Regulatory Science Virtual Symposium: “Principles of Global Clinical Research for Medical Devices” Session 5: Developing Clinical Evaluations (2021)

1. Learning Objectives
a. What is clinical data
b. What is clinical evaluation
c. How is clinical evaluation performed and documented
d. Why is clinical evaluation important
2. Clinical Evaluation
a. Defining Clinical data
b. Sources of Clinical data: literature, clinical experience, and clinical investigation of device
3. Clinical Evaluation General Principles
a. Definition: Procedure to collect, assess, and analyze clinical data (pre- and post-market) on a medical device and comparable device; to evaluate safety, clinical performance, and/or effectiveness
4. ISO/TR 2041 6:2020
5. Clinical evaluation and life cycle of medical device
a. Pre-market research development
b. Clinical Investigation
c. Device on the market
d. Post Market study, registry
e. Clinical Evaluation process is also linked to risk management, PMS, and labeling (IFU, label)
6. Clinical Evaluation History
a. GHTF Clinical Evaluation
b. IMDRF Clinical Evaluation
c. Used and implemented globally
7. General Principles
a. Sufficient clinical evidence to confirm compliance with Essential Principles for safety and performance and “generally acknowledged state of the art”
b. Benefits and risks specified, acceptable
c. Claims related to safety, clinical performance, and effectiveness
8. When is clinical evaluation undertaken and why is it important?
a. Ongoing throughout life cycle of medical device
b. Used to indicate whether a clinical investigation is necessary, or significant risk exists etc., defines safety and performance standards
c. Part of a regulatory/marketing submission
9. Process
a. Refer to Figure 1 from IMDRF guidance
b. Indicates iterative nature of the process
10. Clinical Evaluation CEF Template Appendix G
a. Describes the format on how you would document clinical evaluation report
b. Incorporating different, varying processes/aspects of CT development into one coherent document
11. How detailed it should be?
a. Devices are developed or modified by incremental innovation, so they are not completely novel
b. Detail depends on type of device
c. Higher on novelty scale then more likely to conduct clinical investigations of medical device
12. Who should perform the clinical evaluation?
a. Qualified individual or team with knowledge on device technology and application, research methodology (including engineering, clinicians, stats) etc.
13. Clinical Evaluation Scope (Stage 0)
a. Identifying Essential Principles (EP) required support from clinical data
b. Define the scope
14. Clinical Evaluation – Identification of Pertinent Data (Stage 1)
a. Three categories of sources of data:
i. Literature pertaining to the device or comparable device
ii. Clinical experience of device or similar
iii. Clinical investigation
15. Data generated through literature review (Stage 1)
a. Sources of data
b. Scientific literature databases i.e. NIH PubMed, M Base (EU)
i. For the United Kingdom, one might look into NICE database
16. Citation Assessment Flowchart
17. Identification of Pertinent Data (Stage 1)
a. Examples include complaints, sales figures, individual customer feedback etc. 
18. Data generated through literature searching
a. For some devices, sometimes majority of data is from literature review searching
19. Appraisal of Pertinent Data (Stage 2)
a. Evaluate methodological quality of work done by the authors and from that, the scientific validity of the information
b. Appraisal can be qualitative or quantitative
c. Weight contribution
i. No single well-established method
ii. Justified basis current knowledge/state of the art
iii. Qualitative and quantitative
iv. RCT
v. Appendix F
20. Weight Contribution Appendix F, A Possible Method of Appraisal, Suitability 
21. Weight Contribution, Oxford Centre for Evidence-based Medicine (March 2009)
22. Example New Appraisal Values Safety and Performance of the Device
23. Example Data Contribution Appraisal table Safety and Performance of the Device
24. Clinical Evaluation Analysis of the Data (Stage 3)
a. Data on the device/comparable devices
b. Requirement on safety as per IMDRF 5.1.1
c. Requirement on acceptable benefit/risk profile per IMDRF 5.1.2, 5.1.8
d. Requirement on performance per IMDRF 5.1.1
e. Requirement on acceptability of side-effects per IMDRF 5.1.8
25. Example Summary Clinical Data Table
26. Requirement on Safety Mitigation of Clinical Risks
27. Requirement Acceptable Benefit/Risk Comparison Table State of the Art/Current Knowledge
28. Clinical Evaluation Analysis of the Data (Stage 3) Conclusions
a. Clear statement concerning compliance to EP
b. Acceptability of the benefit/risk profile according to current knowledge/the state
c. Adequacy of the information materials supplied by the manufacturer
d. Suitability of the device, including its IFU, for the intended users
e. Adequacy of claims
f. Consistency between the clinical data, the IFU, and RM docs
g. Consistency between these docs and the state of the art
h. Whether any residual risks, uncertainties, unanswered questions are acceptable for CE marking 
i. Follow up during PMS/post market studies
29. CER (Stage 4)
a. An independent party should be able to understand CER
b. Should contain cross references to support documents
c. Should be clear which statements are supported by which data, and which reflect the conclusions or opinions of the evaluators
d. Report should outline different stage of the evaluation
30. Concluding remarks
a. Clinical evaluation is an on-going iterative methodical process
b. Clinical evidence to confirm compliance with EPs for safety and performance, considered as “state of the art”
c. Data sources: literature, clinical experience, clinical investigations
d. Consistency in regulatory documents
e. Documented in CER, which are revised and reviewed on-going
31. Polls

Accompanying text created by Annie Ly | Graduate Student, Regulatory Science, USC School of Pharmacy lyannie@usc.edu