policY AnAlYsis

A Comparison of US Food and Drug Administration and European Medicines Agency Regulations for Pharmaceutical Risk Management: Report of the International Society for Pharmacoeconomic and Outcomes Research Risk Management Working Group
Yvonne Lis, PhD, Consultant, PAREXEL International, Uxbridge, UK; Je J. Guo, PhD, Professor of Pharmacoeconomics, University of Cincinnati Medical Center College of Pharmacy, Cincinnati, OH, USA; Melissa H Roberts, MS, Senior Research Associate, LCF Research, Albuquerque, NM, USA; Shital Kamble, PhD, Duke Clinical Research Institute, Duke University, Durham, NC, USA; Dennis W. Raisch, PhD, Professor, University of New Mexico, College of Pharmacy, Albuquerque, NM, USA

Introduction

As a response to the withdrawal of high prole drugs over the last few years such as, VioXX [1], Seldane [2], Rezulin [3], Propulsid [4], Baycol [5] and Trasylol [6], the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have changed emphasis from the reactive collection of safety data to a more proactive risk management approach. Increased public scrutiny has also been driving the focus on drug safety surveillance, increasing the demand for more rened pharmacovigilance tools. Both agencies independently have implemented proactive approaches for drug safety surveillance which have reframed the traditional business model of the pharmaceutical industry. The purpose of this document is to describe the current characteristics of the FDA and EMA regulatory guidelines as they have been implemented and to compare their respective approaches.

The FDA Approach

The FDA identies risk management as an iterative process designed to optimize the benet-risk balance for regulated medicines throughout the product life cycle [7]. In March 2005, three guidance documents were issued which dened the formal basis of risk management. These were: Premarketing Risk Assessment [8], Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment [9] and the Development and Use of Risk Minimization Action Plans (RiskMAPs) [10]. These three documents became the building blocks for the more recent Risk Evaluation and Mitigation Strategies (REMS) [11]. The FDA Premarketing Risk Assessment Guidance aims at improving the adequacy of clinical trials for characterizing a products safety prole.

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The focus is on the generation, acquisition, analysis and presentation of premarketing safety data and the document contains a comprehensive set of recommendations for conducting clinical studies. The Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment Guidance denes pharmacovigilance as, all observational post-approval scientic and data gathering activities relating to the detection, assessment and understanding of adverse events with the goals of identifying and preventing these events to the extent possible. It contains recommendations for reporting and analytical practices to monitor safety concerns and risk associated with medical products. The guidance also recognizes the heterogeneous nature of benet and risk assessment stating that, because different products pose different benet risk considerations including seriousness of the disease, the nature and frequency of the safety signal, it is impossible to delineate a universal set of criteria to identify the point at which a pharmacoepidemiologic safety study should be initiated. The RiskMAP was dened as a strategic safety program designed to minimize known risks of a product while preserving its benets. It described how industry could address specic risk-related goals and objectives, suggesting various tools to minimize the risks of drug and biological products. The FDA recommended that a plan should target at the achievement of particular health outcomes related to known safety risks and be stated in absolute terms. For example patients prescribed drug X should not also be prescribed drug Y. The FDA also recognized that a variety of tools could be used to minimize risk, including: targeted education and outreach, reminder systems and performance based systems. Enacted in March 2008, the Food and Drug Administration Amendments Act of 2007 (FDAAA) [11] provides the FDA with authority to request a REMS at any point during a products life cycle. The REMS requirement which effectively replaces the RiskMAP applies to all new drug applications (NDAs), abbreviated new drug applications (ANDAs), and biologics license applications (BLAs). Certain products approved prior to March 2008, and those with elements to assure safe use, were deemed to have an approved REMS but were also required to submit a proposed REMS within 180 days of the FDAAA. Currently there are no set rules or direct guidance for when the FDA might impose a REMS, however, considerations that drive their decision include: the estimated size of the patient population; the seriousness of a disease or condition; the expected benet of the intervention; the anticipated duration of treatment; the seriousness of known or potential adverse events; and whether the drug is a new chemical entity. Other considerations after approval may include new evidence that REMS requirements are needed to ensure that the benets of the drug outweigh its risks. Where required, the REMS is intended to manage known or potentially serious risks and the REMS elements vary according to the severity of identied risks, the population likely to be exposed, and other factors. The REMS guidance provides a general framework for mandated post marketing safety activities and incorporates many of the principles in the original RiskMAP guidance [12]. The requirements may include the provision of a medication guide, a patient package insert, a communication plan or other Elements to Assure Safe Use (ETASU). ETASUs may include such provisions as dispensing only by pharmacies or practitioners in health care settings that are specially certied, the product only being dispensed where there is evidence of safeuse conditions, or monitoring of patients either individually or by enrolment in a registry. Provision must also be made for monitoring the implementation of ETASU requirements. Evaluation of each REMS is conducted by the FDAs Drug Safety and Risk Management Advisory Committee comprised of various stakeholders including patients, physicians, pharmacists and other health care professionals who provide input on implementation requirements and management strategy. After approval, timings for routine assessment of the program are 18 months, 3 years

