Everything You Need to Know About Clinical Trials Registration and Results Reporting Requirements

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Everything You Need to Know About Clinical
Trials Registration and Results Reporting
Requirements

• Deborah A. Zarin, M.D.
• ClinicalTrials.gov
• October 2009

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Background
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Recent Events
February 27, 2009
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February 26, 2009
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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 1324(7349)1287-8.
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Zarin DA, Tse T. Medicine. Moving toward
transparency of clinical trials. Science. 2008
Mar 7319(5868)1340-2.
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Levels of Transparency
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Zarin DA, Tse T.. Science. 2008 Mar
7319(5868)1340-2.
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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

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ClinicalTrials.govthe basics
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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

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New Registrations Continue to Increase
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ClinicalTrials.gov Statistics (as of 10/05/09)

• Number Percent
• Total 79,605 100
• Type of Trial
• Observational 12,956 16
• Interventional 66,649 83
• Drug Biologic 54,208
• Surgical Procedure 8,470
• Behavioral, Gene
• Transfer, Other 13,369
• Device 4,742
• International Sites (172 countries)
• US only 37,271 47
• Non-US only 28,263 35
• US Non-US mixed 5,686 7
• Missing 8,385 11

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231 delayed posting device trials included in
total, but excluded from other statistics
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ClinicalTrials.gov Statistics (cont.)(as of
10/05/09)
Number Percent
Trials by Sponsor US Federal (including
NIH) 10,777 14 Industry 25,737
32 University, Other 43,091 54
Total 79,605
User Statistics Page Views per month 60
Million Unique visitors per month 900,000
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Value-Added Links
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Search Interface
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Legal and other requirements
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ICMJE Policy

• Editorial 2004 and updates
• Registration required for manuscript
  consideration for following
• Interventional studies
• Any phase
• Any intervention
• ClinicalTrials.gov or WHO Primary registry
• Registration prior to enrollment first participant

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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

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Enforcement Provisions

• Notices of non-compliances
• Civil monetary penalties up to 10,000/day
• Withholding of NIH grant funds

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Key Terms

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

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Key Milestones FDAAA - Sec.801 Expanded
Clinical Trial Registry

• December 26, 2007
• New registration requirements effective
• Linking to existing results
• September 27, 2008
• Basic Results reporting requirements effective
• April 2009 - Public Meeting
• September 27, 2009 Adverse Events
• September 27, 2010 Rulemaking Due

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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.

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Basic Results Database
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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

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Adverse Events

• If the Secretary fails to issue regulation by
  March 2009, default provisions take effect in
  September 2009
• SERIOUS ADVERSE EVENTS
• Table of anticipated unanticipated serious
  adverse events
• Grouped by organ system
• Number and frequency of event in each clinical
  trial arm
• FREQUENT (other) ADVERSE EVENTS
• Table of anticipated unanticipated adverse
  events
• Exceed a frequency of 5 percent within any trial
  arm
• Grouped by organ system
• Number and frequency of event in each trial arm

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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

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Current Status Basic Results(as of 02/06/09)

• Functional Web-based Data Entry System
• Launched in September 2008
• 662 Results Records have been submitted
• Industry 449 records from gt 100 data providers
• NIH 24 records
• Rate of submission continues to increase
• 40 records per week now
• Anticipate about 150 per week

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Sample Posted Results
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Participant Flow

• A table ..., including the number of patients
  who dropped out of the clinical trial and the
  number of patients excluded from the analysis, if
  any.
• Sec. 282(j)(3)(C)(i)

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Reasons Not Completed
An Investigational Drug on Clinical Outcomes in
Patients With Aortic Stenosis NCT00092677
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Arms
Milestone
Reasons Not Completed
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Baseline Measures

• A table of the demographic and baseline data
  collected overall and for each arm of the
  clinical trial
• Sec. 282(j)(3)(C)(i)

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Default Required Measures
User-Specified Measure
Categories
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Outcome Measure

