1. Medical Device Consultants, Inc. Investing in a Clinical Program: Advice in a Challenging Economic Time MassMEDIC Medical Device Clinical Trials Update June 19, 2009 Presented by: Michael Feldstein, VP and Principal Biostatistician

2. 2June 19, 2009Medical Device Consultants, Inc. Introduction Economic downturn has put increased pressures on medical device companies to curtail spending Clinical trials can be very expensive

3. 3June 19, 2009Medical Device Consultants, Inc. Regulatory Considerations: Pre-IDE Meetings – a no-cost (almost) opportunity Non-binding, informal Opportunity for early collaboration Meet before significant preclinical work or clinical studies Confirm device classification, regulatory pathway Address questions related to preclinical testing, clinical trials, endpoints

4. 4June 19, 2009Medical Device Consultants, Inc. Other Considerations Will the study be NSR (non-significant risk) or will an IDE be required? When the product is cleared, what will the reimbursement be?

5. 5June 19, 2009Medical Device Consultants, Inc. Other Considerations (continued) Take FDA “suggestions” seriously Balance between urgency of timeline and thoroughness of planning and execution Right First Time Collaboration vs. confrontation

6. 6June 19, 2009Medical Device Consultants, Inc. The Scope of the Clinical Program – Time and Cost What is the likely cost of the clinical program? What is the likely duration of the program? How prepared are you to fund the program (expenditure of money over time)? Does your board/investor(s)/company understand:  The probable timeline?  What could go wrong?  Costs if something goes wrong?

7. 7June 19, 2009Medical Device Consultants, Inc. Costs for Clinical Trials: Where does the money go? CRO Hospitals/Clinics/Investigators (per patient and overhead) Subjects (possibly, for expenses and inconvenience) Liability Insurance

8. 8June 19, 2009Medical Device Consultants, Inc. Costs for Clinical Trials: CRO Statistical Input Protocol development/review Case Report Form development (and subject binders) Study Handbooks for Investigative Sites Informed Consent Document Find/Qualify Investigative Sites Statistical Analysis Plan

9. 9June 19, 2009Medical Device Consultants, Inc. Costs for Clinical Trials: CRO Site Initiation Visits Routine Monitoring Visits Close-out Visits

10. 10June 19, 2009Medical Device Consultants, Inc. Costs for Clinical Trials: CRO Project Management Study Coordination (with sponsor and sites)

11. 11June 19, 2009Medical Device Consultants, Inc. Costs for Clinical Trials: CRO Develop database/data entry screens Develop data management plan Data Entry Data Management

12. 12June 19, 2009Medical Device Consultants, Inc. Costs for Clinical Trials: CRO Routine administrative reporting (study progress) Interim statistical analysis (if applicable) Final statistical analysis Statistical report of Clinical findings (per statistical analysis plan for insertion into Regulatory submission) Safety Reporting (MedDra Coding, etc.)

13. 13June 19, 2009Medical Device Consultants, Inc. Costs for Clinical Trials: CRO On-going consultation (statistics, regulatory) Appearances at FDA (on sponsor’s behalf) Meetings (DSMB, CEC, special meetings)

14. 14June 19, 2009Medical Device Consultants, Inc. How can a Biostatistician help?  Is the sequence of studies in the program mapped out?  Any useful human data available (safety and/or effectiveness)?  What are the relevant study endpoints (that match the regulatory strategy)?  Is there any controversy about how endpoints are measured?  Are the endpoints clinically “relevant” and intuitive?  Has a clinically meaningful outcome (“success”) been defined?

15. 15June 19, 2009Medical Device Consultants, Inc. More help  What is the best study design?  What sample size is needed for the chosen design?  Does the sample size meet the cost/time constraints?

16. 16June 19, 2009Medical Device Consultants, Inc. Rules of Thumb for Clinical Studies/Trials  They always cost more than expected  They almost always take longer than expected  They require constant attention and discipline

17. 17June 19, 2009Medical Device Consultants, Inc. What are the Riskiest Things to do Yourself? Study monitoring Data management

18. 18June 19, 2009Medical Device Consultants, Inc. Critical Good Clinical Practice Requirements 21 CFR outlines the regulatory requirements (various parts) Two key elements of the regulations address study monitoring and data management Various guidance documents

19. 19June 19, 2009Medical Device Consultants, Inc. Study Monitoring Sponsor can contract out but cannot delegate this responsibility to a third party Competent monitoring is critical to study success (a PMA can be stopped in its review tracks by BIMO even before the PMA is reviewed) Sponsor needs to carefully read all monitoring reports in real time and act as necessary to bring matters into compliance

20. 20June 19, 2009Medical Device Consultants, Inc. Data Management Data management practices must conform to the regulatory requirements Briefly: if you can’t keep track of and store every single keystroke in an electronic data base, the system is not in compliance with the regulatory requirements

21. 21June 19, 2009Medical Device Consultants, Inc. How to Decide What to Outsource? Review and understand all applicable regulatory requirements Evaluate your current staff for proven experience with the necessary tasks Define the “gaps” and decide if hiring/buying makes sense Decide if you can objectively execute a task (e.g. monitoring)- danger: pandering to/coddling investigative sites and investigators, tolerating study protocol deviation, tolerating poor performance Your goal is to make decisions that eliminate bias and any appearance of bias throughout the entire clinical process

22. 22June 19, 2009Medical Device Consultants, Inc. Thank You For additional information: Michael Feldstein Vice President & Principal Biostatistician feldstein@mdci.com (508) 643-0434