Pharmacogenetics and pharmacogenomics in drug development and regulatory decision making: report of the first FDA-PWG-PhRMA-DruSafe Workshop

The use of pharmacogenetics and pharmacogenomics in the drug development process, and in the assessment of such data submitted to regulatory agencies by industry, has generated significant enthusiasm as well as important reservations within the scientific and medical communities. This situation has arisen because of the increasing number of exploratory and confirmatory investigations into variations in RNA expression patterns and DNA sequences being conducted in the preclinical and clinical phases of drug development, and the uncertainty surrounding the acceptance of these data by regulatory agencies. This report summarizes the outcome of a workshop cosponsored by the Food and Drug Administration (FDA), the Pharmacogenetics Working Group (PWG), the Pharmaceutical Research and Manufacturers of America (PhRMA), and the PhRMA Preclinical Safety Committee (DruSafe). The specific aim of the workshop was to identify key issues associated with the application of pharmacogenetics and pharmacogenomics, including the feasibility of a regulatory "safe harbor" for exploratory genome-based data, and to provide a forum for industry-regulatory agency dialogue on these important issues.     

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 FDA's 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.     

The Importance of Legislative Reform of the Fda

Abstract

The US Food and Drug Administration (FDA) has raised the regulatory burden on drug companies by continually introducing new requirements and policies, regardless of their potential to hinder the delivery of new and innovative therapies to patients who need them. the drug development system in the United States has become the slowest and most expensive in the world. In a climate of deregulation, FDA has sought to cultivate the image of an agency reforming itself from within—lessening the burden on regulated industry and lowering review times—but such “improvements” are largely illusory. FDA has shown itselfincapable of reforming itself, and only carefully crafted legislation will significantly improve the oversight of drug development.     

Regulatory challenges for new drugs to treat obesity and comorbid metabolic disorders

Obesity is a major cause of morbidity and mortality through cardio- and cerebrovascular diseases and cancer. The metabolic consequences of obesity include dyslipidaemia, hypertension, proinflammatory atherogenesis, pre-diabetes and Type 2 diabetes. For a significant proportion of patients, pharmacotherapy to tackle obesity is required as adjunctive support to diet, exercise and lifestyle modification. To this end, the pharmaceutical industry is pursuing many novel drug targets. Although this view is probably not justified, the recent tribulations of rimonabant have created a perception that the regulatory bar for the approval of antiobesity drugs has been raised. Although >5% of placebo-subtracted weight loss maintained over 1 year is the primary efficacy end-point, it is improvements in cardiovascular risk factors that the Food and Drug Administration (FDA) and European Medicines Agency (EMEA) require to grant approval. Safety aspects are also critical in this indication. Many companies are now switching development of their antiobesity drug candidates into other metabolic disorders. Type 2 diabetes is accepted by the industry and FDA, but not EMEA, as the most appropriate alternative. On the other hand, improvements in plasma lipids produced by antiobesity drugs are moderate compared with established therapies, suggesting dyslipidaemia is not a viable development option. Metabolic Syndrome is not accepted by FDA or EMEA as a discrete disease and the agencies will not licence antiobesity drugs for its treatment. The regulatory environment for antiobesity drugs and the spectrum of indications for which they can be approved could change dramatically if positive data for sibutramine emerge from the SCOUT outcome trial.     

4th Annual Pharmacogenomics and Medicine Lectures

In the future, pharmacogenomics will play an important role in the treatment of patients by making it possible to predict drug response based on an individual's genetic make-up. Similarly, pharmacogenomics may be used to reduce the probability that adverse effects will occur. The use of a patient's genetic information will lead to greater predictability in clinical outcomes and personalisation of medical care. Pharmacogenomic information can also aid in drug development by helping to select individuals that are likely to respond to a medication for participation in clinical trials. Integration of pharmacogenomics into the healthcare system has a number of potential economic benefits, including reduced costs of healthcare and drug discovery. The FDA has no specific plans to regulate therapy-guiding pharmacogenomic tests, which are different from diagnostic genetic tests. There are a number of ethical issues related to pharmacogenomics, including the credibility of the system for protecting the rights and welfare of human research subjects, general concerns about genetic research, privacy issues and equitable distribution of the technology. To ensure integration of pharmacogenomics into the healthcare system it will be important to obtain public support through education about the benefits and risks of this technology.     

