Everything You Ever Wanted to Know About ClinicalTrials.gov (Slides for presentation only.) Deborah A. Zarin, M.D. Director, ClinicalTrials.gov May

Background 2

What’s All The Fuss About? Suppression of research results impedes the scientific process Suppression of clinical trial data is particularly problematic: –Trials depend on human volunteers; –Trial results inform our medical decisions 3

“The results of Study 15 were never published or shared with doctors, even as less rigorous studies that came up with positive results for Seroquel were published and used in marketing campaigns aimed at physicians and in television ads aimed at consumers.” “The results of Study 15 were provided only to the Food and Drug Administration -- and the agency has strenuously maintained that it does not have the authority to place such studies in the public domain.” Screen shot of Washington Post article. A Silenced Drug Study Creates An Uproar. By Shankar Vedantam Wednesday, March 18, 2009

“Eli Lilly & Co. urged doctors to prescribe Zyprexa for elderly patients with dementia, an unapproved use for the antipsychotic... after [it] sent study results to the U.S. Food and Drug Administration” showing Zyprexa didn’t alleviate dementia symptoms in older patients…” Screen shot of : Lilly Sold Drug for Dementia Knowing It Didn’t Help, Files Show By Margaret Cronin Fisk, Elizabeth Lopatto and Jef Feeley

N Eng J Med Nov 12;361: Screen shot of : The New England Journal of Medicine Outcome Reporting in Industry-Sponsored Trials of Gabapentin for Off-Label Use S. Swaroop Vedula, M.D., M.P.H., Lisa Bero, Ph.D., Roberta W. Scherer, Ph.D., and Kay Dickersin, Ph.D.

7 Reasons to Register Clinical Trials and Report Results Human Subject Protections –Allows potential participants to find studies –Assists ethical review boards and others to determine appropriateness of studies being reviewed (e.g., harms, benefits, redundancy) –Promote fulfillment of ethical responsibility to human volunteers – research contributes to medical knowledge Research Integrity –Facilitates tracking of protocol changes –Increases transparency of research enterprise Evidence Based Medicine –Facilitates tracking of studies and outcome measures –Allows for more complete identification of relevant studies Allocation of Resources –Promotes more efficient allocation of resources

8 Levels of “Transparency” Zarin DA, Tse T.. Science Mar 7;319(5868):

10 th Anniversary of ClinicalTrials.gov

10 History of ClinicalTrials.gov FDAMA 113 (1997): Mandates Registry –IND trials for serious and life-threatening diseases ClinicalTrials.gov Launched in February 2000 ClinicalTrials.gov Accommodates Other Policies –Registration Int’l Committee of Medical Journal Editors (ICMJE) World Health Organization (WHO) –Registration and Results Reporting Maine State Law; State Attorneys General European Medicines Agency (EMA) FDAAA 801 (2007): Expands Registry and Adds Results Database 10

11 FDAAA Sec.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 11

Trial Reporting: The Bottom Line Based on All Policies Register all interventional studies prior to enrollment of the first participant Keep entries up to date Report results for trials subject to FDAAA: –Drugs, devices, biologics –Not Phase 1 –One year after “primary completion date” (unless special circumstances apply) 12

ClinicalTrials.gov—the Basics 13

14 ClinicalTrials.gov Statistics (as of 5/24/2010) NumberPercent Total90, % Type of Trial Observational 15,252 17% Interventional74,107 83% –Drug & Biologic53,628 –Behavioral, Gene Transfer, Other 15,373 –Surgical Procedure 9,227 –Device* 5,538 International Sites (172 countries) US only41,513 46% Non-US only33,414 37% US & Non-US mixed 5,823 6% Missing 9,387 10% *287 applicable device clinical trials submitted, but qualify for “delayed posting” under FDAAA 14

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16 User Statistics Page Views per month 70 Million Unique visitors per month 950,000 NumberPercent Trials by Sponsor US Federal (including NIH)10,828 12% Industry29,233 32% University, Other50,076 55% Total 90,137 ClinicalTrials.gov Statistics (cont.) (as of 5/24/10)

ClinicalTrials.gov Visitors by “Role” (N=13,097) Source: American Customer Satisfaction Index (ASCI) Online Consumer Survey; Six-Month Period in 2007 Patient - Volunteer23% Researcher14% Family/Friend 13% Patient - Learn 12% Provider 10% Other 9% Trial Team Personnel 7% Student/Educator 4% Healthy Volunteer 3% Investor2% Journalist 1% Healthcare Admin 1% Advocate 1% Screen shot of : Map of the World indicating number of studies with locations in that region.

