1. EU Clinical Trial Regulation(CTR)
Are you prepared
November 2015
A.N. Moult

2. Employment Disclaimer
The views and opinions expressed in the following PowerPoint slides are those of the individual presenter. They are brought together as a result in participation in EFPIA Technical Development Expert Group and its Work Groups however they are not formal EFPIA policy The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to the company the speaker is employed by (Daiichi-Sankyo Development or any other Daiichi-Sankyo Group companies)

3. Contents CTR status CTR highlights
Stages and their currently projected timings
CTR highlights
One point of application
Consequential legal changes (delegated acts) for IMPs and their status
Areas for clarification and or concern

4. Approval & implementation
Entry into force
Earliest applicability *
Publication
EU-CTR
17 June 2014
27 May 2014
Q4/2017
(estimate)
Q4/2018*
Q4/2020*
EU-CTD A B
Repealed by EU-CTR
Applicability
Independent audit of EU Portal & Database functionality published in Official Journal 6-months before application
A: Clinical trials may still be submitted and started under EU-CTD
B: Clinical trials submitted under A may continue to be governed by EU-CTD until Q1/2020 (earliest)
Reference: EU-CTR Article 98
*Subject to EMA IT development (EU-CTR Article 82) 4

5. CTA simplification Regulation Art. 5, 6, 7 and 8

6. Outline of clinical trial authorisation (CTA) dossier content
Part I – «General»
One Dossier
Part II – «National»
Classification as a low-intervention clinical trial
Therapeutic & public health benefit aspects
Risks & inconveniences for the subject
Manufacturing/importation of IMPs/AMPs
IMPD
Labelling
Investigator’s brochure
Informed consent
Compensation/ rewarding arrangements
Recruitment arrangements
Data protection rules
Suitability of - individuals - trial sites
Damage compensation
Biological samples
Content
Submission
EU Portal (by EMA)

7. CT Authorisation Concept (simplified) Regulation Art. 5, 6, 7 and 8
Dossier (Part I & II) Submission to EU Portal
Validation
Part I – «General»
Lead: reporting MS (rMS)
Part II – «National»
Lead: concerned MS (cMS)
days
Confirmation of rMS and Validation
45-76 days*
rMS conducts review, drafts AR, cMS comment, rMS incorporates input from cMS**
45-76 days*
Assessment
Part I Assessment report & conclusion
Part II
Assessment report & conclusion
Acceptable
(w/wo conditions)
Not acceptable
5 days
Exception: Qualified opt-out scenarios
Inferior treatment compared to normal clinical practice in cMS
Infringement of national legislation (on use of cells)
Disagreement with conclusion based on safety, data reliability and robustness
If no notification:
Conclusion of
Part I
Assessment report shall be considered the decision (tacit approval)
Decision
Default: No opt-out of cMS
cMS accepts positive conclusion of assessment report
Conclusion of national assessment Part II
EU Portal – One Single decision per cMS and Notification
Start of Clinical trial Art. 2(25)
* Maximal timeline with clock stop for questions.
** rMS can extend assessment time by 50 days for ATMPs and products derived from rDNA technology

8. Directive v’s CTR additional legal landscape
Legislation / Other document
CTD (2001/20/EC)
CTR (536/2014)
Status
GMP Directive for MP and IMP
Directive 2003/94/EC
Will be Implementing act for MP – Legal basis 2001/83/EC and Delegated Act for IMP – Legal basis 536/2014
Both under consultation until 24 Nov Industry commenting via EFPIA and a draft response has been prepared.
Annex 13
A detailed guidance for IMP
Under consultation until 24 Nov Industry commenting via EFPIA and a draft response has been prepared
NIMP
Covered by CTR only (as AMPs)
Detailed Guidance is not anticipated

9. Some changes to terminology and Trial Definition
Low- Interventional Clinical Trial
Commercial product within the MA or strict boundaries away from MA
Aimed at Clinical Practice improvement rather than new product / indication
Less stringent rules (at least intended only opinions vary)
Auxiliary Medicinal Product (covered by Esther).
Tip read labelling requirements very carefully.
Very easy to miss read and think everything has to be re-labelled

10. Areas for clarification and or concern
It is a significant change in the way Clinical Trials are instigated
The portal is taking shape only taking time
Outside of the world of IMP many other functions are undergoing preparations for the changes at a time of significant political pressure on many aspects of health care and drug development.
There are some aspects of the CTR that Industry / EMA (inspectorate) and Commission are now only understanding as demonstrated in the consultation on “delegated acts”, portal etc. for IMP these include
Annex VI. identified early – current status – no change
Inspections outside EU
UK specific – Transitional QPs – ( R. Smith)
In many functional areas questions are being raised and pragmatic solutions found.

