Meeting the Clinical Evaluation Requirements for CE Marking: Challenges for Innovative Start-ups Sarah Sorrel, MedPass International SAS

Transcription

1 Meeting the Clinical Evaluation Requirements for CE Marking: Challenges for Innovative Start-ups Sarah Sorrel, MedPass International SAS TÜV SÜD America Clinical Workshop Carlsbad, CA - January 27, 2015

2 The Full Services Medical Device CRO Regulatory Affairs Strategic Consulting CRO Services - Trial Management - Site Management - Data Management - Monitoring - Statistics EU AR and LR - Roadmaps - Lit Reviews - CEPs/CERs EU Reimbursement and Pricing

3 MedPass International Expertise 20% of staff in Strategic Consulting/Regulatory Affairs Class IIb, III, AIMD, drug-device, animal tissues mostly breakthrough technologies Regulatory Expertise: Pre and post market Clinical Trial Approvals 383 EC submissions in CA notifications in 2013 Clinical Trial Agreements Data protection Approvals Adverse Event and Vigilance Reporting 3

4 Challenges for Start-ups with Innovative Devices: What we will discuss Getting the Regulatory Roadmap Right Pre-Clinical Test Requirements Clinical Evaluation Plan Conducting the Clinical Investigation Notified Body/ Competent Authority Review/Consultation EU Regulatory Challenges and Site Selection Study Design Issues Compliance with EN ISO :2011 Study Implementation and Quality Control Training of investigators Use of the device interaction between physician and product Patient selection and suitability 4

5 Regulatory Roadmap Pre-clinical Biocompatibiltiy Combinations Prototype Medical device? Classification? Clinical Evaluation Plan Pre-market clinical Clinical evaluation Clinical investigation Conformity Essential Requirements Post-market Surveillance Vigilance/PMCF Classification/Regulatory advice Technical Risk assessment Standards Requirements Regulatory advice/input into standrards Review of applications to conduct research Clinical strategy review Member States Ethics Committees Notified Body (specific for medical device type) Designation & oversight Joint Assessment Vigilance assessment/market surveillance Member States Competent Authorities 5

6 Challenges for innovative devices Amendment 2007/47/EEC emphasizes clinical evaluation for all devices and clinical investigations for all innovative and/or high risk devices PIP scandal has led to increased enforcement both pre- and post-market Expectations of NBs and NCAs: Use of equivalency argument strictly limited (piecemeal equivalence no longer acceptable) Clinical indications must be specific and backed up by clinical data Sample size must be statistically justified PMCF mandatory (unless duly justified) and must be defined in advance Study design must be based on literature review, risk assessment, intended use and patient population 6

7 Clinical Evaluation - New Definition with 2007/47/EC Pre-market Post-market Clinical Evaluation Report Post-Market Clinical Follow-up Literature Review Clinical Study Report Clinical Investigation Plan 7

8 The Clinical Evaluation process 8

9 Clinical Investigation as a part of Clinical Evaluation Identify and review relevant published data Gap analysis Identify critical endpoints and timescales Literature review Justification of sample size Clinical Evaluation Report Clinical Study Report Clinical investigation Plan

10 Clinical Evaluation Plan From the Literature Review, identify and define: evidence-based clinical need clinical performance specifications (design input ) proof of concept degree of equivalence with existing therapeutic options state of the art for performance (efficacy of existing therapies) state of the art for safety (complication rates for existing therapies) From this, the Clinical Evaluation Plan needs to define: clinical data requirements (via gap analysis) (including pre- and post-market requirements)

11 Development of a Clinical Evaluation Plan 1. Identify residual risks, benefits and uncertainties 2. Determine critical uncertainties in the risk assessment Consider risk estimate and degree of uncertainty and identify any risks that are not clearly outweighed by anticipated benefits 3. Can a positive clinical benefit:risk balance be shown from pre-clinical data? 4. Determine the need for clinical data in the pre- and post-market phases to: demonstrate a positive clinical benefit:risk balance reduce uncertainties in the risk estimate confirm clinical performance (or efficacy, if necessary in post-market phase)

