regulation (eu) no 536/2014 of the european parliament and of the council of 16 april 2014 on...

REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 April

2014 on clinical trials on medicinal products for human use

Overview of key aspects

Pieter Neels, MDIndependent Regulatory Expert

Associate Professor University of NamurAdvisory Board Member of NDAreg

Ex- CHMP member for BelgiumEx- Vice-chair VWP (EMA)

NDA Advisory Services

NDA Advisory Services

• Although I have been a member of the CHMP, my presentation might not be the view of the CHMP, the European Medicines Agency (EMA), the Belgian Medicines Commission, neither of the Vaccine Working Party.

• My presentation is a personal viewpoint and binds in no way the organisations mentioned before.

2

Disclaimer

3NDA Advisory Services

Declaration of interest

3

• I signed a non-exclusivity consultancy contract with

Novartis VCrucell Holland BVNDAregGSKInovigateGileadJanssenTakedaITS…


To set the scene… question to the audience

Company Z wants to test a challenge virus (let ‘s say a flu H1N1) to find the best dose in order to test a new vaccine in a second step.They ask scientific advice @ the authority to be reassured that the production of this challenge virus is acceptable by the authorities.

But… Z claims that this is not a clinical trial, as a challenge virus is not a medicinal product, thus no IMP…



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

Definitions:

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



To help you: DIRECTIVE 2004/27/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 31 March 2004

Definitions:

Medicinal product:(a) Any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or(b) Any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis.’

However



To help you: REGULATION (EC) No 726/2004 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 31 March 2004

Definitions:Any medicinal product not appearing in the Annex may be granted a marketing authorisation by the Community in accordance with the provisions of this Regulation, if:(a) the medicinal product contains a new active substance which, on the date of entry into force of this Regulation, was not authorised in the Community; or(b) the applicant shows that the medicinal product constitutes a significant therapeutic, scientific or technical innovation or that the granting of authorisation in accordance with this Regulation is in the interests of patients or animal health at Community level.



Is this a clinical trial?

REGULATION (EU) NO 536/2014 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL

OF 16 APRIL 2014 ON CLINICAL TRIALS ON MEDICINAL PRODUCTS FOR HUMAN USE

OVERVIEW OF KEY ASPECTS

AM Georges, EUVACRA consulting, March 2015

Clinical Trials: facts (from DG Sanco,2011)

4 400 clinical trials applied every year:24% of EU CTs are multinational (today approved separately by each individual country),67% of subjects enrolled in multinational clinical trials.

Clinical Trials Directive (2001, in force since 2004) = most heavily criticised piece of EU-legislation: patients, industry, academic research...Applications for clinical trials fell by 25 %

10

FACTS (2)

Costs for conducting clinical trials have increased.Staff needs for industry to handle CT authorisation

process = + 107 %.For non-commercial sponsors, increase due to Directive

2001/20/EC = 98% in administrative costs.Insurance fees have increased by 800 % for industry since

10 yrsThe average delay for launching a clinical trial has

increased by 90 % to 152 days.

19/04/23

11

New Regulation: Overview of key aspects-1Change from Directive to Regulation= harmonisation.In force not before May 2016Same scope as Directive (interventional trials)Single EU CTA dossier submitted to a single EU Portal (+)Dossier content/requirements identical for all EU

countries (+)Coordinated scientific assessment by MSs involved in

the trial, in parallel to the national Ethical review, all to be completed within the same timelines (+)

Single decision from each MS covering scientific and ethical parts. (+)

19/04/2312

Authorisation Process Timelines

CTAs: 60 – 106 days* Amendments: 49 – 95 days* Addition of new MS: 52 – 83 days

* Additional time (+ 60ds possible for Advanced Therapy and Biotechnogicals)

19/04/2313

Overview of key aspects 2. Approval process: Concept of tacit approval if a decision is not communicated in the regulated time – enforces timelines (+)Tacit withdrawal provisions if sponsor does not respond in regulated time (+)Timelines : long, especially for Advanced Therapy + rDNA biot.Additional reporting requirements/ events

Start/end of recruitment and trial in each MS Changes in informed consent and safety reporting provisions Possible co-sponsorship Transparency increased Documents in a EU database : Summary CT results, layperson’s

summary... (+ CSR after MA granted).

