Clinical Investigations:

1. Clinical Investigations: The IMB Application and Review Process Thursday 13th September –ICRIN/IMDA Paul Scannell PhD Human Products Authorisation and Registration

2. IMB Mission Statement To protect and enhance public and animal health through the regulation of medicine, medical devices and healthcare products

3. Agenda Clinical Investigation • Role & structure of the Irish Medicines Board • What requires IMB submission • How to submit and the review process • IMB review approach versus notification approach

4. The Role of the IMB • Review and approve applications to conduct clinical investigations involving medical devices in Ireland • Ensure benefit > risk and residual risk has been minimised as much as possible • Protect patient & clinician – safety of investigational device, valid & robust investigation • Need to also consider balance of regulatory requirements against need for innovation, competitiveness, access to new therapies

5. Structure of the IMB (in terms of CI’s) Medical Devices & Medicinal Products Declaration of Confidentiality & Conflict of Interests Medical Devices • Niall MacAleenan • Paul Scannell • Juliet Doran • Amanda McCormick

6. What Requires IMB Submission? What? Assumption: you are planning a clinical study regardless of device classification requirements

7. What Requires Submission? Clinical Investigations Requiring review by IMB: • New/novel devices (non-CE marked) • Device containing previously untested materials • Modification of existing device • Device is proposed for a new indication, purpose or function • Existing materials used in a new location or for longer duration of use 2 – 5 generally refer to devices which have been previously CE marked

8. What Requires Submission? Clinical Investigations Generally Not Requiring review by IMB: • IVD Performance Evaluations • Clinical/Academic research: • devised by clinicians/academics and device used within professional and ethical boundaries • for research purposes only • no commercial intent • off-label studies – liability transfer • Post-market studies – commercial sponsor: • carried out on a CE marked product for research, marketing or regulatory reasons • within CE mark • IMB request voluntary notification but no review • Reviewed on a case-by-case basis

9. How to Submit & the IMB Review Process

10. Clinical Investigation – Submission • Consultative approach with, but not consultants to, sponsors • Pre-submission meeting - approaching completion of application - initial draft review • Discuss process, timeframe & requirements • Highlight documentation required / discuss draft/ potential pitfalls • Facilitate process as much as possible • Request notification prior to submission • Pre-notification of intent to submit allows for appropriate review team to be in place Pre-submission meeting with IMB

11. Clinical Investigation – Submission Application form and fee Supporting documentation x 2 Electronic copy

12. Clinical Investigation –IMB Review Process Both IMB and local Ethics Committee approval is required before commencing a clinical investigation... …Requires two applications to be made: IMB & EC

13. Clinical Investigation –IMB Review Process Both IMB and local Ethics Committee approval is required before commencing a clinical investigation... …Requires two applications to be made: IMB & EC Parallel Review • EC Approval site specific • Multi-site – at least 1 EC application submitted in parallel • The full opinion of the EC must be submitted to the IMB prior to the IMB finalising its review and granting an opinion on the application.

14. Clinical Investigation –IMB Review Process • Incoming validation • Application form, administrative details, payment, hard (2) and electronic copies of submission • Clinical investigation documentation: • EC opinion (if available) • Informed consent • CIP & CIB • Insurance • Labeling & IFU • ER statement/checklist • Statements (animal tissue/blood derivatives) • Passed validation – Day 1 of 60 day* process Pre-submission meeting with IMB CI Application to IMB Day 0 Day 1 Day 1 Annex VIII *calendar days

15. Clinical Investigation –Documentation 1 • Clinical Investigators Brochure (CIB) content (non-exhaustive) • Full device identification and description including all accessories • Device classification • Summary of experience with any similar devices • Benefit/Risk analysis* incl. what actions have been taken to minimise or eliminate the identified risks • Summary* and analysis of pre-clinical testing and experimental data: • Mechanical/electrical testing • Software validation • Animal studies • Design drawings • Details of any new or previously untested features of the device * • Identification of any pharmacological components • Biocompatibility and sterilisation data • Labelling & IFU • Standards used (used in full or in part) • *Commonly found shortcomings

16. Clinical Investigation –Documentation 2 • Clinical Investigation Plan (CIP) content (non-exhaustive) • Identification of • sponsor, manufacturer, PI and other clinical investigator(s) • investigational sites and other institutions playing a critical role in the investigation e.g. CRO • A summary of necessary training experience for use of device in question and training records, if applicable. • Copy of informed consent or the draft informed consent submitted in parallel to the Ethics Committee. • Copy of draft Case Report Form (CRF) • Rationale and justification of the clinical investigation (akin to a CIB summary) • Objectives and investigation design (randomised, controlled etc.) • Numbers of subjects and duration of study with estimated start and finish dates and proposed follow up period (with justification) *. • Inclusion and exclusion criteria • Description of endpoints and justification of statistical design which demonstrate safety and performance *. • SAE Reporting • *Commonly found shortcomings

