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111
Update on Clinical Trials Registration and
Results Reporting Requirements
Deborah A. Zarin, M.D.ClinicalTrials.gov
February 24, 2009
The investigation was launched following concerns…
• …although the ENHANCE trial ended in April 2006, the data had not yet been released.
• …[the sponsors] did not register the clinical trial in a timely manner.
• …[the sponsors] attempted to change the study endpoints, and thus the study results, prior to the public release of the results.
ENHANCE
Source: Kastelein JJ, Sager PT, de Groot E, Veltri E. Am Heart J. 2005 Feb;149(2):234-9.
12
3
Primary Outcome Measures:
• Change in ultrasound-determined average carotid artery intima-media thickness (IMT) on a per subject basis between baseline and endpoint. [ Time Frame: 24 months ]
Primary Outcome Measures:
• Change in ultrasound-determined average carotid artery intima-media thickness (IMT) on a per subject basis between baseline and endpoint. [ Time Frame: 24 months ]
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 1;324(7349):1287-8.
10
“The Neurontin Legacy – Marketing through Misinformation and Manipulation”
• Studies “designed and commissioned specifically to promote Neurontin use.”
• Seeding trial “to give neurologists the opportunity to titrate to higher doses [up to twice the FDA-approved limit] when needed”
• Delayed publication of negative results to mitigate damage to “neurontin’s marketing success”
• Summary: “the documentation of comprehensive manipulation of research and publication related to Neurontin is remarkable.”
Landefeld CS, Steinman MA. NEJM. N Engl J Med 360:103-6
161616
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
1717
Policies and Users
ClinicalTrials.gov
FDAMA 113BPCA
Maine
FDAAA Sponsor Policy(e.g., NIH, VA)
ICMJE
WHO
OttawaStatement
Recruitment (e.g., patients,
physicians)Journal Editors
Research Funders
IRBsHealth Policy
Makers
18
ClinicalTrials.gov Statistics(as of 02/03/2009)
Number Percent
Total 67,064 100%Type of Trial*
Observational 10,690 16%Interventional 57,119 84%– Drug & Biologic 42,684 – Surgical Procedure 8,585 – Behavioral, Gene Transfer, Other 7,997 – Device** 3,862
International Sites (161 countries)US only 32,772 49%Non-US only 23,109 34%US & Non-US mixed 4,064 6%Missing 7,119 11%
*171 records missing Study Type information**173 device trials – “delayed posting”
19
ClinicalTrials.gov Statistics (cont.)(as of 02/03/2009)
User Statistics
Page Views per month 40 Million Unique visitors per month 500,000
Number Percent
Trials by Data Provider
US Federal (including NIH)18,088 27%Industry 21,072 31%University, Other 28,820 42%
Total 67,980
Search Features• Powerful Search Engine
– Synonymy• E.g., can find V501 studies by searching “Gardasil”
– Hierarchies• E.g., can find Crohn’s disease by searching for IBD
– Spelling relaxation
• Interface allows for field specific searching– E.g., can find “condition” without finding
“exclusion criterion”
26262626
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
Enforcement Provisions
• Notices of non-compliances
• Civil monetary penalties up to $10,000/day
• Withholding of NIH grant funds
Key Terms
• Applicable Clinical Trials– Interventional trials– Phase 2-4 drug, biologic, device– >= one site in U.S.– Ongoing as of 9/27/07, or later
• Responsible Party– Sponsor, grantee– PI if designated
• (Primary) Completion Date
What Information Is In the Trial Registry?
• Basic Protocol Details– Condition, intervention(s), design, outcome
measures, key dates
• Administrative Information– NCT#, other IDs, Responsible Party, PI
• Recruitment and location status• Linkages
– PubMed, FDA resources, consumer health info
31
New Registrations Continue to IncreaseNumber of New Records Since May 1, 2005
0
10,000
20,000
30,000
40,000
50,000
60,000
70,000
start to 12/31/2005
1/30/2005
3/6/2005
4/10/2005
5/15/2005
6/19/2005
7/24/2005
8/28/2005
10/2/2005
11/6/2005
12/11/2005
1/15/2006
2/19/2006
3/26/2006
4/30/2006
6/4/2006
7/9/2006
8/13/2006
9/17/2006
10/22/2006
11/26/2006
12/31/2006
2/4/2007
3/11/2007
4/15/2007
5/20/2007
6/24/2007
7/29/2007
9/2/2007
10/7/2007
11/11/2007
12/16/2007
1/20/2008
2/24/2008
3/30/2008
5/4/2008
6/8/2008
7/13/2008
8/17/2008
9/21/2008
10/26/2008
Registration of Phase 1 and Device Trials
• 2100 device trials registered between 9/07 and 1/09– 175 are in “lock box”
• 162 Industry• 13 Other
• Phase 1 trials– 186/month in fy 2008 (73% increase from 07)– 205/month in fy 2009* (10% increase from 08)
* First four months
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.”
