The New Regulation – How will the outcome affect the needs of Europe The New Regulation – How will the outcome affect the needs of Europe? Regulation (EU) No. 536/2014 DIA , 23 September 2014 Presented by: Fergus Sweeney, Head, Inspections and Human Medicines Pharmacovigilance Division

A little bit of history 1965 - Directive 65/65/EC founds European pharmaceutical legislation but excludes medicines used for research purposes from its scope 1990 - EC GCP published 1991 - Directive 91/507/EC studies included in MAA to be run to GCP 1991 - Commission discussion paper on a future clinical trials legislation 2001 - Directive 2001/20/EC published includes clinical trial authorization and GCP and GMP requirements for IMPs in European Pharmaceutical legislation 2004 - Directive 2001/20/EC comes into force 2012 - Commission proposal for a Regulation on clinical trials 2014 - Regulation (EU) N0. 536/2014 (clinical trial Regulation) published 2018 - Regulation (EU) No. 536/2014 comes into application And now …….Europe’s opportunity to enhance its global status as the base for innovation in clinical research and medicines development

http://ec.europa.eu/health/files/eudralex/vol- 1/reg_2014_536/reg_2014_536_en.pdf http://ec.europa.eu/health/files/eudralex/vol-1/reg_2014_536/reg_2014_536_en.pdf

Regulation (EU) No. 536/2014 Key Objectives: Streamlining the clinical trial application and supervision process – enabling research and underpinning EU as a location of clinical trials at global level Single electronic application dossier for whole EU Coordinated assessment Strict timelines Transparency of clinical trial authorisation, conduct and results

Scope of clinical trial Regulation (EU) No. 536/2014 Interventional clinical trials on medicines conducted in the EU/EEA (i.e. with at least one investigator site in EU/EEA) Clinical trials authorized under the new Regulation or still ongoing three years after it comes into application

Regulation Key components and objectives Scope (unchanged) – interventional clinical trials of medicinal products Single EU portal and database to support: One application dossier for each clinical trial or modification to it Coordinated approach to clinical trial authorization and supervision Transparency of clinical trial authorization, conduct and results Protection of trial subjects, including special provisions to enable trials in emergency situations and cluster trials Streamlined safety reporting for SUSARs and Annual Safety Reports Proportionate approach to trial supervision and conduct

Single EU portal and database One clinical trial application form and supporting dossier to cover: One or more Member States, and all regulatory and ethics assessment Public registration of the trial and its subsequent updates, including the necessary elements of international registration at WHO ICTRP portal Providing the trial design elements to support subsequent entry and publication of the summary of results EU numbers to identify of products and substances to underpin linking and aggregation of information on IMPs (with MA via art 57, without MA EU number provided via CT system before or during CT assessment) EU trial number – one per trial

Processes for each stakeholders in the system 28 April 2017 Processes for each stakeholders in the system This slide depicts the processes each stakeholder will be able to complete in the new EU Portal and Database: Submission of CSR Submission of Union Control Reports Submit submission package (CTA & dossier) / Address request for information Notification of willingness to be RMS(Part 1)/Decision on RMS Update of Clinical Trial information re non substantial modifications Applicant of a MA Commission Submit notifications: Withdrawal Start of trial First visit first subject End of recruitment End of trial (in each MS, All MS, Global) Temporary halt Restart of trial Early termination Serious Breaches Unexpected events which affect risk/benefit Submission of requests for information Notification of the final validation (initial, additional MS or Substantial Modification) Sponsors Member States Submission final AR Part 1 and 2 Final single decision notification Submission Inspection Information Search and view CT related information saved in the EU database (that is not confidential) Submission of clinical study result summary General public Communication disagreement to part 1 assessment Submission of Inspection Reports of third country authorities EMA Runs the system but does not undertake any specific processes in the EU Portal and Database Communication on implementation of corrective measures

Authorisation procedure Part I – including joint assessment for trial in more than one MS (role of the RMS) + Part II national part Single assessment of Part I with single set of questions and responses and single outcome, regardless of the number of MS involved (1-28), Combines and consolidates best expertise of the MS involved Strictly defined timelines Ethics committees involved in the assessment in parts I and II as applicable according to the law of the MS concerned (no derogation from timelines) Single decision per MS (including regulatory and ethics review) in line with coordinated assessment of Part I Tacit approval if the MS fails to comply with deadline

Transparency EU database publically accessible by default, with exceptions justified on any of the following grounds: Protection of personal data; Protection of commercially confidential information in particular taking into account the MA status of the medicinal product, unless there is an overriding public interest in disclosure; Protecting confidential communication between MS in relation to the preparation of the assessment report; Ensuring effective supervision of the conduct of a clinical trial MSs.

