Michael A. Pacanowski

Pharmacogenomics in the assessment of therapeutic risks versus benefits: inside the United States Food and Drug Administration.

Pharmacogenomics is the study of how genetic variations influence responses to drugs, diagnostics, or biologic agents. The field of pharmacogenomics has significant potential to enhance drug development and aid in making regulatory decisions. The United States Food and Drug Administration (FDA) has supported pharmacogenomics for nearly a decade by providing regulatory advice and reviewing applications, with the intent of discovering and applying genetic determinants of treatment effects. The FDA will continue to develop policies and processes centered on genomics and individualized therapeutics to guide rational drug development. It will also continue to inform the public of clinically relevant pharmacogenomic issues through various mechanisms of communication, such as drug labeling. In this review, we provide a perspective on several pharmacogenomic activities at the FDA. In addition, we attempt to clarify what we believe are several misperceptions regarding the FDAs pharmacogenomic initiatives. We hope this perspective provides a window into some ways in which the FDA is enabling individualized therapeutics through its mission‐critical activities.

Racial/ethnic differences in drug disposition and response: Review of recently approved drugs

Race and ethnicity can contribute to interindividual differences in drug exposure and/or response, which may alter risk–benefit in certain populations. Approximately one‐fifth of new drugs approved in the past 6 years demonstrated differences in exposure and/or response across racial/ethnic groups, translating to population‐specific prescribing recommendations in a few cases. When data from diverse populations were lacking, additional postmarketing studies were recommended. In this review we highlight several cases where race/ethnicity was central to regulatory decision‐making.

Effectiveness of clopidogrel dose escalation to normalize active metabolite exposure and antiplatelet effects in CYP2C19 poor metabolizers.

Carriers of two copies of the loss‐of‐function CYP2C19*2 variant convert less clopidogrel into its active metabolite, resulting in diminished antiplatelet responses and higher cardiovascular event rates. To evaluate whether increasing the daily clopidogrel dose in poor metabolizers (PM) overcomes the effect of the CYP2C19 * 2 variant, we enrolled 18 healthy participants in a genotype‐stratified, multi‐dose, three‐period, fixed‐sequence crossover study. Six participants with the *1/*1 extensive (EM), *1/*2 intermediate (IM), and *2/*2 poor metabolizer genotypes each received 75 mg, 150 mg, and 300 mg each for 8 days. In each period, maximal platelet aggregation 4 hours post‐dose (MPA4) and active metabolite area under the curve (AUC) differed among genotype groups (P < .05 for all). At day 8, PMs needed 300 mg daily and IMs needed 150 mg daily to attain a similar MPA4 as EMs on the 75 mg dose (32.6%, 33.2%, 31.3%, respectively). Similarly, PMs needed 300 mg daily to achieve active metabolite concentrations that were similar to EMs on 75 mg (AUC 37.7 and 33.5 ng h/mL, respectively). These results suggest that quadrupling the usual clopidogrel dose might be necessary to overcome the effect of poor CYP2C19 metabolism.

Personalized Cardiovascular Medicine Today: A Food and Drug Administration/Center for Drug Evaluation and Research Perspective.

Over the past decade, personalized medicine has received considerable attention from researchers, drug developers, and regulatory agencies. Personalized medicine includes identifying patients most likely to benefit and those most likely to experience adverse reactions in response to a drug, and tailoring therapy based on pharmacokinetics or pharmacodynamic response, as well. Perhaps most exciting is finding ways to identify likely responders through genetic, proteomic, or other tests, so that only likely responders will be treated. However, less precise methods such as identifying historical, demographic, or other indicators of increased or reduced responsiveness are also important aspects of personalized medicine. The cardiovascular field has not used many genetic or proteomic markers, but has regularly used prognostic variables to identify likely responders. The development of biomarker-based approaches to personalized medicine in cardiovascular disease has been challenging, in part, because most cardiovascular therapies treat acquired syndromes, such as acute coronary syndrome and heart failure, which develop over many decades and represent the end result of several pathophysiological mechanisms. More precise disease classification and greater understanding of individual variations in disease pathology could drive the development of targeted therapeutics. Success in designing clinical trials for personalized medicine will require the selection of patient populations with attributes that can be targeted or that predict outcome, and the use of appropriate enrichment strategies once such attributes are identified. Here, we describe examples of personalized medicine in cardiovascular disease, discuss its impact on clinical trial design, and provide insight into the future of personalized cardiovascular medicine from a regulatory perspective.

