Optimal Approach to the Clinical Evaluation Process Tami Abudi, President and CEO BBA
Agenda • Placing the Clinical Evaluation process in historical perspective • Understanding the requirements and placing them into practice • Discussing case examples for the entire product lifecycle: – During product development – Pre-CE marking – Updates during the post-market phase
The Evolution of Clinical Evaluation
The Evolution of Clinical Evaluation
The Evolution of Clinical Evaluation • New? • More stringent? • No more literature only route??? • Difficult to meet?
This Lecture.. Is NOT about, comparing old version to the current version Rather – Explain the concept – Does the clinical evaluation process apply to my device? – Explore how the process ties to other processes in your daily work – Provide practical tools for key steps – Use case studies from past CERs: • Throughout the device lifecycle
What is Clinical Evaluation? • Clinical Evaluation is a process • Methodological and scientifically sound collecting, appraisal, analysis and reporting of clinical data related to a medical device • Allows determining whether there is sufficient clinical evidence supporting safety and performance of the device – i.e., whether the relevant essential requirement are met The requirements for clinical evaluation apply to ALL classes of medical devices Clinical investigations with the device under evaluation are required for implantable and class III devices unless it can be duly justified to rely on existing clinical data alone
Complete Definitions – in MEDDEV 2.7/1
Clinical Evaluation Process (CEP) • An ongoing process • Throughout the device Product lifecycle Development Identify Data and Risks • Tied to other processes in your daily work at a CER medical device company Post Pre-CE Market Marking Demonstrate Update and Monitor conformity
Demonstration of Safety and Performance Product Development Post-Market Clinical Surveillance Evaluation Risk Management
During Product Development • Premarket R&D should be guided by clinical evaluation and risk management • CEP at this stage is intended for: – Define needs associated with clinical safety and clinical performance – If possible equivalence: • Are clinical data available? • Determine equivalence – Perform gap analysis to determine: • Which data need to be generated? • Whether clinical investigations are required? – If yes, define study design The clinical evaluation should generally commence in advance of any clinical investigation
In Support of CE Marking For conformity assessment CE marking placing the device on the market Sufficient clinical evidence available for conformance with relevant • Essential Requirements Which aspects need to be addressed during Post-Marketing Surveillance • (PMS), e.g., via post market clinical follow-up studies (PMCF studies) or other PMS means: – Estimation of residual risks – Uncertainties, unanswered questions (rare complications, long term performance, safety under “real world” use)
Post-Market Updates • Data derived from Post Market Surveillance (PMS) activities – Evaluate whether to change the risk/benefit profile, clinical safety or clinical performance • Updated clinical evaluation – Feeds back in to PMS and risk management • Assess potential changes to IFU and risk management documents • If insufficient clinical evidence for safety and performance: – Stop placing the device on the market; or – Take necessary corrective and preventive actions
Post-Market Updates (2) • When? – New information that potentially changes the current evaluation – Periodic updates – risk dependent: • At least annually if device carries significant risk or not well established • Every 2-5 years if no significant risk or well established
Who Shall Conduct the Clinical Evaluation? Suitably qualified individual or a team • – May require an independent KOL Knowledge in: • – Research methodology – Information management – Regulatory requirements – Medical writing – The device technology and its application – The therapeutic area/disease state Training and education • – Degree from higher education and 5 years work experience – 10 years of documented professional experience Declaration of interest •
Correlate to Relevant Essential Requirements The Clinical Evaluation should support compliance with the following • Essential Requirements (ER): – MDD ER1, ER3, ER6 – AIMDD ER1, ER2, ER5 MDD ER1, AIMDD ER1: • – Requirement on safety – Requirement on acceptable benefit/risk profile MDD ER3, AIMDD ER2: • – Requirement on performance MDD ER6, AIMDD ER5: • – Acceptability of undesirable side effects
Clinical Evaluation Process Stage 4 Stage 0 Clinical evaluation report, including Scoping, Plan PMS/PMCF plan Stage 3 Stage 1 Analysis of the Identification of clinical data pertinent data Stage 2 Appraisal of pertinent data 17
Case Study 1: During Product Development A catheter based system for renal denervation in treatment of drug resistant hypertension Class IIb • Stage 0: Scoping / plan – CER intended to summarize knowledge related to state-of-the-art – Assist in developing study design: • Number of patients; Eligibility criteria; Endpoints; Follow-up duration and assessments ( what’s out there? ) – Identify clinical data sources – Define search criteria, duration, 'eligibility criteria’, weighing grades
Case Study 1: During Product Development • Stage 1: Identification of data sources – Clinical data held by the manufacturer ( None ) – Relevant pre-clinical studies ( bench, animal ) – Data retrieved from the literature - different databases, general internet search, dedicated associations’ websites ( identified 6 comparable devices ) • Stage 2: Appraisal of pertinent data – Determine the methodological quality of the data set – Determine the relevance to the clinical evaluation – Weigh contribution of each data set – Excluded data sets should be identified and explained in CER
Case Study 1: During Product Development • Stage 3: Data analysis – Summarize safety and performance ( abstracting / key results + comparison tables ) – Draw conclusions ( there are sufficient data out there, justified to assess a slightly different methodology, using similar study design ) – Note: • Use sound methods • Make a comprehensive analysis • Determine if additional clinical studies or other measures are needed • Determine post market clinical follow-up (PMCF) needs
Case Study 1: During Product Development • Stage 4: Clinical Evaluation Report – Address the different stages – Controlled document – Suggested format provided in MEDDEV 2.4/1 – The renal denervation company report: • ~20 pages long document, with the literature report (summarizing 7 articles out of initial 100 identified) and technical comparison as appendices • Justified FIH and pivotal studies’ design • Submitted in Germany • Continued clinical evaluation throughout product approval, new information from competition became relevant
Case Study 2: In Support of CE Marking with Clinical Study Data US company developing a computer vision system intended to aid clinicians in the detection of early melanoma Class IIa • Clinical Evaluation approach: – Relied heavily of data from US studies (6 in total, thousands of patients / lesions conducted as non-significant risk device studies in the US) – Literature review for summarizing state-of-the-art – Present pre-clinical testing, identify recognized standards
Case Study 3: In Support of CE Marking without Clinical Study Data Israeli company seeking approval for a PTCA balloon Catheter Class III • Clinical studies are not-feasible for such a device ('accessory device’) • Clinical Evaluation approach: – Literature review: well established technology – Comparison to 5 competitive similar devices – Extensive pre-clinical testing, including GLP animal study – Justify no need for a clinical study
Case Study 3: In Support of CE Marking without Clinical Study Data Are clinical studies needed? Gap analysis vs. similar devices: • New design features, incl. new materials? – New intended purposes, incl. new medical indications or new target populations – New claims – New types of users ( e.g. , lay persons) – Seriousness of direct and/or indirect risks – Contact with mucosal membranes or invasiveness – Increasing mode of use (duration, # of applications) – Incorporation of medicinal substances – Use of animal tissues – Availability of medical alternatives with lower risks or greater benefits – Have new risks been recognized? –
Case Study 4: Annual Update Israeli company marketing a bare metal coronary stent system CE marking since 2013 • Annual updates since then • CEP Purpose: – Annual update – Comply with MEDDEV 2.7/1 Rev 4 – Address audit findings: no alignment between CER, IFU and risk documents
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