11. How prepared is your company
Do you have a cross functional preparedness program / initiative
SOPs for all functions
Most companies will be looking at the impacts via SOPs.
Most SOPs will not change or be very minor such as substitution for references /20/EC to 536/2014.
A significant minority of SOPs will have a major re-write over terminology
A small number of processes will change significantly – Such as around submissions via the EU Portal
Are these identified and plans in place to work differently even if the exact details are not fully known e.g. Portal information –
Worse case - Exactly how it works will emerge around Mid 2017 after the audit or emerging elements may become clear as it is built in 2016.

12. How prepared is your company continued
IMP preparation.
SOP as previous
Annex VI
Even with Annex VI worst case perhaps 80% of studies will not be impacted
Are the 20% identified and what is the cost of mitigation or other changes needed.
If Annex VI does not change waiting to find out may be too late
Is a subset of the preparedness program looking at the Consultation documents – Delegated Act and Detailed Guidance on GMP for IMPs as well as in the GCP aspects of Inspections of Trials by MS’s

13. Questions and Answers

14. Clinical trials - Regulatory framework
Good Clinical Practice
Directive 2005
Good Clinical Practice
1996 1⁰
Legn e.g.
CT Reg 536/2014
1⁰legislation e.g. CT Directive 2001/20/EC
Implementing Regulations/ Delegated Acts in GMP/ GCP
Commission guidance e.g. CT1 (CT authorisation, amends & end), CT2 (ethics applications) and CT3 (safety) & additional supporting documents e.g. Q&As
Transcribed into national law – UK Medicines Act – additional national requirements
Transcribed into EU Member State law
Declaration
of Helsinki
520/2012 – published after 2010 pharmacovigilance legislation with requirements for the PSMF
CT1: Detailed guidance on the request to the competent authorities for authorisation of a clinical trial on a medicinal product for human use, the notification of substantial amendments and the declaration of the end of the trial (CT-1)
CT2: Detailed guidance on the application format and documentation to be submitted in an application for an Ethics Committee opinion on the clinical trial on medicinal products for human use – 2006
CT3: Detailed guidance on the collection, verification and presentation of adverse event/reaction reports arising from clinical trials on medicinal products for human use (‘CT-3’) – 2011
The Declaration of Helsinki is a set of ethical principles regarding human experimentation developed for the medical community by the World Medical Association (WMA). It is widely regarded as the cornerstone document of human research ethics.[2][3][4]
It is not a legally binding instrument in international law, but instead draws its authority from the degree to which it has been codified in, or influenced, national or regional legislation and regulations.[5] Its role was described by a Brazilian forum in 2000 in these words "Even though the Declaration of Helsinki is the responsibility of the World Medical Association, the document should be considered the property of all humanity".[5] Updated October 2013 (originally adopted 1964)

15. Understanding EU law A simple view
A Directive = EU legislation that requires member states to enact via their own legislation the provisions of the directive.
It sets a minimum standard only each member state is allowed to make more stringent provisions as it translates the directive into national law
A Regulation = EU legislation that becomes law in all member states.
It needs no further legislation and is identical in all member states
Delegated act – The What
May be a Regulation or Directive that stems from primary legislation
Are considered closer to actual law-making
The extent of the delegation has to be clearly determined in the original legislation
Their content is more likely to be politically sensitive.
Implementing act – The How
May be a regulation or Directive that stems from primary legislation
Is considered to be inherently more procedural (templates, procedures, deadlines)
A pure, practical implementation of rules that already exist in the original legislation.

16. Points to consider in any implementation plans for Annex VI compliance
Back up slides Annex VI
For those who are not aware of EFPIA concerns the video is available.   
Points to consider in any implementation plans for Annex VI compliance
the type of pack and duration of study including potential for date extension
the time during the one year transition period after Q that your company wishes to submit CTA . In addition, you may wish to consider if the choice of timing should be dependent on the pack type / study length or other factors.
if the trial will be ongoing beyond the Q4 2020, which is the earliest point at which all clinical trials in Europe should be compliant with the Regulation. If so will the label strategy be compliant currently or will a change in design mid study be employed?