Next-generation medicines: past regulatory experience and considerations for the future.

Application of personalized medicine in drug development and regulation has been limited by similar logistical, informatics, and cultural barriers that limit use of pharmacogenetics in the clinic. An additional challenge is coordinated codevelopment of new drugs and diagnostic tests. Nevertheless, the impact of personalized medicine strategies (e.g., pharmacogenomics) is being realized. We highlight some of our experiences to date and considerations for the development of the next generation of targeted therapies.

Pharmacogenomic information in FDA‐approved drug labels: Application to pediatric patients

Pharmacogenomic (PGx) information is increasingly being incorporated into US Food and Drug Administration‐approved drug labels. We reviewed the data source (adults vs. pediatrics) of PGx information in approved drug labels and assessed the suitability of applying adult‐derived PGx information and related prescribing recommendations to the care of pediatric patients. We identified 65 drugs with labels containing PGx information and that have also been evaluated in children and found that in the majority of cases (56/65, 86%), the PGx information described was derived from adult studies. The application of PGx information from adults to pediatrics was deemed suitable for 71.4% (n = 40) of the drugs and unclear for 28.6% (n = 16). An ontogeny effect, limited or conflicting data regarding ontogeny of the genetic biomarker, or a difference in the pathophysiology or progression of the adult vs. pediatric disease were the primary reasons for deeming direct application from adults to pediatrics unclear.

Clinical Trial Designs to Support Clinical Utility of Pharmacogenomic Testing

Advancing the use of biomarkers and pharmacogenomics has been a key priority area for the U.S. Food and Drug Administration (FDA). The FDA offers prescribing recommendations to manage ~100 gene‐drug interactions, and multiple institutions around the United States and abroad have incorporated genomic testing into patient care. However, the penetration of pharmacogenomic testing remains incomplete. In this perspective, we summarize the evidence streams to support the clinical utility of pharmacogenomic testing and its transition into clinical practice.

Research Directions in Genetic Predispositions to Stevens–Johnson Syndrome / Toxic Epidermal Necrolysis

Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is one of the most devastating of adverse drug reactions (ADRs) and was, until recently, essentially unpredictable. With the discovery of several risk alleles for drug‐induced SJS/TEN and the demonstration of effectiveness of screening in reducing incidence, the stage is set for implementation of preventive strategies in populations at risk. Yet much remains to be learned about this potentially fatal complication of commonly used drugs.

Trial geography, pharmacogenetics, and global drug development

Drug development is increasingly global. The benefits of multiregional trials include worldwide evaluation of safety and efficacy. However, clinical practice, environmental, and genetic factors can vary across geographic regions, significantly influencing trial outcomes within a specific geographic region or the global population relative to the United States (US). Genomic technologies and research discoveries continue to advance at a remarkable pace, offering opportunities to explore intrinsic factors that could account for regional variability in drug pharmacokinetics or response.

white Supra Shoes Footwear Gum Black Chino Men's xgqprYx at uber-traffic.com

Summary The U.S. Food and Drug Administration recently marked 10 years since first updating the labeling for warfarin (often referred to as the “poster child” of pharmacogenomics) to include information regarding the potential impact of CYP2C9 and VKORC1 genetic variation on warfarin dosing requirements and risks. Herein, we opine on the experience updating the warfarin labeling, highlighting more generally the enabling factors and challenges encountered when considering incorporation of pharmacogenomic information into the prescribing recommendations for already approved drugs. We also provide a historical perspective of implemented changes in regulatory policies related to personalized medicine.