AESGP Workshop

London | 23-24 October 2013

Making the European marketing authorisation procedures work for non-prescription medicines European and national regulators and industry representatives participated at the AESGP Workshop in Canary Wharf, London, on 23-24 October 2013 and discussed the performance of the European marketing authorisation system in connection with nonprescription medicines and how the efficiency of the system could be improved to allow European citizens timely access to non-prescription medicines. AESGP President Hans REGENAUER remarked in his welcome address that AESGP had held many conferences in this area of London since the creation of the European Medicines Agency in January 1995. These meetings certainly acquired a new dimension through the opening to non-prescription medicines of the centralised procedure in 2005. Expectations were high but the actual results were rather at the lower end of the scale: three centralised authorisations after almost 10 years cannot really be regarded as a big success, in spite of the excellent cooperation with the authorities through the EMA - AESGP platform. Higher than expected were however the number of referrals for nonprescription medicines in the recent past, said Regenauer. He wondered in this context whether the European and
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national regulators were taking proper account of the health and societal benefits of non-prescription medicines. He encouraged the authorities to follow the new benefit-risk assessment model for nonprescription medicines developed by Eric Brass et al. and presented at two AESGP conferences with the Heads of EU 1 Medicines Agencies (HMA) . The Executive Director of the European Medicines Agency, Guido RASI (left) welcomed the opportunity provided by the workshop to discuss the topics raised by the AESGP President. He also outlined the highlights of the ongoing reorganisation at the Agency which were to be presented in more detail by Nol Wathion. Rasi indicated the three pillars

driving the new structure:

- Better support the scientific

work of the EMA scientific committees

- Better share the knowledge

and information EMA holds throughout the EU Regulatory Network

- Better meet the needs of

EMA partners and stakeholders. According to Rasi, the changes should eventually lead to a one-stop shop where applicants could get all their business dealt with at the same time. Implementation of this scheme would be accomplished by appointing two new lines of managers who would bring fresh energy to the Agency.

See the AESGP website: http://www.aesgp.eu/events/Copenhag en2012/report/ and http://www.aesgp.eu/events/Dublin201 3/

See the AESGP website: http://www.aesgp.eu/events/Copenhagen2012/report/ and http://www.aesgp.eu/events/Dublin2013/

Non-prescription medicines in the centralised procedure

Nol WATHION of the European Medicines Agency (EMA) expanded on Rasis words by showing the details of the three pillars of the EMAs new organisation. The main changes concern the creation of:

publication of agendas and minutes of the EMAs Scientific Committees. Wathion also explained in detail what was discussed at the recent EMA Workshop on access to clinical trial data. Concerning the use of the centralised procedure for non-prescription medicines, Wathion indicated that the main issues are: (1) Improving the benefit-risk evaluation methodology for work is in progress using the (qualitative) EMA Effects Table. The pilot is to be extended until May 2014, after which the outcome will be analysed (2) Revision 6 of the Guideline on the acceptability of names for human medicinal products processed through the centralised procedure, on which AESGP had submitted major comments. The comments made will be discussed during a workshop with interested parties (including AESGP) on 15 November 2013

- a new operating model for how medicines are

managed throughout their entire lifecycle,

- four new divisions dealing with human medicines,

- a new division for stakeholders and communication

- advisory functions to advise the Executive Director on policy, operational and scientific issues. The Road map towards greater transparency has resulted in various new initiatives, including the

Mark GRIFFITHS of Pfizer Consumer Health raised certain industry concerns related to the use of the centralised procedure for non-prescription medicines. The benefits and issues are summarised in the chart to the right. Griffiths pointed in particular to certain national differences in the implementation of a CHMP decision on prescription status, and concluded that it was difficult to harmonise national views in the centralised proc edure. The limited experience so far points to a precautionary approach on the part of the European regul ators in assessing non-prescription medicines, where benefits are frequently misunderstood and overlooked and risks are increasingly seen as outweighing the benefits.
AESGP Workshop | London 23-24 October 2013
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Griffiths therefore asked for an honest debate on making the centralised procedure work for non prescription medicines within the current legal framework. The presence of OTC experts within the CHMP would be helpful, concluded Griffith.

Making better regulation a reality This session looked at ongoing work in the framework of achieving Administrative Simplification and Smart regulation for manufacturers of non-prescription medicines. Dagmar STAR of the European Commissions Directorate-General for Health and Consumers outlined the work being carried out by the Commission to implement the EUs new pharmacovigilance provisions, including Commission Implementing Regulations (EU) No 520/2012 (see slide) and (EU) No 198/2013 (on the Black symbol ()).

