Experience with the EMA Pharmacovigilance Risk Assessment Committee

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challenges in the optimization of their safe and effective use. Proactively managing the risk of In the first 18 months of its operation, the PRAC has considered risk management marketed drugs: experience with plans for 160 medicinal products. In this work the PRAC has focused on ensuring fea- the EMA Pharmacovigilance Risk sible, evidence-based and risk-proportionate planning4. Assessment Committee The collection of individual reports of suspected adverse drug reactions (ADRs) is one of the foundations of drug surveil- Peter Arlett, Geraldine Portier, Roberto de Lisa, Kevin Blake, Noel Wathion, lance, and the reporting rules have been Jean-Michel Dogne, Almath Spooner, June Raine and Guido Rasi strengthened. These now include the formal introduction of patient reporting in all EU This journal has previously reported on The PRAC has a broad remit covering member states (to enable patient engage- initiatives to increase proactivity in the sur- all aspects of pharmacovigilance, ment), the provision of instructions on veillance and management of drugs on the including risk management planning and reporting in drug leaflets for patients, as market and considered how this might influ- post-marketing benefit–risk assessment. well as the labelling of new drugs and those ence drug (medicinal product) development Its mandate includes specific reference to under close safety surveillance with a black programmes (Nature Rev. Drug Discov. 11, the fact that risk management and assess- triangle symbol indicating the need for 255 (2012))1. We now report on the imple- ment should be pursued with due regard enhanced reporting. mentation of a new European Union (EU) for the therapeutic effect of the medicinal The data shown in FIG. 1a indicate an initiative to improve the promotion and product. The PRAC mandate also places a overall increase in reports received from the protection of public health through better strong focus on the Committee’s role in the European Economic Area (EEA) in the first planning for, and management of, drugs on design and evaluation of post-authorization year of operation of the new legislation, and the market. studies to ensure they contribute meaning- a proportionately greater increase in patient The new EU pharmacovigilance legisla- fully to sustainable life-cycle benefit–risk reporting. More and better-documented tion became operational in July 2012, and management. Just as the EMA works spontaneously reported suspected ADRs, after 18 months of operation we suggest within the European regulatory network of together with results from studies (inter- that this initiative is starting to demonstrate national drug agencies, the PRAC provides ventional and non-interventional), provide results in terms of patient safety, and that its advice and recommendations to the key data and information inputs for signal there could be wider implications in terms network, and for many procedures these detection. The PRAC has a crucial role in the of more safe and effective drugs being made recommendations are considered by the prioritization of potentially new or changing available in the future2,3. Coordination Group or the Committee safety issues (safety ‘signals’) and in making The new legislation is centred on the for Medicinal Products for Human Use recommendations on the management of Pharmacovigilance Risk Assessment (CHMP) before they become legally binding these — for example, for further investiga- Committee (PRAC) at the European (see the EMA website for further information or for drug labelling changes. FIGURE 1b Medicines Agency (EMA). The PRAC was tion on the PRAC). shows the number of signals evaluated by formally established in July 2012 and its All applications for drug marketing the PRAC in its first 18 months and, for the membership was completed in spring 2013 authorizations now have to, by law, include completed evaluations, the number that with the appointment of patient and health- a risk management plan (RMP) document- resulted in recommendations for changes in care professional organization representa- ing the proposed risk management system drug labelling. The results demonstrate that tives as full voting members. The Committee to be implemented if a marketing authoriza- by prioritizing and evaluating signals, the includes independent experts in pharma- tion is granted. The PRAC is systematically PRAC is able to ensure that new or changed coepidemiology, clinical pharmacology, bio- consulted in the risk management planning safety issues can be translated into drug logics, signal detection, risk communication for all new innovative drugs and for impor- labelling updates, including new restrictions and vaccine vigilance. tant changes to existing drugs that pose on use and advice on optimal drug use.

a b Total number of signals: 128 1 year post- 172,092 24,887 implementation 1 year pre- Number of assessments 137,286 15,371 implementation ﬁnalized: 79

Other Patients

0 50,000 100,000 150,000 200,000 Update of RMP No further regulatory label: 61 update: 2 action: 16 Number of reports

Figure 1 | Impact of the new European legislation on pharmacovigilance. implementation of the legislation in July 2012. b | Number of safety signals a | Number of cases of spontaneous reports of adverse drug reactions within evaluated by the Pharmacovigilance RiskNature Assessment Reviews Committee | Drug Discovery (PRAC) the European Economic Area in the 12-month periods before or after the in its first 18 months and the outcomes of the finalized evaluations.

