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Risk Management in Pharmacovigilance
CHAPTER
RISK MANAGEMENT IN PHARMACOVIGILANCE
30 Rajinder K. Jalali
Sun Pharmaceutical Industries Ltd, Gurgaon, Haryana, India
Risk management in Pharmacovigilance is a global activity to safeguard health of patients. A medicinal product is authorized on the basis of results of preclinical and clinical studies. These studies are usually conducted on a small number of patients in controlled environments, e.g., restricted age, comorbidity, comedication, and excluding special populations such as elderly population, children, pregnant and lactating women. At the time of authorization, risk-benefit is judged to be positive. However, not all actual or potential risks have been identified at the time of authorization. Risk management is a set of activities performed for identification of risk, risk assessment, risk minimization or prevention, and risk communication [1,2]. Risk Management Plan (RMP) is developed in accordance with applicable regulations and guidelines. However, in absence of guidelines for a country, the plan is prepared in line with ICH E2E guideline on pharmacovigilance planning [3]. The FDA identifies risk management as an iterative process designed to optimize the benefit-risk balance for regulated products throughout the product lifecycle. In March 2005, the FDA issued three guidance documents that defined the formal basis of risk management. These were Premarketing Risk Assessment, Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment, and the Development and Use of Risk Minimization Action Plans (RiskMAPs). These three documents subsequently provided the building blocks for the more recent risk evaluation and mitigation strategies (REMS). The final content of a product’s REMS, however, reflects the unique mix of product attributes as well as the intended prescriber and patient populations [4]. The REMS program seeks to manage known or potential serious risks, and the content must have a timetable for submission of assessments. Additional components for a particular REMS program vary according to the severity of identified risks, the population likely to be exposed, and other factors. The EU RMP is an engagement of wider scope than the US REMS, and is binding on a larger set of medicines. The US REMS is compulsory only for some medicines, and can be limited to two years’ post product launch. The REMS concerns itself with communication of risk, with the prescriber information—the package insert (PI), being central to risk minimization. Components of a typical FDA REMS are a communication plan; patient selection; web-based materials and a medical scientific liaison; elements to assure safe use; an implementation system; a patient or physician survey and patient understanding of risk. The EU RMP is a more comprehensive, more extensive safety package that the sponsor is obligated to follow throughout the lifecycle of all new drugs or biologics [5]. Pharmaceutical Medicine and Translational Clinical Research. DOI: http://dx.doi.org/10.1016/B978-0-12-802103-3.00031-6 © 2018 Elsevier Inc. All rights reserved.
429
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CHAPTER 30 RISK MANAGEMENT IN PHARMACOVIGILANCE
European Union (EU) legislation necessitates that, when required, a description of the risk management system should be submitted in the form of an EU-RMP. Accordingly, risk management has the following stages: (1) identification and characterization of the safety profile of the medicinal product including what is known or not known (with emphasis on important identified and important potential risks and missing information) about the product and, importantly, which risks need to be further characterized or managed proactively (the “safety specification”); (2) planning of pharmacovigilance activities to characterize and quantify clinically relevant risks and to identify new adverse reactions and to increase the knowledge in general about the safety profile of the medicinal product (the “pharmacovigilance plan”), (3) planning and implementation of risk minimization measures and mitigation and assessment of the effectiveness of these activities (the “risk minimization plan”), and (4) document postapproval obligations that have been imposed as a condition of the marketing authorization [2]. All these activities together constitute Risk Management Plan (RMP), which is required to be submitted during the authorization of the drug. An updated RMP is required when there are significant changes to the safety profile of the drug. The overall aim of risk management is to ensure that the benefits of medicinal product outweigh the risks by a wide margin for the treatment of a particular indication both at individual level and for the target population as a whole. RMP is structured [2] with the following elements: • •
• • • • •
Part I: Product overview Part II: Safety specification • Module SI: Epidemiology of the indication(s) and target population • Module SII: Nonclinical part of safety specification • Module SIII: Clinical trial exposure • Module SIV: Populations not studied in the clinical trials • Module SV: Postauthorization experience • Module SVI: Additional requirements for the safety specification • Module SVII: Identified and potential risks • Module SVIII: Summary of the safety concerns Part III: Pharmacovigilance plan (including postauthorization safety studies) Part IV: Plans for postauthorization efficacy studies Part V: Risk minimization measures and evaluation of the effectiveness of the risk minimization activities Part VI: Summary of the risk management plan Part VII: Annexes