Imaging as a tool in drug development

Medical imaging has experienced a huge increase in exploratory technologies over the past 20 to 30 years. From drug discovery to drug development to routine clinical practice, the advent of functional imaging is about to revolutionize both medicine and pharmaceutical drug development. Currently, a number of technologies are in competition. Positron emission tomography (PET) and magnetic resonance imaging (MRI) have advanced furthest as useful adjuncts to clinical drug development, even though data from both remain, at best, biomarkers that alone will not suffice for regulatory approval. However, the high-risk proof-of-concept and early proof-of-efficacy trial programs can be accelerated with judicious use of PET or MRI. The U.S. Food and Drug Administration (FDA) is currently working to establish guidelines for these new imaging methods, which might accelerate drug development and improve treatment of individual patients.     

Enabling pharmacogenomic clinical trials through sampling

Discussion and output from the US FDA and the pharmaceutical industry from the Drug Information Association/FDA 5th Workshop in a series on pharmacogenomics entitled: 'Generating and Weighing Evidence in Drug Development and Regulatory Decision Making'. A major topic area at the 5th FDA/Industry Workshop on Pharmacogenomics, February 2-4, 2010 in Bethesda (MD, USA), was enabling pharmacogenomic clinical trials through collection of future use samples. The importance of the collection of samples with permission for future analyses was affirmed by both industry and the FDA. In addition, current barriers for the collection of such samples were detailed and possible solutions for overcoming barriers at sites, as well as globally within countries, were discussed. The importance of international concordance on collection of these samples was emphasized, and potential areas for industry to harmonize sample collection practices. A standalone workshop on issues related to sampling was determined to be a key step for solving issues related to future use sample collection during drug development.     

Clinical pharmacology applications in clinical drug development and clinical care: A focus on Saudi Arabia

Drug development, from preclinical to clinical studies, is a lengthy and complex process. There is an increased interest in the Kingdom of Saudi Arabia (KSA) to promote innovation, research and local content including clinical trials (Phase I-IV). Currently, there are over 650 registered clinical trials in Saudi Arabia, and this number is expected to increase. An important part of drug development and clinical trials is to assure the safe and effective use of drugs. Clinical pharmacology plays a vital role in informed decision making during the drug development stage as it focuses on the effects of drugs in humans. Disciplines such as pharmacokinetics, pharmacodynamics and pharmacogenomics are components of clinical pharmacology. It is a growing discipline with a range of applications in all phases of drug development, including selecting optimal doses for Phase I, II and III studies, evaluating bioequivalence and biosimilar studies and designing clinical studies. Incorporating clinical pharmacology in research as well as in the requirements of regulatory agencies will improve the drug development process and accelerate the pipeline. Clinical pharmacology is also applied in direct patient care with the goal of personalizing treatment. Tools such as therapeutic drug monitoring, pharmacogenomics and model informed precision dosing are used to optimize dosing for patients at an individual level. In KSA, the science of clinical pharmacology is underutilized and we believe it is important to raise awareness and educate the scientific community and healthcare professionals in terms of its applications and potential. In this review paper, we provide an overview on the use and applications of clinical pharmacology in both drug development and clinical care.     