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Although signal evaluations usually processes to support timely, high-quality science base for regulatory decision-making, focus on one or a small number of specific assessments to optimize the safe and effec- continuing efforts to ensure efficient man- ADRs, more global risk or benefit–risk tive use of medicines though drug labelling agement of workload and optimized use assessments of a drug or group of drugs take changes and, when necessary, restrictions. of regulatory tools, and further increasing place through assessments of Periodic Safety Transparency in the regulation of medi- stakeholder engagement, with the overall Update Reports (PSURs; also referred to as cines is considered to be crucial in allowing objective of delivering strengthened Periodic Benefit Risk Evaluation Reports)5 or stakeholders to follow and engage in the public health promotion and protection. EU Pharmacovigilance Referrals. Both types processes, to understand the rationale and The PRAC ensures its decision-making is of assessment procedures are conducted by evidence supporting recommendations supported by robust and timely assessment the PRAC and both result in legally binding and actions affecting drugs and care, and in based on all relevant evidence and drawing outcomes, following specified procedural building trust. To this end, a key aim of the on the best available expertise6. The PRAC’s steps that are conducted within timeframes new legislation is to increase transparency, focus on efficiency, combined with quality, laid down by law. These outcomes can range and this has included making suspected is achieved through improvement of pro- from a requirement for further study to ADR data publicly available (see the EMA’s cesses based on measurement and analysis drug labelling changes or drug restrictions European database of suspected adverse and, where appropriate, based on evidence and withdrawals. In the 18 months from drug reaction reports for further informa- from regulatory sciences7. July 2012, the PRAC has considered and tion) and ensuring public posting of post- Looking forward, the EMA, its scientific issued recommendations on 486 PSURs authorization studies, with 202 studies committees and the EU regulatory network and 22 Referrals have been initiated. Of the posted up to January 2014 in the EU PAS are focusing on efficiency and simplifica- latter, 13 have had a Coordination Group Register. The work of the PRAC has been tions to free up resources that can then be or CHMP decision in the same timeframe. characterized by an unprecedented level reinvested to deliver more for public health. TABLE 1 lists the outcomes and time from of transparency before, during and after Initiatives include: the development of a initiation to decision for these. the meetings, with real-time publication of literature monitoring service by the EMA to The data show an average time of agendas, meeting highlights, notifications negate the need for companies to conduct 6.4 months for the finalization of these of referrals, lists of questions and minutes. duplicative literature reporting; further Referrals. This indicates that the PRAC has The PRAC has placed an emphasis development of the EU system for reporting rapidly operationalized new practices and on the importance of strengthening the and analysing ADRs (EudraVigilance) to

Table 1 | Finalized PRAC referrals from July 2012 to December 2013 Drug or drug group Issue Started Finalized Outcome Duration Codeine Use in children October 2012 June 2013 Change to product labelling 8 months (variation) Diclofenac Cardiovascular safety October 2012 June 2013 Change to product labelling 8 months (variation) SABAs (short-acting beta Use in pregnancy November 2012 October 2013 Change to product labelling 11 months agonists) (variation) HES (hydroxyethyl starch Risks of renal injury and November 2012 October 2013 Change to product labelling 11 months solution) mortality (variation) Almtrine Risks of peripheral November 2012 May 2013 Product withdrawn (revocation) 6 months neuropathy and weight loss Laropiprant/nicotinic acid Negative benefit–risk January 2013 January 2013 Product withdrawn (suspension) 3 weeks balance Tetrazepam Serious skin reactions January 2013 April 2013 Product withdrawn (suspension) 3 months Medicines containing Risk of thromboembolism February 2013 May 2013 Change to product labelling 3 months cyproterone acetate (2 mg) (variation) and ethinylestradiol (35 mg) Combined hormonal Risk of thromboembolism February 2013 November 2013 Change to product labelling 9 months contraceptives (variation) Flupirtine Hepatotoxicity March 2013 June 2013 Change to product labelling 3 months (variation) Nicotinic acid and related Negative benefit–risk March 2013 December 2013 Change to product labelling 9 months substances (acipimox, balance (variation) xantinol nicotinate) Kogenate Bayer/Helixate Inhibitor formation March 2013 December 2013 Change to product labelling 9 months NexGen (variation) NUMETA G13%E, NUMETA Magnesium overdose June 2013 September 2013 Suspension of one formulation; 3 months G16%E emulsion for infusion change to product labelling and associated names (variation) of the other PRAC, Pharmacovigilance Risk Assessment Committee.

