EU regulatory update - innovative marketing authorisation approaches and regulatory transparency policies CMC Strategy Forum Latin America 2015 Meliá Brasil Hotel, Brasilia, Brasil August 24-25, 2015 Niklas Ekman, Ph.D. Senior Researcher Finnish Medicine Agency (FIMEA), Helsinki, Finland [email protected]

Content 1. Adaptive pathways for marketing authorisation 2. Transparency in EU pharmaceutical sector – Publication of clinical reports

Disclaimer The views expressed are my personal views and should not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties.

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European regulatory network • EMA coordinates the evaluation, supervision and pharmacovigilance of human and veterinary medicinal products • The scientific resources are provided by the 28 EU member states with more than 4900 European experts listed (regulators and experts from hospitals and universities) EMA, London, UK

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Marketing authorisation application in the EU • Medicinal products can be authorised in EU through national, MRP/DCP or the centralised procedure • The centralised procedure (EC 726/2004) is mandatory for biotechnology products, advanced therapy medicinal products, orphan medicines and for drugs containing new active substance for the treatment of certain diseases • • • •

Coordinated by EMA 277 days active evaluation/ decision time (210 days + 67 days) One scientific opinion based on the benefit/risk balance issued by the CHMP One marketing authorisation granted by the European Commission and valid in all EU member states

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New innovative approach for marketing authorisation - main drivers* • Patient expectations

• Demand for timely access of effective and safe drugs for the individual patient, not for the virtual “average” patient. Drugs for rare diseases should also be available

• Healthcare systems under pressure

• Affordable medicines - Regulatory approval is no longer a sufficient precondition for patient access

• Pharma/investors

• Drug development needs to be sustainable

• Emerging science

• Fragmentation of treatment populations and early disease interception.

*) Mainly based on Eichler HG et al. From adaptive licensing to adaptive pathways: delivering a flexible life-span approach to bring new drugs to patients. Clin Pharmacol Ther. 2015 Mar;97(3):234-46 Lääkealan turvallisuus- ja kehittämiskeskus

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The Adaptive Approach/ Adaptive Licensing • Progressive (or staggered) approval of a medicine based on a prospectively planned, lifespan approach

• Aim to balance timely access for patients with the need to provide adequate evolving information on benefits and risks • Particularly relevant for medicines with the potential to treat serious conditions with an unmet medical need • Initial authorisation in a restricted patient population, possibly on the basis of surrogate markers • Iterative phases of evidence gathering and licensing adaptations • Uncertainty is reduced through the collection and use of real-world, post-authorisation data, as a complement to randomised clinical trial data Lääkealan turvallisuus- ja kehittämiskeskus

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• Involves early discussion between a wide range of stakeholders; • Regulator, industry, health-technology-assesment (HTA) bodies, organisations issuing clinical treatment guidelines, patient and consumer organisations, healthcare professionals, researchers and academics

• Aims to guide applicants, through this multi-stakeholder dialogue to make the best use of available regulatory processes in order to achieve early patient access • Scientific advice • Centralised compassionate use • Conditional marketing authorisation (for medicines addressing life-threatening conditions) • Marketing authorisation under exceptional circumstances • Patient registries and pharmacovigilance tools Lääkealan turvallisuus- ja kehittämiskeskus

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Current scenario Post-licensing, treatment population grows rapidly; treatment experience does not contribute to evidence generation Adaptive Approach After initial earlier license, number of treated patients grows more slowly, due to restrictions; patient experience is captured to contribute to realworld information Slide kindly provided by Spiros Vamvakas, EMA Lääkealan turvallisuus- ja kehittämiskeskus

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• The main aim of the pilot is to help develop an understanding of how future adaptive pathways might be designed for different types of products and indications • Confidential discussions enabling all participants to freely explore different pathways/solutions without any early commitments • Aim is to promote and establish early dialogue, not to preassess suitability of data Lääkealan turvallisuus- ja kehittämiskeskus

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• The pilot project was initiated in March 2014. For Stage I discussions,10 applications were selected. Stage II meetings with longer, in-depth discussion(s) are ongoing

Some thoughts on CMC • Limited CMC data package at the time of initial MAA submission. Need for rolling review and deep considerations with regard to available data vs risk/ risk management. For example; • Process validation; Use of concurrent validation protocol? • New manufacturing site and/or scale; Use of Post Approval Change Management Protocols (PACMPs)? • Specifications; Probably not fixed, reviewed post-approval based on pre-defined criteria? • Stability; Use of prior knowledge, stability models etc.?

