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; Jeff 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


As a response to the withdrawal of high profile 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 refined 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 identifies risk management as an iterative process designed to optimize the benefit-risk balance for regulated medicines throughout the product life cycle [7]. In March 2005, three guidance documents were issued which defined 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 product’s safety profile.

10 September/October 2011 ISPOR CONNECTIONS

acquisition. 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 identified. The Summary of Product Characteristics and Patient Information Leaflets are the prime vehicles for communicating any potential risks to prescribers and patients. The process comprises a Safety Specification with a Pharmacovigilance Plan (Part I) and a Risk Minimisation Plan (Part II). Evaluation of each REMS is conducted by the FDA’s Drug Safety and Risk Management Advisory Committee comprised of various stakeholders including patients. 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 product’s lifecycle [16]. An RMP is required when routine pharmacovigilance practice for medications is considered to be insufficient. including: targeted education and outreach. In 2005. suggesting various tools to minimize the risks of drug and biological products. or for which there is a significant change in indication or for which serious or potentially serious safety risks have been previously identified. pharmacists and other health care professionals who provide input on implementation requirements and management strategy. and other factors. Currently there are no set rules or direct guidance for when the FDA might impose a REMS. The REMS requirement which effectively replaces the RiskMAP applies to all new drug applications (NDAs). the seriousness of a disease or condition. 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. with continuing efforts to improve the spontaneous reporting scheme.” It contains recommendations for reporting and analytical practices to monitor safety concerns and risk associated with medical products. 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 product’s life cycle. Once the overall RMP has been approved. considerations that drive their decision include: the estimated size of the patient population. a key strategic area identified for optimization is the safe use of medicines. the nature and frequency of the safety signal. analysis and presentation of premarketing safety data and the document contains a comprehensive set of recommendations for conducting clinical studies. the European Network of Centres of Pharmacoepidemiology and Pharmacovigilance (ENCePP). set up in 2006. ‘The European Medicines Agency Road Map to 2015’ [21]. timings for routine assessment of the program are 18 months. a template for a Risk Management Plan (RMP). or monitoring of patients either individually or by enrolment in a registry. The EMA Approach Within the European Union (EU). for which a safety concern requiring additional risk minimisation activities has been identified [20]. It requires a summary of important identified and significant potential risks of a medicinal product. An RMP is also required for biological medicinal products and generic/hybrid medicinal products. the anticipated duration of treatment. the population likely to be exposed. physicians. 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 RiskMAP was defined as a strategic safety program designed to minimize known risks of a product while preserving its benefits. Provision must also be made for monitoring the implementation of ETASU requirements. and new regulations governing pharmacovigilance [19]. The FDA also recognized that a variety of tools could be used to minimize risk. Certain products approved prior to March 2008. ETASUs may include such provisions as dispensing only by pharmacies or practitioners in health care settings that are specially certified. a recommended approach for communicating important drug safety information to the public [14]. For example ‘patients prescribed drug X should not also be prescribed drug Y’. were deemed to have an approved REMS but were also required to submit a proposed REMS within 180 days of the FDAAA. The Road Map to 2015 > September/October 2011 ISPOR CONNECTIONS 11 . In support of this EMA strategy. Accurate and timely communication of emerging data on risk is considered an essential part of pharmacovigilance with risk education. Plans include revisions to the overall risk management concept and enhancements to current pharmacovigilance activities including the on-going strengthening of post authorisation monitoring. the product only being dispensed where there is evidence of safeuse conditions. Part II requires details of any additional pharmacovigilance or risk minimisation activities planned. It described how industry could address specific risk-related goals and objectives. The Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment Guidance defines pharmacovigilance as. information on populations potentially at risk together with any outstanding safety questions which warrant further investigation. and biologics license applications (BLAs). legislation formalised the introduction of risk management plans [18] and subsequently the European Medicines Agency (EMA) issued guidelines on risk management systems.The focus is on the generation. the expected benefit of the intervention. a patient package insert. “because different products pose different benefit risk considerations including seriousness of the disease. updated documents including any reported adverse event signals and safety evaluations should be submitted along with the periodic safety update report (PSUR). recommend early and full consultation with appropriate experts. however. it is impossible to delineate a universal set of criteria to identify the point at which a pharmacoepidemiologic safety study should be initiated. and those with elements to assure safe use. a communication plan or other Elements to Assure Safe Use (ETASU). assessed and managed. Enacted in March 2008. Part I is intended to enable determination of whether routine post authorisation pharmacovigilance will be sufficient or whether there is a need for additional pharmacovigilance activities. “all observational post-approval scientific and data gathering activities relating to the detection. With the introduction of REMS requirements. the focus has also been on a proactive approach in ensuring patient safety. After approval. The guidance also recognizes the heterogeneous nature of benefit and risk assessment stating that. The guidance does. risk management and any risk minimization activities being essential components. reminder systems and performance based systems. assessment and understanding of adverse events with the goals of identifying and preventing these events to the extent possible. 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. In the recent EMA draft. Other considerations after approval may include new evidence that REMS requirements are needed to ensure that the benefits of the drug outweigh its risks. Products containing a new active substance. 3 years and 7 years. The requirements may include the provision of a medication guide. generally fall into this category. abbreviated new drug applications (ANDAs). the REMS is intended to manage known or potentially serious risks and the REMS’ elements vary according to the severity of identified risks. 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. was charged with conducting independent multi-centre post-authorisation studies focused on investigating safety and a lack of efficacy [22]. the FDA also issued a number of guidance documents relating to specific safety issues which include: drug-induced liver injury [13]. however. the seriousness of known or potential adverse events. and whether the drug is a new chemical entity. Where required.