The RMP is part of the scientific dossier of a product and as such should be science-based and not promotional. The submitted RMP should follow the RMP template. The amount of information—particularly in RMP Part II—to be provided will depend on the type of medicinal product, its risks, and where it is in its lifecycle. RMP part I “Product(s) overview” is a complete overview of the product. This includes complete information on the active substance(s) and all related administrative information on RMP. RMP part II “Safety specification” consists of a synopsis of complete safety profile of the medicinal product and summarizes important identified risks (an untoward occurrence for which
RISK MANAGEMENT IN PHARMACOVIGILANCE
431
there is adequate evidence of an association with the medicinal product of interest), important potential risks (an untoward occurrence for which there is some basis for suspicion of an association with the medicinal product of interest but where the association has not been confirmed) and missing information, i.e., gaps in knowledge about a medicinal product, related to safety or use in particular patient populations, which could have clinical significance [2,6]. It also addresses populations potentially at risk and identifies the need for specific data collection to answer outstanding safety information that could have relevance to patient safety. The safety specifications facilitate understanding of the risk-benefit profile during postapproval period and construction of pharmacovigilance plan and basis of risk minimization activities. The safety specification consists of eight RMP modules of which RMP modules SI SV, SVII, and SVIII correspond to safety specification headings in ICH-E2E. RMP module SVI includes additional elements required to be submitted in the EU. For generic medicinal products the expectation is that the safety specification is the same as that of the reference product or of other generic products for which an RMP is in place. RMP summaries for most recently approved centrally authorized medicinal products (CAPs) are published on EMA website [7]. RMP part III “Pharmacovigilance plan”: The purpose of the pharmacovigilance plan is to discuss how the marketing authorization holder plans to identify and/or characterize the risks identified in the safety specification. It provides structured plan for: (1) the identification of new safety concerns; (2) further characterization of known safety concerns including elucidation of risk factors; (3) the investigation of whether a potential safety concern is real or not; and (4) how missing information will be sought [2]. In short, pharmacovigilance plan describes routine and additional pharmacovigilance activities and, thereof, action plans for each safety concern elucidated. Further, it specifies actions to be taken, in addition to procedures in place to detect safety signals, to address identified safety concerns. The pharmacovigilance plan focuses on the safety concerns summarized in RMP module SVIII of the safety specifications and should be proportionate to the benefits and risks of the product. The action plan for each safety concern is presented and justified according to the following structure: safety concern, objective of proposed actions, actions proposed, rationale for proposed actions, monitoring by the MAH for safety concerns and proposed actions, milestone for evaluation and reporting [6]. RMP part IV “Plans for postauthorization efficacy studies” includes a list of postauthorization efficacy studies (PAES) imposed as conditions of the marketing authorization (MA) or when included as specific obligations in the context of a conditional MA or a MA under exceptional circumstances. Not all medicines require postauthorization studies. However, there may be situations when efficacy of products may vary over time and longer-term efficacy data postauthorization is necessary. In addition, regulations on pediatric medicinal products [8] and advanced therapy medicinal products [9] require long-term efficacy as part of postauthorization surveillance for these types of medicinal products. RMP part V “Risk minimization measures (including evaluation of the effectiveness of risk minimization activities)” provides details of the risk minimization measures which will be taken to reduce the risks associated with respective safety concerns. Some safety concerns may be adequately addressed by the proposed actions in the pharmacovigilance plan, but for others the risk may be of a particular nature and seriousness so that risk minimization activities are required. It is
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CHAPTER 30 RISK MANAGEMENT IN PHARMACOVIGILANCE