Status of Stanford Trials
• 73 may be “applicable”– 65 have outcome measure– 2 have RP– 62 have start date– 1 has “primary completion date”– 8 have “completion date”
• How many “results” are due?
35
Enforcement Provisions
• Notices of non-compliances
• Civil monetary penalties up to $10,000/day
• Withholding of NIH grant funds
Bottom Line
• Register prior to enrollment:– 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!37
3939393939
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”
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
4141
Current Status – “Basic Results”(as of 02/06/09)
• Functional Web-based Data Entry System • Launched in September 2008• Ongoing system of feedback and
improvements
• 410 Results Records have been submitted• Industry: 293 records from 72 data providers• Other: 117 records from 80 data providers• Anticipate greatly increased rate of
submission
60
Design Requirements
• Display consists of data tables with minimal text—must be self-explanatory
• System must accommodate range of study designs and facilitate comparison across studies
• NLM directed to: – Consider different methods of display based on
principles of risk communication for different audiences
– Ensure the data are searchable in many ways
• Structured data entry required to facilitate search and display needs 60
61
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 measures—some are pre-set,
others are customized for each study– Type of measure determines specific design
of “cells”
• Attempt to balance fixed structure with flexibility
62
Principles for Using the Basic Results Database
• Submitted data are used to develop basic tables for the public display
• Tables must be interpretable by people not familiar with each particular study
• Labels for rows, columns, and units of measure must be meaningful and precise
Who is the Audience?PI and Clinical Research Team (You!)
Other Medical Researchers in same field
[Study Sponsor]
Other Medical Researchers in other fields
Other Readers of the medical literature
Science Writers
Lay Public (readers of consumer health literature)
Resources to Help Data Providers
• “Helpful Hints”– Illustrates process for entering different study
designs (parallel, crossover, diagnostic accuracy, bioequivalence—in progress)
• Webinar• “Common Errors” • Individual discussions regarding particular
studies• Presentations
72
Interesting Findings to Date
• Large numbers of submitted Outcome Measures and Statistical Analyses
• Power of Defaults (e.g., “Baseline Measures”)– Age > 65– Race and Ethnicity– Region of Enrollment
• Problems with imprecise entries
Lessons Learned from Early Submissions of Basic Results
• Many iterations with the QA staff are necessary to reach minimal quality standards and to correct serious flaws
• Data Providers must be able to understand the study design and data analysis– Typically, the investigator and a
statistician will need to be involved
73
Quality Assurance Challenges
• Data tables will be the public representation of the study—must be clear and informative;
• NLM QA Focuses on:– Apparent Validity (when possible)– Meaningful Entries– Internal consistency/logic– Format
7575
Common Quality Concerns
• Reporting of percentage without reporting absolute numbers
• Improper use of terms• Incidence• Proportion and Ratio• Frequency
• Reporting a change—lack of specificity• Subtraction: minuend vs. subtrahend• Ratio: nominator vs. denominator
• Complicated outcomes that cannot be understood
Registration and Results Data Must be Consistent
• Participant Flow Numbers and Enrollment
• Study Design and Results Tables– Number of Arms
7777
Actual Enrollment: 229Study Start Date: June 2006Study Completion Date: October 2007Primary Completion Date: October 2007 (Final data collection date for primary outcome measure)
Summary Protocol Section:
Basic Results Section:
Placebo Drug X
STARTED 220 211
COMPLETED 218 210
NOT COMPLETED 2 1
Participant Flow: Initial Treatment