where the two Agencies have made different decisions in response to the safety issues identified in currently marketed products. they must be rigorously monitored and action taken to reduce risk to patients. to further characterize known or potential risks and to fill specific safety information gaps. however. Communication to the patient is principally through the Patient Information Leaflet provided as a package insert with every prescription. serious adverse effects. varying medical practice and diversity of cultures among the 27 EU Member States and 3 EE/EA countries that EMA oversees.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 benefit/risk evaluation. One example is the case of pioglitazone. in December 2010 EMA suspended Avandia®. implementing a standard approach to monitoring and measurement is currently both practically and politically challenging. A summary of conceptually similar FDA REMs and EMA RMP elements are detailed in Table 1. there is also merit in systematically gaining information on the benefits of a medicinal product throughout its lifecycle. For example. As a result. both Agencies allow flexibility in the determination of product specific actions required. Although the central concept for both agencies is assessing risk and determining if it is acceptable. decided only to restrict access and the REMS was modified accordingly in May 2011. while components not shared by the two agencies are shown in Table 2. both agencies have the power to assure that manufacturers adequately implement approved REMS/RMPs. There are cases. contraindications and special warnings. however. supplemented with advice from the physician at the time of prescribing. new label models. the Medication Guide represents the basic vehicle for communicating information on medicinal risks to patients. none of the current guidelines directly define risk acceptability. Therefore. 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. A communication plan for ensuring that risks are fully communicated to health care professionals is not always required. the FDA requires monitoring and measurement to be Table 2. Table 1. recognizing the dependency on differing potential concerns. From an enforcement perspective. In today’s global market environment such similar data requirements facilitate the exchange of information between the regulators. national agencies may still take independent action. In the EU. monitoring and minimization of risk. where recently available five year results indicated a possible increased risk of bladder cancer in some patients. When serious safety concerns are identified. the EMA relies principally on routine adverse event reporting and regular PSUR submission to detect risk experienced in clinical practice. Avandamet® and Avaglim® on the basis of data suggesting elevated risk of heart attacks in patients treated with rosiglitzone. One other dimension to consider is that while the EMA has an overarching role within Europe. There are differences in emphasis for the communication of risk to patients and physicians. including data on treatment effects. The authors had not expected to find significant 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 identification. however. The FDA. patient inserts. The EMA indicates that although the risk management plans are increasing the knowledge of a medicine in the post-authorization phase. Conceptually similar components between Food and Drug Administration’s (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 leaflet Summary of Product Characteristic (SPC) contraindications SPC special warnings and precautions for use Summary of Product Characteristic (SPC) contraindications Educational programmes Specific adverse event and pharmacovigilance surveillance reporting requirements Prospective observational studies Additional trial and study data Specific 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 identification. the French Medicines Agency (Afssaps) has already suspended its use pending the review of available evidence. Both the FDA and EMA are currently reviewing the risks and benefits pending any decision on the marketing status of the product. Similarly. 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. monitoring and minimization of risk to patient safety. Differences in the timing of the approval or revisions to REMS/RMPs for the same product are also known to occur. strengthening the EudraVigilance system and harmonizing access across member states. in its single market. implemented through the ETASU plan. however. Given the range of health care systems. such as Registries. In the United States. Like the FDA it also places emphasis on additional data collection in the form of prospective studies. the Summary of Product Characteristics is the key communication to physicians. these are usually driven by the timing of entry into the different markets and the new information that becomes available as a result. they frequently lead to the generation of similar data needs. special advertising and mandatory registry monitoring have become established risk minimization tools. Implementation of REMS and RMP requirements initiated new risk management approaches for pharmacovigilance. Requirements not shared between Food and Drug Administration’s (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 Specification 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 12 September/October 2011 ISPOR CONNECTIONS . Modified standards of approval. Where there are known safety concerns.

