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Another aspect that would need clarification if evidence is to be shared is the difference in validity of the data that are required by the different assessors. Whereas regulators prefer the internal validity provided by the RCT, payers are more interested in the external validity obtained from real-life clinical practice or observational studies. Though ideally all assessors prefer data obtained over the longest possible period of time, regulators are more accepting of shorter time horizons as evidenced in the duration of clinical trials. The payers are more interested in longer time horizons, for example, through the long-term follow-up of MS patients in the patient access scheme in the United Kingdom. It is unclear whether a requirement for RE assessment is likely to streamline this process. to provide more evidence on the comparative value of their new products, it is evident that the actual implementation requires more detailed discussions around process, methodology, timelines and tasks. IC Even if all these questions can be answered, many remain on matters of implementation and methodology, such as how RE will be implemented in practice and who would be responsible. Current thoughts are that the EMA may be given responsibility, however, this aspect still remains unclear. Even if such a requirement were implemented, it is possible that evidence on RE will not be required for all licensing decisions but could be reserved for cases where there is a clear comparator or a substantial innovation. As part of any procedure, in case RE assessment takes place, an appeals/complaints procedure will need to be established. This is a substantial undertaking. Further thoughts should be given as to how and to what extent data will be made publicly available. The RE assessment may include substantial commercial-in-confidence data which will not be suitable for publication, and so mechanisms will need to be put into place to ensure the confidentiality of these data, while still sharing results with the wide public. 3. Backhouse ME, Wonder M, Hornby E, et al. Early dialogue between the developers of new technologies and pricing and reimbursement agencies: a pilot study. Value Health 2011;14:608-15. References 1. European Medicines Agency. The European Medicines Agency Road Map to 2015: The Agency’s Contribution to Science, Medicines, Health. 2010. Available from: http:// www.ema.europa.eu/docs/en_GB/document_library/Report/2010/01/WC500067952. pdf. [Accessed August 10, 2011]. 2. Eichler HG, Bloechl-Daum B, Abadie E, et al. Relative efficacy of drugs: an emerging issue between regulatory agencies and third-party payers. Nat Rev Drug Discov 2010;9:277-91. 4. Jonsson B. Relative effectiveness and the European pharmaceutical market. Eur.J Health Econ 2011;12:97-102. 5. Hoaglin DC, Hawkins N, Jansen JP, et al. Conducting indirect-treatment-comparison and network-meta-analysis studies: Report of the ISPOR task force on indirect treatment comparisons good research practices-Part 2. Value Health 2011;14:429-37. 6. Jansen jp, fleurence r, devine b, et al. interpreting indirect treatment comparisons and network meta-analysis for health-care decision making: Report of the ISPOR task force on indirect treatment comparisons good research practices: Part 1. Value Health 2011;14:417-28. 7. European Commission - High Level Pharmaceutical Forum. Core principles on relative effectiveness. Available from: http://ec.europa.eu/pharmaforum/docs/rea_principles_ en.pdf. [Accessed September 18, 2010]. In conclusion, though the reasoning behind the need for RE assessments is clear, and even though this type of assessment could result in important time savings and manufacturers should, regardless of the requirements, aim 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 Introduction 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. 10 September/October 2011 ISPOR CONNECTIONS 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. 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 defines pharmacovigilance as, “all observational post-approval scientific 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 benefit and risk assessment stating that, “because different products pose different benefit 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 defined as a strategic safety program designed to minimize known risks of a product while preserving its benefits. It described how industry could address specific 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 product’s 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 benefit 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 benefits 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 identified 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 certified, 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 FDA’s 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 identified, assessed and managed. With the introduction of REMS requirements, the FDA also issued a number of guidance documents relating to specific 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 product’s 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 insufficient. Products containing a new active substance, or for which there is a significant change in indication or for which serious or potentially serious safety risks have been previously identified, 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 identified [20]. The process comprises a Safety Specification 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 sufficient or whether there is a need for additional pharmacovigilance activities. It requires a summary of important identified and significant 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 Leaflets 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 identified 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 efficacy [22]. The Road Map to 2015 > September/October 2011 ISPOR CONNECTIONS 11 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. 