• a table of values for each of the primary and
  secondary outcome measures for each arm of the
  clinical trial
• Sec. 282(j)(3)(C)(ii)

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Categories
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Statistical Analysis

• a table of values for each of the primary and
  secondary outcome measures, including the
  results of scientifically appropriate tests of
  the statistical significance of such outcome
  measures.
• Sec. 282(j)(3)(C)(ii)

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Statistical Analysis
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Statistical Analysis
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Statistical Analysis
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Serious Adverse Events

• A table of anticipated and unanticipated serious
  adverse events grouped by organ system, with
  number and frequency of such event in each arm of
  the clinical trial.
• Sec. 282(j)(3)(I)(iii)(I)

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Frequent Adverse Events

• A table of anticipated and unanticipated adverse
  events that are not included in the Serious
  Adverse Events table that exceed a frequency
  of 5 percent within any arm of the clinical
  trial, grouped by organ system, with number and
  frequency of such event in each arm of the
  clinical trial.
• Sec. 282(j)(3)(I)(iii)(II)

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Definition of Adverse Event

• Definition Unfavorable changes in health,
  including abnormal laboratory findings, that
  occur in trial participants during the clinical
  trial or within a specified period following the
  trial.

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Definition of Serious AE

• Serious Adverse Events include adverse events
  that result in death, require either inpatient
  hospitalization or the prolongation of
  hospitalization, are life-threatening, result in
  a persistent or significant disability/incapacity
  or result in a congenital anomaly/birth defect.
• Other important medical events, based upon
  appropriate medical judgment, may also be
  considered Serious Adverse Events if a trial
  participant's health is at risk and intervention
  is required to prevent an outcome mentioned.

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Design Features

• Tables are constructed by the data provider
• Columns are pre-set as study arms, but can be
  changed by the data provider
• Rows are measuressome are pre-set, others are
  customized for each study
• Type of measure determines specific design of
  cells
• Attempt to balance fixed structure with
  flexibility

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http//prsinfo.clinicaltrials.gov/fdaaa.html
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Issues in Reporting Results
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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 (lt500 words) abstract
  or table.

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Who is the Audience?
PI and Clinical Research Team Other Medical
Researchers in same field Other Medical
Researchers in other fields Other Readers of the
medical literature Science Writers Lay Public
(readers of consumer health literature)
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Quality Assurance Challenges

• Data tables will be the public representation of
  the studymust be clear and informative
• NLM QA Focuses on
• Apparent Validity (when possible)
• Meaningful Entries
• Internal consistency/logic
• Format

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What Does QA Address?

• Data must make sense
• Measure name, units, and data must match
• No invalid entries
• E.g., 823 hours/day time to survival
• No illogical tables
• No missing parameters or data
• Tables should convey study design, conduct and
  analysis

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Tables Must Be Informative

• Scales should include
• Full name
• Construct or domain (e.g., pain)
• Direction of scores (Best/Worst Value)
• Other information as necessary
• Measures Have Useful Descriptions
• Avoid Abbreviations

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Measure Information Must be Precise and Accurate

• Avoid misuse of terms, e.g.,
• proportion
• ratio
• incidence
• State what is being measured and how
• Do not provide results in measure description
  field

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Data in All Tables Must be Internally Consistent
and Logical

• Participants must flow
• Number analyzed must be consistent with
  participant flow data
• Avoid Illogical Entries