Concerning Post-Authorisation Efficacy Studies (public consultation Nov 2012- Feb 2013; expert group discussions Mar-Oct 2013); most respondents agreed that such an act may provide legal certainty but that its imposition should take place on a case-by-case basis. Under the Joint Action on Pharmacovigilance 2013-2016 (signature of project agreement by end 2013), the Directorate-General for Health and Consumers DG SANCO) will support Member States to find solutions for organising and running their pharmacovigilance systems. As regards the Commissions Pharmacovigilance fee proposal of this issue for discussions in the European Parliament), Star mentioned that the Lithuanian Council Presidency is trying to reach an early agreement to ensure adequate financing of the pharmacovigilance activities at EU level. Other topics mentioned by Star included:

- An update on the implementation of the provisions on falsified medicines.

- Commission reports: Five-yearly report on the Paediatric Regulation: published; Readability of PIL and
SmPC: preparatory study ongoing. During the ensuing discussion, AESGP Director General Hubertus Cranz expressed AESGPs c oncerns with regard to the requirement for post-authorisation efficacy studies (PAESs). Non-prescription status already guarantees a products safety. A general revision of all old products is certainly not what the legislator had in mind, said Cranz.

Marcus MLLNER, Past Director General of Austrias AGES PharmMed, mentioned that this would be his last official presentation in his current function as a member of the Heads of EU Medicines Agencies (HMA). By coincidence, my first official speech eight years ago was also at an AESGP conference. When asked then Do we really need a competent authority in each Member State, I answered with an unequivocal yes. If you were to ask me the same question again, I would not be so sure, said Mllner.

Repeat-use mutual recognition procedures involving 28 Member States and three observers may not be the most efficient route. It may therefore be better to go down the medical devices route, said Mllner. A clear plan is however needed for the sharing of responsibilities, leading to a better balanced workload for the agencies. I favour a free market approach on this, said Mllner, with the work being done by who is best qualified in order to avoid duplication. Concerning de-regulation, Mllner mentioned that many

old provisions often remained in place when new legislation was adopted. We need to have a close look at this, because well meant is often not the same as well done. Other topics mentioned by Mllner included risk management and communication, the information required to be fed into the EU database under Article 57(2) and legal status. Mllner thought in particular that a centralised legal status might be envisaged in light of the current lack of homogeneity.

Pictured at the AESGP Workshop in London on 23-24 October 2013 (from l.): Peter BACHMANN, Chair, Co-ordination Group for Mutual Recognition and Decentralised Procedures (CMDh); Marcus MLLNER, Past Director General, AGES PharmMed, Austria; Dagmar STAR, Directorate General for Health and Consumers, European Commission; Hubertus CRANZ, Director General, AESGP; Filip BABYLON, Member of the Pharmacovigilance Risk Assessment Committee (PRAC); Christelle ANQUEZ-TRAXLER, Regulatory and Scientific Affairs Manager, AESGP; and Elmar KROTH, German Medicines Manufacturers Association (BAH)

AESGP Workshop | London 23-24 October 2013

With the arrival at the European Medicines Agencys Pharmacovigilance Risk Assessment Committee (PRAC) in April 2013 of healthcare professional representative Filip BABYLON, some pragmatism was added to the committees discussions. Patient safety in general and the safe use of medicines in particular has always been a top priority in my work as a community pharmacist, said Babylon. I am convinced that this is the case for my colleagues all over Europe and in fact for all health professionals. I am very happy to contribute with this expertise to the management

of benefits and risks of medicines at a European level. My main objective is to make sure that the full potential of health professionals in Europe is used to the benefit of the patient. Babylon looked at how uncertainty is tackled at the product level (through regulation) and at the indication level (through guidelines). However, noted Babylon, it is sometime difficult to find the right balance. He also remarked that it was important to distinguish relative and absolute risks. In order to improve medication safety, continued Babylon, continuity of care should be

supported as well as better communication between the members of the healthcare team (doctors, pharmacists, other caregivers, etc.). He suggested linking patientspecific information from the patient health records with medicines safety and efficacy information. Patients should be supported in their medicines taking with consistent messages in lay language. Reporting of Adverse Drug Reactions (ADRs) and medication errors should moreover be simplified, said Babylon. Too much, inadequate or unbalanced information kills the message!

