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Multicenter Trials Industry-sponored Trials

Multicenter Trials Industry-sponored Trials. Steve Cummings, MD Director, SF Coordinating Center. Outline. Multicenter studies NIH-style studies Industry-sponsored studies Being a site in an industry study How to work with industry Publications Heresies. NIH-style studies.

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Multicenter Trials Industry-sponored Trials

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  1. Multicenter TrialsIndustry-sponored Trials Steve Cummings, MD Director, SF Coordinating Center

  2. Outline • Multicenter studies • NIH-style studies • Industry-sponsored studies • Being a site in an industry study • How to work with industry • Publications • Heresies

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

  4. 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, assessing clinical outcomes

  5. NIH studies: DCC/CCC model Data Coordinating Center - Makes forms & manuals - Compiles data for analysis - Works with sites about data entry Clinical Coordinating Center -Designs and leads the clinical scientific aspects - Oversees implementation of the protocol

  6. NIH-style studies • Overall CCC PI • Got the grant; leads the clinical study • Overall DCC PI • Contributed data methods to the grant; leads the technical functions • Clinical site PIs • Run the sites; variable say re: the study • Steering Committee • Usually represents all sites and CC’s • Sets the policies; ultimate arbiter

  7. Publications Committee • Publications and Analysis Committee • Usually a subset of the Steering Committee • Reviews and approves proposals for analyses for papers and abstracts. • Reviews proposals for and ancillary studies • Usually democratic

  8. Ideally • You will be the PI of the multicenter study • Multicenter study proposals are complex, difficult and usually considered years into a career

  9. Reasons to be a siteNIH multicenter study • Participate in scientific investigation • Get an inside track on using study-wide data for publications • Get promoted • Support a research staff

  10. Industry sponsored trials Sponsor - Designs the trial - Analyzes data* Sponsor CRO* CRO (hired by sponsor) - Chooses the sites* - Creates the forms - Collects/collates data - Monitor sites Clinical sites - Recruit subjects - Transmits data to CRO CRO = ‘Contract Research Organization Companies that provide research services

  11. Most industry trials • Sponsor and CRO do it all • Design study, develops forms and protocols • Analyze data; selects authors; write the articles • Investigators • Paid to recruit patients • Investigator meetings • No role in decisions

  12. 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 • Attend investigator meetings

  13. Being a site in an industry trial

  14. Reasons to be a site in the typical industry trial • Funding for you and staff • New treatment alternatives to patients • Profit

  15. Why industry money is greener • NIH and industry funding can be used for travel to scientific meetings (if its in the budget) and journal subscriptions • Only industry funds can be saved for a ‘rainy day’ • Future salary support • Future ‘sabbatical’ • Industry funds can be used for more discretionary purposes not related to the industry study • Other unfunded research ($ for measurements, staff) • Staff appreciation lunches • Equipment

  16. Reasons to be a site in the typical industry trial • Funding for you and staff • New treatment alternatives to patients • Profit • A chance for correlative science? • A step toward larger roles with the sponsor • Appear on publications • Value for promotion??

  17. Industry studies and promotion • Participating as a site and coauthor gets little respect • Scientific leadership (lead authorship) in trials gets more respect • Grants from industry for independent research usually get less respect than the same research funded by NIH

  18. Disadvantages of being a site in industry trials • Can lose money • Can lose a lot of money

  19. 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. 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. Would you like to be a site?

  22. What Industry looks for in sites • Past performance • Number recruited • Number recruited • Not a ‘problem site’ • Current capability to recruit • Reputation of the investigator • Key Opinion Leader (“KOL”) • Also contributes to science and publications

  23. Being a site in NIH studiesWhat we (SFCC) look for in a site Past performance • Rapid recruitment of large numbers • Responsive and involved colleagues • Fun to work with • Avoid complainers and nonresponders Scientific expertise

  24. 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

  25. 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

  26. Other types of support from industry • “IIT” grants • Small • Free drug for your own research • Support for other types of studies (epidemiology, cost-effectiveness studies) • Educational funds

  27. Publications and industry

  28. Anatomy of a pharma sponsor • Research or ‘Clinical Development’ unit • Usually scientists • Goal: FDA approval of a safe and effective treatment • Marketing • Usually business professionals • Goal: make $ • They usually have more $$ than Development • Greater potential for bias

  29. PublicationsThe usual approach • Sponsors own the data • Data are usually analyzed by • the sponsor’s statistician and medical writer • a hired “Medical Communications” firm • External authors invited to author a paper • They are given the analyses or a draft • May write a draft or just ‘edit’ the sponsor’s draft

  30. An example of guests and ghosts - Rofecoxib trials - The communications company completed analyses (and drafts) then invited the 1st author JS Ross, et al. JAMA 2008;299:1800-12

  31. An example of guests and ghosts - Rofecoxib trials - The communications company completed analyses (and drafts) then invited the 1st author - The initial draft of papers were written by the sponsor and sent to the author for editing. JS Ross, et al. JAMA 2008;299:1800-12

  32. Concerns about guests and ghosts “Some sponsors and contract communications companies analyze data and provide nearly complete draft articles for academic investigators who are then listed as 1st authors.” DeAngelis & Fontanarosa. JAMA 2008;299:1833-5

  33. JAMA Principles, 2008 • “For profit companies…should not be solely or primarily involved in…conducting the data analysis, and preparing the manuscript reporting study results. These responsibilities should primarily…be performed by academic investigators who are not employed by the company… DeAngelis & Fontanarosa. JAMA 2008;299:1833-5

  34. NEJM and JAMA NEJM asks • Who wrote the 1st draft? • Who employs the statistician? NEJM, JAMA, and a few others ask that a description in the the specific roles of sponsor be put in the paper

  35. Industry is changing its practices • More careful about ghost writing • Requiring that investigators participate, at least in conference calls • Requiring authors to have some level of contribution to the paper (or at least ‘see and agree’) • But they still largely choose the topic • They draw from data without a prospective plan for the paper • Must report ALL money paid to physicians for anything

  36. Analyses of Industry (and other) Trial Results

  37. Usual approach to analyses • Authors search through the data for interesting results • Adverse events reported based on unspecified and different criteria • Important, related, 1%, 5% • Example: raloxifene and ankle fractures

  38. Analysis Plans • Specified before results are unblinded • What subgroups will be included • At what frequency and statistical significance will AEs be reported? • Example: FREEDOM trial • 9 subgroups • AE criteria: 1% in either group; P<0.01

  39. An ideal approach to publishing 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 analysis by independent statistician • Writing the paper • Based on an analysis plan before unblinding • By external authors • No commercial medical writers; or writers simply assist investigators with tables, figures, editing.

  40. Examples • FREEDOM Trial of Denosumab (Amgen) • Steering and Publications Committee: 1 scientist scientists from Amgen • Publication guidelines • Had a prospective analysis plan • Wrote the 1st draft - input from Amgen scientists • Reviewed and approved by Pub Comm • No reimbursement for time spent writing • We own a copy of the data set • Repeated all of the analyses

  41. Heresy Access to the data The ‘Right to Publish’

  42. 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

  43. 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

  44. Summary • Many advantages to participating as a site in multicenter NIH trials • Industry studies offer opportunities – and new treatments, but allow less participation • You can make – or lose – money • Encourage sponsors to follow principles for analyses and publications

  45. Thank you!

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