Update on Clinical Trials Registration and Results Reporting Requirements

1. Update on Clinical Trials Registration and Results Reporting Requirements Deborah A. Zarin, M.D. ClinicalTrials.gov February 24, 2009 1 1

2. Context: Continuing Concerns About Lack of Transparency of Clinical Trial Information

3. Recent Events: Lack of Transparency in Clinical Research

4. Source: Figure 1A. Turner et al. (NEJM, 2008)

5. The investigation was launched following concerns… • …although the ENHANCE trial ended in April 2006, the data had not yet been released. • …[the sponsors] did not register the clinical trial in a timely manner. • …[the sponsors] attempted to change the study endpoints, and thus the study results, prior to the public release of the results.

6. ENHANCE 2 1 3 Source: Kastelein JJ, Sager PT, de Groot E, Veltri E. Am Heart J. 2005 Feb;149(2):234-9.

7. Primary Outcome Measures: • Change in ultrasound-determined average carotid artery intima-media thickness (IMT) on a per subject basis between baseline and endpoint. [ Time Frame: 24 months ] • Primary Outcome Measures: • Change in ultrasound-determined average carotid artery intima-media thickness (IMT) on a per subject basis between baseline and endpoint. [ Time Frame: 24 months ]

8. Source: Silverstein FE et al. JAMA. 2000 Sep 13;284(10):1247-55.

9. Kaplan-Meier estimates for ulcer complications according to traditional definition. Results are truncated after 12 months, no ulcer complications occurred after this period. Adapted from Lu 2001. Source: Jüni P, Rutjes AW, Dieppe PA. BMJ. 2002 Jun 1;324(7349):1287-8.

10. “The Neurontin Legacy – Marketing through Misinformation and Manipulation” Studies “designed and commissioned specifically to promote Neurontin use.” Seeding trial “to give neurologists the opportunity to titrate to higher doses [up to twice the FDA-approved limit] when needed” Delayed publication of negative results to mitigate damage to “neurontin’s marketing success” Summary: “the documentation of comprehensive manipulation of research and publication related to Neurontin is remarkable.” 10 Landefeld CS, Steinman MA. NEJM. N Engl J Med 360:103-6

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12. (WSJ, Aug 2008)

14. PLoS Med. 2008;5(11): e217

15. Lee K, Bacchetti P, Sim I. PLoS Med. 2008;5(9): e191

16. History of ClinicalTrials.gov FDAMA 113 (1997): Mandates Registry IND trials for serious and life-threatening diseases or conditions ClinicalTrials.gov Launched in February 2000 Calls for Increased Transparency of Clinical Trials Maine State Law; State Attorneys General Journal Editors (2004) ClinicalTrials.gov Accommodates Other Policies FDAAA 801 (2007): Expands Registry and Adds Results Database 16 16 16

17. Policies and Users Ottawa Statement Sponsor Policy (e.g., NIH, VA) FDAAA ICMJE Maine FDAMA 113 BPCA WHO ClinicalTrials.gov Recruitment (e.g., patients, physicians) Health Policy Makers IRBs Journal Editors Research Funders 17 17

18. ClinicalTrials.gov Statistics(as of 02/03/2009) • Number Percent • Total 67,064 100% • Type of Trial* • Observational 10,690 16% • Interventional 57,119 84% • Drug & Biologic 42,684 • Surgical Procedure 8,585 • Behavioral, Gene • Transfer, Other 7,997 • Device** 3,862 • International Sites (161 countries) • US only 32,772 49% • Non-US only 23,109 34% • US & Non-US mixed 4,064 6% • Missing 7,119 11% *171 records missing Study Type information **173 device trials – “delayed posting” 18

19. ClinicalTrials.gov Statistics (cont.)(as of 02/03/2009) NumberPercent • Trials by Data Provider • US Federal (including NIH) 18,088 27% • Industry 21,072 31% • University, Other 28,820 42% • Total 67,980 • User Statistics • Page Views per month 40 Million • Unique visitors per month 500,000 19

20. Search Features • Powerful Search Engine • Synonymy • E.g., can find V501 studies by searching “Gardasil” • Hierarchies • E.g., can find Crohn’s disease by searching for IBD • Spelling relaxation • Interface allows for field specific searching • E.g., can find “condition” without finding “exclusion criterion”

