1. Methodological Issues in Implantable Medical Device(IMDs) Studies Abdallah ABOUIHIA Senior Statistician, Medtronic

2. Objectives  Introduction  Key factors that impact IMD safety & effectiveness  Methodological issues related to Comparative Studies of IMDs  Summary & Recommendations  Medical Device Working Group

3. Introduction Medical Devices

4. Introduction IMDs are ubiquitous inside/ outside clinical practice Use and complexity are increasing Device-related adverse events & Product problems are significant Technical complexity & operator training have great impact on public health Device-operator interaction plays an important role in device safety and Effectiveness

5. Introduction Environment for evidence generation of IMD outcome different than that for drug Trial is methodologically challenging: randomization, blinding….. Design of trails requires care and innovative approaches Observational studies of IMDs have their own challenges

6. Key factors that impact IMD safety & effectiveness

7. Key factors that impact IMD Safety & Effectiveness Selection of Comparator Characteristics of the Device Characteristics of the Operator Characteristics of the Procedure/Intervention Characteristics of the Intervention Setting Characteristics of the Patient Selection and Measurement of Outcome

8. Selection of Comparator Choice has a critical implications and challenging issues RCT: blinding and allocation concealment issues more pronounced Observational study: blinding and allocation concealment not possible Need more data on factors that drive therapeutic choices Long term follow-up for device to optimal management comparative studies

9. Characteristics of the Device Mechanical performance and reliability of the device battery life duration, physical wear of the implant Identify variable associated with device failure IMDs continually evolve thus difficult to accurately assess safety and effectiveness

10. Characteristics of the Operator Interpretation of evidence and preference are critical factors for adopting a new technology Skill and learning curve are factors for adoption and use Many large trials of IMDs procedure are conducted by highly skilled operator Important implication in designing studies and evaluating the evidence in real world Operator preferences driven by many factors: training, institutional, reimbursement condition…

11. Characteristics of the Procedure/Intervention Understand various procedural factors related to IMDs Documentation of surgical techniques/approaches Recognize and account for procedural choices, invasiveness of treatment

12. Characteristics of the Intervention Setting Evaluate hospital and access factors Determine the groups of patients able to receive IMDs Understand reasons for offering a particular IMD technology Financial & organizational reasons behind hospital’s choice

13. Characteristics of the Patient Learn about specific patient population Impact of diffusion of new technology on outcomes of the IMD Real-world use might create difficulties in real- world evaluations of IMDs Patient outcomes important to the assessment of Safety & Effectiveness not systematically collected

14. Selection and Measurement of Outcome Choice of outcome affect the strength of the evidence Clinically meaningful outcomes are preferred Use of surrogate endpoint can very challenging Outcomes are combined into indexes due to small sample sizes Use of disease specific measures of health status become quit important Lack of information on QoL or Functional Status

15. Methodological issues related to Comparative Studies of IMDs Blinding and Masking is difficult to achieve Inclusion/Exclusion is affected after initial Intent/randomization Impacts analytical approach including Intention to treat Learning curve issues affect the outcome of the IMD

16. Methodological issues related to Comparative Studies of IMDs Small Sample Size is a reality in IMDs Device modification and changes to medical practice during study Potential for imbalances among treatment groups Generalizibility is affected when less sick patient, Elite operators participate

17. Summary of Methodological issues and recommendations

18. Medical Device Working Group  Communication with decision makers in medical device industry  Lack of product development model similar to drug business  Review ICH and FDA guidelines to assess their applicability to device setting  Pursue methodological work on this area Contact for membership: roland.marion-gallois@medtronic.com Abdallah.abouihia@medtronic.com

19. Thank you