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Everything You Ever Wanted to Know About ClinicalTrials.gov. (Slides for presentation only.) Deborah A. Zarin, M.D. Director, ClinicalTrials.gov May 2010. Background. What’s All The Fuss About?. Suppression of research results impedes the scientific process
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Everything You Ever Wanted to Know About ClinicalTrials.gov (Slides for presentation only.) Deborah A. Zarin, M.D. Director, ClinicalTrials.gov May 2010
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
Screen shot of Washington Post article. A Silenced Drug Study Creates An Uproar. By Shankar Vedantam Wednesday, March 18, 2009 • “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 : Lilly Sold Drug for Dementia Knowing It Didn’t Help, Files Show By Margaret Cronin Fisk, Elizabeth Lopatto and JefFeeley “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 : The New England Journal of Medicine Outcome Reporting in Industry-Sponsored Trials of Gabapentin for Off-Label Use S. SwaroopVedula, M.D., M.P.H., Lisa Bero, Ph.D., Roberta W. Scherer, Ph.D., and Kay Dickersin, Ph.D. N Eng J Med. 2009 Nov 12;361:1963-71
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
Levels of “Transparency” 8 Zarin DA, Tse T.. Science. 2008 Mar 7;319(5868):1340-2.
10th Anniversary of ClinicalTrials.gov 2000 - 2010
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 10 10
FDAAASec.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 11 11 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)
ClinicalTrials.gov Statistics(as of 5/24/2010) • Number Percent • Total 90,137 100% • Type of Trial • Observational 15,252 17% • Interventional 74,107 83% • Drug & Biologic 53,628 • Behavioral, Gene • Transfer, Other 15,373 • Surgical Procedure 9,227 • Device* 5,538 • International Sites (172 countries) • US only 41,513 46% • Non-US only 33,414 37% • US & Non-US mixed 5,823 6% • Missing 9,387 10% 14 *287 applicable device clinical trials submitted, but qualify for “delayed posting” under FDAAA
ClinicalTrials.gov Statistics (cont.)(as of 5/24/10) NumberPercent • Trials by Sponsor • US Federal (including NIH) 10,828 12% • Industry 29,233 32% • University, Other 50,076 55% • Total 90,137 • User Statistics • Page Views per month 70 Million • Unique visitors per month 950,000 16 16 16
Screen shot of : Map of the World indicating number of studies with locations in that region. Patient - Volunteer 23% Researcher 14% Family/Friend 13% Patient - Learn 12% Provider 10% 9% Other 7% Trial Team Personnel 4% Student/Educator 3% Healthy Volunteer Investor 2% 1% Journalist 1% Healthcare Admin 1% Advocate ClinicalTrials.gov Visitors by “Role”(N=13,097) Source: American Customer Satisfaction Index (ASCI) Online Consumer Survey; Six-Month Period in 2007
Sample Registry Record 18 18 18
Screen shot of ClinicalTrials.gov number in The New England Journal of Medicine
Screen shot of journal citation in PubMed highlighting Secondary Source ID
Screen shot highlighting Clinical Trials in U.S. FDA 510 (k) Premarket Notification
Basic Results Database Basic Results Database 28
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 29 29 29 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
Sample Posted Results 31 31 31
Screen shot of Participant Flow: Overall Study Arms Milestone Reasons Not Completed 33
Screen shot of Baseline Characteristics “Default” Required Measures User-Specified Measure Categories
Screen shot of Measures Values and Statistical Analysis Statistical Analysis
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.] 39
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
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
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
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
For thoseseeking study results… • Linkages to PubMed • Summary Results in database • Results for all prespecified outcome measures • Standardized format facilitating comparisons
Screen shot of ClinicalTrials.gov Advanced Search Outcome Measures = “Six Minute Walk” Age Group = “Child (birth-17)”