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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
  • Background
  • 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
  • Screen shot of Washington Post article. A Silenced Drug Study Creates An Uproar.By Shankar VedantamWednesday, March 18, 2009
  • Screen shot of :Lilly Sold Drug for Dementia Knowing It Didn’t Help,Files ShowBy Margaret Cronin Fisk, Elizabeth Lopatto and JefFeeley
  • Screen shot of :The New England Journal of MedicineOutcome Reporting in Industry-Sponsored Trials of Gabapentin for Off-Label UseS. SwaroopVedula, M.D., M.P.H., Lisa Bero, Ph.D., Roberta W. Scherer, Ph.D., and Kay Dickersin, Ph.D.
  • Reasons to Register Clinical Trials and Report ResultsHuman Subject ProtectionsAllows potential participants to find studiesAssists 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 enterpriseEvidence Based MedicineFacilitates tracking of studies and outcome measuresAllows for more complete identification of relevant studiesAllocation of ResourcesPromotes more efficient allocation of resources
  • 10th Anniversary of ClinicalTrials.gov2000 - 2010
  • History of ClinicalTrials.govFDAMA 113 (1997): Mandates RegistryIND trials for serious and life-threatening diseasesClinicalTrials.gov Launched in February 2000ClinicalTrials.gov Accommodates Other PoliciesRegistrationInt’l Committee of Medical Journal Editors (ICMJE)World Health Organization (WHO)Registration and Results ReportingMaine State Law; State Attorneys GeneralEuropean Medicines Agency (EMA)FDAAA 801 (2007): Expands Registry and Adds Results Database
  • FDAAASec.801 Expanded Clinical Trial RegistryEnacted on September 27, 2007Requires Trial Registration (Dec 2007)Phase II-IV drug and device trials for all diseasesData elements: ClinicalTrials.gov + ~ WHO/ICMJERequires Results Reporting (Sept 2008)Trials of FDA-approved or cleared drugs and devices“Basic” Results: Baseline Characteristics, Primary & Secondary Outcomes, Statistical AnalysesAdverse Events (Sept 2009)“Expansion” of results by rulemaking (Sept 2010)Added enforcement provisions
  • Trial Reporting:The Bottom Line Based on All PoliciesRegister 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)
  • ClinicalTrials.gov—the Basics
  • ClinicalTrials.gov Statistics(as of 5/24/2010)
  • Screen shot of :Map of the World indicating number of studies with locations in that region.
  • ClinicalTrials.gov Statistics (cont.)(as of 5/24/10)
  • ClinicalTrials.gov Visitors by Role
  • Sample Registry Record
  • Screen shot of ClinicalTrials.gov showing Full Text View
  • Screen shot of ClinicalTrials.gov showing Tabular View
  • Screen shot of ClinicalTrials.gov showing archive
  • Screen shot of ClinicalTrials.gov showing archive
  • Screen shot of NLM Technical Bulletin article
  • Screen shot of journal citation in PubMed highlighting Secondary Source ID
  • Screen shot highlighting U.S. FDA Resources
  • Screen shot highlighting Clinical Trials in U.S. FDA 510 (k) Premarket Notification
  • Basic Results Database
  • Basic Results Reporting RequirementsResults of FDA-approved/cleared productsGenerally, submission within 12 months of the earlier of estimated/actual primary completion dateDelayed Submission of ResultsSeeking initial approval Seeking approval of a new use Extensions for “good cause”
  • Basic Results ModulesParticipant Flow Baseline and Demographic CharacteristicsOutcome MeasuresAdverse Events (summary data)Other Information“Certain Agreements” Restricting Results DisclosureOverall Limitations and CaveatsResults Point of Contact
  • Sample Posted Results
  • Screen shot highlighting Clinical Trials in U.S. FDA 510 (k) Premarket Notification
  • Screen shot of Participant Flow: Overall Study
  • Screen shot of Baseline Characteristics
  • Screen shot of Outcome Measures
  • Screen shot of Primary Outcomes Measure
  • Screen shot of Measures Values and Statistical Analysis
  • Screen shot of Serious Adverse Effects
  • 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
  • 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 domainfor some trials, results will become public
  • 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 domainfor some trials, results will become public
  • Screen shot of ClinicalTrials.gov Advanced Search
  • Screen shot of ClinicalTrials.gov List Results
  • For those concerned with research integrity…Relatively complete list of trialsDescription of protocolTracking of changes to protocolsIdentifying all outcome measuresProviding results, regardless of journal publication status
  • Screen shot of ClinicalTrials.gov Advanced Search
  • 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
  • Screen shot of ClinicalTrials.gov Advanced Search
  • Screen shot of ClinicalTrials.gov List Results
  • Resources
  • Help for Users
  • Screen shot of ClinicalTrials.gov Online Training
  • Screen shot of ClinicalTrials.gov Online Training
  • Help for Trial Sponsors & Investigators
  • Screen shot of ClinicalTrials.gov Protocol Registration System
  • Screen shot of ClinicalTrials.gov Protocol Registration System
  • Additional BackgroundTse 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.
  • 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.
  • 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.
  • 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
  • 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, ORHave one or more sites in the U.S.
  • 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).
  • Additional InformationEmail LISTSERV and other FDAAA information:http://prsinfo.clinicaltrials.gov/fdaaa.htmlOther general information:http://prsinfo.clinicaltrials.govQuestions?register@clinicaltrials.gov

Everything You Ever Wanted to Know About ClinicalTrials.gov(Slides ... Everything You Ever Wanted to Know About ClinicalTrials.gov(Slides ... Presentation Transcript

  • Everything You Ever Wanted to Know About ClinicalTrials.gov
    (Slides for presentation only.)
    Deborah A. Zarin, M.D.
    Director, ClinicalTrials.gov
    May 2010
    1
  • 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 JefFeeley
  • 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. SwaroopVedula, 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. 2008 Mar 7;319(5868):1340-2.
    8
  • 10th Anniversary of ClinicalTrials.gov
    2000 - 2010
    9
  • 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
    History of ClinicalTrials.gov
    10
  • 11
    11
    11
    11
    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
  • 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
  • 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
    14
  • 15
  • 16
    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
    ClinicalTrials.gov Statistics (cont.)(as of 5/24/10)
  • 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
    Screen shot of :
    Map of the World indicating number of studies with locations in that region.
  • Sample Registry Record
    18
    18
    18
    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
  • Basic Results Database
    28
    28
    Basic Results Database
  • 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 Reporting Requirements
    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
  • Sample Posted Results
    31
    31
    31
    31
  • 32
    Screen shot of Clinical Trials Study Results
  • 33
    Arms
    Milestone
    Reasons Not Completed
    33
    Screen shot of Participant Flow: Overall Study
  • “Default” Required
    Measures
    User-Specified
    Measure
    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
    “…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
    ICJME
  • 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
    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 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 thoseseeking 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
    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 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
    Email LISTSERV and other FDAAA information:
    http://prsinfo.clinicaltrials.gov/fdaaa.html
    Other general information:
    http://prsinfo.clinicaltrials.gov
    Questions?
    register@clinicaltrials.gov
    65