Impact of pharmacometrics on drug approval and labeling decisions: A survey of 42 new drug applications

The value of quantitative thinking in drug development and regulatory review is increasingly being appreciated. Modeling and simulation of data pertaining to pharmacokinetic, pharmacodynamic, and disease progression is often referred to as the pharmacometrics analyses. The objective of the current report is to assess the role of pharmacometrics at the US Food and Drug Administration (FDA) in making drug approval and labeling decisions. The New Drug Applications (NDAs) submitted between 2000 and 2004 to the Cardio-renal, Oncology, and Neuropharmacology drug products divisions were surveyed. For those NDA reviews that included a pharmacometrics consultation, the clinical pharmacology scientists ranked the impact on the regulatory decision(s). Of about a total of 244 NDAs, 42 included a pharmacometrics component. Review of NDAs involved independent, quantitative evaluation by FDA pharmacometricians, even when such analysis was not conducted by the sponsor. Pharmacometric analyses were pivotal in regulatory decision making in more than half of the 42 NDAs. Of the 14 reviews that were pivotal to approval related decisions, 5 identified the need for additional trials, whereas 6 reduced the burden of conducting additional trials. Collaboration among the FDA clinical pharmacology, medical, and statistical reviewers and effective communication with the sponsors was critical for the impact to occur. The survey and the case studies emphasize the need for early interaction between the FDA and sponsors to plan the development more efficiently by appreciating the regulatory expectations better.     

Some applications of pharmacogenomics and epigenetics in drug development and use in pursuit of personalized medicine

Personalized medicine has become the most recent mantra of the pharmaceutical industry. While truly affordable bespoke drugs may never be totally achievable, pharmacogenomics and epigenetics will play significant roles in developing targeted therapy tailored to subpopulations of disease sufferers most likely to benefit. Personalized medicine is a very attractive concept, but an extremely difficult reality to achieve due to theoretical and practical considerations. Foremost among the theoretical reasons is our dearth of knowledge of individual physiology and metabolism, as well as the interactions of genetics and environment in the development of most diseases. Amongst the practical reasons, there is the cost of new drug development, considered to be about 800 million to one billion dollars (J Health Econ 22:151-185, DiMasi et al. 2003; Health Econ 19:130-141, Adams and Vu Brantner 2010) and the fact that many drugs now on the market do display reasonable efficacy in large segments of the population with acceptable side effects. Thus, the market for "personalized" drugs may not be large enough to support the costs of development. Another factor is the limitations put on healthcare by governments and insurance companies which promote the use of generics rather than the creation of new chemical entities. Finally, there are the social and ethical considerations of turning individual biology into noughts and ones with the possibility of such information becoming public and/or being used to constrain the way one lives or the care one receives (Nat Rev Drug Discov 1:300-308, Issa 2002). That said, to the degree that personalized medicine does become possible, pharmacogenomics and epigenetics will play significant roles in drug development and use.     

Repercussions of the Drug Price Competition and Patent Term Restoration Act of 1984

Recently enacted legislation involving patent terms and the approval of new generic equivalent drug products is described, and the law's potential repercussions are discussed. The Drug Price Competition and Patent Term Restoration Act of 1984 (PL 98-417) consists of two titles that affect introduction procedures and patent requirements for certain types of generic new drug products. Title I allows drug manufacturers to use an abbreviated new drug application when seeking approval to make generic copies of drug products that were approved by the FDA after 1962. Title II encourages drug manufacturers to assume the increased costs of research and development of certain products that were subject to premarketing clearance by restoring some of the time lost on patent life while the product was awaiting FDA approval. Legislative analysts continue to question whether the short-term gains of eased market access to the generic manufacturers will be outweighed by the long-term benefits of patent extensions to the pioneer drug companies. The potential difficulties in the implementation of the Act and unresolved questions of law surrounding the new law are discussed. The possible effects of the new law on the drug manufacturing industry and market composition are described. Since PL 98-417 was implemented in September 1984, little has been settled in the way of implementing its provisions or accurately measuring its nonregulatory impact. It seems certain that the bill will be difficult to regulate and that litigation will proliferate. Furthermore, the impact of the statute on the composition of the drug industry will undoubtedly be substantial.     

Utilisation of pharmacokinetic-pharmacodynamic modelling and simulation in regulatory decision-making.