19/04/2314

Overview key aspects 3 : the portal and accessibility to Public

A single portal for submitting a request to begin a clinical trial, conducted in one or more EU countries

A publicly accessible EU database: register of all trials conducted in the EU. Trials registered and a summary must be uploaded within a year of completion.

Data contained in CSRs not considered commercially confidential once marketing authorization completed

EU portal - single entry point/ interface EU database - single data repository

19/04/23

15

Application (initial dossier, substantial and non-substantial amendments and addition of new MS)

Assessment reportMember States’ decisionsNotifications (start, temporary halt, (early) termination)CT results (summary results, lay friendly summary...)Serious breaches Inspection Documents (intention, inspection reports EU

and by third countries)Penalties in case of non-compliance with submission

requirements

Documents in EU Portal and EU Database

16Reference: Core provisions in Art. 77 – 78a

19/04/23

Overview of key aspects 417

Tighter rules for informed consent to ensure freedom and frame in easily understood language

New rules on reporting safety issues in clinical trials; investigator responsible for reporting all serious adverse events to the sponsor, which should assess the information and report any SUSARs to the EMA

New rules regarding GCP, GMP, manufacturing and import of investigational medicinal products, labelling, investigator‘s brochure, etc.

National contact pointsClinical Trials Coordination and Advisory Group (CTAG)

(exchange of information among member states and the European Commission on experience with the regulation)

19/04/23

Overview of key aspects 5

Principal investigator’s dutiesTraceability productsSuitability of sitesRecording infoProtection of subjects, information to be provided and

conditions/procedures Specific populations: minors, incapacitated, pregnant women, Specific conditions: emergency Reporting breaches CT master file to be kept for 25 yearsRepresentative of sponsor shall be located in the EUControls by MSs and by the Commission

19/04/23

18

Overview of key aspects: 6 Sponsor

One or several sponsors.Sponsor may delegate, (written contract), tasks to an

individual, a company, an institution or an organisation. Does not change responsibility of the sponsor, in

particular regarding the safety of subjects and reliability and robustness of data generated in clinical trial.

Investigator and sponsor may be the same person.

19/04/23

19

Overview of key aspects 7: Co-sponsorship

Each get full responsibilities unless written contractSponsors jointly responsible for establishing:

a) a sponsor responsible for compliance with the obligations of a sponsor in authorisation procedures

b) a sponsor responsible for being a contact point for questions from subjects, investigators, MSs

c) a sponsor responsible for implementing the corrective measures asked by MSs

19/04/23

20

CTA Regulatory Procedure

Dossier through common single portal, leading to one single assessment by concerned MSs (part 1, main dossier)

Submission in 2 parts:National matters (part 2): liability, ethics, protection,

compensations, suitability of the clinical trial site…. Withdrawal feasible up to reporting day (sponsor) If refusal of a trial, ressubmission feasible

19/04/23

21

Procedure: major changes introduced

Facilitation multinational clinical trials:Straightforward authorisation procedure

After submission, assessment by RMS and CMSs resulting in one single assessment outcome. (Part I)

Authorisation procedure allows EU MSs to define the roles of the bodies in charge of the assessment, (independence; expertise required)