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Illogical Results Table
Drug X, Week 10 Drug X, Change from Week 10 to 18
Number of Participants Analyzed units participants 88 80
Treatment Satisfaction QuestionnaireAfter 18 Weeks of Treatment units Score Mean Standard Deviation 81 17.46 7.9 12.16
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Unclear Outcome Measure
Measure Name Time to Disease-Free Survival
Measure Description Time from date of treatment to date of survival
Time Frame 5 years
Drug A Drug B
Number of Participants Analyzed units participants 648 645
Time to Disease-Free Survival units participants 246 277
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Problematic Entry
Intervention X Control
Number of Participants Analyzed units participants 28 27
Hours Per Day of Sleep units Average Hours per Day Mean Standard Deviation 823 92 864 106
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Problematic Entry
Measure Name Clinician Assessment After Injection
Measure Description Physicians assessment of SIJ pain 5 point-Likert scale, Change of finger to floor cm and Schober test mm
Time Frame 8 months
Sacroiliac Injection
Number of Participants Analyzed units participants 29
Clinician Assessment After Injection units Units on a scale 100
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Informative Entry
Measure Name Pregnancy Rate (Pearl Index)
Measure Description Pearl Index (100)(number of pregnancies)(4 cycles/year)/number of 91-day cycles completed.
Time Frame After the onset of treatment and within 14 days after the last combination pill (approx. 1 year of treatment)
DR-1011
Number of Participants Analyzed 1735
Pregnancy Rate (Pearl Index) units Pregnancies per 100 woman years exposure 2.74
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Informative Entry
Measure Name Time to Progressive Disease
Measure Description Time from study enrollment to the first date of disease progression. Time to disease progression was censored at the date of death if death was due to other cause.
Time Frame Every other 21 day cycle (6-8 cycles) and every 3 months during follow-up
Drug X
Number of Participants Analyzed 50
Time to Progressive Disease units weeks Median ( 95 Confidence Interval ) 45.1 ( 37.9 to 56.9 )
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Number of Results Recordswithout Revision by
Quarter Posted
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Number of Records Posted Without Revision
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Quarter Posted
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Results Posting - Caveats

• Posting does not assure that all review criteria
  were met
• Data provider is responsible for ensuring that
  records meet review criteria
• ClinicalTrials.gov may note issues and request
  revisions after results have been posted publicly
  
• Additional comments may suggest improvements, but
  are not necessarily required changes prior to
  posting

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Lessons Learned from Early Submissions of Basic
Results

• Data Providers must be able to understand the
  study design and data analysis
• Typically, the investigator and a statistician
  will need to be involved

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Interesting Scientific Issues
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Interventional vs. Observational

• Interventional studies in human beings in which
  individuals are assigned by an investigator based
  on a protocol to receive specific interventions.
  Subjects may receive diagnostic, therapeutic or
  other types of interventions. The assignment of
  the intervention may or may not be random. The
  individuals are then followed and biomedical
  and/or health outcomes are assessed.
• Observational studies in human beings in which
  biomedical and/or health outcomes are assessed in
  pre-defined groups of individuals. Subjects in
  the study may receive diagnostic, therapeutic, or
  other interventions, but the investigator does
  not assign specific interventions to the subjects
  of the study.

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Interventional or Observational?

• Example Evaluation of PillCam Colon Capsule
  Endoscopy (PCCE) in the Visualization of the
  Colon
• Capsule Endoscopy versus Colonoscopy for the
  Detection of Polyps and Cancer
• Van Gossum et al. NEJM (2009)

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Interventional (as of 8/3/09)
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Observational (before 8/3/09)
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How Should You Describe the Outcome Measures?
Level of Detail
Low

• Anxiety
• Hamilton Anxiety Rating Scale
• Hamilton Anxiety Rating Scale at 12 weeks
• Change in Hamilton Anxiety Rating Scale at 12
  weeks from baseline
• Proportion of patients with improvement in
  Hamilton Anxiety Rating Scale at 12 weeks from
  baseline
• Proportion of participants with a change of 11
  points at 12 weeks from Baseline on the Hamilton
  Anxiety Rating Scale

High
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Goals for Registration of Outcome Measures

• Inform potential participants
• Provide details to inform other researchers,
  systematic reviewers, etc.
• Monitor integrity of research
• Track additions/deletions
• Track significant changes

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CLASS Study Data by Follow-up Period
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 1324(7349)1287-8.
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ENHANCE Prespecified Endpoints
2
1
3
Source Kastelein JJ et al. Am Heart J. 2005
Feb149(2)234-9.
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Bottom LineReporting Outcome Measures

