1. European Clinical Trial Regulation  Liz Philpots, head of research, AMRC

2. Summary
About me & AMRC
About the EU Clinical Trials Regulation – what’s new
Implementation timeline
What does this mean for UK ethicists?

3. AMRC established 1987
133 member charities…from large to the small
All fund medical research
Spend more than £1Bn on research
1/3 of medical research in UK
Strong drive to benefit people affected by their condition
30% of studies in the NHS

4. A brief history of trial regulation
pre national regulation (e.g. CTX Scheme in the UK)
GAFREC – ethics committees
- EU ‘Clinical Trials’ Directive 2001/20/EC
2004 – UK law - Medicines for Human Use (Clinical Trials) Regulations
Good Clinical Practice Directive 2005/28/EC
BUT – EUCTD seen as a barrier to research:
25% drop in trials in EU
increased costs
massive increase in delay to get trial started
2012 – proposal for new regulation
EUCTD - introduced regulatory principles and framework for regulation of Clinical Trials in Europe
GCP directive supplemented the CTD, strengthening the legal basis for requiring Member States to comply with the principles and guidelines of good clinical practice as set out in the ICH-GCP (international) guidelines

5. Some major issues with EUCTD
interpretation by Member States not consistent
lack of clarity over definitions and requirements
cumbersome procedures, particularly for multi-centre clinical
trials in different Member States

6. The New EU Regulation on Clinical Trials
the new EU Regulation (No 536/2014) on clinical trials on
medicinal products for human use (and repealing Directive 2001/20/EC)
was adopted on 16th April 2014
it entered into force on 16 June 2014, but will apply no earlier than
28 May 2016 (in the meantime existing provisions continue to apply)
it’s a regulation - will apply directly to each EU Member
States

7. What’s different -processes?
a streamlined application procedure via a single entry point - an EU portal
and database
a single authorisation procedure for all clinical trials
a lighter regulatory regime for low risk clinical trials
streamlined safety reporting
strengthened transparency for clinical trials data

8. What’s different - principles
clinical trials are a subset of clinical studies
trial participants should represent the population that might benefit from the treatment
co- sponsorship
encouragement for clinical trials in rare diseases or of orphan products
ethics committees should be independent and involve lay people

9. What’s different - consent
enrolment without informed consent in emergency situations
simplified consent process for ‘cluster trials’
special consideration for
incapacitated subjects
minors
pregnant & breast feeding women
military personnel, prisoners, people in residential care institutions
Emergency situations – but only if the intervention might provide direct benefit to the person
Cluster trials – where groups are the subjects rather than individuals – IE when people in one GP practice receive one treatment, and another one gets a comparator treatment – both being standard care

10. What’s different - jargon
RMS
CMS
Low intervention clinical trials

12. Processes - streamlined application procedure
sponsor must submit an application via an EU online portal
single entry point for application, assessment and subsequent data submission
better communication between sponsor and authorities, and between authorities in the relevant Member State
greater transparency of CTs and of the results of CTs
BUT - the portal needs to be built…..

13. Processes - single authorisation procedure - I
for multinational CTs all Member States will be involved in the assessment, although a ‘Reporting’ Member State (RMS) will lead and coordinate the assessment
Member States will retain responsibility for aspects which are entirely national for example, informed consent, and compensation arrangements
authorisation process timelines are specified whilst retaining the concept of ‘tacit authorisation’
possible to extend the CT to additional Member States and clarifies when a new CT authorisation is required

14. Processes - single authorisation procedure - II
Each country (CMS) inputs into Part I and conducts its own Part II assessment.
Part I:
Reporting member state (RMS) –scientific assessment
Part II: National assessment by each country of site details, ethics, etc :
Part 1 assessment
Is it low intervention?
Scientific review
Risk & inconvenience to participants
Manufacturing authorisation/ import
Labelling
Investigators brochure
Part 2 assessment
Ethics
Consent
Liability
Payment to investigators & subjects
Investigator suitability
Site suitability
Damages/compensation
Sample storage/biobanks

15. Processes for authorisation
How authorisation will work – each country has its national competent authority

16. Processes - low interventional clinical trials
proportionate rules for monitoring, reporting, traceability and storage of investigational products
‘low interventional’ means
- authorised medicines used within the terms of their authorisation
OR - ‘off-label’ use of medicines that is supported by appropriate evidence
AND - trial procedures with minimal additional risk or burden to the safety of the trial participants
one criticism of the existing Directive was that there were the same obligations for all CTs regardless of level of risk
The MHRA & DH in the UK developed Risk-adapted Approaches to the Management of trials – a variation on these are being adopted by the new regulation

17. Processes - transparency
EU portal provides a systematic and transparent way to log CT lifecycle events
sponsors must submit a publically available summary of the results of the
CT within one year of its end, irrespective of the outcome of the trial
where an EU Marketing Authorisation is granted, a full clinical study report will have to be submitted for publication on the EU database
all CT must also provide a simplified summary of results for public audience
Sponsor must notify the portal within 15 days
- the start of the trial
First patient first visit
End of patient recruitment
Any temporary halts
End /early termination of a trial

18. Portal fully functional….. Dec 2015?
16 April 2014
Adopted
Portal fully functional….. Dec 2015?
28 May 2016
Entry into force
Implementation timeline
6 MONTHS

19. What does this mean for UK ethicists?
Much stays the same
It’s all about the portal …
portal needed for implementation
national systems need to ‘speak’ to the portal
planned –Dec ….. watch this space

20. Dr Liz Philpots l.philpots@amrc.org.uk www.amrc.org.uk
Thank you
Dr Liz Philpots
Regulation: