RECENT DECSIONS BEFORE THE TRADEMARK TRIAL AND APPEAL BOARD ON REGISTRATION OF TRADE DRESS
Expansion of Clinical Trial Registration and Results Reporting Requirements
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Transcript of Expansion of Clinical Trial Registration and Results Reporting Requirements
May 2008 1
Expansion of Clinical Trial Registration and Results Reporting
Requirements
Deborah A. Zarin, M.D.ClinicalTrials.gov
National Library of Medicine
May 2008 2
History of ClinicalTrials.gov
• FDAMA 113: Mandates Registry (1997)• ClinicalTrials.gov Launched in Feb 2000• Calls for Increased Transparency of Clinical Trials
– Maine State Law; State Attorneys General– Journal Editors (2004);
• ClinicalTrials.gov Accommodates Other Policies• PL 110-85, Sec. 801: Expands Registry (2007)
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Steady Growth
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ClinicalTrials.gov Statistics(from 4/3/2008)
Number Percent
Total 53,956 100%Type of Trial*
Observational 8,171 15%Interventional 45,737 85%– Drug & Biologic 34,903 – Medical Procedure 11,200 – Behavioral, Gene Transfer, Other 5,484 – Device 2,839
International SitesIn the US only 27,056 50%At least 1 site in the US 4,141 8%
Outside the US 17,229 32%Missing 5,530 10%
* 48 Missing Study Type Information
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ClinicalTrials.gov Statistics Cont.(from 4/3/2008)
Trials by Data Provider
University, other 21,480 40%US Federal (including NIH)16,808 31%
Industry 15,668 29%
User Statistics
Page Views per month 20 Million Unique visitors per month 500,000
Number Percent(N = 53,956)
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Search Engine
• 56,000 trials in Registry• Search Engine makes it useful• Features
– Spelling correction/relaxation• Alzimers = Alzheimer’s
– Synonymy from UMLS• Heart attach = myocardial infarction
– Search within a field– Hierarchy from MeSH
• Crohn’s is a type of IBD
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Overview of New Requirements
FDAAA
PL 110-85
9/27/07
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Key Milestones
• December 26, 2007– New registration requirements effective– Linking to existing results
• September 27, 2008– BASIC Results reporting requirements effective
• September 27, 2009 – Adverse Events
• September 27, 2010 – ENHANCED results implemented
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New Registration Requirements
• Drug and device trials – Exclude “phase 1”
• 12 Previously optional data elements now required
• 4 new data elements are required
• Registration due within 21 days of first enrollment
• Penalties for non-compliance
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Other Registration Issues
• Trials for devices that are not approved/cleared are not posted publicly (“lock box”)
• Updates– As necessary to keep information accurate– Within 30 days of recruitment status change– At least every 12 months for other changes– Changes are date stamped and tracked
publicly
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Who Must Register?“Responsible Party”
• The sponsor of the clinical trial
-- OR --
• The principal investigator (PI) of such clinical trial if so designated by a sponsor, grantee, contractor, or awardee, so long as the PI is responsible for conducting the trial and has sufficient data rights.
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May 2008 13
Requirements for Results Reporting
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Links to Existing Results
• December 26, 2007 (90 days after enactment)• FDA Information, including
– Advisory Committee summary document– Posted assessment of drug clinical trial results– Public health advisories regarding drug or device– Drug action package for approval document– Safety and effectiveness summary (devices)
• NIH Information– MEDLINE - Citation of published results– DailyMed – FDA structured product labels
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Basic Results Database
• Which trials? – trials of approved drugs/devices
• When? – 12 months after “completion date” if approved
product– or later if submitting an sNDA– or 30 days after product approval
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Basic Results: Statutory Requirements
• Demographic and baseline characteristics
• Primary and secondary outcomes
• Point of contact
• Certain agreements– Restrictions on PI to discuss or publish results
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Basic Results Tables
• Participant flow
• Demographic and baseline characteristics– Overall and by arm
• Values for primary and secondary outcomes– By arm– Scientifically appropriate tests of statistical
significance
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Overall Approach to Collecting Results Information
• Results tables are similar to those found in journal articles
• Data entry systems will use terms familiar to investigators
• Technical items (e.g., statistical tests) would be necessary for any official study report
• Multiple modalities of user support services will be important (e.g., online, telephone)
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Published Participant Flow
Source: Kimmick GG et al. Breast J. 2006 Mar-Apr;12(2):114-22.
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Published Baseline Data
Source: Kimmick GG et al. Breast J. 2006 Mar-Apr;12(2):114-22.
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Published Primary Outcome
Source: Kimmick GG et al. Breast J. 2006 Mar-Apr;12(2):114-22.
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Challenges and Goals for Data Entry System
• Need to accommodate full range of study designs and data types
• Need for structure to optimize data quality and search capabilities, and to allow for control over data display
• Need to be usable by full range of international trial community– Large data providers (e.g., drug companies, NIH ICs)– Academic medical centers– Individual investigators
• Desire to promote “good trial practices”, but must accommodate all practices
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Data Entry Mechanisms
• Electronic Data Interchange – upload data in XML format
• Manual Data Entry – enter data using a Web-based Results Registration System (RRS)– analogous to the Protocol Registration
System (PRS) for the registry
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Basic Results Data Entry System
• Prepopulates certain data elements from registry, if provided (e.g., Arm Description)
• Lists some prespecified baseline demographics (e.g., gender, ethnicity)
• Allows users to enter and edit tables– Column labels: e.g., Arms– Row labels: e.g., demographics, outcome
measures– Cells: e.g., measurement values
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Measurement Types
Dichotomous
Continuous (Years)
Multiple Categories
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Time To Event
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Participant Flow
• Number entered study
• Number completed study
• Number not completed study
• Other details– Phase specific information– Study specific information– Number achieved milestones, as specified by
registrant
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Demographic & Baseline Characteristics
• Commonly used measures– Age (continuous and categorical)– Gender– Race/Ethnicity– Region of enrollment
• Measures specific to each trial• For each measure
– Name of measure– Value, total and by arm– Names and values of categories, if categorical– Measure of dispersion, if continuous– Other details, if time-to-event
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Outcomes
• Pre-specified primary and secondary outcome measures from registry
• For each measure– Description– Units– Value by arm or other comparison group
• Names and values for categories, if categorical• Measure of dispersion, if continuous• Other details if time to event
– Statistics (cont. next slide)
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Outcomes
• Statistics (cont.)– Test of non-inferiority? (y/n)
• If yes, other details
– For each p-value provided• Name of test (e.g., Chi-squared, ANOVA)• Other details/comments
– For each confidence interval provided• % (e.g., 95% confidence interval)• Name of estimate (e.g., OR, RR)• Value of estimate• Other details/comments
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Issues to Consider in Developing Public Display
• Simple, tabular format (“just the facts”)• Provide context
– Study design– Background information– Display links to other similar trials
• Consider linking to systematic reviews and other resources
• Link to published articles and FDA reviews, when available
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Data Display Mechanisms
• Summary result records displayed in a Results Database at ClinicalTrials.gov
• Results records linked to registry records via NCT number
• Similar search engine and “look and feel”
• Details to be determined
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How to Facilitate Rational Use of Data
• Provide context– Study design
– Background information
• Consider linking to systematic reviews
• Link to other resources
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Seeking Public Input
• Updated information on status of implementation
– http://prsinfo.clinicaltrials.gov/fdaaa• Public comment on early versions is critical• Short timeline for development – May to September 2008
– Describes rulemaking process for expanded registry and results database
• Public Meeting by March 2009 to inform rulemaking for “expanded” results database
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