Drug development in Parkinson’s disease The regulatory perspective, and how can we help coping with the bottlenecks Presented by: Pavel Balabanov, MD PhD Human Medicines Evaluation Division, Scientific and regulatory management department, CNS and ophtalmology

Main topics Who are we at EMA and what is our regulatory experience in Parkinson’s disease (PD) Initiatives available at EMA to stimulate and support new drug development in PD: What can we offer? When and what you should use the different initiatives for? Presentation title (to edit, click View > Header and Footer)

The European Medicines Agency –who are we? Responsible for the scientific evaluation of medicines developed by pharmaceutical companies for use in the European Union. Main task – the centralized procedure but also: A significant role in stimulating innovation and research in the pharmaceutical sector: Publishing guidelines on the requirements for the quality, safety and efficacy testing of medicines Providing scientific advice to companies on the development of new medicines; special assistance to micro, small and medium-sized enterprises (SMEs); Issue opinions on orphan designation for medicines for rare diseases; Innovation task Force (ITF) -a group that provides a forum for early dialogue with applicants. Presentation title (to edit, click View > Header and Footer)

Regulatory experience in PD 25 October 2017 Number of licenced products since 1997: 25 Dopamine agonists – 8 (pramipexole -6, rotigotine -2) Entacapone/tolcapone – 5 levodopa / carbidopa / entacapone – 2 MAO inhibitors – 1 ioflupane (123l) – 1 (diagnostic agent) Rivastigmine – 8 (symptomatic treatment of dementia in PD) Number of PD products that received scientific advice in the last five years: 15 (mainly dopamine agonists, L-DOPA/carbidopa combinations, adenosin 2a agonists, mGluR5 antagonists, and a couple of diagnostic tools) Only a couple PD products were seen in Innovation task force (ITF) platform Presentation title (to edit, click View > Header and Footer)

Regulatory? Scientific? Both? How can we help tackle them? Bottlenecks? Regulatory? Scientific? Both? How can we help tackle them? Presentation title (to edit, click View > Header and Footer)

EMA initiatives to support drug development What do we provide? Scientific guidelines designed to help applicants prepare marketing-authorisation applications for human medicines. Guidelines provide a basis for practical harmonisation of how the EU Member States and the Agency interpret and apply the detailed requirements for the demonstration of quality, safety and efficacy. PD guideline last updated in June 2012 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/ WC500129601.pdf What can stakeholders do? Comments on the guideline can be sent during the consultation phase or at any other point in time. Presentation title (to edit, click View > Header and Footer)

EMA initiatives to support drug development 25 October 2017 What do we provide? 2. Innovation Task Force (ITF) platform and meetings meetings are free and provide an open environment for a dialogue with experts a multidisciplinary group that includes scientific, regulatory and legal competences. provide regulatory advice to applicants on the eligibility to Agency procedures as a medicinal product increase awareness and learning in emerging therapies and technologies at the Agency What can it be used for? a discussion platform for early dialogue with applicants to proactively identify scientific, legal and regulatory issues of emerging therapies and technologies (e.g. growth factors, gene and cell therapy, any significant therapeutic innovation in PD;) http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000334.jsp&mid= WC0b01ac05800ba1d9 Presentation title (to edit, click View > Header and Footer)

EMA initiatives to support drug development 25 October 2017 What do we provide? 3. Qualification of novel methodologies procedure CHMP Qualification Opinion on the acceptability of a specific use of the proposed method (e.g. use of a biomarker) in a research and development context (non-clinical or clinical studies), based on the assessment of submitted data. CHMP Qualification Advice - for further method development towards qualification; What can it be used for? To qualify for the intended use (and make acceptable in a regulatory sense) different: - Biomarkers - Models -Diagnostic tools - Scales, PROs etc. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000319. jsp&mid=WC0b01ac0580022bb0 Presentation title (to edit, click View > Header and Footer)

EMA initiatives to support drug development 25 October 2017 What do we provide? 4. Scientific advice (SA) and protocol assistance (PA) Scientific Advice can be given on ANY scientific question on quality, non-clinical and clinical development at any time point of the development (post-marketing advice is also available) Strictly confidential What should it be used for? to present and justify a new strategic scientific approach in drug development especially when: no guideline is available OR when development plans to go against the guideline recommendations (for a scientific reason) Treatments are developed for rare diseases and conditions as well as in the case of advanced therapies In the clinical development - SA on primary endpoints, statistics and comparator should be sought – analysis shows that when these have been agreed upon in SA, the success rate for a positive opinion at marketing authorization stage increases http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000 049.jsp&mid=WC0b01ac05800229b9 Presentation title (to edit, click View > Header and Footer)

Scientific advice and protocol assistance 25 October 2017 Scientific advice and protocol assistance Incentives and benefits The financial side: For small- and medium-sized-enterprises (SMEs) fee waiver is available PA for orphan drugs – reduced fee (no fee if applicant is a SME) Paediatric only developments – no fee The scientific and regulatory side: Saves time and resource by providing solutions to difficult issues in the early stages (before too much time and resources have been committed) Advices are peer reviewed by the CHMP (for advanced therapies CAT is involved) – same experts that will review the marketing authorisation application Complying with SA/PA is significantly associated with positive outcome – around 97% of applications compliant with received SA have been granted a positive opinion at marketing authorization stage; Presentation title (to edit, click View > Header and Footer)

Take home messages 25 October 2017 The European Medicines Agency offers a number of initiatives to stimulate and support new drug development, that can help tackle important scientific and regulatory issues The initiation of early dialogue is essential and recommended. The active and targeted scientific dialogue with the regulator increases the chances for positive results at marketing authorization stage Presentation title (to edit, click View > Header and Footer)

Come and talk to us! Drug development Presentation title (to edit, click View > Header and Footer)

Other useful links and more information: Small and medium sized enterprises: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/genera l/general_content_000059.jsp&mid=WC0b01ac05800240cc Orphan drugs: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/genera l/general_content_000029.jsp&mid=WC0b01ac05800240ce EMA scientific guidelines: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/genera l/general_content_000043.jsp&mid=WC0b01ac05800240cb Advanced therapies: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/genera l/general_content_000294.jsp&mid=WC0b01ac05800241e0 Presentation title (to edit, click View > Header and Footer)