1. NCIs Clinical Trials Reporting Program (CTRP) vs. Clinicaltrials.gov
What Study Teams Need to Know

2. Session Objectives
Outline the differences between CTRP and clinicaltrials.gov
Discuss the process associated with each protocol registration mechanism
Define upcoming requirements

3. NCI’s Clinical Trial Reporting Program (CTRP)
Overview

4. Clinical Trial Reporting Program: Goal
The CTRP goal is to provide NCI with a more global view of emerging knowledge from cancer trials and to identify important patterns and insights in a timely way in order to assure patient safety and an optimal return on the nation's investment in cancer clinical trials.
This goal enhances NCI's commitment to protecting human research participants in NCI-supported trials, safeguarding the integrity of the data resulting from this research, and applying measures to enable effective monitoring of research.
Based on a June 2005 recommendation from the Clinical Trials Working Group (CTWG)

5. CTWG Recommendations
Single “source of record” for NCI on trial statuses
Comprehensive list of trials
Includes data from other sponsors (public and private)
Leverages experience and expertise of NCI and community in the construction of clinical trials databases

6. CTRP Definitions CTRO: Clinical Trials Reporting Office
Submitting Organization: Grantee and/or site supplying data to CTRO to satisfy CTRP requirements

7. CTRP Pilot Deployment Pilot Sites Dana-Farber/Harvard Cancer Center
Northwestern
Mayo
St. Jude
Wake Forest

8. CTRP Timeline January-March 2009 April-June 2009
Five pilot sites ONLY, register NEW trials only, no amendments
April-June 2009
Solicited “early adopter” Cancer Centers begin registering NEW trials
Allow amendments and existing OPEN trials
Pilot sites should register all OPEN trials by 6/20/2009

9. CTRP Timeline cont. July-September 2009 (provisional)
Non-Cancer Center grantees begin entering NEW trials
Cancer Centers should register all OPEN trials
Begin collection of accrual date
January-March 2010 (provisional)
Begin pilot reporting of outcomes, adverse events
Potentially add observational, ancillary/correlative studies

10. CTRP Compliance Compliance:
“The grants management office has responsibility for the enforcement of regulations related to non-compliance or performance. Grantees may receive an extension in order to become compliant. Non-compliant grantees may face termination of their grant award. “

11. Clinical Trial Reporting Program: Key Processes
Protocol Registration*
All intervention trials regardless of funding type
Within 21 days of activation
Excludes CTEP/DCP trials already being reported
Validation
Checking of registration entries by CTRO staff for duplication or inconsistency with protocol document
Abstraction
CTRO staff abstracts data elements from submitted protocol document (i.e. Disease/Conditions and Interventions)
Trial Summary Report
Accrual Submission*
Patient specific or aggregated data dependent on trial type
Report Generation
Cancer Center Summary 4 Reports, Clinicaltrials.gov registration

12. CTRP: Protocol Registration
Trial Details
Lead Organization/Trial Id (Protocol #)
Title
Trial Type (Treatment, Prevention etc.)
Phase
Current Trial Status & Current Trial Status Date
Lead Organization/PI
NIH Grant Information, if applicable
Trial Related Documents
Protocol, NCT ID number or limited data set
List of Participating Sites
Informed Consent Document
IRB Approval Document

13. CTRP DF/HCC Process
Centralized trial submission within the Quality Assurance Office for Clinical Trials (QACT)
Responsible for manual entry of registration information
Batch uploads of accrual data
Still working out processes as part of Pilot program for additional reporting

14. CTRP RECAP: What does this mean for the study team?
CTRP registration will be done by Quality Assurance Office for Clinical Trials (QACT)
PI/Study teams will NOT be responsible for meeting registration deadlines
Additional information about process will be disseminated as it becomes available

15. Clinicaltrials.gov

16. Clinicaltrials.gov:
Public registry of federally and privately supported clinical trials conducted in the United States and around the world.
gives information about a trial's purpose, who may participate, locations, and phone numbers for more details.
The U.S. National Institutes of Health (NIH), through its National Library of Medicine (NLM), developed the site in collaboration with the Food and Drug Administration (FDA),