Simplified reporting procedures (no separate reports in MSs)Concept of tacit agreement to all assessors, to avoid delaysMSs allowed to stop a CT in that country, if considering it

endangers health of subjects

19/04/23

22

One DossierOne Dossier

• Cover letter• Therapeutic & public health

benefit aspects• Risks & inconveniences for the

subject• Manufacturing/importation of

IMPs/AMPs• Labelling• Investigator’s brochure

• Cover letter• Therapeutic & public health

benefit aspects• Risks & inconveniences for the

subject• Manufacturing/importation of

IMPs/AMPs• Labelling• Investigator’s brochure

• Informed consent• Compensation/ rewarding

arrangements• Recruitment arrangements• Data protection rules• Suitability of

- individuals- trial sites

• Damage compensation• Biological samples

• Informed consent• Compensation/ rewarding

arrangements• Recruitment arrangements• Data protection rules• Suitability of

- individuals- trial sites

• Damage compensation• Biological samples

Application Dossier – Content (harmonised)

23

Part I – «General»

Part II – «National»

EU Portal (EMA)EU Portal (EMA)19/04/23

Authorisation procedure - overview24

Submission

Part I- cMS to take up conclusion (eventually with conditions) of rMS- Disagreement with conclusions in defined situations («opt out»)

Part I- cMS to take up conclusion (eventually with conditions) of rMS- Disagreement with conclusions in defined situations («opt out»)

Single decision per cMSEach cMS to authorise (possibly subject to conditions) or refuse authorisation via EU portal

Notification to sponsor

Single decision per cMSEach cMS to authorise (possibly subject to conditions) or refuse authorisation via EU portal


Decision

Part IINo notification of decision by cMS

in defined period = tacit agreement on conclusion on Part I

and thus overall decision on the trial

Part IINo notification of decision by cMS

in defined period = tacit agreement on conclusion on Part I

and thus overall decision on the trial

Two-part procedure

Part I – «General»rMS coordinates joint review with cMS

Part II – «National»Each cMS assesses local and ethical aspects

Two-part procedure

Part I – «General»rMS coordinates joint review with cMS

Part II – «National»Each cMS assesses local and ethical aspects

Assessment

Single EU portal/ database

( EMA)For all communications

and resultsbetween sponsor and MS

Single EU portal/ database

( EMA)For all communications

and resultsbetween sponsor and MS

Single submission dossierOne format/ content as

defined in legislation (Annexes)

Single submission dossierOne format/ content as

defined in legislation (Annexes)

Sponsor Reporting Member State (rMS) &Concerned Member States (cMS)

Each Concerned Member State (cMS)

24 19/04/23

Submission-Reporting MS

Sponsor submits application dossier to intended Member States concerned through ‘EU portal’.

Sponsor suggests a MS concerned as reporting MS. If another MS concerned wants to report or the proposed MS refuses,

notification through EU portal to all MS concerned (3 ds) If only one MS concerned wishes to report or if the trial involves only

one MS, that one reports If no MS concerned or more than one willing to report selection by

agreement. If no agreement proposed reporting Member State reports (confirm, 6 ds).

19/04/23

25

Validation

Within 10 days of submission, reporting MS validates application taking into account remarks of other MS concerned (7ds) and notify sponsor, through EU portal:

(a) clinical trial applied within the scope of Regulation; (b) dossier is complete If not notified trial applied for deemed to fall within the

scope and dossier considered complete

19/04/23

26


If dossier not complete, or trial applied for not within the scope, sponsor informed

10 ds for comments or complete. 5 days from comments/data, RMS to notify sponsor if

OK. No notification, trial deemed to be OK. If no sponsor’s comments, application lapsed.Validation date = notification.

TACIT WITHDRAWAL AND TACIT APPROVAL IF NO NOTIFICATION

19/04/23

27

Assessment scope

RMS assesses application:• Compliance re/ therapeutic + public health benefits

o characteristics /knowledge IMPo relevance of trial, including whether subjects represent

population to be treated, or explanation/ justification o state of scientific knowledge; trial recommended or imposed

by regulatory authorities in charge of the assessment / authorisation of licensing; any PDCO opinion

19/04/23

28

Assessment scope (2)

Reliability/robustness of data obtained in the trial, (statistical approaches, design, methodology, sample size, randomisation,

comparator, endpoints); Risks for subjects,

Characteristics and knowledge about product Characteristics compared to normal clinical practice Safety measures, risk minimisation, monitoring, safety reporting, and plan; Risk to subject medical condition for which the product is investigated;

Compliance manufacturing, import, labellingInvestigator's brochure

19/04/23

29

Assessment report Part I

Conclusion on Part I : (a) conduct of trial is acceptable

(b) conduct of trial is acceptable, but subject to compliance (conditions listed ) (c) conduct of trial is not acceptable.

