1. SF Coordinating Center Multicenter Trials Pilot Studies Steve Cummings, MD

2. SF Coordinating Center Outline Multicenter studies Industry-sponsored trials Pilot studies for trials

3. SF Coordinating Center Dr. D Large dermatology practice Interest in psoriasis Wants to participate in multicenter trials of new treatments

4. SF Coordinating Center Multicenter studies Anatomy Physiology How to work with them Example: MrOS

5. SF Coordinating Center Anatomy: NIH-style studies Data Coordinating Center - Makes forms & manuals - Compiles data for analysis Clinical sites - Recruit subjects - Transmits data to CC

6. SF Coordinating Center Anatomy: NIH-style studies Data Coordinating Center - Makes forms & manuals - Compiles data for analysis Clinical sites - Recruit subjects - Transmits data to CC Other functions depend on the study Design, analysis

7. SF Coordinating Center Physiology Data Coordinating Center - Makes forms & manuals - Compiles data for analysis Clinical sites - Recruit subjects - Transmits data to CC Other functions depend on the study Design, analysis

8. SF Coordinating Center Physiology: NIH-style studies Overall PI  Got the grant; leads the study Clinical site PIs  Run the sites; variable say re: the study Steering Committee  Represents all sites and CC  Sets the policies; ultimate arbiter

9. SF Coordinating Center Physiology: NIH-style studies Publications and Analysis Committee  Usually a subset of the SComm  Develops guidelines for approval  Reviews and approves proposals for analyses, papers (and ancillary studies)  Democratic

10. SF Coordinating Center Anatomy: Industry sponsored trials Sponsor - Designs the trial - Chooses sites - Analyzes data Clinical sites - Recruit subjects - Transmits data to CRO CRO CRO (hired by sponsor) - Creates the forms - Collects/collates data - Monitor sites Sponsor

11. SF Coordinating Center Physiology: Most industry trials Sponsor does it all  Designs study, develops forms and protocols  Analyzes data; selects authors; write the articles Investigators  Paid to recruit patients  Investigator meetings  No representation in decisions

12. SF Coordinating Center Physiology: A few industry trials More collaborative with investigators  ‘Lead’ investigators involved in design  Steering Committee (a few investigators)  Publications Committee Investigators  Most still just paid to recruit patients  Investigator meetings Example: AMG 216 (FREEDOM Trial)

13. SF Coordinating Center A few (ideal) industry trials Steering Committee  Minority representation from sponsor  Real authority (official charter)  Changes in design. Stopping the trial. Publications and Analysis Committee  Minority representation from sponsor  Publication guidelines (a contract)  Develop and review analysis plans  Review and approve papers

14. SF Coordinating Center Reasons to be a site NIH multicenter study Participate in scientific investigation Use data; publish Support staff

15. SF Coordinating Center Reasons to be a site in the typical industry trial Funding for you and staff Profit (industry funds are worth more than NIH funds) New treatment alternatives to patients A chance for correlative science? A step toward larger roles with the sponsor Appear on publications Value for promotion?

16. SF Coordinating Center What we (SFCC) look for in a site Past performance Rapid recruitment of large numbers Responsive and involved colleagues  (Avoid complainers and nonresponders) Scientific expertise High quality work (clean data)

17. SF Coordinating Center What Industry looks for in sites Past performance  Number recruited  Not a ‘problem site’ Current capability to recruit Reputation of the investigator  Thought leader  Active contributor: expertise, consulting, productive writer.

18. SF Coordinating Center Would you like to be a site? Get a reputation  Become a local or national leader  Recruit successfully Borrow a reputation  Have a mentor or experienced colleague make contacts (Industry: Contact your local ‘rep’)

19. SF Coordinating Center Competitive recruitment Trials have set recruitment goal Industry pays per subject Those who recruit most make most  Possible to make $$$  Possible to lose $$$  The case of the “Lone Academic” Top recruiter is often 1st author

20. SF Coordinating Center Disadvantages of being a site in industry trials Can lose money Distraction from other types of work or research Hassles  Site monitoring  FDA inspections

21. SF Coordinating Center How to be a great clinical site An excellent study coordinator A registry of patients (subjects)  Characteristics  Consent to be contacted for research Excellent responsive support  Contracts office  IRB

22. SF Coordinating Center Publications and industry

23. SF Coordinating Center Publications Sponsors own the data Data analyzed and drafted by  The sponsor statistician and medical writer  A hired “CME” firm External authors invited to author a paper  Provided analyses or draft  May write a draft or ‘edit’ the sponsors draft

24. SF Coordinating Center Universities: investigators must have ‘access to the data’ “Access to data” is meaningless  Sponsors employ the data analysts  Sponsor’s team directs and selects analyses  Authors are rarely involved (or skilled) in data analysis, rarely look at data output

25. SF Coordinating Center Universities: investigators must have ‘the right to publish’ “Right to publish” is usually meaningless  Your data is one small part of the larger trial; would be wrong to publish a part  Hard to analyze and publish without support for analysis and writing  Investigators should not have a ‘right to publish’ results that are wrong

26. SF Coordinating Center An ideal approach to publications from from industry Insist on a Publications Committee  With guidelines as a contract  Reviews plans and papers before submission  Minority voting representation from the sponsor Data available for analysis by independent statistician-analyst  Some journals are insisting Writing the paper  No medical writers?  Or writers assist investigators

27. SF Coordinating Center Pilot studies

28. SF Coordinating Center Why pilots Feasibility  To determine if you can do it.  To convince funders you can do it To improve the study  More efficient  Prevent screw-ups

29. SF Coordinating Center Example: T trial Green tea has been associated with lower risk of breast cancer Inexpensive and safe Proposal  Large randomized trial to test green tea extract vs. placebo X 3 years  Randomize women who attend mammography units and have high breast density to capsules of placebo or green tea

30. SF Coordinating Center T trial Easy to recruit from the Center  Breast density can be assessed on the mammogram  No need for exclusions  45,000 women get mammography / year Periodically mail study supplements to home Follow-up by internet and future mammography visits Ascertain cancer by emailed or phoned self- report or periodic search of the SEER registry

31. SF Coordinating Center T trial Idea has been enthusiastically received A group is meeting to develop a proposal to NCI

32. SF Coordinating Center Pilot studies To test feasibility of recruitment  Review records  Survey participants  Conduct a ‘pilot trial’ To test the feasibility of interventions, procedures and measurements  How much green tea to have an effect?  Side effects of large doses?  Will women adhere?

33. SF Coordinating Center Pilot studies To determine power  Variability of the main measurement  Rates of outcome in real participants To estimate costs and need for staffing And others…

34. SF Coordinating Center How big should pilots be? “It depends” Sample size estimates sometimes useful  (Hologic wanted ‘100’ when 30 will do) Traditions and guesses  NCI phase I trials start with 3  Dry runs: 3 to 10 of same age, health

35. SF Coordinating Center Do pilots need control groups? It depends New treatments  Determining the highest tolerable dose of green tea?  Determining the effect of green tea on breast density? Feasibility?  Generally irrelevant (e.g., potential participants’ eligibility and willingness to enroll).

36. SF Coordinating Center Funding for pilots Local institution  Academic Senate… Disease foundations Industry reps Mentors… Can often be done with volunteer help

37. SF Coordinating Center IRB approval for pilots Pilots involving people (or medical records) generally need IRB approval Testing questionnaire or strength testing devise with staff?