25. Update on Clinical Trial Registration

26. Public Law 110-85Sec.801 Expanded Clinical Trial Registry Enacted on September 27, 2007 Requires Trial Registration (Dec 2007) Phase II-IV drug and device trials for all diseases Data elements: ClinicalTrials.gov + ~ WHO/ICMJE Requires Results Reporting (Sept 2008) Trials of FDA-approved or cleared drugs and devices “Basic” Results: Baseline Characteristics, Primary & Secondary Outcomes, Statistical Analyses Adverse Events (Sept 2009) “Expansion” of results by rulemaking (Sept 2010) Added enforcement provisions 26 26 26 26

27. Enforcement Provisions Notices of non-compliances Civil monetary penalties up to $10,000/day Withholding of NIH grant funds

28. Key Terms Applicable Clinical Trials Interventional trials Phase 2-4 drug, biologic, device >= one site in U.S. Ongoing as of 9/27/07, or later Responsible Party Sponsor, grantee PI if designated (Primary) Completion Date

29. Wood AJJ. Progress and deficiencies in the registration of clinical trials. NEJM. 2009

30. Wood AJJ. Progress and deficiencies in the registration of clinical trials. NEJM. 2009

31. What Information Is In the Trial Registry? • Basic Protocol Details • Condition, intervention(s), design, outcome measures, key dates • Administrative Information • NCT#, other IDs, Responsible Party, PI • Recruitment and location status • Linkages • PubMed, FDA resources, consumer health info

32. New Registrations Continue to Increase

33. Registration of Phase 1 and Device Trials • 2100 device trials registered between 9/07 and 1/09 • 175 are in “lock box” • 162 Industry • 13 Other • Phase 1 trials • 186/month in fy 2008 (73% increase from 07) • 205/month in fy 2009* (10% increase from 08) * First four months

34. Key Points: Memo from Dr. Kington, Acting Director, to NIH Grant Awardess • “For grants, NIH is generally not the sponsor … and, as such, NIH would not be the responsible party.” • “Responsible parties who have not yet registered their clinical trials should do so immediately.” • “Thank you for your attention to this important matter and your commitment to helping enhance the transparency of NIH funded clinical trials.”

35. Status of Stanford Trials • 73 may be “applicable” • 65 have outcome measure • 2 have RP • 62 have start date • 1 has “primary completion date” • 8 have “completion date” • How many “results” are due?

36. Enforcement Provisions Notices of non-compliances Civil monetary penalties up to $10,000/day Withholding of NIH grant funds

37. Bottom Line • Register prior to enrollment: • Phase 2-4 interventional trials that include a drug, device or biologic • Regardless of whether or not the trial is being used to support an FDA application • Report results: • Any trial described above once the drug, device or biologic has been approved; OR • Within one year of “primary completion date” • Keep all information up to date! 37

38. Basic Results Database 38

39. Basic Results Database: General Characteristics Results of “applicable clinical trials” of FDA-approved/cleared medical products Generally, submission within 12 months of the earlier of estimated or actual trial completion date (of primary outcome) Delayed Submission of Results Seeking initial approval Seeking approval of a new use Extensions for “good cause” 39 39 39 39 39

40. Basic Results Modules Participant Flow Baseline and Demographic Characteristics Outcome Measures Adverse Events (summary data) Other Information “Certain Agreements” Restricting Results Disclosure Overall Limitations and Caveats Results Point of Contact

41. Current Status – “Basic Results”(as of 02/06/09) • Functional Web-based Data Entry System • Launched in September 2008 • Ongoing system of feedback and improvements • 410 Results Records have been submitted • Industry: 293 records from 72 data providers • Other: 117 records from 80 data providers • Anticipate greatly increased rate of submission 41 41

42. Sample Posted Results 42 42 42

43. Published Participant Flow 43 Source: Kimmick GG et al. Breast J. 2006 Mar-Apr;12(2):114-22.

45. Arms Milestone Reasons Not Completed

46. Crossover Design Multiple “Periods”

47. Published Baseline Data Source: Richter JE et al. Am J Gastroenterol. 2001 Mar;96(3):656-65.

48. “Default” Required Measures User-Specified Measure Categories

49. Arms

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