12 Content of a Clinical Evaluation Report 1. Context of the evaluation (therapeutic background, extent of problem, limitations and drawbacks of current therapies, evidence-based clinical need) from Literature Review 2. Describe device characteristics and intended application 3. Establish the state of the art against which to measure safety and performance from Literature Review 4. Evaluate risks from pre-clinical data and scientific literature and perform gap analysis to establish clinical data requirements - from Literature Review, design verification studies and pre-clinical assessment 5. Summary of clinical investigations (objectives, design, methods, results, conclusions) 6. Risk assessment (design and clinical risk analyses, benefits, residual risks and uncertainties and clinical risk:benefit assessment) 7. Post-market surveillance plan (including PMCF plan) - based on risk assessment 8. Conclusions on conformity with ERs - based on clinical risk assessment

13 Challenges for Start-ups with Innovative Devices: What we will discuss Getting the Regulatory Roadmap Right Pre-Clinical Test Requirements Clinical Evaluation Plan Conducting the Clinical Investigation Notified Body/ Competent Authority Review/Consultation EU Regulatory Challenges and Site Selection Study Design Issues Compliance with EN ISO :2011 Study Implementation and Quality Control Training of investigators Use of the device interaction between physician and product Patient selection and suitability 13

14 Challenges in meeting regulations Study documentation Extensive requirements Literature review, Pre-clinical data validation, Risk Assessment, List of the Standards Complete Design Validation Regional variation in regulation, procedures and expectations Ethics Committees Competent Authorities 14

15 Variables in the Ethics Committee submission Identification of the Ethics Committee(s): Local, National, etc. Who submits? Specific form (if applicable) and template Take into account the submission fees (if applicable) Deadline for submission Frequency of meetings Timelines for review 15

16 Variables in the Competent Authority Notification Specific form (if applicable) or template (more or less detailed) Notification and ethics committee submission in parallel or sequential? Who notifies? Where? Submission fees (if applicable) Timelines and conditions for review (e.g. check for completeness) 60 day waiting period - how long is it in practice? 16

17 France: Specificities PROs Submission to CA & EC in parallel Submission & approval from one leading EC in case of multicentric study 5 days to acknowledge dossier (for CA) Waiting period of 60 days (Starts at the reception of the complete dossier) Authorization might be sent before 60 days No submission fees CONs Contracts process with hospital to be finalized before the study starts Unique contract process to be put in place to facilitate contract negociation Data protection GLP animal studies 17

18 Germany: Specificities PROs Submission to CA & EC in parallel Approval from one leading EC Online submissions via DIMDI website day CA approval timeline (with 15 days for responses) CONs CA clock does not start for long period and stops for questions Lack of transparency re/ expectations of CA Inconsistency in CA expectations (varies with reviewer) Onerous SAE reporting requirements Review of risks/benefits balance Full sterilization validation Full reports of pre-clinical testing Radiation safety requirements Device modification = new device Implantable device: plans after study completion 18

19 UK: Specificities PROs Submission to CA & EC in parallel Centralized application via IRAS to central EC and CA Approval from one leading EC in case of multicentric study CA review takes maximum of 60 days (no clock stops) CA review is logical and consistent CONs EC process takes a long time (60 days in theory only!) CA has high (but predictable) expectations of documentation required Site participation needed for validation of application LREC and R&D Department approval needed for local approval / contract Site Contract: takes time - start the process early 19

20 CA Timelines (days) FR DE UK IT NL ES CA in parallel with EC Yes Yes Yes No No Yes Pre-checking (days) Yes (5) Yes (10) No Yes No Yes (10) Review period (days) None 60 Clock stop No Yes No Yes N/A Yes 20

21 Study design problems: Endpoints and timescales need to be right Example Investigation of a leadless pacemaker Sponsor wanted performance endpoint at 1 month Literature Review and pre-clinical studies indicated stable inflammatory response around electrode helix achieved at 3 months Pacing function measured at 3 months 21

22 Study design problems: Local clinical circumstances must be considered Examples Investigation of coronary stent in AMI patients Implantation carried out in large specialised centres in NL Patients transferred to local hospitals for post-op recovery and follow-up 30-day ECG was not available to investigator Investigation of targeted radiotherapy using transponder implanted in lung FDA protocol required administration of antibiotics following implantation Investigators considered antibiotics were not standard of care FDA auditor considered these major protocol deviations Similar situation with lab tests for FDA study not routinely performed in EU See next slide 22

