0. 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

1. A little bit of history
Directive 65/65/EC founds European pharmaceutical legislation but excludes medicines used for research purposes from its scope
EC GCP published
Directive 91/507/EC studies included in MAA to be run to GCP
Commission discussion paper on a future clinical trials legislation
Directive 2001/20/EC published includes clinical trial authorization and GCP and GMP requirements for IMPs in European Pharmaceutical legislation
Directive 2001/20/EC comes into force
Commission proposal for a Regulation on clinical trials
Regulation (EU) N0. 536/2014 (clinical trial Regulation) published
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

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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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.

10. 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

11. 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.

12. 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

13. 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.

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

15. 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.

16. 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.

17. 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
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

18. 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

19. European Medicines Agency
28 April 2017
Thank you for your attention
Further information
European Medicines Agency
30 Churchill Place • Canary Wharf • London E14 5EU • United Kingdom
Telephone +44 (0) Facsimile +44 (0)
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