Actual enrollment (229) displayed in the protocol section does not match total number started in the basic results section (220 + 211 = 431)
BEFORE Revision (Public View)
7979
Measured ValuesDrug X, Week 10
Drug X, Change from Week 10 to 18
Number of Participants Analyzed 88 80
Treatment Satisfaction QuestionnaireAfter 18 Weeks of Treatment
[units: Score]
Mean ± Standard Deviation
81 ± 17.46 7.9 ± 12.16
Inconsistency between columns and rows: Measure “at week 10” and Measure “after 18 weeks of treatment”
BEFORE Revision (Public View)
8181
Measured ValuesIntervention X Control
Number of Participants Analyzed 28 27
Hours Per Day of Sleep
[units: Average Hours per Day]
Mean ± Standard Deviation
823 ± 92 864 ± 106
Inconsistency between Units of Measure, “average hours per day,” and Measure Data: value provided is greater than the total number of hours in a day
BEFORE Revision (Public View)
8282
Measure Type Secondary
Measure Name Use of Community Health Resources
Measure Description Evaluation of visits to primary care pediatrician, hospital emergency and re-hospitalization
Time Frame Up to 3 months after discharge
Safety Issue No
Secondary Outcome Measure: Use of Community Health Resources
Measured ValuesEarly
DischargeStandard Discharge
Number of Participants Analyzed 90 86
Use of Community Health Resources
[units: Number]
4.4% 10.5%
• Data are inconsistent: percentages of what?
• Invalid entry: needs to be numerical (cannot include “%”)
BEFORE Revision (Public View)
Implies number of health resources used – how was it measured?
8383
Measure Type Primary
Measure Name Frequency and Magnitude of Antibody Response
Measure Description Nasal secretions to Virus A/12 and B/14. Antibody Response: Three-fold increase after immunization
Time Frame Visit 3 (Week 15)
Safety Issue Yes
Secondary Outcome Measure: Frequency and Magnitude of Antibody Response
Measured ValuesVaccine,
Low Dose
Vaccine, High Dose
Number of Participants Analyzed 35 34
Frequency and Magnitude of Antibody Response
[units: Participants]
17 21
May mean “three-fold or greater increase”
BEFORE Revision (Public View)
Same unit cannot represent measures of “frequency” and “magnitude”
“Participants” is not a unit of measure for “frequency” or “magnitude”
Best to provide both categories for a dichotomous measure:
• < 3x increase• ≥ 3x increase
Best to provide both categories for a dichotomous measure:
• < 3x increase• ≥ 3x increase
Measure Type Primary
Measure Name Maximum Tolerated Dose (MTD) Determination as Measured by Dose Limiting Toxicity (DLT)
Measure Description The primary variable for determination of the MTD was the occurrence of DLT during the first treatment cycle. MTD has been exceeded if >=2 of 6 patients experience a DLT.
Time Frame Cycle 1
Safety Issue Yes
Primary Outcome Measure: Maximum Tolerated Dose (MTD) Determination …
Measured ValuesDose A.1
Dose A.2
Dose B.1
Dose B.2
Dose C.1
Dose C.2
Number of Participants Analyzed 6 7 3 6 7 4
Maximum Tolerated Dose (MTD)…
[units: Participants]
Number (#) of DLT 1 3 0 2 1 0
# Patients at dose level < MTD 0 0 0 0 7 4
# Patients at dose level = MTD 6 0 3 0 0 0
# Patients at dose level > MTD 0 7 0 6 0 0
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
8686
Investigational Drug X
GOG Performance Status
[units: Score]
0 48
1 27
2 4
BEFORE Revision (Public View)
Need information about this scale• Full Name• Construct/domain• Range and directionality
Baseline MeasuresNeed information about these values(e.g., is “0” better or worse than “2”?)
Need to change to “participants” – data represent “number of participants” with a particular score
Are these the only possible scores?
Open Label
Number of Participants Analyzed 403
Duration (Days)
[units: Days]
Mean ± Standard Deviation
195.5 ± 43.87
Measure Type Secondary
Measure Name Duration (Days)
Measure Description Extent of Exposure for All Treated Subjects
Time Frame Duration of Study
Safety Issue No
Secondary Outcome Measure: Duration (Days)
Measured Values
BEFORE Revision (Public View)
Needs description: Duration of what?
Needs Arm Label: What is the intervention?
