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

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

NCI’s Clinical Trial Reporting Program (CTRP) Overview

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)

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

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

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

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

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

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. “

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

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

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

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

Clinicaltrials.gov

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),

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

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

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

Clinicaltrials.gov: History Public Law 110-85 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

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

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

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

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

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

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

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”)

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 https://register.clinicaltrials.gov/ 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 617-582-8310 617-424-4140 snelson0@partners.org vmirabello@partners.org

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

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

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 email 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)

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”

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

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)

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

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

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 2009. 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

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

CTRP vs. Clinicaltrials.gov A Recap of Important Points

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)

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? qcc@partners.org CTEO cteo@dfci.harvard.edu

Questions?