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 benefits 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. A Comparison of Approaches The current sets of FDA and EMA guidance are driven by similar objectives for the identification, monitoring and minimization of risk to patient safety. As a result, they frequently lead to the generation of similar data needs. In today’s 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 define risk acceptability. Implementation of REMS and RMP requirements initiated new risk management approaches for pharmacovigilance. When serious safety concerns are identified, they must be rigorously monitored and action taken to reduce risk to patients. Modified 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 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, monitoring and minimization of risk. Similarly, both Agencies allow flexibility in the determination of product specific 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 identified 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 modified 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 Leaflet 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 12 September/October 2011 ISPOR CONNECTIONS 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 fill specific 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 five year results indicated a possible increased risk of bladder cancer in some patients. Both the FDA and EMA are currently reviewing the risks and benefits 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 Administration’s (FDA) Risk Evaluation and Mitigation Strategies (REMS) and European Medicines Agency (EMA) Risk Management Plans (RMPs) FDA – REMSEMA – RMPs Medication guides Patient alert cards Patient information sheet Patient information leaflet Container labels Summary of Product Characteristic (SPC) contraindications SPC special warnings and precautions for use Provider communication plan Provider information sheet Highlighted information for prescribers Training of healthcare professionals Summary of Product Characteristic (SPC) contraindications Educational programmes Monitoring of patients receiving medication Specific adverse event and pharmacovigilance surveillance reporting requirements Prospective observational studies Prescriber and patient database Additional trial and study data Post marketing studies Registry Specific adverse event and pharmacovigilance surveillance reporting requirements Registry Table 2. 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 – REMSEMA – 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 Although neither agency currently provides specific guidance for risk versus benefit assessment [25], the need for a more consistent, 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 [26,27]. 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. The FDA is also working towards developing a framework for a more structured approach to risk benefit assessment [29]. In summary, both FDA REMS and EMA RMPs currently provide broadly comparable comprehensive post approval guidance for the identification, 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 References 1. Merck and Company, letter concerning withdrawal of Vioxx. Available from: http:// www.vioxx.com/rofecoxib/vioxx/consumer/index.jsp. [Accessed December 10, 2010]. 2. FDA US Food and Drug Administration. Appendix G - Market Withdrawals. Available from: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatients andProviders/ucm106274.htm. [Accessed December 10, 2010]. 3. FDA US Food and Drug Administration. Department of Health and Human Services. Federal Register. Vol. 68, No. 7 / Friday, January 10, 2003 / Notices. Available from: http:// www.fda.gov/OHRMS/DOCKETS/98fr/03-493.pdf. [Accessed December 2010]. 4. FDA US Food and Drug Administration. MedWatch. FDA Safety Information and adverse event reporting programme. Propulsid (cisapride) April 2000. Available from: http://www. fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ ucm175000.htm. [Accessed December 10, 2010]. 5. FDA US Food and Drug Administration. MedWatch. FDA Safety Information and adverse event reporting programme. Baycol August 2001. Available from: http://www. fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ ucm172268.htm. [Accessed December 10, 2010]. 6. FDA US Food and Drug Administration. MedWatch. FDA Safety Information and adverse event reporting programme. Traysol (aprotinin injection) Nov 2007. Available from: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm152878.htm. [Accessed December 10, 2010]. 