18 Sample Registry Record 18

19 Screen shot of ClinicalTrials.gov showing Full Text View

20 Screen shot of ClinicalTrials.gov showing Tabular View

21 Screen shot of ClinicalTrials.gov showing archive

22 Screen shot of MedlinePlus

23 Screen shot of ClinicalTrials.gov number in The New England Journal of Medicine

24 Screen shot of NLM Technical Bulletin article

25 Screen shot of journal citation in PubMed highlighting Secondary Source ID

26 Screen shot highlighting U.S. FDA Resources

27 Screen shot highlighting Clinical Trials in U.S. FDA 510 (k) Premarket Notification

28 Basic Results Database 28 Basic Results Database

29 Basic Results Reporting Requirements Results of FDA-approved/cleared products Generally, submission within 12 months of the earlier of estimated/actual primary completion date Delayed Submission of Results –Seeking initial approval –Seeking approval of a new use –Extensions for “good cause” 29

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 30

31 Sample Posted Results 31

32 Screen shot of Clinical Trials Study Results

33 Reasons Not Completed Milestone Arms Screen shot of Participant Flow: Overall Study

User-Specified Measure “Default” Required Measures Categories 34 Screen shot of Baseline Characteristics

35 Screen shot of Outcome Measures

36 Screen shot of Primary Outcomes Measure

Statistical Analysis 37 Screen shot of Measures Values and Statistical Analysis

38 Screen shot of Serious Adverse Effects

39 ICJME “…will not consider results posted in the same primary clinical trials register in which the initial registration resides as previous publication if the results are presented in the form of a brief, structured (<500 words) abstract or table.” [NOTE: Only about 23% of results records have associated publications at this time.]

Uses of ClinicalTrials.gov 40

For those concerned with human subjects protections… Complete list of ongoing and completed trials of relevance Assurance that information about the trial of interest –is in the public domain –for some trials, results will become public 41

For those with medical conditions… Finding a trial in which to participate Finding an expanded access drug Finding a center of research for a given condition/intervention 42

For those concerned with human subjects protections… Complete list of ongoing and completed trials of relevance Assurance that information about the trial of interest –is in the public domain –for some trials, results will become public 43

44 Screen shot of ClinicalTrials.gov Advanced Search

45 Screen shot of ClinicalTrials.gov List Results

For those concerned with research integrity… Relatively complete list of trials Description of protocol Tracking of changes to protocols Identifying all outcome measures Providing results, regardless of journal publication status 46

47 Screen shot of ClinicalTrials.gov Advanced Search

48 Screen shot of ClinicalTrials.gov List Results

For those seeking study results… Linkages to PubMed Summary Results in database Results for all prespecified outcome measures Standardized format facilitating comparisons 49

50 Outcome Measures = “Six Minute Walk” Age Group = “Child (birth-17)” Screen shot of ClinicalTrials.gov Advanced Search

51 Screen shot of ClinicalTrials.gov List Results

Resources 52

Help for Users 53

54 Screen shot of ClinicalTrials.gov Online Training

55 Screen shot of ClinicalTrials.gov Online Training

Help for Trial Sponsors & Investigators 56

57 Screen shot of ClinicalTrials.gov Protocol Registration System

58 Screen shot of ClinicalTrials.gov Protocol Registration System

Additional Background Tse T, Williams RJ, Zarin DA. Update on registration of clinical trials in ClinicalTrials.gov. Chest 2009;136: Tse T, Williams RJ, Zarin DA. Reporting basic results in ClinicalTrials.gov. Chest 2009;136: Zarin DA, Tse T. Moving toward transparency of clinical trials. Science 2008;319: Wood AJ. Progress and deficiencies in the registration of clinical trials. N Engl J Med 2009;360:

Common “Myths” about ClinicalTrials.gov “ClinicalTrials.gov matches –patients who are interested in participating in research with recruiting trials OR –investigators who want to conduct trials with study sponsors.” FALSE. ClinicalTrials.gov does not provide any such matching services. ClinicalTrials.gov does not endorse the trials that it lists. 60

Common “Myths” about ClinicalTrials.gov “Study data displayed in the ClinicalTrials.gov registry and results database are provided by the NIH.” FALSE. Data about each study are provided by the study sponsor or investigator. 61

Common “Myths” about ClinicalTrials.gov “If I register my trial late and ClinicalTrials.gov accepts the registration, then my trial satisfies the requirements of FDAAA or the ICMJE policy.” FALSE. Although ClinicalTrials.gov will accept registrations at anytime during the study life cycle –FDAAA requires applicable clinical trials to be registered no later than 21 days after enrollment of the first subject –ICMJE requires trials to be registered prior to enrollment 62

Common “Myths” about ClinicalTrials.gov “FDAAA only applies to clinical trials conducted under an investigational new drug application (IND) or an investigational device exemption (IDE).” FALSE. FDAAA applies to ALL non-phase 1 interventional studies (with one or more arms) of drugs, biological products, or devices that: –Have an IND/IDE, OR –Have one or more sites in the U.S. 63

Common “Myths” about ClinicalTrials.gov “Grantees do not need to register NIH-funded trials because NIH automatically registers all studies that it funds.” FALSE. NIH does not register grant-funded trials. Grantees are responsible for registering trials in accordance with relevant laws and policies (e.g., ICMJE). 64

Additional Information LISTSERV and other FDAAA information: – Other general information: – Questions? 65