Session 2: Expanded Clinical Trials Registry

Deborah A. Zarin, M.D.

NLM Accomplishments

Impact to Date

Specific Data Element Issues

Accomplishments To Date

• ClinicalTrials.gov registration system (PRS) modified to enable compliance with expanded registration requirements (11/27/07)
• Links established from registry to NIH/NLM and FDA results information
• Information developed for affected communities
  • NLM Data Element Definitions and Fact Sheet
  • NIH Guide Notices (2) and FAQs – including instructions for initial NIH grantee/contractor compliance

Enforceability of Data Elements

• Need to collect information not explicitly listed in the law
  • More detail required than specified in law (e.g., "study design")
  • Additional information necessary to comply with law (e.g, data required to implement search requirements)
• Competing concerns
  • Congressional intent to establish registry quickly
  • Difficulty of enforcing all necessary data elements without regulation
• HHS is considering rulemaking

Revisions to Registry

• "Data providers" are alerted to items that (may be) required by the FDAAA
• Omission of these items does not block acceptance of the record, and an NCT # is assigned
• Items in question include those with some complexity, those that are required to implement the law, and one that reflects NIH policy
• HHS is considering rulemaking

Study Record

Enhanced Registry Activity

(12/1/07-1/20/08)

• New Study Submissions: 2,932
  • 419 records/week
• Updated Studies: 10,558
  • 1,508 records/week
• Overall Studies: 13,490
  • 1,927 records/week; 100% increase
• New PRS Accounts: 252
  • 36/week; 64% increase
• Current Backlog: ~600 records (~10 days)

Overall Characteristics: New Studies

(12/1/07-1/20/08)

(+27 delayed posting)

* 23 records missing “Study Types” information

Overall Characteristics: New Studies

(12/1/07-1/20/08)

Overall Characteristics: Updated Studies

(12/1/07-1/20/08)

*4 records missing “Study Types” information

Overall Characteristics: Updated Studies

(12/1/07-1/20/08)

Delayed Posting of Device Trial Registrations

• Law appears to prohibit public posting of trials of devices that have not been approved/cleared by FDA – even when desired by registrant
• Would therefore:
  • Require removal from current database of some device trials voluntarily posted prior to passage of law
  • Preclude use of ClinicalTrials.gov for recruitment
  • Preclude use of ClinicalTrials.gov to comply with registration policy of journal editors (ICMJE)
  • Limit transparency of such trials funded by NIH or other gov’t agencies
• Complaints received from some companies; some registrants are omitting approval/clearance status of devices to circumvent
• HHS is studying possible options

Device Studies: Delayed Posting

• Must answer "yes" to following:
  • Indicate whether this is an unapproved or uncleared device trial for which posting to ClinicalTrials.gov should be delayed in accordance with US Public Law 110-85, Title VIII, Section 801.
• 32 studies in "lock box" as of 2/7/08

Overall Interventional Device Studies

(12/1/07-1/20/08)

Delayed Posting General Characteristics

• Total: 32 studies (as of 2/7/08)
  • Provider Type
    • 27 Industry
    • 5 Other
  • Study Type
    • 27 Interventional
    • 4 Expanded Access
    • 1 Observational

Analysis of Response: OVERALL

Data Completion Statistics for Overall

Active Phase II-IV Drug/Device Interventional

Trials Submitted (12/1/07 - 1/20/08)

Top Device Companies

* Source: Not so Lonely at the Top. Medical Product Outsourcing (MPO), July/August 2007

** All device interventional and observational studies registered at ClinicalTrials.gov as of 2/4/08

*** Active, phase II-IV device interventional trials

****Includes: BiosenseWebster, ConorMedsystems, Cordis, Dupuy*, Ensure, Ethicon*, LifeScan, Visioncareinc

Top Pharmaceutical Companies

* Source: Top 10 Companies by U.S. Sales. IMS Health, IMS National Sales Perspective.3/2007

** All interventional and observational studies registered at ClinicalTrials.gov as of 2/4/08

*** Active, phase II-IV drug/biologic interventional trials

Specific Data Element Issues

Public Law 110-85, Section 801

PL 110-85 Implementation

NIH Policy

Evolution of Data Elements

• ClinicalTrials.gov has included data elements necessary to accommodate many policies
  • FDAMA
  • ICMJE
• Specific wording and structure of data elements has evolved with experience
• FDAAA has incorporated previously optional ICMJE data elements—usually identified by overall title (without details)

NIH Policy – "Board Approval"

• Submitted studies should have approval from a human subjects review board prior to the recruitment of the first patient
• Studies may be registered prior to board approval, if status is "Not yet recruiting"
• Data Elements
  • Board Approval Status (e.g., "Submitted, exempt")
  • Board Name
  • Board Affiliation
  • Board Contact

Interventional "Study Design"

• Each of the following elements is required
  • Intervention Model – intervention assignments (e.g., parallel arms)
  • Number of Arms – number of comparative groups
  • Masking – knowledge of intervention assignments (e.g., double blind)
  • Allocation – participant assignment to intervention arm (e.g., randomized)
• Sources: ICH E3, 21 CFR 314.126

"Intervention Name"

• Provides sufficiently detailed description of the intervention(s) and to link intervention(s) to arm(s)
• Data Elements
  • Intervention Name: generic name for drugs; for others, sufficient detail to distinguish from similar interventions (e.g., devices)
  • Intervention Description: e.g., dosage
  • Arm Name or Label: way to identify arm
  • Arm Type: e.g., experimental, active comparator
  • Arm Description: if different from intervention description

ENHANCE Trial

NCT00552097

CATIE

NCT00014001

"Outcome Measure"

• Specific measurement that will be used to measure the effect of experimental variables in a study
• Requires the following
  • Outcome Measure: Description of the specific measure
  • Outcome Time Frame: Time point(s) at which outcome measure is assessed
  • [Safety Issue? (yes/no)]

PL 110-85 Implementation

• Safety Issue? – "the safety issue, if any, being studied in the clinical trial as a primary or secondary outcome"
• Facility Contact – location information (e.g., city, state, country) to be able to search by "location of the clinical trial"
• Applicable Clinical Trial?
  • FDA Regulated Intervention? (Yes/No)
  • Section 801 Clinical Trial? (Yes/No)
  • Delayed Posting? (Yes/No)

Other Questions to Address

• Cut-off for modifying registry records?
  • Estimated completion date
  • Outcome measures
  • Target enrollment
• Good enough outcome measure?
• How should changes be displayed?