possible that the risk minimization activities may be limited to ensuring that suitable warnings are included in the product information or by careful use of labeling and packaging, i.e., routine risk minimization activities. However, for some risks, routine risk minimization activities will not be sufficient and additional risk minimization activities will have to be performed. If these are required, they should be described in the risk minimization plan. Additional risk minimization methods include education training material or training programs for medical practitioners, pharmacists, and patients and controlled access programs, and other risk minimization measures [2,6,10]. Consideration must be given to the risk proportionality of the risk minimization activity proposed, the feasibility of implementing any additional risk minimization activity, whether the proposed measures are necessary for the safe and effective use of the product in all patients, and the possibility to adapt distribution modalities [6,10]. For each safety concern, the following information should be provided: (1) objective of the risk minimization activities; (2) routine risk minimization activities; (3) additional risk minimization activities (if any), individual objectives, and justification of why needed; (4) how the effectiveness of each risk minimization activity will be evaluated in terms of attainment of their stated objectives; (5) criteria for judging success; and (6) milestones for evaluation and reporting [2]. This helps to improve risk communication with healthcare professionals and patients and reduced harm caused by new drugs [11]. Evaluation of the effectiveness of risk minimization activities is required beyond the pharmacovigilance plans. Assessment is performed for each safety concern whether any risk minimization activities are needed. The success of risk minimization activities needs to be evaluated throughout the lifecycle of a product to ensure that the burden of adverse reactions is minimized and hence the overall benefit-risk balance is optimized. RMP part VI “Summary of the risk management plan” shall be made publicly available and shall include the key elements of the risk management plan. The audience of RMP summaries is very broad. To ensure that the summary can satisfy the different needs, it should be written and presented clearly, using a plain-language approach. The summary of the RMP part VI should be consistent with the information presented in RMP part II modules SVII, SVIII, and RMP parts III, IV, and V. The summary must include key elements of RMP with a specific focus on risk minimization activities. Regarding safety specification of the medicinal product, it should contain important information on potential and identified risks as well as missing information [2]. The summary of the RMP should be formatted as below: • • • •
• • • •
Overview of disease epidemiology Summary of treatment benefits Unknowns relating to treatment benefits Summary of safety concerns • Important identified risks • Important potential risks • Missing information Summary of risk minimization activities by safety concern Planned post authorization development plan Studies which are a condition of the marketing authorization Major changes to the risk management plan over time
REFERENCES
433
The information provided in each section should be brief and focused. RMP part VII provides for the “Annexes to the risk management plan.” Both REMS and RMPs provide positive guidance for identification, monitoring, and minimization of risk to patient safety. The importance of risk management cannot be over-emphasized and the regulatory burden is increasing, and appropriately so. It is in the interests of patients, industry, and agencies that the least harm and maximum benefit results from taking a medicine; risk strategies such as the US REMS and the EU RMP contribute to this. They also channel drug developers to give greater consideration to how patients can avoid some adverse reactions to drugs and achieve better tolerance, by paying attention to criteria such as contraindications, warnings, and precautions. The EU RMP is an engagement of wider scope, and is binding on a wider set of medicines than the US REMS [5].
REFERENCES [1] Dieck GS, Sharrar RG. Preparing for safety issues following drug approval: pre-approval risk management considerations. Ther Adv Drug Saf 2013;4:220 8. [2] Guidelines on good Pharmacovigilance practices (GVP). Module V Risk management systems (Rev 2). European Medicines Agency; March 2017. [3] ICH E2E Pharmacovigilance Planning, November 2004. [4] Yvonne Lis, Meissa H. Roberts, Shital Kamble, Jeff J. Guo, Dennis W. Raisch, December 2012 Volume 15, Issue 8, Pages 1108 1118// ,http://www.valueinhealthjournal.com/article/S1098-3015(12)03797-7/ pdf.. [5] Dr. Hoss A. Dowlat, Bio Practice, Reference: Regulatory Reporteur Vol 8, No 2 Feb 2011. ,www. biopractice.com/biosimilar/EU_RMP_US_REMS.pdf.. [6] Begona Calvo and Leyre Zuniga. Risk Management Plan and Pharmacovigilance System Biopharmaceuticals: Biosimilars. ,www.intechophen.com.. [7] ,http://www.ema.europa.eu.. [8] Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for pediatric use. [9] Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products. [10] Guideline on good pharmacovigilance practices (GVP): Module XVI Risk minimization measures selection of tools and effectiveness indicators (Rev 2), March 2017. [11] Frau S, Font Pous M, Luppino MR, Conforti A. Risk Management Plans: are they a tool for improving drug safety? Eur J Clin Pharmacol 2010;66:785 90.