Process: 45 days from the validation date (extension advanced therapy/biotech) Final Part I assessment report and conclusion through the EU portal, to

sponsor and MSs concerned For trials in more than one Member State assessment includes three phases:

(a) initial assessment phase by RMS (26 ds) from validation (draft circulated to other MS concerned; (b) coordinated review (12 ds) from initial assessment involving all MS concerned; (c) consolidation phase (7 ds) = reporting date

19/04/23

30

Assessment report Part II, national

Each MS concerned IN PARALLEL WITH Part I (45 ds from validation, + possible questions [+ 12 ds] and extension [+ 19 ds]) compliance with: informed consent rewarding or compensating subjects/ investigators recruitment of subjects investigators and facilities compliance damage compensation rules for collection, storage and future use of biological samples of the

subject.Lapsed in this Ms if no answer, (through portal)

19/04/23

31

Decision on the trial/disagreement

Each Member State concerned notifies sponsor (portal) re/ authorisation or conditions, or refusal.

Notification by one single decision (5 ds from reporting). If conclusion of RMS Part I is positive (or conditions), this is

conclusion of MSs concerned. Principle of tacit approval MSs concerned may disagree with RMS: grounds =

a) participation in trial leading to an inferior treatment than in normal practice in the MS

b) infringement of national law re/ product c) considerations safety and reliability /robustness

19/04/23

32

Decision and Disagreement

MS refusal communicated with justification, (EU portal), to Commission, all MSs, sponsor.

MS refuses to authorise trial if not agreeing Part I or Part II or where national ethics committee has a negative opinion.

If one Ms concerned has not notified sponsor of its decision within the relevant periods, Part I of the assessment report shall be deemed to be the decision

If no subject has been included in a MS concerned, 2 yrs after notification date, authorisation expires in that MS unless an extension, on request of the sponsor approved

19/04/23

33

Limiting applications to parts I or 2

Sponsor may apply for authorisation of a clinical trial, limited to the aspects covered by Part I of the assessment report.

After notification of the conclusion sponsor may within two years apply for an authorisation limited to Part II

Sponsor shall declare that he is not aware of new substantial scientific information that would change the validity of application covered by Part I

Application shall be assessed as Part II. In MSs where sponsor does not apply for an authorisation limited to aspects covered by Part II within two years, application on Part I lapsed.

19/04/23

34

Authorisation procedure - General overview

35

Initial Procedure (Part I & II)

Validation(from

submission)

Assessment (from validation to questions

& reassessment of responses)

Clock Stop (Sponsor to

answer questions)

Decision (from

assessment)

Total

CT 10 to 25 days 45 to 64 days 12 days 5 days 60 to 106 days

Advanced Therapy and r-DNA

idem Up to 114 idem Idem 60 to 156

Additional CMS (Part I & II)

Validation(from

submission)




answer questions)

Decision (from

assessment)

Total

CT NA 52 to 71 days 12 days 0 days 52 to 83 days

Substantial Modification(Part I & II)

Validation(from

submission)




answer questions)

Decision (from

assessment)

Total

CT 6 to 21 days 38 to 57 days 12 days 5 days 49 to 95 days

Advanced Therapy and r-DNA

38 to 107 days 49 to 145 days

19/04/23

Subsequent addition of a new MS Can only be done after notification of initial authorisation decision,

and if no substantial modifications are ongoing Using same rMS Submit through EU portal For part I:

• New MS communicates considerations/questions to rMS (and cMS)

• rMS requests additional information from sponsor For part II:

• New MS assesses within same timelines as for Part I Timelines : 52-83 days (includes 12 days clock stop to answer

questions).