CMC could become a time limiting factor Lääkealan turvallisuus- ja kehittämiskeskus

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www.n-r-c.com

EMA Transparency measures* Pivotal principles

• Transparency is a pivotal element in building trust and confidence in the Agency’s operation hence contributing to the promotion and protection of public and animal health. • In addition it fulfils the right of EMA stakeholders for impartial and comprehensible information about the medicines regulated by the Agency and their use for the benefit of public and animal health. *Partly based on slides kindly provided by M. Harvey Allchurch, EMA Lääkealan turvallisuus- ja kehittämiskeskus

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Transparency in the beginning… • European public assessment reports, EPAR (1995) • Same information for patients and healthcare professionals in all EU languages, all accessible on a single website (1995) • Publication of all European experts (1996)

…and some more recent examples • CVs and declarations of interests published for all committee members, European experts, management board and staff • More information on workshops and meetings at EMA, more meetings broadcast live with recordings available • More opportunities for feedback on e.g. draft guidelines • EudraCT and clinical trials register websites • EMA access to documents policy (latest from 2010) Lääkealan turvallisuus- ja kehittämiskeskus

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What is currently in the public domain? • Compared to 10-15 years ago, not much of the submission and review cycle remains systematically confidential • Either because applicants put the information into public domain.. ..or because EMA publishes • Committees agendas, meeting highlights and minutes • EPARs at approval, pending EC decisions, rejection or withdrawal • On-going procedures • Monthly statistics reports on medicinal products for human use, monthly INN list, SMOPs (Summary of Opinion) • Orphan drug designation, paediatric investigation plan decisions, etc. Lääkealan turvallisuus- ja kehittämiskeskus

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Transparency during centralised Marketing Authorisation Application • Information on medicines under evaluation

• Committee agendas, minutes and highlights • Positive outcomes • • • • •

Summaries of Opinions Product information (SPC, PL) EPAR (European Public Assessment Report) Assessment history Authorisation details

• Negative outcomes • Withdrawal letter and Q&A • Refusal Q&A Lääkealan turvallisuus- ja kehittämiskeskus

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Medicines under evaluation

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EPAR

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The next step in transparency – Publication of clinical reports • Clinical reports* will be available on the EMA website once the concerned procedure has been finalised

• The new policy entered into force on 1 Jan 2015 *) Clinical reports include module 2.5 (clinical overview), module 2.7 (clinical summary), module 5 (clinical study reports (CSRs) and appendices 16.1.1 (protocol and protocol amendments), 16.1.2 (sample case report form) and 16.1.9 (documentation of statistical methods)) Lääkealan turvallisuus- ja kehittämiskeskus

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Objectives of the policy • To take the decision-making one step closer to EU citizens and promote better-informed use of medicines • To promote medicine development by allowing medicine developers and the scientific community to learn from past successes and failures

• To allow third parties to verify the original analysis and conclusions, to conduct further analyses, and to examine and challenge the regulatory authority's positions • While increasing transparency, the principles of protecting personal data (patients’ identity), protecting commercially confidential information, and protecting the Agency's and the European Commission's deliberations and decision-making process will be secured Lääkealan turvallisuus- ja kehittämiskeskus

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Thank you for your attention! Adaptive licensing http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_ 000601.jsp&mid=WC0b01ac05807d58ce

Transparency http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_cont ent_000526.jsp&mid=WC0b01ac0580789730

Publication of clinical reports http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_cont ent_000555.jsp&mid=WC0b01ac0580607bfa Niklas Ekman, Ph.D.

Senior Researcher, Quality/CMC Assessor Finnish Medicine Agency (FIMEA), Helsinki, Finland [email protected] Lääkealan turvallisuus- ja kehittämiskeskus Aug 24, 2015

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