23 Snapshot

24 ISO 14155: Scope General requirements intended to: Protect the rights, safety and well-being of human subjects (as per Declaration of Helsinki) Ensure the scientific conduct of the clinical investigation and the credibility of the results Define the responsibilities of the sponsor and principal investigator Define GCP for the design, conduct, recording and reporting of clinical investigations

25 ISO 14155: Planning and Conduct Justification for the design of a clinical investigation The design of the clinical investigation shall be justified, based on the evaluation of pre-clinical data and the results of a clinical evaluation The clinical investigation shall be designed to evaluate whether the investigational device is suitable for the purpose(s) and the population(s) for which it is intended Document and data control Defines requirements for all documents and data in order to assure control and traceability Responsibilities of sponsor and investigator defined

26 ISO 14155:2011 and ICH GCP The general principles are the same despite different focus Historically, ICH GCP has been more widely adopted ISO had been seen by some as weaker than ICH GCP ISO has been revised to address these weaknesses now generally accepted as harmonised with ICH GCP Those differences that remain reflect the differences between device and drug studies

27 ISO 14155:2011 and Risk Assessment requirements Two types of risk analysis need to be conducted, combined and balanced against the benefit expected from the treatment: A technical risk analysis, based on EN ISO 14971:2012 Based on objective review of scientific data Estimates risks associated with the device Needs to identify residual risks A clinical risk analysis, based on clinical experience Based on data from literature review and clinical investigations Estimates risks to the subject associated with the use of the device Appraisal of nature and rate of complications / adverse effects Used for identification of anticipated adverse device effects MedPass International Regulatory Affairs Department

28 Study conduct problems Examples Investigation with device for acute myocardial infarction Treatment is time-critical 2-phase consent form devised - Abbreviated consent before treatment Sponsor interpreted FDA requirements as needing 7 page consent form No recruitment! Investigation with device for acute myocardial infarction Many ECGs required Many non-conformities due to different ECG practices in USA and EU 28

29 Significant Deviations Example

30 Challenges for Start-ups with Innovative Devices: What we will discuss Getting the Regulatory Roadmap Right Pre-Clinical Test Requirements Clinical Evaluation Plan Conducting the Clinical Investigation Notified Body/ Competent Authority Review/Consultation EU Regulatory Challenges and Site Selection Study Design Issues Compliance with EN ISO :2011 Study Implementation and Quality Control Training of investigators Use of the device interaction between physician and product Patient selection and suitability 30

31 Training of investigators Inadequate training on use of the device can result in: SADEs Device recalls Study suspension Implications for sites in other countries 31

32 Initiation visit objectives Introduction Team Protocol review train the study staff Regulatory and ISO training Answer questions XXX stusy/protocol - Site Visit Initiation 32

33 Training of patients Inadequate training of patient can result in Lack of understanding and therefore lack of compliance Patient training should not be left to the investigator alone but should be carefully planned Shared with study nurse, etc. Training of support people (family and friends) Hotline for patients Targeted to the age group and circumstances of use 33

34 The increasing importance of training as device use becomes more technique-sensitive Examples Investigation of active implant for obstructive sleep apnoea Principal Investigator did not attend training Implants placed in wrong location No stimulation of target nerve Investigation of mitral valve repair system Only one size of implant available Incorrectly sized device implanted Conversion to surgery Investigation of Left Ventricular Assist Device Proctor trained in implantation of device did not turn up Investigators implanted device anyway, leading to SADEs 34

35 The importance of subject selection in line with appropriate inclusion and exclusion criteria Example Investigation of device for renal denervation Protocol required compliance with antihypertensive drug regime and confirmation of resistant hypertension through ambulatory assessment Rapid recruitment promised Most subjects failed screening New centres required 35

36 Conclusions Clinical investigations for innovative devices are a critical component of innovative device development Careful planning is required to ensure necessary data is obtained in a timely and cost effective manner Study design based on clinical evaluation principles Site selection based on capabilities and regulatory considerations Study conduct based on ISO Careful attention to training is of particular relevance to innovative devices: Consider learning curve, use of proctor etc. Consider patient training if necessary Consider patient recruitment materials prior to EC submissions 36