RISK MANAGEMENT IN PHARMACOVIGILANCE
30 Rajinder K. Jalali
Sun Pharmaceutical Industries Ltd, Gurgaon, Haryana, India
Risk management in Pharmacovigilance is a global activity to safeguard health of patients. A medicinal product is authorized on the basis of results of preclinical and clinical studies. These studies are usually conducted on a small number of patients in controlled environments, e.g., restricted age, comorbidity, comedication, and excluding special populations such as elderly population, children, pregnant and lactating women. At the time of authorization, risk-benefit is judged to be positive. However, not all actual or potential risks have been identified at the time of authorization. Risk management is a set of activities performed for identification of risk, risk assessment, risk minimization or prevention, and risk communication [1,2]. Risk Management Plan (RMP) is developed in accordance with applicable regulations and guidelines. However, in absence of guidelines for a country, the plan is prepared in line with ICH E2E guideline on pharmacovigilance planning [3]. The FDA identifies risk management as an iterative process designed to optimize the benefit-risk balance for regulated products throughout the product lifecycle. In March 2005, the FDA issued three guidance documents that defined the formal basis of risk management. These were Premarketing Risk Assessment, Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment, and the Development and Use of Risk Minimization Action Plans (RiskMAPs). These three documents subsequently provided the building blocks for the more recent risk evaluation and mitigation strategies (REMS). The final content of a product’s REMS, however, reflects the unique mix of product attributes as well as the intended prescriber and patient populations [4]. The REMS program seeks to manage known or potential serious risks, and the content must have a timetable for submission of assessments. Additional components for a particular REMS program vary according to the severity of identified risks, the population likely to be exposed, and other factors. The EU RMP is an engagement of wider scope than the US REMS, and is binding on a larger set of medicines. The US REMS is compulsory only for some medicines, and can be limited to two years’ post product launch. The REMS concerns itself with communication of risk, with the prescriber information—the package insert (PI), being central to risk minimization. Components of a typical FDA REMS are a communication plan; patient selection; web-based materials and a medical scientific liaison; elements to assure safe use; an implementation system; a patient or physician survey and patient understanding of risk. The EU RMP is a more comprehensive, more extensive safety package that the sponsor is obligated to follow throughout the lifecycle of all new drugs or biologics [5]. Pharmaceutical Medicine and Translational Clinical Research. DOI: http://dx.doi.org/10.1016/B978-0-12-802103-3.00031-6 © 2018 Elsevier Inc. All rights reserved.
429
430
CHAPTER 30 RISK MANAGEMENT IN PHARMACOVIGILANCE
European Union (EU) legislation necessitates that, when required, a description of the risk management system should be submitted in the form of an EU-RMP. Accordingly, risk management has the following stages: (1) identification and characterization of the safety profile of the medicinal product including what is known or not known (with emphasis on important identified and important potential risks and missing information) about the product and, importantly, which risks need to be further characterized or managed proactively (the “safety specification”); (2) planning of pharmacovigilance activities to characterize and quantify clinically relevant risks and to identify new adverse reactions and to increase the knowledge in general about the safety profile of the medicinal product (the “pharmacovigilance plan”), (3) planning and implementation of risk minimization measures and mitigation and assessment of the effectiveness of these activities (the “risk minimization plan”), and (4) document postapproval obligations that have been imposed as a condition of the marketing authorization [2]. All these activities together constitute Risk Management Plan (RMP), which is required to be submitted during the authorization of the drug. An updated RMP is required when there are significant changes to the safety profile of the drug. The overall aim of risk management is to ensure that the benefits of medicinal product outweigh the risks by a wide margin for the treatment of a particular indication both at individual level and for the target population as a whole. RMP is structured [2] with the following elements: • •
• • • • •
Part I: Product overview Part II: Safety specification • Module SI: Epidemiology of the indication(s) and target population • Module SII: Nonclinical part of safety specification • Module SIII: Clinical trial exposure • Module SIV: Populations not studied in the clinical trials • Module SV: Postauthorization experience • Module SVI: Additional requirements for the safety specification • Module SVII: Identified and potential risks • Module SVIII: Summary of the safety concerns Part III: Pharmacovigilance plan (including postauthorization safety studies) Part IV: Plans for postauthorization efficacy studies Part V: Risk minimization measures and evaluation of the effectiveness of the risk minimization activities Part VI: Summary of the risk management plan Part VII: Annexes