The decentralised/mutual recognition procedures (DCP-MRP) for non-prescription medicines: Where do we stand? In this session, two members of the Co-ordination Group for the Mutual Recognition and Decentralised Procedures Human (CMDh) and an industry speaker shared their experience on the procedures. Colette MCCREEDY of the United Kingdoms Medicines and Healthcare products Regulatory Agency (MHRA) provided background on the following three issues. dialogue is started at the CMDh if clarification is required or consensus cannot be reached.

- The CMDh Best Practice Guide for the decentralised procedure for non-prescription medicines provides best practices specific to non-prescription medicines. One of the key elements is that authorities should involve assessors with relevant experience in self-care and be open to pre-meetings with the industry. Also, an early dialogue should be started at the CMDh if clarification is required or consensus cannot be reached.

- In case of switch applications, it is important that applicants understand the reclassification procedures in all Member States involved, that they engage early with Reference and Concerned Member States and that they prepare well for pre-submission / scientific advice / regulatory meetings. Competent authorities are encouraged to share experiences and approaches to reclassification, and

- The CMDh Best Practice Guide for the decentralised procedure for non-prescription medicines provides best practices in the processing of applications for new marketing authorisations. One of the key elements is that authorities should involve assessors with relevant experience in self-care and that an early

- The main findings from the EU Platform

Working Group on Promoting a Good Governance of Non-Prescription Medicines (part of the so-called Tajani project) were, according to McCreedy, that:

o o

Safety is the main priority for all stakeholders; but should be seen in the context of benefit People need information and support to help them make informed decisions Doctors and pharmacists have an important role to play in supporting people in self-care; patients expect them to be proactive in providing information and advice.

McCreedy recommended that informal forums be established within the competent authorities to resolve self-medication matters, especially in the non-regulatory field. Moreover, national selfmedication platforms such as the one set up in the United Kingdom under the aegis of MHRA and the appointment of a self-medication champion could help, she said.

Christine EISING of Novartis Consumer Health presented the results of the AESGP 2012 Survey on Key Performance Indicators with regard to mutual recognition and decentralised procedures (MRP/DCP) involving non-prescription medicines. The survey provided a continuation of the survey presented in January 2010 and looked at the real-life uptake of the CMDhs recommendations in the Best Practice Guide issued in February 2012. The survey was based on anonymised data from 42 respondents. According to Eising, the DCP is the procedure of choice for new registrations of nonprescription medicines (28 DCPs v 14 repeat-use MRPs). In 14 cases a pre-submission meeting took place with the RMS (7 DCPs and 7 R-U MRPs), all of which were found useful by the participants. Interesting to see were the statistics Eising presented on the number of times the Member States were chosen to act as Reference Member State in both procedures and the rating companies gave to the role played by the Reference Member State during the procedures (see graphs). Other aspects examined during the survey included the slot-booking process and the validation, clock-stop and national phases. For the national phase, significant delays were found to be due to specific requirements such as artwork, trade names and reimbursement / pricing approval. Industry wondered whether the Reference Member State could provide support to resolve some problems encountered during the national phase.

AESGP Workshop | London 23-24 October 2013

Eising concluded that the survey had shown a good uptake of the CMDhs Best Practice Guide on nonprescription medicines, with as particular highlights the successful communication in pre-submission meetings and the high accessibility of Reference and Concerned Member States. She added that it was important that the advice given during pre-submission meetings be kept by national competent authorities. However, the long delays encountered during the validation, clock-stop and national phases remained a critical issue.

Keith McDONALD the UKs representative on the Co-ordination Group for Mutual Recognition and Decentralised Procedures (CMDh), reported on the work of the Groups Process Improvement Working Party established in 2009 to improve the operation of the decentralised procedure. The main areas for improvement were identified as the validation phase; the clock-stop phase; and the national phase. For the validation phase the CMD veterinary started a pilot in September 2013 with an enhanced role for the Reference Member State. A validation template exists which should be used by NCAs. National requirements are still numerous and are displayed on the CMDh website in a transparent manner. The CMD veterinary pilot will be a useful learning source for the human sector, noted McDonald.. For electronic submissions to the Common Submission Portal (CESP), a pilot on RMS technical validation for marketing authorisation applications in the DCP in eCTD format was started on 1 March 2012. Results would be shared with industry at the next joint CMDh-Interested parties meeting on 18 November 2013. For the clock-stop phase, the issues are its variable duration. Extensions are sometime requested by applicants; and the flexibility element is important It is also unsure when the procedure will restart. Therefore it was agreed that reasons for delay or extension should be identified to improve predictability. This would also be further explored at the 18 November 2013 meeting. In the national phase the issues mainly seem to relate to translations. Member States are exchanging best practices to improve the issue and are looking at several solutions, including approval of the marketing authorisation without translations as well as an active translation tracking role for the RMS.