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allow simpler reporting for industry and in knowledge can be robustly addressed 5. International Conference of Harmonisation of Technical Requirements for Registration of better data analysis; and the development once the product is on the market. This is Pharmaceuticals for Human Use. ICH Harmonised of a central reporting, storage and access further supported through transparency Tripartite Guideline Periodic Benefit-Risk Evaluation system for PSURs from industry to simplify measures for building public trust. In sum- Report (PBRER) E2C (R2). ICH [online], http://www.ich.org/fileadmin/Public_Web_Site/ICH_ their reporting and analysis. mary, proactive, effective and transparent Products/Guidelines/Efficacy/E2C/E2C_R2_Step4.pdf These are early days for the operation of pharmacovigilance, leading to confidence (2012). 6. Arlett, P. et al. The European Medicines Agency’s use the new EU pharmacovigilance legislation and trust, supports product development to of prioritised independent research for best evidence and the establishment of the PRAC as a pub- fulfil unmet medical needs and helps ensure in regulatory action on diclofenac. Pharmacoepidemiol. Drug Saf. 23, 431–434 (2014). lic health body. Early signs, however, based that any knowledge gaps are addressed in a 7. Arlett, P. & Kurz, X. New approaches to strengthen on process indicators such as those reported timely manner and in the best interests of pharmacovigilance. Drug Discov. Today Technol. 8, 8 e15–e19 (2011). here for RMPs, ADRs, signals, PSURs and public health . 8. Eichler, H. G. et al. The risks of risk aversion in drug EU Pharmacovigilance Referrals, point to Peter Arlett, Geraldine Portier, Roberto de Lisa, regulation. Nature Rev. Drug Discov. 12, 907–916 (2013). more systematic and proportionate risk Kevin Blake, Noel Wathion and Guido Rasi are at the European Medicines Agency, 7 Westferry Circus, management planning, the promotion of Acknowledgements Canary Wharf, London E14 4 HB, UK. reporting (including from patients), greater We thank all the participating member states and the coordination of real-time signal manage- Jean-Michel Dogné is at the Federal Agency for National Competent Authorities for their constant support of Medicines and Health Products, Victor Horta Place, the Pharmacovigilance Risk Assessment Committee (PRAC), the PRAC itself and the PRAC Secretariat. We also thank ment, faster assessment and decision- 40/40, 1060 Brussels, Belgium. making, and thus strengthening of the link the European Medicines Agency (EMA) colleagues who have Almath Spooner is at the Irish Medicines Board, contributed data. between pharmacovigilance assessments and Earlsfort Terrace Dublin 2, Ireland. Disclaimer regulatory actions such as labelling changes June Raine is at the Medicines and Healthcare The views expressed in this article are the personal views of to optimize safe and effective drug use. products Regulatory Agency, 151 Buckingham the authors and may not be understood or quoted as being Palace Road, London SW1W 9SZ, UK. made on behalf of or reflecting the position of the European Finally, how could proactivity in the Medicines Agency or one of its committees or working surveillance and management of drugs on Correspondence to P.A. parties. e‑mail: [email protected] the market influence drug development Competing interests statement programmes? After 18 months of opera- doi:10.1038/nrd3713-c1 The authors declare no competing interests. tion of the PRAC, we suggest that more safe 1. Mullard, A. Unleashing the Mini-Sentinel. Nature Rev. and effective drugs can be made available Drug Discov. 11, 255–257 (2012). FURTHER INFORMATION 2. European Medicines Agency. EMA recommends 81 EMA Pharmacovigilance Risk Assessment Committee through planning, engagement and trans- medicines for marketing authorisation in 2013. (PRAC): http://www.ema.europa.eu/ema/index. parency, as well as rapid assessment and European Medicines Agency [online], http://www.ema. jsp?curl=pages/about_us/general/general_content_000537. europa.eu/ema/index.jsp?curl=pages/news_and_ jsp&mid=WC0b01ac058058cb18 regulatory action. Proactivity and effective- events/news/2014/01/news_detail_002006. EudraVigilance: https://eudravigilance.ema.europa.eu/ ness in the surveillance and management of jsp&mid=WC0b01ac058004d5c1 (2014). highres.htm 3. Eichler, H. G. et al. Adaptive licensing: EU PAS Register: http://www.encepp.eu/encepp_studies/ drugs on the market increases stakeholder taking the next step in the evolution of drug approval. indexRegister.shtml confidence in medicines regulation and, Clin. Pharmacol. Ther. 91, 426–437 (2012). European database of suspected adverse drug reaction 4. Prieto, L. et al. Evaluation of the effectiveness of risk reports: http://www.adrreports.eu/ at the time of authorization, also increases minimization measures. Pharmacoepidemiol. Drug ALL LINKS ARE ACTIVE IN THE ONLINE PDF the confidence of regulators that any gaps Saf. 21, 896–899 (2012).

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