The RMP is part of the scientific dossier of a product and as such should be science-based and not promotional. The submitted RMP should follow the RMP template. The amount of information—particularly in RMP Part II—to be provided will depend on the type of medicinal product, its risks, and where it is in its lifecycle. RMP part I “Product(s) overview” is a complete overview of the product. This includes complete information on the active substance(s) and all related administrative information on RMP. RMP part II “Safety specification” consists of a synopsis of complete safety profile of the medicinal product and summarizes important identified risks (an untoward occurrence for which
RISK MANAGEMENT IN PHARMACOVIGILANCE
431
there is adequate evidence of an association with the medicinal product of interest), important potential risks (an untoward occurrence for which there is some basis for suspicion of an association with the medicinal product of interest but where the association has not been confirmed) and missing information, i.e., gaps in knowledge about a medicinal product, related to safety or use in particular patient populations, which could have clinical significance [2,6]. It also addresses populations potentially at risk and identifies the need for specific data collection to answer outstanding safety information that could have relevance to patient safety. The safety specifications facilitate understanding of the risk-benefit profile during postapproval period and construction of pharmacovigilance plan and basis of risk minimization activities. The safety specification consists of eight RMP modules of which RMP modules SI SV, SVII, and SVIII correspond to safety specification headings in ICH-E2E. RMP module SVI includes additional elements required to be submitted in the EU. For generic medicinal products the expectation is that the safety specification is the same as that of the reference product or of other generic products for which an RMP is in place. RMP summaries for most recently approved centrally authorized medicinal products (CAPs) are published on EMA website [7]. RMP part III “Pharmacovigilance plan”: The purpose of the pharmacovigilance plan is to discuss how the marketing authorization holder plans to identify and/or characterize the risks identified in the safety specification. It provides structured plan for: (1) the identification of new safety concerns; (2) further characterization of known safety concerns including elucidation of risk factors; (3) the investigation of whether a potential safety concern is real or not; and (4) how missing information will be sought [2]. In short, pharmacovigilance plan describes routine and additional pharmacovigilance activities and, thereof, action plans for each safety concern elucidated. Further, it specifies actions to be taken, in addition to procedures in place to detect safety signals, to address identified safety concerns. The pharmacovigilance plan focuses on the safety concerns summarized in RMP module SVIII of the safety specifications and should be proportionate to the benefits and risks of the product. The action plan for each safety concern is presented and justified according to the following structure: safety concern, objective of proposed actions, actions proposed, rationale for proposed actions, monitoring by the MAH for safety concerns and proposed actions, milestone for evaluation and reporting [6]. RMP part IV “Plans for postauthorization efficacy studies” includes a list of postauthorization efficacy studies (PAES) imposed as conditions of the marketing authorization (MA) or when included as specific obligations in the context of a conditional MA or a MA under exceptional circumstances. Not all medicines require postauthorization studies. However, there may be situations when efficacy of products may vary over time and longer-term efficacy data postauthorization is necessary. In addition, regulations on pediatric medicinal products [8] and advanced therapy medicinal products [9] require long-term efficacy as part of postauthorization surveillance for these types of medicinal products. RMP part V “Risk minimization measures (including evaluation of the effectiveness of risk minimization activities)” provides details of the risk minimization measures which will be taken to reduce the risks associated with respective safety concerns. Some safety concerns may be adequately addressed by the proposed actions in the pharmacovigilance plan, but for others the risk may be of a particular nature and seriousness so that risk minimization activities are required. It is
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CHAPTER 30 RISK MANAGEMENT IN PHARMACOVIGILANCE