• Be as specific as possible
• Primary and Secondary outcome measures
• Designation should be consistent with statistical
  analysis plan
• Other prespecified and post hoc should be
  used for measures that are not in the statistical
  analysis plan

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Outcome Measure Statistics ClinicalTrials.gov
(as of 8-27-09)

• 701 Results records posted
• 1,592 POMs
• Mean 2.3
• Median 1
• Range 1-71
• 3,402 Secondary OMs
• 498 Results records with 1
• Mean 5
• Median 2
• Range 0-85

Other Pre-specified 43 Records, 156 OMs,
Range 1-31 Post-Hoc 11 Records, 18 OMs,
Range 1-6
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Diagnostic Accuracy Studies

• Studies in which the results are generally
  displayed in a 2 x 2 table
• Columns with disease and without disease
  based on a reference standard
• Rows test positive and test negative based
  on the experimental diagnostic test.
• ClinicalTrials.gov can be used to create 2 x 2
  tables

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Applicable Clinical Trials?

• Components involve devices and/or drugs
• ImageChecker DMax computer-aided detection
  system, version 8.1 (Hologic/R2 Technology)

Gilbert FJ et al. N Engl J Med 20083591675-84.
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Device or Procedure?

• What Is the Intervention Type?
• Device
• Procedure/Surgery
• Example The Stress Incontinence Surgical
  Treatment Efficacy Trial
• Burch Colposuspension versus Fascial Sling to
  Reduce Urinary Stress Incontinence
• Albo ME et al. NEJM (2007)

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Procedure Burch Modified Tanagho Procedure
Autologous Fascia Sling
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Bottom Line

• Determine who is the Responsible Party
• Register prior to enrollment (or within 21d)
• 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!

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Next Steps

• September 27, 2010 Expansion by Rulemaking
• Expect announcement in October about plans for
  rulemaking

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Key Issues in Expansion

• Expand results reporting to trials of unapproved
  products?
• Include narrative summaries? Can it be done
  w/out being promotional and misleading?
• Technical
• Lay Language
• Data Quality Verification
• Process (e.g., Pilot Quality Control Project)
• External Sources
• Full protocol versus extract necessary to help
  evaluate the results

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EMEA Unapproved Products

• Publically Accessible Results Database
• Required no later than 6 months after trial
  completion (i.e., last patient, last visit)
• Applies to EU-regulated clinical trials of
  medicines, regardless of authorization status
• Applies to trials of pediatric and adult drugs
• Interaction to harmonize EudraCT and
  ClinicalTrials.gov databases policies

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Resources
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Finding Results at ClinicalTrials.gov

• From Homepage
• Go to Search for Clinical Trials
• Select Advanced Search
• Select Studies with Results from the menu for
  the Study Results field
• Select study record from results list
• Click Study Results tab

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Additional Information(at http//prsinfo.clinical
trials.gov/fdaaa.html)

• "Basic Results" Data Element Definitions
• Helpful Hints - tips on entering results data,
  including examples of common study models (e.g.,
  crossover design)
• Detailed Review Items - describes items
  evaluated by the QA/QC staff at NLM
• Common Errors - overview of common types of
  errors identified in submitted records with
  "basic results"

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Additional Background

• Tse T, Williams RJ, Zarin DA. Update on
  registration of clinical trials in
  ClinicalTrials.gov. Chest 2009136304-5.
• Tse T, Williams RJ, Zarin DA. Reporting basic
  results in ClinicalTrials.gov. Chest
  2009136295-303.
• Zarin DA, Tse T. Moving toward transparency of
  clinical trials. Science 20083191340-2.
• Wood AJ. Progress and deficiencies in the
  registration of clinical trials. N Engl J Med
  2009360824-30.

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Additional Information

• Email LISTSERV and other FDAAA information
• http//prsinfo.clinicaltrials.gov/fdaaa.html
• Other general information
• http//prsinfo.clinicaltrials.gov
• Questions?
• register_at_clinicaltrials.gov

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