Everything You Ever Wanted to Know About ClinicalTrialsgov Slides for presentation only Deborah A Zarin MD Director ClinicalTrialsgov May 2010 1 Background 2 Whats All The Fuss About Suppression of research results impedes the scientific process ID: 768387
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Everything You Ever Wanted to Know About ClinicalTrials.gov (Slides for presentation only.)Deborah A. Zarin, M.D.Director, ClinicalTrials.govMay 2010 1
Background 2
What’s All The Fuss About? Suppression of research results impedes the scientific processSuppression 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. 2009 Nov 12;361:1963-71 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 ProtectionsAllows 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 IntegrityFacilitates tracking of protocol changesIncreases 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 . 2008 Mar 7;319(5868):1340-2. 8
10th Anniversary of ClinicalTrials.gov 2000 - 20109
10 10 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 11 11 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 participantKeep entries up to dateReport results for trials subject to FDAAA: Drugs, devices, biologicsNot Phase 1One year after “primary completion date” (unless special circumstances apply) 12
ClinicalTrials.gov—the Basics 13
14 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% * 287 applicable device clinical trials submitted, but qualify for “delayed posting” under FDAAA 14
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16 16 16 16 User Statistics Page Views per month 70 Million Unique visitors per month 950,000 Number Percent Trials by Sponsor US Federal (including NIH) 10,828 12% Industry 29,233 32% University, Other 50,076 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 - Volunteer 23% Researcher 14% Family/Friend 13% Patient - Learn 12% Provider 10% Other 9% Trial Team Personnel 7% Student/Educator 4% Healthy Volunteer 3% Investor 2% Journalist 1% Healthcare Admin 1% Advocate 1% Screen shot of : Map of the World indicating number of studies with locations in that region.
18 18 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 29 29 29 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 CharacteristicsOutcome Measures Adverse Events (summary data)Other Information“Certain Agreements” Restricting Results Disclosure Overall Limitations and CaveatsResults Point of Contact 30
31 31 31 Sample Posted Results 31
32 Screen shot of Clinical Trials Study Results
33 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 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 38 Screen shot of Serious Adverse Effects
39 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 relevanceAssurance 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 participateFinding an expanded access drugFinding 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 relevanceAssurance that information about the trial of interest is in the public domain for some trials, results will become public 43
44 44 44 Screen shot of ClinicalTrials.gov Advanced Search
45 45 Screen shot of ClinicalTrials.gov List Results
For those concerned with research integrity… Relatively complete list of trialsDescription of protocolTracking of changes to protocols Identifying all outcome measuresProviding results, regardless of journal publication status 46
47 Screen shot of ClinicalTrials.gov Advanced Search
48 Screen shot of ClinicalTrials.gov List Results
For thoseseeking study results… Linkages to PubMedSummary Results in databaseResults for all prespecified outcome measuresStandardized 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 http://clinicaltrials.gov/ct2/info
54 http://www.nlm.nih.gov/bsd/viewlet/ct/index.html Screen shot of ClinicalTrials.gov Online Training
55 Screen shot of ClinicalTrials.gov Online Training
Help for Trial Sponsors & Investigators 56 http://prsinfo.clinicaltrials.gov
57 http://prsinfo.clinicaltrials.gov/icmje.html Screen shot of ClinicalTrials.gov Protocol Registration System
58 http://prsinfo.clinicaltrials.gov/fdaaa.html 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;136:304-5.Tse T, Williams RJ, Zarin DA. Reporting basic results in ClinicalTrials.gov. Chest 2009;136:295-303.Zarin DA, Tse T. Moving toward transparency of clinical trials. Science 2008;319:1340-2.Wood AJ. Progress and deficiencies in the registration of clinical trials. N Engl J Med 2009;360:824-30. 59
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 cycleFDAAA 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 Email LISTSERV and other FDAAA information:http://prsinfo.clinicaltrials.gov/fdaaa.htmlOther general information: http://prsinfo.clinicaltrials.govQuestions?register@clinicaltrials.gov 65