The new pharmacovigilance legislation: Impact on the role and work of the CMDh The role and competences of the CMDh were considerably expanded through the addition of new provisions on pharmacovigilance to the EUs pharmaceutical legislation. Speakers in this session discussed the practical experience so far.

June RAINE, who chairs the European Medicines Agencys Pharmacovigilance Risk Assessment Committee (PRAC), quoted one of the recommendations from the June 2013 report on Promoting a Good Governance for NonPrescription Medicines, i.e. Stakeholders should develop ideas together on use of post authorisation studies, questionnaires and algorithms

within models of supply of non-prescription medicines. Raine set out the legislative aims of the EUs pharmacovigilance legislation. The EUs public health challenge is that 5% of all hospital admissions are due to Adverse Drug Reactions (ADRs) and that 5% of all hospital patients experith ence an ADR. ADRs are the 5 most common cause of hospital deaths, meaning that

197,000 deaths per year in the EU are caused by ADRs, for a total societal cost of 79 billion.

Looking back at the PRACs first year of operation, Raine mentioned that PRAC experts were appointed by the European Commission and played a strong role in applying scientific expertise. The Patient and Healthcare Professional repre-

sentatives added last April contributed across all areas of the committee work, she said. The PRAC had a rigorous focus on adhering to the legallybased remit and collaborated well with other Committees, in particular the Committee for

Medicinal Products for Human Use (CHMP) and the Coordination Group for the Mutual Recognition and Decentralised Procedures Human (CMDh) .

PRACs public healths pillars are: Proactive safety monitoring, Prompt benefit risk action and Transparency and communication. The signal outcomes in the first year are shown in the graph below. Raine also showed the distribution of safety referrals per Member State and per legislative Article (20, 107i or 31). One third of PRAC time is spent on referrals. About 25% of cases were referred by the French Agency (ANSM) and 25% by the European Commission. Among the ongoing referral procedures one ingredient (domperidone) has nonprescription status in some countries. Out of the 243 periodic safety update report PRAC recommendations, a variation to the marketing authorisation was issued in 16%

of cases. No suspensions or revocations were issued. According to Raine, implementation of the pharmacovigilance legislation is on the right track, with significant progress being seen towards benefit-risk monitoring throughout a products life cycle, also through improved stakeholder engagement. Looking at possible improve-

ments, the PRAC key challenges are: efficient management of the workload, optimising cooperation with CHMP and CMDh, increasing stakeholder engagement, strengthening the science base (notably through (ENEPP) and making a demonstrable impact on public health protection. The focus now is on efficiency and riskproportionality, said Raine.

AESGP Workshop | London 23-24 October 2013

Elmar KROTH of the German Medicines Manufacturers Association (BAH) presented the self-care industrys take on the PRACs first year of operation. AESGP supported the objectives of the legislation: strengthening and rationalising the EUs existing pharmacovigilance provisions and making requirements more proportionate to risks. AESGP also appreciated the relief from routine periodic safety update report (PSUR) generation for generic and bibliographic applications and registered products, and proposed applying the new provisions in a pragmatic manner, i.e. exempting all well-established use products authorised on the basis of a full application before the bibliographic legal basis existed as well as homeopathic medicinal products. According to the European Commissions Impact Assessment of the new provisions, important savings could be achieved. Kroth showed however that on the basis on the European Commissions pharmacovigilance fee proposal of June 2013, the total impact of the new fees on industry (annual flat fees, PSUR fees, Post-authorisation safety study (PASS) fees and referral fees) would be 39 million or more rather than the 10.6 million estimated by the European Commission in its impact assessment. AESGP has in this context made the following proposal, also in light of the fact that major parts of the pharmacovigilance services are currently not available to marketing authorisation holders (MAHs): Public health services carried out under the EMAs remit should be financed from European Union funds rather than by industry. As a minimum gesture, no fees should be levied until the corresponding services are fully operational, and annual fees for authorised herbal and homeopathic medicinal products should be waived given that the pharmacovigilance activities are still at the national level. In connection with the central literature monitoring, AESGP is still awaiting clarification on several points, in particular that the MAH

