Union referral procedures Kaoutar AKOUH AREIPS 2016/2017

Definition of a referral Types of safety referrals Article 107i and assessment Article 31 and assessment Drugs assessed under articles 31 and 107i

WHAT IS A REFERRAL ? It may concern : safety quality, efficacy B/R balance EMA : scientific assessment committees (PRAC, CHMP/CMDh) Procedure : used to resolve issues of a medicine or a class of medicine http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general

WHAT ABOUT THE ASSESSMENT ? All other referrals : assessed only by CHMP Safety-related referrals : PRAC recommendation then either by the CHMP (at least one centrally authorized product) or by the CMDh (no centrally authorized products) EC decision if applicable 50% of the referrals http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general

SAFETY-RELATED REFERRALS Directive 2001/83/CE : Article 31 : Union interest referral Article 107i : Urgent union procedure Regulation EC No 726/2004 : Article 20 : Union interest referral (for CAP) Article 5(3) : scientific opinion http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general

ARTICLE 107i : URGENT UNION PROCEDURE In which cases ? safety issue (result of evaluation of PhV data) urgent action is needed Procedure initiated before a decision is taken : suspension or revocation of a MA prohibition of supply of a medicine deletion of indication, reduction of the recommended dose, new contraindication MAH : interruption the placing on the market of a medicinal product, action to have a MA withdrawn has not applied for the renewal of a MA for a safety reason http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_detail_000131.jsp&mid=WC0b01ac058061f6fb

URGENT UNION PROCEDURE ARTICLE 107i : URGENT UNION PROCEDURE Who can initiate this procedure ? Competent authority of a member state European commission Notification : details on the safety issue, sent to the EMA, all MS and the EC by the initiator Which products ? all the medicines : with a valid MA generics or not a range of medicines a therapeutic class affected by urgent safety issue the product has to be authorized in several MS http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_detail_000131.jsp&mid=WC0b01ac058061f6fb

ARTICLE 107i : URGENT UNION PROCEDURE Assessment by the PRAC : 60 days, without clock-stop assessment based on data collected (anyone can submit data in relation to the issue via a dedicated mailbox during 20 days) 60 days maximum time limit to issue a recommendation public hearing is possible (doctors, patients can present relevant data for the assessment, not mandatory). temporary measures can be taken at any time to protect public health: by the MS by the EC when a centrally authorized product is involved ex: suspension of the MA, prohibition of the product http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_detail_000131.jsp&mid=WC0b01ac058061f6fb

ARTICLE 107i : URGENT UNION PROCEDURE Outcome of the assessment by the PRAC : no further action or evaluation is required at the union level the MAH should : conduct further evaluation of data sponsor a post-authorisation safety study the MS or the MAH should implement risk minimisation measures the MA should be suspended, revoked or not renewed the MA should be varied (SmPC, package leaflet) http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_detail_000131.jsp&mid=WC0b01ac058061f6fb

ARTICLE 107i : URGENT UNION PROCEDURE Assessment by the CHMP/CMDh : 30 days CMDh (only nationally authorized products) : agrees immediately with the PRAC recommendation or within 30 days position by consensus : sent to the MS and the MAH position by majority vote : sent to the EC for a decision CHMP (at least one centrally authorized product) : agrees immediately with the PRAC recommendation disagree with the PRAC recommendation : a timeframe of 30 days begins the opinion is sent to the EC for a final decision the EMA, MAH, MS receive the final decision by the EC http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_detail_000131.jsp&mid=WC0b01ac058061f6fb

ARTICLE 107i : PROCEDURAL STEPS 2 months http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_detail_000131.jsp&mid=WC0b01ac058061f6fb

DRUGS ASSESSED UNDER ARTICLE 107i Cyproterone and EE containing medicines 2013 : initiated at the request of France assessment of the B/R balance : serious thromboembolic events + extensive off-label use as a contraceptive only PRAC recommendation : Diane 35 and its generics outweigh the risks CMDh endorsed by majority the PRAC recommendation the CMDh position was sent to the EC for a final decision : MA is maintained with risk minimisation measures to minimise the risk of thromboembolism : updating of the product information providing educational material to prescribers and patients highlighting the risks of thromboembolism http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/cyproterone_ethinylestradiol_107i/European_Commission_final_decision/WC500147176.pdf

ARTICLE 31 : UNION INTEREST REFERRAL In which cases ? safety issue Interests of the Union = interest of public health no urgent action is required (possible clock-stop) before a decision is taken about a MA : an application a suspension a revocation http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a q_and_a_detail_000144.jsp&mid=WC0b01ac0580789970

UNION INTEREST REFERRAL ARTICLE 31 : UNION INTEREST REFERRAL Who can initiate this procedure ? Member state European Commission MA holder => a MS or the commission has to confirm the union interests Initiator refers the matter to the PRAC : notification (details on the safety concern, how the union interests are involved) Which products ? a specific medicinal product a range of medicinal products (same active substance) a therapeutic class of medicinal products affected by a safety issue http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a q_and_a_detail_000144.jsp&mid=WC0b01ac0580789970

UNION INTEREST REFERRAL ARTICLE 31 : UNION INTEREST REFERRAL Assessment by the PRAC : 60 days, possible clock-stop can be extended to 120 days (to take into account the MAH views, in case of public hearing) PRAC recommendation adopted by consensus or by majority after PRAC recommendation, the MAH has 15 days to request a re-examination after this 15 days, the PRAC recommendation considered final and is sent to the CMDh or CHMP Outcome of the assessment by the PRAC : the MA can be maintained under certain conditions : MAH has to conduct a drug use study and/or to implement other minimisation risk measures the MA should be varied : product information should be corrected the MA should be suspended or revoked http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a q_and_a_detail_000144.jsp&mid=WC0b01ac0580789970

UNION INTEREST REFERRAL ARTICLE 31 : UNION INTEREST REFERRAL Assessment by the CHMP/CMDh : 30 days the final PRAC recommendation is forwarded to the CHMP or CMDh if the MAH disagree with the CMDh position or the CHMP opinion : possible re-examination, 15 days after the decision or position. CMDh position or CHMP opinion immediately or within 30 days EC final decision if applicable http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a q_and_a_detail_000144.jsp&mid=WC0b01ac0580789970

ARTICLE 31 : PROCEDURAL STEPS 2 months http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a q_and_a_detail_000144.jsp&mid=WC0b01ac0580789970

DRUGS UNDER EVALUATION IN 2016 : ARTICLE 31 Paracetamol modified and prolonged release tablets : initiated at the request of Sweden assessment of the B/R balance : overdoses how to minimise the risk of overdoses ? (the standard procedures of immediate-release paracetamol are not enough) review will be carried out by the PRAC + CMDh Factor VIII medicines : initiated at the request of Paul Ehrlich Institute assessment of the risk of developing inhibitor proteins in patients starting treatment for hemophilia A (publication of a study : risk FVIII made by DNA recombinant > risk FVIII derived from blood) EMA : assessment of the data of this study, necessity of minimisation risk measures or modifications in the MAs review will be carried out by the PRAC + CHMP https://www.afmps.be/fr

TO SUM UP http://dgra.de/media/pdf/studium/masterthesis/master_stadler_b.pdf

Thank you for your attention !