Modelling and simulation (M&S) play an important role in regulatory decision-making that affects both the public and industry. Technological advances in various fields related to drug development call for more focus on ways to optimise current drug development practices. Recognition of the potential of M&S by regulatory agencies inevitably has a substantial impact on drug development. The objective of the current review is to present the various regulatory initiatives for application of M&S to clinical drug development. The relevant parts of the various recommendations issued by the US Food and Drug Administration (FDA), via guidance documents and advisory committee meeting proceedings, are highlighted. Application of M&S to a variety of activities, such as integrating pharmacokinetic-pharmacodynamic knowledge across a new drug application and designing efficient trials, is discussed. Some of the challenges that pharmaceutical institutions currently face when implementing M&S projects, such as team structure, communication with regulators, training and time constraints, are also presented, and solutions are proposed.     

Integrating pharmacogenomics into pharmacy practice via medication therapy management: American Pharmacists Association

ObjectiveTo explore the application and integration of pharmacogenomics in pharmacy clinical practice via medication therapy management (MTM) to improve patient care.Data sourcesDepartment of Health & Human Services (HHS) Personalized Health Care Initiative, Food and Drug Administration (FDA) pharmacogenomics activity, and findings from the Utilizing E-Prescribing Technologies to Integrate Pharmacogenomics into Prescribing and Dispensing Practices Stakeholder Workshop, convened by the American Pharmacists Association (APhA) on March 5, 2009. Participants at the Stakeholder Workshop included diverse representatives from pharmacy, medicine, pathology, health information technology (HIT), standards, science, academia, government, and others with a key interest in the clinical application of pharmacogenomics.SummaryIn 2006, HHS initiated the Personalized Health Care Initiative with the goal of building the foundation for the delivery of gene-based care, which may prove to be more effective for large patient subpopulations. In the years since the initiative was launched, drug manufacturers and FDA have begun to incorporate pharmacogenomic data and applications of this information into the drug development, labeling, and approval processes. New applications and processes for using this emerging pharmacogenomics data are needed to effectively integrate this information into clinical practice. Building from the findings of a stakeholder workshop convened by APhA and the advancement of the pharmacist's collaborative role in patient care through MTM, emerging roles for pharmacists using pharmacogenomic information to improve patient care are taking hold. Realizing the potential role of the pharmacist in pharmacogenomics through MTM will require connectivity of pharmacists into the electronic health record infrastructure to permit the exchange of pertinent health information among all members of a patient's health care team. Addressing current barriers, concerns, and system limitations and developing an effective infrastructure will be necessary for pharmacogenomics to achieve its true potential.ConclusionTo achieve integration of pharmacogenomics into clinical practice via MTM, the pharmacy profession must define a process for the application of pharmacogenomic data into pharmacy clinical practice that is aligned with MTM service delivery, develop a viable business model for these practices, and encourage and direct the development of HIT solutions that support the pharmacist’s role in this emerging field.     

The impact of pharmacogenomics research on drug development

Over the last two decades, identification of polymorphisms that influence human diseases has begun to have an impact on the provision of medical care. The promise of genetics lies in its ability to provide insight into an individual's susceptibility to disease, the likely nature of the disease and the most appropriate therapy. For much of its history, pharmacogenomics (PGx) has been limited to relatively simple phenotypes such as plasma drug levels. Progress in genetic technologies has broadened the scope of exploratory PGx and its implementation into safety and efficacy studies, impacting a broad spectrum of drug discovery and development activities. Recent PGx data show the ability of this approach to generate information that can be applied to target selection, dose selection, efficacy determination and safety issues. This in turn will lead to significant opportunities to influence the approaches to drug discovery, clinical development and the probability of success. In particular, adverse drug reactions are critical issues for pharmaceutical companies and for the patients who will benefit from these new medicines. In this review, we outline current progress in PGx, using examples to highlight the influence of polymorphisms, and discuss contemporary challenges for both researchers and clinicians.     