Transparency – results of clinical trials Specific obligations on sponsor to submit summary of results and lay person summary one year after the end of the trial this applies to all clinical trials authorised under the new regulation or transitioned to it. MAH required to submit the CSR once the MA procedure is complete (positive or negative) or withdrawn by the applicant this applies to trials in a MA with EU sites and authorised under the new regulation – hence not to non-EU trials or trials in EU authorised under current legislation. MS introduce the penalties for breach of transparency provisions

Streamlined safety reporting Central reporting to EudraVigilance of SUSARs Central reporting of Annual Safety Reports Rerouting of these to Member States Protocol may provide that not all AE and serious AE recorded and reported; Same rules for annual reporting for all IMPs; Possibility to have a grouped annual safety reporting when several IMPs are used; Cooperation between MS in the assessment of safety.

Protection of trial subjects Clear requirements for informed consent, including in specific populations Clinical trials on incapacitated subjects Clinical trials on minors Clinical trials on pregnant or breastfeeding women - Emergency clinical trials: CT expected to produce a potential direct clinical relevant benefit for the subject; Minimal risk and minimal burden in comparison with standard treatment. - MS may maintain additional national measures for clinical trials in persons performing mandatory military service, prisoners, persons in residential institutions - Possible cluster trials with simplified informed consent

Proportionate approaches to regulation Low intervention trials – marketed product in accordance with labeling or established therapeutic uses Dossier requirements adapted to marketing authorization status, simplified IMPD etc Safety reporting – core requirements but adaptable to the needs and objectives of the protocol in line with knowledge of the safety profile Monitoring – the extent and nature to be determined based on trial characteristics including : whether the trial is a low-intervention trial, its objectives and methodology the degree of deviation of the intervention from normal clinical practice.

Other Provisions Supervision: - Inspections reports submitted to the EU database Union controls Serious Breaches Co-sponsorship Legal representative/contact person Damage compensation

Clinical Trial Regulation A real opportunity for EU to innovate and to lead in clinical trial regulation and in innovation of new medicines and better use of existing medicines, Streamlined, coordinated, proportionate and transparent Single electronic submission of data and documents to cover trial application, modification, registration and results reporting Streamlined and coordinated clinical trial between and within MS, using best expertise in the MS concerned Streamlined safety reporting, Proportionate supervision of clinical trials, Transparency supporting public confidence, participation and critique and enabling innovation.

Supporting Cooperation with China The clinical trial Regulation: Facilitates Multi Regional Clinical Trials (MRCTs) Enabling China to develop medicines destined for the EU market by readily including investigator sites in EU in MRCTs Medicines being developed internationally in MRCTs should equally include patients relevant for the patients of China, so that one set of clinical trials can fulfil all markets needs including EU and China.

Supporting cooperation with China – supply chain aspects China currently a major source of supply of medicines – particularly APIs >200 EU inspections carried out in China 2013-2015 EU wants to move towards greater reliance on Chinese inspections – Provided they are Based on international standards ( equivalent to EU) Performed by trained inspectors Independence and conflict of interest rules apply Facility to exchange information in case of problems EU/EMA offers possibility for Chinese authorities to observe EU inspections EU/EMA can offer training and staff exchange possibilities Working together towards a more global approach and best use of global resources

Cooperation with China Broad based Clinical Trials The Clinical Trial Regulation broadens the opportunities for such cooperation Manufacturing APIs and finished products China is an important source of medicines for EU Building the framework to sustain the quality of this supply is important to EU and to China

European Medicines Agency 28 April 2017 Thank you for your attention Further information GCP@ema.europa.eu EMAInternational@ema.europa.eu European Medicines Agency 30 Churchill Place • Canary Wharf • London E14 5EU • United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact Note: This slide is OPTIONAL. It uses the 'Closing slide' layout. Delete if not needed. Follow us on @EMA_News