FDA Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment (Pharmacovigilance Guidance) March 2005. 19. Bian B. 6.pdf. Mulchrone B. [Accessed December 10. Cone M. Available from: http:// www. Federal Register.gov/datacncl/datadir.pdf. 25.com/elements/media/ inthenews/reviewing-existing-risk-management-plans. [Accessed May 5. Bull J. Available from: http:// www. 14. FDA Guidance for Industry: Development and Use of Risk Minimization Action Plans (RiskMAP Guidance). Propulsid (cisapride) April 2000.htm.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FoodandDrugAdministrationAmendmentsActof2007/default. 2011].eu/pdfs/general/direct/ EMAwp/004901en. 21. Guidance for Industry Postmarketing Studies and Clinical Trials — Implementation of Section 505(o)(3) of the Federal Food. [Accessed May 5. April 2005. Guidance for Industry Q9 Quality Risk Management.pdf. Appendix G . 2011]. structured yet flexible approach by the Regulator to the evaluation of risks versus benefits is being discussed by both European and United States constituents with ongoing initiatives to identify acceptable methodologies [26. MedWatch.fda. Walker S. Available from: http://eur-lex. 29.europa.Although neither agency currently provides specific guidance for risk versus benefit assessment [25]. Drug Alcohol Depend 2009. [Accessed May 5.eu/docs/en_GB/document_ library/Regulatory_and_procedural_guideline/2010/01/WC500069634. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER). Available from: http://www. Value Health 2010. June 2006.htm.encepp. Wai K. Garrison LP Jr. Available from: http://ec. 13. Assessing A Structured. 2011]. EMA Work programme for the European Agency for the evaluation of Medicines.pdf.europa.fda. Washington D. the need for a more consistent. 15.com.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM172001.htm. PhD.pdf.do?uri=OJ:L:2010:348:0074:0099:EN:PDF. Department of Health and Human Services. No. 2010]. Available from: http://www.fda.gov/downloads/ RegulatoryInformation/Guidances/UCM126830.europa. 11. Using a health outcomes model to assess drug safety and benefits together could promote consistency and comparability across products and diseases. 7.pdf.ema. Guidelines on Pharmacovigilance for Medicinal Products for Human Use in: The rules Governing Medicinal Products in the European Union. at: bonnie. Chapter 43 in Pharmacovigilance (2nd ed. Directive 2010/84/EU 15 Dec 2010.emea. 26 January 2010 EMA/299895/2009. RAJ Pharma 2010. [Accessed June 15. monitoring and minimization of risk to patient safety with some differences in respective implementation toolkits.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ ucm175000.fda.donato@bms. [Accessed July 23. 2010]. 2.fda. and Cosmetic Act.hhs.gov/OHRMS/DOCKETS/98fr/03-493. including research. contact Bonnie M. [Accessed December 15. The HHS is comprised of 11 operating divisions which are responsible for a wide variety of tasks and services. 2003 / Notices.uk/home/groups/es-policy/ documents/websiteresources/con028325. The European Medicines Agency Road Map to 2015: The Agency’s Contribution to Science.do?uri=OJ:L:2010:348:0001:0016:EN:PDF. Eds. FDA US Food and Drug Administration. Committee for medicinal products for human use (CHMP). [Accessed December 10. September/October 2011 ISPOR CONNECTIONS 13 . MD: New York Academy of Sciences. 2010].EMA. Medicines. [Accessed December 10. U. Andrews E. Available from: http://www. The directory was designed to capture data resources that are of interest to a wide variety of audiences. both FDA REMS and EMA RMPs currently provide broadly comparable comprehensive post approval guidance for the identification. 9. [Accessed December 15. Doyle J. A review of current risk-benefit assessments for drug safety.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/ucm073107. WEB CONNECTIONS The US Department of Health and Human Services (HHS) (http://www. 2010]. Jenkins J.eu/#. 2011].gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090. 2010]. London.europa. European Commission 2007. The EMA reflection paper issued in 2008 [28] was followed by a benefit risk methodology project aimed at providing a more consistent and transparent approach for evaluating the risks and benefits of medicines. [Accessed December 15.fda. [Accessed December 15. Vol.. The value of reviewing existing EU risk management plans. 2011]. Available from: http://www.