New era in drug interaction evaluation: US Food and Drug Administration update on CYP enzymes, transporters, and the guidance process

Predicting clinically significant drug interactions during drug development is a challenge for the pharmaceutical industry and regulatory agencies. Since the publication of the US Food and Drug Administration's (FDA's) first in vitro and in vivo drug interaction guidance documents in 1997 and 1999, researchers and clinicians have gained a better understanding of drug interactions. This knowledge has enabled the FDA and the industry to progress and begin to overcome these challenges. The FDA has continued its efforts to evaluate methodologies to study drug interactions and communicate recommendations regarding the conduct of drug interaction studies, particularly for CYP-based and transporter-based drug interactions, to the pharmaceutical industry. A drug interaction Web site was established to document the FDA's current understanding of drug interactions (http://www.fda.gov/cder/drug/drugInteractions/default.htm). This report provides an overview of the evolution of the drug interaction guidances, includes a synopsis of the steps taken by the FDA to revise the original drug interaction guidance documents, and summarizes and highlights updated sections in the current guidance document, Drug Interaction Studies-Study Design, Data Analysis, and Implications for Dosing and Labeling.     

Drug interactions evaluation: An integrated part of risk assessment of therapeutics

Pharmacokinetic drug interactions can lead to serious adverse events or decreased drug efficacy. The evaluation of a new molecular entity's (NME's) drug-drug interaction potential is an integral part of risk assessment during drug development and regulatory review. Alteration of activities of enzymes or transporters involved in the absorption, distribution, metabolism, or excretion of a new molecular entity by concomitant drugs may alter drug exposure, which can impact response (safety or efficacy). The recent Food and Drug Administration (FDA) draft drug interaction guidance (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072101.pdf) highlights the methodologies and criteria that may be used to guide drug interaction evaluation by industry and regulatory agencies and to construct informative labeling for health practitioner and patients. In addition, the Food and Drug Administration established a “Drug Development and Drug Interactions” website to provide up-to-date information regarding evaluation of drug interactions (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm). This review summarizes key elements in the FDA drug interaction guidance and new scientific developments that can guide the evaluation of drug-drug interactions during the drug development process.     

Clinical pharmacogenomics: applications in pharmaceutical R&D

Within the pharmaceutical industry, the application of clinical pharmacogenomics promises to enhance the discovery of drug response markers, reduce the size and expense of clinical drug trials and provide a new tool for addressing regulatory approval issues. Today, pharmacogenomics is primarily applied early in clinical drug development by prospective genotyping in Phase I trials, to ensure that a subject population is representative with respect to drug metabolism phenotypes. The banking of genetic material from later stage trials for retrospective studies on drug response is becoming more frequent, but is not yet standard in the industry. This article provides an overview of the driving forces that are encouraging pharmacogenomic strategy development in the pharmaceutical industry, and the significance of polymorphisms in drug metabolizing enzymes (DMEs) and target proteins.     

Key issues in the pharmaceutical industry: consequences on R&D

Drug discovery is hard, and is becoming progressively harder, with the passage of time! No other field has to handle such an interplay of scientific, fiscal and political factors. The rewards are, nonetheless, worth it: people now live healthier and longer lives than at any point of time in the past. Times are, however, hard for pharmaceutical companies: research and development (R&D) costs are spiralling out of control. New drug approvals, on the other hand, have hit a record low; and the situation is expected to worsen, now that the FDA seems to be exhibiting stricter drug approval standards. Other issues also exacerbate circumstances: huge numbers of blockbuster medicines, which drugmakers rely on to generate their incomes, are coming off patent, and generic competition is intensifying. Both public and investor confidence in the industry have fallen drastically owing to rising drug prices, product safety concerns and late-stage clinical trial failures. This article discusses the key issues that pharmaceutical companies face and in particular the implications they have for the R&D process. I finish by suggesting how drugmakers should change their R&D strategies to succeed.