36 19/04/23

Substantial Modifications to a protocolChange to any aspect of the clinical trial after notification of the

decision, likely to have substantial impact on safety or rights of subjects or on reliability and robustness of data generated in the clinical trial

Assessment of Parts I and II can be done in parallel or sequentially -Part I: Same rMS as for initial CT procedure: assessment

report -Part II: Assessment by each cMS, national procedures in

parallel Timelines: 49 – 95 days (includes 12 days to answer questions).

Note: AT and products derived from rDNA – ppossible additional 50 days, 49 -145 days

37 19/04/23



Clarification of the legal status of the study was obtained by submitting the protocol to the UK Medicines and Healthcare products Regulation Agency (MHRA) which confirmed it as a ‘‘Characterization Study’’ and not a Clinical Trial of an Investigational Medicinal Product (non-CTIMP/NIMP). Although not a clinical trial, we registered this study protocol on ClinicalTrials.gov (NCT00949572) prior to subject recruitment.



Definitions: REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 April 2014



Question: Is this an interventional clinical trial?


42

• Sponsor to adequately monitor the conduct of the trial, verify subjects rights, safety and well-being protected, data reliable and robust, conduct in compliance with Regulation

• Principal investigator has a responsibility of ensuring compliance at the clinical trial site

• Extend and nature of the monitoring to be determined based in trial characteristics including:– Whether the trial is low-intervention trial– Objective and methodology of clinical trial– Degree of deviation of intervention from normal clinical practice

Monitoring


43

• It is the principal investigator responsibility for ensuring compliance – this will now be law once implemented.

• Sites often tend to see the monitor as their main method of QC - which although part of QC, is really on behalf of the sponsor, not the site which should have their own methods for assessing compliance.

• There will be a lot of education needed.

Monitoring


44

Informed ConsentTighter requirements for obtaining informed consent (i.e.

incapacitated subjects, minors, breastfeeding and pregnant women etc.)

Provisions for obtaining informed consent in cluster trials, where groups of subjects rather than individual subjects are allocated to IMP (Art. 29a)

Possibility of broad consent: use of data outside of CT protocol for scientific purposes if subject agrees (consent can be withdrawn at any time by the subject)

Subject must be informed that the summary of the results of the trial and a summary for laypeople will be made available in the EU database, irrespective of the trial outcome

Interview can be conducted by a member of the investigating team who is appropriately qualified according to national legislation. Allow time.It should be verified that the subject has understood the information

BACK-up slides

45 19/04/23

Clinical Trial Regulation HistoryCommission proposal July 2012

Parliament proposed over 1,000 amendments. 290 final amendments were adopted in May 2013,

Parliament and Council proposed amendments entered the trialogue with Commission in 4Q2013,

Agreement on the final text reached in trialogue on 20th December 2013,

Ratification by Parliament in April 2014, adoption by Council and publication in the OJ (May 27th).

Implementation dependent on having a functional EU Portal/database: Comes into effect six months after new EU portal and database for clinical trial applications becomes functional, no earlier than 28 May 2016).

Other work to do towards implementation 46

Annexes to the regulation

ANNEX 1: Dossier contentANNEX 2: Submission of trial modificationANNEX 3: Safety reportingANNEX 4: CONTENT OF THE SUMMARY OF THE RESULTS

OF THE CLINICAL TRIAL to publishANNEX 5: CONTENT OF THE SUMMARY OF THE RESULTS OF

THE CLINICAL TRIAL FOR LAYPERSONSANNEX 6: LABELLING OF INVESTIGATIONAL MEDICINAL

PRODUCTS AND AUXILIARY MEDICINAL PRODUCTS

19/04/23

47

48

19/04/23

regulation (eu) no 536/2014 of the european parliament and of the council of 16 april 2014 on...

Documents

scene question

imp slide

disclaimer slide

medicinal products

european parliament

regulation ec

regulation eu

human beings