is not liable for the literature searches carried out by the European Medicines Agency, otherwise two systems would have to run in parallel, thereby defeating the benefits of central monitoring. With regard to the experience gathered on the referral procedures of the last 12 months, Kroth noted that the majority involved products that had already been on the market for decades and that the narrow time frame hampered a joint industry response. AESGP is therefore proposing for the PRAC to focus on the evaluation of new risks and for the CHMP/CMDh to focus on the overall benefit-risk assessment. In general, no national measures should be implemented before the European Commission takes a decision. Moreover, the time frame of the Communication Plan is unrealistic when a European Commission decision is necessary. In the area of signal assessment, AESGP is asking for better involvement of, and communication with, the marketing authorisation holders and more clarity concerning national implementation. AESGP also voiced a number of concerns concerning the implementation of the Article 57(2) database, in particular concerning maintenance, updates and requirement changes. AESGP is also uncertain about industrys role in the new EU Telematics Governance structure and project groups, said Kroth.

Wendy BOOTH of GlaxoSmithKline Consumer Health presented an AESGP proposal for simplification of the Risk Management Plan (RMP) requirements for wellestablished products in the context of the new pharmacovigilance provisions requiring an RMP for all new marketing authorisation applications. . She explained that the Good Pharmacovigilance Practice (GVP) Module V usually focuses on newer products and that limited feedback has been received on the requirements for older products.

In light of the considerable resource required to draw up these RMPs and the limited added value for well-established products without risk minimisation, industry proposes that the RMP should be a concise document whose length and structure are dictated by relevant content only. All stakeholder resources should focus on key product issues and on patient safety, said Booth. Both the research-based industry and AESGP would like to make the EU RMP more aligned to the stage in the products life cycle, similar to the abridged EU RMP for generics (see graph). This would allow more modules to be omitted as well as greater flexibility on detail in the remaining sections. All information on identified and potential risk minimisation activities would be included but non-critical information could be removed. This may apply in specific situations, e.g. for new applications for a product with new indications where the marketing authorisation applicant already has products with the same active substance authorised for 10 years or for an initial risk management plan for medicinal products on the market in the EU for 10 years. In case this is not acceptable, industry proposes basing the RMP on the EU template but omitting modules / annexes not required given the stage in a products life cycle. In short, said Booth, we should consider a more effective, targeted tool to describe key risks and activities to minimise or mitigate these risks for older products.

Peter BACHMANN, who chairs the Co-ordination Group for Mutual Recognition and Decentralised Procedures (CMDh), explained the impact of the new pharmaceutical legislation on the role and work of the CMDh. He indicated in which cases the CMDh takes binding decisions by a majority vote and where marketing authorisation holder (MAH) and Member States are bound by a consensus vote. The latter situation

applies in particular in case a PRAC recommendation is endorsed by a CMDh consensus vote. Concerning interaction with the PRAC, Bachmann noted this is not totally new territory as experience has been gained with the EURD list, which is updated monthly for nationally approved medicinal products. He further mentioned that the

single periodic safety update report assessment for purely national substances was postponed as the pharmacovigilance fee regulation would not be adopted until 2014 and the European Medicines Agency has to deal with resource / financial problems. In the meantime, the CMDh has to close the gap by drawing up a transitional PSUR list. The group also has to implement evaluated PRAC signals, which

AESGP Workshop | London 23-24 October 2013

are all listed in one spot on the EMA website. Bachmann mentioned that the European Medicines Web Portal on which safety issues are to be reported was to be

linked to the websites of the national competent authorities (NCAs). In case of pharmacovigilance referrals, the CMDh has 30 days to reach a position, with a

possibility for a re-examination request within 15 days under Article 31. This flexibility is not provided in Article 107i urgent pharmacovigilance referrals.

Bachmann concluded that there is close interaction between the PRAC and the CMDh. Experience had been gained so far with several ingredients, on the decisions of which he provided some additional details. One of the questions on tetrazepam was, for instance, whether practical experience or the scientific view was more important for old products, and whether the narrow majority in favour of

suspension (15 v 12) really was sufficient to suspend a marketing authorisation. Of major importance is the communication to the public and to health professionals, as well as the timing of any pharmacovigilance announcement, said Bachmann. Bachmann finally mentioned the ongoing CMDh discussions on how safety conditions

can be implemented in case of several marketing authorisation holders, how these MAHs can be stimulated to coordinate their resources in case a clinical study or a Postauthorisation safety study (PASS) is requested, and how changes in the product information can be implemented in a harmonised way.

7 avenue de Tervuren, Brussels, Belgium Tel.: + 32 2 735 51 30 Fax: + 32 2 735 52 22 E-mail: info@aesgp.eu http://www.aesgp.eu

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