possible that the risk minimization activities may be limited to ensuring that suitable warnings are included in the product information or by careful use of labeling and packaging, i.e., routine risk minimization activities. However, for some risks, routine risk minimization activities will not be sufficient and additional risk minimization activities will have to be performed. If these are required, they should be described in the risk minimization plan. Additional risk minimization methods include education training material or training programs for medical practitioners, pharmacists, and patients and controlled access programs, and other risk minimization measures [2,6,10]. Consideration must be given to the risk proportionality of the risk minimization activity proposed, the feasibility of implementing any additional risk minimization activity, whether the proposed measures are necessary for the safe and effective use of the product in all patients, and the possibility to adapt distribution modalities [6,10]. For each safety concern, the following information should be provided: (1) objective of the risk minimization activities; (2) routine risk minimization activities; (3) additional risk minimization activities (if any), individual objectives, and justification of why needed; (4) how the effectiveness of each risk minimization activity will be evaluated in terms of attainment of their stated objectives; (5) criteria for judging success; and (6) milestones for evaluation and reporting [2]. This helps to improve risk communication with healthcare professionals and patients and reduced harm caused by new drugs [11]. Evaluation of the effectiveness of risk minimization activities is required beyond the pharmacovigilance plans. Assessment is performed for each safety concern whether any risk minimization activities are needed. The success of risk minimization activities needs to be evaluated throughout the lifecycle of a product to ensure that the burden of adverse reactions is minimized and hence the overall benefit-risk balance is optimized. RMP part VI “Summary of the risk management plan” shall be made publicly available and shall include the key elements of the risk management plan. The audience of RMP summaries is very broad. To ensure that the summary can satisfy the different needs, it should be written and presented clearly, using a plain-language approach. The summary of the RMP part VI should be consistent with the information presented in RMP part II modules SVII, SVIII, and RMP parts III, IV, and V. The summary must include key elements of RMP with a specific focus on risk minimization activities. Regarding safety specification of the medicinal product, it should contain important information on potential and identified risks as well as missing information [2]. The summary of the RMP should be formatted as below: • • • •
• • • •
Overview of disease epidemiology Summary of treatment benefits Unknowns relating to treatment benefits Summary of safety concerns • Important identified risks • Important potential risks • Missing information Summary of risk minimization activities by safety concern Planned post authorization development plan Studies which are a condition of the marketing authorization Major changes to the risk management plan over time
REFERENCES
433
The information provided in each section should be brief and focused. RMP part VII provides for the “Annexes to the risk management plan.” Both REMS and RMPs provide positive guidance for identification, monitoring, and minimization of risk to patient safety. The importance of risk management cannot be over-emphasized and the regulatory burden is increasing, and appropriately so. It is in the interests of patients, industry, and agencies that the least harm and maximum benefit results from taking a medicine; risk strategies such as the US REMS and the EU RMP contribute to this. They also channel drug developers to give greater consideration to how patients can avoid some adverse reactions to drugs and achieve better tolerance, by paying attention to criteria such as contraindications, warnings, and precautions. The EU RMP is an engagement of wider scope, and is binding on a wider set of medicines than the US REMS [5].
REFERENCES [1] Dieck GS, Sharrar RG. Preparing for safety issues following drug approval: pre-approval risk management considerations. Ther Adv Drug Saf 2013;4:220 8. [2] Guidelines on good Pharmacovigilance practices (GVP). Module V Risk management systems (Rev 2). European Medicines Agency; March 2017. [3] ICH E2E Pharmacovigilance Planning, November 2004. [4] Yvonne Lis, Meissa H. Roberts, Shital Kamble, Jeff J. Guo, Dennis W. Raisch, December 2012 Volume 15, Issue 8, Pages 1108 1118// ,http://www.valueinhealthjournal.com/article/S1098-3015(12)03797-7/ pdf.. [5] Dr. Hoss A. Dowlat, Bio Practice, Reference: Regulatory Reporteur Vol 8, No 2 Feb 2011. ,www. biopractice.com/biosimilar/EU_RMP_US_REMS.pdf.. [6] Begona Calvo and Leyre Zuniga. Risk Management Plan and Pharmacovigilance System Biopharmaceuticals: Biosimilars. ,www.intechophen.com.. [7] ,http://www.ema.europa.eu.. [8] Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for pediatric use. [9] Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products. [10] Guideline on good pharmacovigilance practices (GVP): Module XVI Risk minimization measures selection of tools and effectiveness indicators (Rev 2), March 2017. [11] Frau S, Font Pous M, Luppino MR, Conforti A. Risk Management Plans: are they a tool for improving drug safety? Eur J Clin Pharmacol 2010;66:785 90.