genotype could place them at risk. ceRegulatoryInformation/Guidances/UCM243702.pdf Drug interaction is not addressed in the PGx 2. Pharmacogenomic Data Submissions. Web. 23 Mar. draft guidance and this is an area in need of research in view of the multiple prescriptions individuals http://www.fda.gov/downloads/Drugs/GuidanceComplian may be taking at one time, particularly in older age ceRegulatoryInformation/Guidances/UCM079849.pdf 3. Guiding Principles for Joint FDA EMEA Voluntary groups. Last month, in February 2012, FDA has Genomic Data Submission Briefing Meetings. Web. 19 published its draft guidance on Drug Interaction Studies – Study Design, Data Analysis, and http://www.ema.europa.eu/docs/en_GB/document_library Recommendations [6]; this follows a preliminary 4. Pharmacogenomic Data Submissions — Companion drug concept paper published by FDA in 2004 on http://www.fda.gov/downloads/Drugs/GuidanceComplian drug interaction studies [7]. This area of regulatory ceRegulatoryInformation/Guidances/UCM079855.pdf science will require development and evaluation 5. FDA Guidance for Industry and FDA Staff: Guidance on alongside that of PGx in clinical pharmacology and Pharmacogenetic Tests and Genetic Tests for Heritable clinical studies: Various complex scenarios of Markers. Web. 2007. http://www.fda.gov/MedicalDevices/DeviceRegulationan potential drug interaction in individuals with various genetic alleles such as CYP variants require 6. FDA: Draft Guidance for Industry: Drug Interaction more in depth understanding such that labeling is Studies — Study Design, Data Analysis, and Implications meaningful and individuals may be dose adjusted for Dosing and Labeling Recommendations. Web. Feb. appropriately. Methods for phenotyping individuals 2012. http://www.fda.gov/downloads/Drugs/GuidanceComplian require greater scientific understanding as well. It is ceRegulatoryInformation/Guidances/UCM292362.pdf hoped there will be future guidances from FDA as 7. FDA: Drug Interaction Studies –Study Design, Data these scientific areas and development products are Analysis, and Implications for Dosing and Labeling, discussed in Exploratory Data Submissions (VXDS) Preliminary Draft Concept Paper. Web. 1 Oct. 2004. and more regulatory approvals are obtained with http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4079B1_04_Topic2-TabA.pdf genomic labeling. The overall goal must be to have benefits and risks clearly predicated and realized in terms of regulatory science, first and foremost for

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