7. Bull J. US activities in risk management of pharmaceutical products. Chapter 43 in Pharmacovigilance (2nd ed.). Eds. Mann R, Andrews E. Wiley, 2007. 8. FDA Guidance for Industry: Premarketing Risk Assessment (Premarketing Guidance). March 2005. Available from: http://www.fda.gov/downloads/RegulatoryInformation/ Guidances/UCM126958.pdf. [Accessed June 15, 2011]. 9. FDA Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment (Pharmacovigilance Guidance) March 2005. Available from: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ UCM126834.pdf. [Accessed June 15, 2011]. 10.FDA Guidance for Industry: Development and Use of Risk Minimization Action Plans (RiskMAP Guidance). March 2005. Available from: http://www.fda.gov/downloads/ RegulatoryInformation/Guidances/UCM126830.pdf. [Accessed June 15, 2011]. 11.Food and Drug Administration Amendments Act (FDAAA) of 2007. Available from: http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FoodandDrugAdministrationAmendmentsActof2007/default.htm. [Accessed June 15, 2011]. 12.Leiderman DB. Risk Management of drug products and the US FDA: Evolution and context. Drug Alcohol Depend 2009;105(Suppl. 1):S9-S13. 13.Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation. July 2009. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf. [Accessed December 15, 2010]. 14.Guidance Drug Safety Information – FDA’s Communication to the Public. March 2007. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory Information/Guidances/ucm072281.pdf. [Accessed December 15, 2010]. 15.Guidance for Industry E2E Pharmacovigilance Planning. April 2005. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/ucm073107.pdf. [Accessed December 15, 2010]. 16.Guidance for Industry Q9 Quality Risk Management. June 2006. Available from: http:// www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ ucm073511.pdf. [Accessed December 10, 2010]. 17.Guidance for Industry Postmarketing Studies and Clinical Trials — Implementation of Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER). April 2011 Drug Safety. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM172001.pdf. [Accessed May 5, 2011]. 18.EMA Work programme for the European Agency for the evaluation of Medicines. EMA/ MB/049/0-EN-Final 2002. Available from: http://www.EMA.europa.eu/pdfs/general/direct/ EMAwp/004901en.pdf. [Accessed December 15, 2010]. 19.European Commission 2007. Volume 9a. Guidelines on Pharmacovigilance for Medicinal Products for Human Use in: The rules Governing Medicinal Products in the European Union. Available from: http://ec.europa.eu/health/documents/eudralex/vol-9/ index_en.htm. [Accessed June 15, 2011]. 20.Key C, Mulchrone B, Wai K. The value of reviewing existing EU risk management plans. RAJ Pharma 2010;79-84. Available from: http://www.quintiles.com/elements/media/ inthenews/reviewing-existing-risk-management-plans.pdf. [Accessed July 23, 2011]. 21.The European Medicines Agency Road Map to 2015: The Agency’s Contribution to Science, Medicines, Health. Draft for Public Consultation. 26 January 2010 EMA/299895/2009. Available from: http://www.ema.europa.eu/pdfs/general/direct/ directory/29989509en.pdf. [Accessed December 10, 2010]. 22.European Network of centres for pharmacoepidemiology and pharmacovigilance. Available from: http://www.encepp.eu/#. [Accessed December 15, 2010]. 23.Regulation (EU) No 1235/2010 15 Dec 2010. Available from: http://eur-lex.europa. eu/LexUriServ/LexUriServ.do?uri=OJ:L:2010:348:0001:0016:EN:PDF. [Accessed May 5, 2011]. 24.Directive 2010/84/EU 15 Dec 2010. Available from: http://eur-lex.europa.eu/LexUriServ/ LexUriServ.do?uri=OJ:L:2010:348:0074:0099:EN:PDF. [Accessed May 5, 2011]. 25.Guo JJ, Pandey S, Doyle J, Bian B, Raisch D. A review of current risk-benefit assessments for drug safety. Value Health 2010;13:657-66. 26.Walker S, Philips L, Cone M. Benefit-Risk Assessment Model for Medicines: Developing a Structured Approach to Decision Making. Report of the Workshop organised by the CMR International Institute for Regulatory Science at the Georgetown Inn, Washington D.C., USA 13-14 June 2005. Available from: http://www.mhra.gov.uk/home/groups/es-policy/ documents/websiteresources/con028325.pdf. [Accessed December 10, 2010]. 27.Garrison LP Jr., Towse A, Bresnahan BW. Assessing A Structured, Quantitative Health Outcomes Approach To Drug Risk-Benefit Analysis. Using a health outcomes model to assess drug safety and benefits together could promote consistency and comparability across products and diseases. Health Affairs 2007;26:684-95. 28.Committee for medicinal products for human use (CHMP). Reflection paper on benefitrisk assessment methods in the context of the evaluation of marketing authorisation applications of products for human use. London, 19 March 2008. Doc. Ref. EMEA/ CHMP/15404/2007. Available from: http://www.emea.europa.eu/docs/en_GB/document_ library/Regulatory_and_procedural_guideline/2010/01/WC500069634.pdf. [Accessed December 10, 2010]. 29.Jenkins J. A United States Regulator’s Perspective on Risk-Benefit Considerations. Risk - Benefit Considerations in Drug Regulatory Decision-Making. Shady Grove Conference Center, Rockville, MD: New York Academy of Sciences; 2010. 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 HHS’s 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: [email protected]. September/October 2011 ISPOR CONNECTIONS 13