Investing in a Clinical Program: Advice in a Challenging Economic Time

1. 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 Medical Device Consultants, Inc.

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

3. 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 Medical Device Consultants, Inc.

4. 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? Medical Device Consultants, Inc.

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

6. 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? Medical Device Consultants, Inc.

7. 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 Medical Device Consultants, Inc.

8. 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 Medical Device Consultants, Inc.

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

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

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

12. 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.) Medical Device Consultants, Inc.

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

14. 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? Medical Device Consultants, Inc.

15. 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? Medical Device Consultants, Inc.

16. 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 Medical Device Consultants, Inc.

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

18. 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 Medical Device Consultants, Inc.

19. 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 Medical Device Consultants, Inc.

20. 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 Medical Device Consultants, Inc.

21. 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 Medical Device Consultants, Inc.

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