and 7 years. If considered appropriate the FDA may stipulate shorter or longer intervals between assessments and can remove the need for assessments after year 3 if serious risks have been adequately identied, assessed and managed. With the introduction of REMS requirements, the FDA also issued a number of guidance documents relating to specic safety issues which include: drug-induced liver injury [13], a recommended approach for communicating important drug safety information to the public [14], pharmacovigilance planning at the time of license application [15] and quality risk management to provide regulators and industry with principles and tools for risk management as a basis for consistent risk-based decisions throughout a products lifecycle [16]. More recent guidance [17] is focused on detailing the circumstances and type of post-marketing studies and clinical trials that may be required for safety evaluation and other agreed upon post marketing commitments.

The EMA Approach

Within the European Union (EU), the focus has also been on a proactive approach in ensuring patient safety, with continuing efforts to improve the spontaneous reporting scheme. In 2005, legislation formalised the introduction of risk management plans [18] and subsequently the European Medicines Agency (EMA) issued guidelines on risk management systems, a template for a Risk Management Plan (RMP), and new regulations governing pharmacovigilance [19]. An RMP is required when routine pharmacovigilance practice for medications is considered to be insufcient. Products containing a new active substance, or for which there is a signicant change in indication or for which serious or potentially serious safety risks have been previously identied, generally fall into this category. An RMP is also required for biological medicinal products and generic/hybrid medicinal products, for which a safety concern requiring additional risk minimisation activities has been identied [20]. The process comprises a Safety Specication with a Pharmacovigilance Plan (Part I) and a Risk Minimisation Plan (Part II). Part I is intended to enable determination of whether routine post authorisation pharmacovigilance will be sufcient or whether there is a need for additional pharmacovigilance activities. It requires a summary of important identied and signicant potential risks of a medicinal product, information on populations potentially at risk together with any outstanding safety questions which warrant further investigation. Part II requires details of any additional pharmacovigilance or risk minimisation activities planned. No precise guidance is given on which activities are to be used in any given situation as each safety concern has to be considered on a case-by-case basis. The guidance does, however, recommend early and full consultation with appropriate experts. Accurate and timely communication of emerging data on risk is considered an essential part of pharmacovigilance with risk education, risk management and any risk minimization activities being essential components. The Summary of Product Characteristics and Patient Information Leaets are the prime vehicles for communicating any potential risks to prescribers and patients. Once the overall RMP has been approved, updated documents including any reported adverse event signals and safety evaluations should be submitted along with the periodic safety update report (PSUR). In the recent EMA draft, The European Medicines Agency Road Map to 2015 [21], a key strategic area identied for optimization is the safe use of medicines. Plans include revisions to the overall risk management concept and enhancements to current pharmacovigilance activities including the on-going strengthening of post authorisation monitoring. In support of this EMA strategy, the European Network of Centres of Pharmacoepidemiology and Pharmacovigilance (ENCePP), set up in 2006, was charged with conducting independent multi-centre post-authorisation studies focused on investigating safety and a lack of efcacy [22]. The Road Map to 2015 >
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also set out several priority challenges, including the development of tools for the anticipation of potential safety issues and the appropriateness of the current legal/regulatory framework with regard to benet/risk evaluation. The EMA indicates that although the risk management plans are increasing the knowledge of a medicine in the post-authorization phase, there is also merit in systematically gaining information on the benets of a medicinal product throughout its lifecycle. Evidence of evolution in the EMA approach can be seen in the recently revised Regulations [23] and Directives [24] effective from July 2012 which is aimed at improving routine pharmacovigilance activities, strengthening the EudraVigilance system and harmonizing access across member states.

implemented through the ETASU plan. Given the range of health care systems, varying medical practice and diversity of cultures among the 27 EU Member States and 3 EE/EA countries that EMA oversees, implementing a standard approach to monitoring and measurement is currently both practically and politically challenging. Therefore, the EMA relies principally on routine adverse event reporting and regular PSUR submission to detect risk experienced in clinical practice. Like the FDA it also places emphasis on additional data collection in the form of prospective studies, such as Registries, to further characterize known or potential risks and to ll specic safety information gaps. One other dimension to consider is that while the EMA has an overarching role within Europe, national agencies may still take independent action. One example is the case of pioglitazone, where recently available ve year results indicated a possible increased risk of bladder cancer in some patients. Both the FDA and EMA are currently reviewing the risks and benets pending any decision on the marketing status of the product; however, the French Medicines Agency (Afssaps) has already suspended its use pending the review of available evidence. A summary of conceptually similar FDA REMs and EMA RMP elements are detailed in Table 1, while components not shared by the two agencies are shown in Table 2. Table 1. Conceptually similar components between Food and Drug Administrations (FDA) Risk Evaluation and Mitigation Strategies (REMS) and European Medicines Agency (EMA) Risk Management Plans (RMPs)
FDA REMS EMA RMPs Medication guides Patient information sheet Container labels Provider communication plan Provider information sheet Highlighted information for prescribers Training of healthcare professionals Monitoring of patients receiving medication Prescriber and patient database Post marketing studies Registry Patient alert cards Patient information leaet Summary of Product Characteristic (SPC) contraindications SPC special warnings and precautions for use Summary of Product Characteristic (SPC) contraindications Educational programmes Specic adverse event and pharmacovigilance surveillance reporting requirements Prospective observational studies Additional trial and study data Specic adverse event and pharmacovigilance surveillance reporting requirements Registry