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
Drug X Drug Y Drug X + Y
Number of Participants Analyzed 351 361 384
Proportion of Patients with Controlled SBP
[units: Participants]186 135 287
Measure Type Primary
Measure Name Proportion of Patients with Controlled SBP
Measure Description Controlled SBP defined as SBP < 130 mmHg
Time Frame Baseline to 12 weeks
Safety Issue No
Primary Outcome Measure: Proportion of Patients with Controlled SBP
Spell out acronym
Not a proportion
BEFORE Revision (Public View)
Not a proportionNot a proportion
Drug X Drug Y Drug X + Y
Number of Participants Analyzed 351 361 384
Change in Sitting DBP From Baseline to End of Study
[units: mmHg]
Lease Squares Mean ± Standard Error
-8.4 ± 0.2 -6.7 ± 0.2 -11.2 ± 0.3
Measure Type Primary
Measure Name Change in Sitting DBP From Baseline to End of Study
Measure Description Change in Sitting DBP
Time Frame Baseline to 12 weeks
Safety Issue No
Primary Outcome Measure: Change in Sitting DBP From Baseline to End of Study
Spell out acronym
Specify calculation details: which value was subtracted from which?
BEFORE Revision (Public View)
Measure Type Secondary
Measure Name To Compare Drug X and Drug Y for Efficacy
Measure Description
Time Frame 4 months
Safety Issue No
Secondary Outcome Measure: To Compare Drug X and Drug Y for Efficacy
State what is being measured, not the purpose
BEFORE Revision (Public View)
Needs description: what is being measured and how?
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
93
Placebo Drug X
STARTED 301 299
COMPLETED 291 285
NOT COMPLETED 10 14
Participant Flow: First Period Number of participants STARTED in second period of Participant Flow needs to be the same as numbers COMPLETED in the first period
BEFORE Revision (Public View)
Placebo Drug X
STARTED 298 290
COMPLETED 288 278
NOT COMPLETED 10 12
Participant Flow: Second Period
9494
Measured ValuesIntervention X Control
Number of Participants 28 27
Hours Per Day of Sleep
[units: Average Hours per Day]
Mean ± Standard Deviation
823 ± 92 864 ± 106
Inconsistency between Units of Measure, “average hours per day,” and Measure Data: value provided is greater than the total number of hours in a day
BEFORE Revision (Public View)
Statistical Analyses
• Must be Logical
• Compatible with Data
• Informative (report informative metrics)
9696
Groups Early Discharge vs. Standard Discharge
Method ANOVA
P-Value 0.05
Mean Difference (Net) 9
Statistical Analysis 1 for Parental Stress
Measured ValuesEarly Discharge Standard Discharge
Number of Participants 100 100
Parental Stress
[units: Points on a Likert Scale]
Mean ± Standard Deviation
9.3 ± 1.2 7.8 ± 2.1
Inconsistency between Measure Data and Method of Estimation
• Reported Mean Difference: “9”• By Inspection: 9.3 – 7.8 = 1.5
BEFORE Revision (Public View)
9797
Placebo Investigational Drug X
Number of Participants 148 153
Time to Relapse of a Mood Episode
[units: Days]
Median (Inter-Quartile Range)
219 (83 to NA) NA (173 to NA)
Measure Type Secondary
Measure Name Time to Relapse of a Mood Episode
Measure Description
Time Frame 24 months
Safety Issue No
Secondary Outcome Measure: Time to Relapse of a Mood Episode
Measured Values
Needs description
Invalid entry
BEFORE Revision (Public View)
98
Where is the Quality Line?
Domains of Quality:
Quality of Entries
Scope of Entries
Not Meaningful Meaningful
Minimal Comprehensive
QA Staff Resources
Who is the Audience?PI and Clinical Research Team (You!)
Other Medical Researchers in same field
[Study Sponsor]
Other Medical Researchers in other fields
Other Readers of the medical literature
Science Writers
Lay Public (readers of consumer health literature)
Bottom Line
• Register within 21 days of enrollment:– 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 within one year of “primary
completion date” OR– once the drug, device or biologic has been approved;
• Keep all information up to date!
100
101101101101101
Additional Information
• Email LISTSERV and other FDAAA information:– http://prsinfo.clinicaltrials.gov/fdaaa.html
• Other general information:– http://prsinfo.clinicaltrials.gov
• Questions?– [email protected]
102102
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