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ ucm172268. Do you know of any websites that you would like to share with the ISPOR community? If so. 8. Available from: http://www. Health.mhra. Guidance for Industry E2E Pharmacovigilance Planning.105(Suppl. [Accessed June 15. US activities in risk management of pharmaceutical products. Available from: http://www.jsp. FDA Guidance for Industry: Premarketing Risk Assessment (Premarketing Guidance). Food and Drug Administration Amendments Act (FDAAA) of 2007.Market Withdrawals. Guidance Drug Safety Information – FDA’s Communication to the Public. A United States Regulator’s Perspective on Risk-Benefit Considerations.pdf. In summary.com/rofecoxib/vioxx/consumer/index. EMEA/ CHMP/15404/2007. 2010.eu/LexUriServ/ LexUriServ. 28. Risk Management of drug products and the US FDA: Evolution and context. 23. Regulation (EU) No 1235/2010 15 Dec 2010. 2010].gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm152878.pdf. 5.gov. 7 / Friday. 19 March 2008. 3. Available from: http://www. Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation. Available from: http://www. March 2005. FDA Safety Information and adverse event reporting programme. Given the variety of data. Rockville. Available from: http://eur-lex.htm. [Accessed June 15. 2011].vioxx. Doc. EMA/ MB/049/0-EN-Final 2002. Volume 9a. FDA US Food and Drug Administration.eu/pdfs/general/direct/ directory/29989509en. 26. 2010]. There is also an increasing tendency towards collaborative efforts between the two regulatory agencies in approaches to monitoring and minimizing risk for patients. [Accessed December 10.79-84. 2010]. Draft for Public Consultation.pdf. 2007. FDA US Food and Drug Administration.13:657-66. [Accessed December 15.pdf. Baycol August 2001. Guo JJ. The FDA is also working towards developing a framework for a more structured approach to risk benefit assessment [29]. 1):S9-S13. 4. Towse A.htm. [Accessed December 10. HHS and the operating divisions publish critical disease and/or therapeutic area data. 2011]. 2011]. Merck and Company. MedWatch.htm.quintiles. letter concerning withdrawal of Vioxx. Wiley. fda. Available from: http://www.. fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ ucm073511.). The directory is available on HHS’s home page on the Internet at: http://aspe. Korenblat Donato. [Accessed June 15.fda.fda. Raisch D. USA 13-14 June 2005.hhs. 24. Philips L. FDA Safety Information and adverse event reporting programme. Available from: http://www. Drug. Reflection paper on benefitrisk assessment methods in the context of the evaluation of marketing authorisation applications of products for human use. 2010]. Bresnahan BW. Available from: http:// www.fda. 2010]. Mann R. 27.S. 20. [Accessed December 10.27]. 16. 18. Available from: http://www. July 2009. 17.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatients andProviders/ucm106274. MedWatch.pdf.C. Pandey S. FDA Safety Information and adverse event reporting programme. Key C. Report of the Workshop organised by the CMR International Institute for Regulatory Science at the Georgetown Inn. Available from: http://www. IC References 1.fda. [Accessed December 10.26:684-95. 2010]. Available from: http://www. 68. Available from: http://www. [Accessed December 10. Risk . [Accessed June 15. Health Affairs 2007.gov/downloads/RegulatoryInformation/ Guidances/UCM126958. January 10. [Accessed December 10. Benefit-Risk Assessment Model for Medicines: Developing a Structured Approach to Decision Making. March 2007. 22. European Network of centres for pharmacoepidemiology and pharmacovigilance.europa. Leiderman DB. HHS has developed a directory of HHS data resources.europa. Available from: http://www. Available from: http://www.pdf. Available from: http://www. March 2005. eu/LexUriServ/LexUriServ.fda. 2011]. [Accessed December 2010]. 2010]. 10. FDA US Food and Drug Administration.eu/health/documents/eudralex/vol-9/ index_en. 2010]. 2010]. Quantitative Health Outcomes Approach To Drug Risk-Benefit Analysis.gov/) encourages and facilitates the collection of national health and other data.gov/downloads/Drugs/GuidanceComplianceRegulatory Information/Guidances/ucm072281. FDA US Food and Drug Administration. Ref. 12. Available from: http://www.pdf. Traysol (aprotinin injection) Nov 2007.Benefit Considerations in Drug Regulatory Decision-Making.pdf. April 2011 Drug Safety.gov/downloads/RegulatoryInformation/Guidances/ UCM126834. Shady Grove Conference Center.

Sign up to vote on this title
UsefulNot useful