A Comparison of Approaches

The current sets of FDA and EMA guidance are driven by similar objectives for the identication, monitoring and minimization of risk to patient safety. As a result, they frequently lead to the generation of similar data needs. In todays global market environment such similar data requirements facilitate the exchange of information between the regulators. Although the central concept for both agencies is assessing risk and determining if it is acceptable, none of the current guidelines directly dene risk acceptability. Implementation of REMS and RMP requirements initiated new risk management approaches for pharmacovigilance. When serious safety concerns are identied, they must be rigorously monitored and action taken to reduce risk to patients. Modied standards of approval, new label models, patient inserts, special advertising and mandatory registry monitoring have become established risk minimization tools. The authors had not expected to nd signicant differences in the approaches to risk management between the FDA and the EMA and a detailed comparison of respective guidance documents suggests similarity in overall objectives with respect to the identication, monitoring and minimization of risk. Similarly, both Agencies allow exibility in the determination of product specic actions required, recognizing the dependency on differing potential concerns. From an enforcement perspective, both agencies have the power to assure that manufacturers adequately implement approved REMS/RMPs. Differences in the timing of the approval or revisions to REMS/RMPs for the same product are also known to occur; however, these are usually driven by the timing of entry into the different markets and the new information that becomes available as a result. There are cases, however, where the two Agencies have made different decisions in response to the safety issues identied in currently marketed products. For example, in December 2010 EMA suspended Avandia, Avandamet and Avaglim on the basis of data suggesting elevated risk of heart attacks in patients treated with rosiglitzone. The FDA, however, decided only to restrict access and the REMS was modied accordingly in May 2011. There are differences in emphasis for the communication of risk to patients and physicians. In the EU, the Summary of Product Characteristics is the key communication to physicians, including data on treatment effects, serious adverse effects, contraindications and special warnings. Communication to the patient is principally through the Patient Information Leaet provided as a package insert with every prescription, supplemented with advice from the physician at the time of prescribing. In the United States, the Medication Guide represents the basic vehicle for communicating information on medicinal risks to patients. A communication plan for ensuring that risks are fully communicated to health care professionals is not always required. There are also differences in monitoring implementation of risk minimization actions and the reporting time requirements which are generally related to geographic and logistic factors. Where there are known safety concerns, in its single market, the FDA requires monitoring and measurement to be

Table 2. Requirements not shared between Food and Drug Administrations (FDA) Risk Evaluation and Mitigation Strategies (REMS) and European Medicines Agency (EMA) Risk Management Plans (RMPs)
FDA REMS EMA RMPs Monitoring of patients receiving medication Specication of distribution or dispensing locations Monitoring of distribution Patient or physician survey to evaluate understanding of risk REMS print advertisement Audit of communication plan Audit of pharmacies SPC undesirable effects Development of diagnostic tests for adverse event

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Although neither agency currently provides specic guidance for risk versus benet assessment [25], the need for a more consistent, structured yet exible approach by the Regulator to the evaluation of risks versus benets is being discussed by both European and United States constituents with ongoing initiatives to identify acceptable methodologies [26,27]. The EMA reection paper issued in 2008 [28] was followed by a benet risk methodology project aimed at providing a more consistent and transparent approach for evaluating the risks and benets of medicines. The FDA is also working towards developing a framework for a more structured approach to risk benet assessment [29]. In summary, both FDA REMS and EMA RMPs currently provide broadly comparable comprehensive post approval guidance for the identication, monitoring and minimization of risk to patient safety with some differences in respective implementation toolkits. There is also an increasing tendency towards collaborative efforts between the two regulatory agencies in approaches to monitoring and minimizing risk for patients. IC

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WEB CONNECTIONS
The US Department of Health and Human Services (HHS) (http://www.hhs.gov/) encourages and facilitates the collection of national health and other data. The HHS is comprised of 11 operating divisions which are responsible for a wide variety of tasks and services, including research. HHS and the operating divisions publish critical disease and/or therapeutic area data. Given the variety of data, HHS has developed a directory of HHS data resources. The directory was designed to capture data resources that are of interest to a wide variety of audiences. The directory is available on HHSs home page on the Internet at: http://aspe.hhs.gov/datacncl/datadir. Do you know of any websites that you would like to share with the ISPOR community? If so, contact Bonnie M. Korenblat Donato, PhD, at: bonnie.donato@bms.com. September/October 2011 ISPOR CONNECTIONS 13