17. Clinical Investigation –IMB Review Process • Initial IMB Review: Days 1 – 30 • Regulatory, clinical & technical review • Additional documentation requested/reviewed: • Biocompatibility – ISO 10993 • Sterilisation • Risk Analysis – ISO 14971 • List of standards used • Design history, solutions, drawing • Pre-clinical testing (simulation, bench, animal etc.) • Freeze design, avoid design iterations • Sufficient pre-clinical testing to address ERs • Potential benefit of investigation > risk • Day 30 – questions/clarifications addressed to sponsor Pre-submission meeting with IMB CI Application to IMB Day 0 Initial Review Day 1 Day 1 Day 30

18. Clinical Investigation –IMB Review Process • Sponsor review of queries: Days 30 – 44 • Sponsor responds to IMB queries by Day 44 • Stop clock* if sponsor requests further time to generate reports, further testing etc. • IMB review of responses: Days 44 – 55 • Review team: Internal and external reviewers • Further queries/clarifications/data can be requested Pre-submission meeting with IMB CI Application to IMB Day 0 Initial Review Day 1 Day 1 Response Review Day 30 44 Day 55 *possible in some circumstances

19. Clinical Investigation –IMB Review Process • IMB Decision: Days 55 – 60 • Review team considerations: • Investigation details • Patient risk/benefit • Adequacy of responses • Recommendation of No Objection or Objection to IMB Management Committee • Decision Notification: Day 60 • No Objection letter including specific conditions & requirements • Objection letter including reasons for objection & appeal timeframe • Other Member States notified of decision Pre-submission meeting with IMB CI Application to IMB Day 0 Initial Review Day 1 Day 1 Response Review Day 30 44 IMB Management Committee Day 55 Day 60

20. Clinical Investigation –IMB Review Process • Post-approval: Day 60 • No Objection decision: • SAE reporting • Status reports • Amendments – administrative and/or technical • Summary report on completion of investigation • Objection decision: • Essential requirements not satisfied to necessary extent • Not subject to controls or requirements of directive or harmonised standard – ISO 14155 • Risk-benefit analysis is inadequate or risk>benefit • Insufficient/inadequate documentation provided • Appeal • Within in specified time-frame Pre-submission meeting with IMB CI Application to IMB Day 0 Initial Review Day 1 Day 1 Response Review Day 30 44 IMB Management Committee Day 55 Post-approval Day 60

21. Clinical Investigation –IMB Review Process Pre-submission meeting with IMB CI Application to IMB Day 0 Initial Review Day 1 Day 1 Response Review Day 30 Still receiving a small number of clinical investigations, typically 5 – 10 per year 44 IMB Management Committee Day 55 Post-approval Day 60

22. Clinical Investigation –IMB Review Process • EUDAMED • European databank for medical devices • Secure web-based portal for rapid information exchange between national authorities • EUDAMED Decision adopted by EC on 19th April 2010 • Decision obliges Member States to use EUDAMED from 1st May 2011 • Article 14a point 1(d) 93/42/EEC – CAs to enter data relating to clinical investigations on EUDAMED • Administrative data – mfr, device, title, objective.. • Decision by CA - refused/halted (Art. 15(6)) • Significant modification/temp. interruption (Art. 15(6)) • Early termination (Art. 15(7)) • Unique CI identification assigned by EUDAMED • Used by every MS in which CI is been undertaken • CIV-CO-YY-MM-XXXXXX Email Notification ID number Month Year Country Identifier (e.g. IE)

23. Review versus Notification V’s Clinical

24. Review versus Notification • European retrospective study of 19 CI applications 2006 (3 Class IIb, 16 Class III) • The specific aim: to assess the quality of technical documentation items. • Most major shortcomings were observed for the items concerning: • risk analysis • control & verification of the design, • sterilisation • labelling • IFU • vigilance

25. Review versus Notification • IMB’s goal……

26. Review versus Notification • IMB’s goal……

27. Review versus Notification • IMB’s goal…… • Facilitates submissions to other European CA’s • More CA’s are now taking a review approach • Revision to MDD: Coordination of Member States' approvals regarding multi-centre clinical investigations • Facilitates submissions to other regulatory jurisdictions: TGA, FDA etc. • Allows for ongoing dialogue with sponsors throughout development process and during IMB review • SMEs, startups, academic spinoffs and non-EU sponsors

28. Thank you for your attention Contact details: Paul Scannell PhD Scientific Officer, Clinical Assessment Human Products Authorisation & Registration Irish Medicines Board | BordLeigheasranahÉireann Kevin O’Malley House, Earlsfort Centre, Earlsfort Terrace, Dublin 2. Tel: +353 1 6764971 Fax: +353 1 6767836 paul.scannell@imb.ie Or clinical.ix@imb.ie Anytime….