17. Clinicaltrials.gov: History
Food and Drug Administration Modernization Act (FDAMA) 1997
Section 113 mandated that DHHS, through the NIH, establish, maintain, and operate a registry of clinical trials
Prescribed the required content
Information must be easily understood by the public
Required the registration of trials testing drugs for life threatening diseases and condition
Clinicaltrials.gov launched in February 2000

18. Clinicaltrials.gov: History
International Committee of Medical Journal Editors (ICMJE) 2004
Calls for increased transparency of Clinical Trials
September of 2004, the ICMJE published an editorial stating that they will only publish clinical trials that were registered on a publicly accessible registry
This included only phase 2 and beyond clinical trials

19. Clinicaltrials.gov: History
September 2007: FDA Amendment Act (FDAAA)
Increased the data elements that must be included
Added provisions for a RESULTS DATABASE

20. Clinicaltrials.gov: History
Public Law Sec. 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
Increased data elements required to include FDAAA/ICMJE/WHO requirements
Requires Results Reporting (Sept 2008)
Trials of FDA-approved or cleared drugs and devices
“Basic” Results: Baseline characteristics, Primary and Secondary Outcomes, Statistical Analyses

21. Clinicaltrials.gov: History
International Committee of Medical Journal Editors (ICMJE) July 1, 2008
Expanded the registration requirements to include ALL clinical trials including Phase I and pharmaco-kinetic trials

22. Requirements for the Timing of Registrations on clinicaltrials.gov
ICMJE requires registration to occur before the first participant is enrolled but after IRB approval
FDAAA requires registration within 21 days after enrolling the first participant

23. Requirements for Updating Information on clinicaltrials.gov
ICMJE requires the updating and verification of study information every six months
FDAAA requires the information be updated at least every 12 months
Additionally the registry must be updated within 30 days of any changes in recruitment status or completion of study

24. Differences in Registration Requirements
ICMJE
FDAAA
What types of trials?
ALL clinical trials including Phase I and pharmaco-kinetic
Phase II and beyond
When to register?
BEFORE the first subject is enrolled
Within 21 days after enrolling the first subject
How often do trials need to be updated?
Every 6 months
Every 12 months

25. Clinicaltrials.gov Definitions
Responsible Party
Sponsor
Designated Principal Investigator
Applicable Clinical Trial
Drug
Device
Completion Date (Primary)
Date that the final subject was examined or received an intervention for the purposes of final collection of data for the PRIMARY outcome
NCT Number
Number assigned to a clinical trial once it is posted on clinicaltrials.gov

26. Who is responsible for registering/ updating information on clinicaltrials.gov?
The “responsible party” is considered the regulatory sponsor of the study
This responsibility can be designated to the Overall PI
In most cases the industry or cooperative group will register the trials they sponsor
Recommend checking with the sponsor to verify
Investigator-Initiated trials, should be registered by the OVERALL PI when any of the following apply:
The PI is the IND/IDE holder
There is no external funding
Industry has provided drug and/or $ but does not “own” the project

27. What does this mean for DF/HCC PI-Initiated Trials?
In order to comply with the new laws and preserve the ability to publish in ICMJE journals
BOTH sets of requirements must be met
Register all PI-Initiated protocols regardless of Phase BEFORE the first participant is enrolled but AFTER IRB approval
Update registry information every 6 months or immediately when recruitment status changes (see CTEO Tips & Tricks sheet on “Updating Trial Information on clinicaltrials.gov”)

28. How do you register a new trial?
The registration process is currently DF/HCC institution specific
Meaning each DF/HCC institution (MGH, BWH, BIDMC, DFCI, CH) has an institutional account on clinicaltrials.gov
User accounts are set-up under each institutional account for INVESTIGATORS ONLY (requires Log-in and Password) on the website
Administrative access to protocol records can be granted to Program Managers or Overall PI designee (DFCI/BIDMC ONLY)
Contact your Protocol Registration System Administrator for detailed directions:
DFCI/BIDMC: Shannon Nelson MGH: Victoria Mirabello

