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

lifecycleProduct

Development

Pre-CE Marking

Post Market

CER

Identify Data and Risks

Update and Monitor Demonstrateconformity

• Tied to other processes in your daily work at a medical device company

Demonstration of Safety and Performance

Product Development

Clinical Evaluation

Risk Management

Post-Market Surveillance

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 MarkingFor 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 0 Scoping, Plan

Stage 1Identification of pertinent data

Stage 2 Appraisal of

pertinent data

Stage 3Analysis of the

clinical data

Stage 4Clinical evaluation report, including PMS/PMCF plan

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 Markingwithout Clinical Study Data

Israeli company seeking approval for a PTCA balloon CatheterClass 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 Markingwithout 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

Case Study 4: Annual Update

• Clinical evaluation approach:– Overview of past clinical studies– Summarize new data from device experience– PMS findings (complaints, MAUDE search, field survey)– Technical comparison to similar devices remains applicable– Compliance with recognized standards– Summarize pre-clinical studies (bench, biocompatibility, animal)– Literature review since last update to confirm no new hazards

Future Directions

• MEDDEV 2.7/1 Rev 4 (2016): in effect• MDR comes into effect in May 2020• Per MDR:

– For implantable devices and class III devices, outcome of clinical evaluation will become public

– “Notified bodies’ (NB) assessments of manufacturers' technical documentation, in particular documentation on clinicalevaluation, should be critically evaluated by the authority responsible for notified bodies”

– For implantable Class III and certain Class II, NB should ask an expert panel review of the clinical evaluation

– Definitions part of MDR– MEDDEV recommendations incorporated into the MDR: Article 61 and Annex

XIV (including requirements related to equivalent devices)