29. Current Registration Process
CTEO is notified when a PI-Initiated protocol is IRB approved
CTEO notifies Overall PI and study contact about the need for registration and offers assistance
CTEO, with approval from PI, will enter in the initial registration information
Once information is entered, the protocol record is then “transferred” to the Overall PIs login account on clinicaltrials.gov and the PI and study contact are notified of completion and the next steps of review/modification and approval
FOR MGH/BWH registrations: Once the protocol record is transferred to the Overall PI, the CTEO no longer has access to view or make changes to the protocol record

30. Current Registration Process Cont.
Once the PI reviews and approves the registration information the protocol is released for posting on clinicaltrials.gov
Posting occurs 2-5 days after release and an NCT number is assigned to the trial

31. Updating Information on Clinicaltrials.gov
The Overall PI (or designee) is responsible for updating/verifying the information posted on clinicaltrials.gov at least every 6 months
Information posted must be reviewed and amended if necessary. The protocol “record verification” date must be changed to reflect most recent review.
Receive reminders from clinicaltrials.gov every 6 months
For newly approved trials, CTEO will send a reminder to Overall PI and study contact when the trial is activated by OHRS (Overall PI must go in and change recruitment status and record verification date)

32. Basic Results Database: General Characteristics
Results of applicable clinical trials of FDA-approved/cleared medical products
Generally, submission within 12 months of the completion date of the primary outcome
Delayed submission of results
Seeking initial approval
Seeking approval of a new use
Extensions for “good cause”

33. Basic Results Database: Current Exemptions*
Trials completed PRIOR to September 27, 2008 do not need results submitted
Drugs not yet approved by the FDA do not need to post results until the drug receives approval (results need to be submitted within 30 days of approval for first indication)
For approved drugs, in which a new, unapproved indication is being studied, reporting can be delayed for up to 2 years regardless of whether the drug is approved for that indication
NO requirement for posting the results of trials of drugs that were never approved

34. Basic Results: Requirements
Demographic & baseline characteristics
Table of values, overall and for each arm
# of patients dropped out & excluded from analysis
Primary and Secondary Outcomes
Table of values for each primary & secondary outcome measure, by arm
Scientifically appropriate tests of statistical significance
Point of contact (for scientific information)
Certain agreements (restrictions on PI to discuss or publish results after trial completion date)

35. Register.clinicaltrials.gov Website used to register trials
“Back end” of clinicaltrials.gov
Overall PIs are set up with accounts to register their trials under
They are considered the “owners” of any protocols registered under their accounts
Make updates, record verifications, and post results by accessing the individual protocol record

40. When verifying information every six months, it is important to update the “Record Verification Date”

41. Clinicaltrials.gov: The Future
September 27th, 2009-Adverse Events
The reporting of adverse events will become mandatory if the Secretary fails to issue regulation by September Reporting will default to:
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% within any trial arm
Number and frequency of event in each trial arm

42. Clinicaltrials.gov: Enforcement Mechanisms
Denial of trial publication (ICMJE)
Public Notices of non-compliance
Civil Monetary Penalties (up to $10,000 per day)
Withholding of NIH funds
FDA Sanctions

43. CTRP vs. Clinicaltrials.gov
A Recap of Important Points

44. Who is the registry intended for? National Cancer Institute
NCIs CTRP
Clinicaltrials.gov
Who is the registry intended for?
National Cancer Institute
General public
What trials are registered by DF/HCC?
Interventional trials that are not CTEP/DCP sponsored
PI-Initiated, in-house trials of all Phases
Who is responsible for the registration?
QACT
Overall PI
(initial trial registration assistance offered by CTEO)

45. Who is responsible for updating the information originally supplied?
NCIs CTRP
Clinicaltrials.gov
Who is responsible for updating the information originally supplied?
QACT
Overall PI
Who is responsible for future requirements?
Who do I contact if I have any questions?
CTEO

46. Questions?