1. ClinicalTrials.gov: Educational Session on Requirements - What You Should Know
HSPH
Partners Quality Improvement Program l Human Research Affairs
Isabel Chico-Calero, D.V.M., Ph.D.
Senior Regulatory Specialist

2. Overview Regulatory context Requirements Consequences of Noncompliance
ClinicalTrials.gov: 101
Considerations for Implementation at Academic Centers
Resources

3. Overview Regulatory context Requirements Consequences of Noncompliance
ClinicalTrials.gov: 101
Considerations for Implementation at Academic Centers
Resources

4. Evolution of Clinical Trial Disclosure Requirements
2007
FDAAA expands ClinicalTrials .gov to include results
2014:
CMS requires qualified trials to list NCT #s by 1/1/15 for Medicare claims
2000:
ClinicalTrials.gov launched
2008 ClinicalTrials.gov results modules added
2010: Proposed Rulemaking due …
1997
FDAMA calls for public registry
2009: ClinicalTrials.gov adds Adverse Event Module
2017:
Final Rule (former FDAAA 801) and NIH Policy
2005:
ICMJE requires registration of trials
2011 EMA rule
2013: BMJ requires anonymize d patient level data availability
Note that expansions have been proposed but not yet finalized. We will touch on this at end of presentation.
Adapted and expanded from :

5. ClinicalTrials.gov: Significance & Purpose
Public federal database used to register and report results for clinical trials. It’s the world’s largest database of clinical trials!
Created in 2000 (FDAMA) and operated by the National Library of Medicine.
Instrument used to fulfill federal requirements and others (Journal Publications, Billing CMS,….).

6. ClinicalTrials.gov: Why was it created?
Historical lack of transparency in human research
Unpublished trials
Biased reporting
Promotes efficient allocation of resources
Avoids unnecessary duplication of studies
Increases trust in clinical research by public

7. Increased Requirements to maximize TRANSPARENCY
Source: Slide 8 form ClinicalTrials.gov Webinar, Overview of the Final Rule - Webinar 1 of 3, Sept. 27, 2016.

8. Clinical Trials Disclosure is Important….
And more…..
Clinical Trials Disclosure is Important….
...and it’s not going away

9. Overview Regulatory context Requirements Consequences of Noncompliance
ClinicalTrials.gov: 101
Considerations for Implementation at Academic Centers
Resources

10. Summary of Requirements
NIH Policy (2017)
Final Rule 42 CFR (FDAAA Sec 801) (2007)
Publishing (ICMJE) (2000)
Additional Requirements (Medical Billing, Funders).

11. Which studies are required to register?
Any human research project that prospectively assigns human subjects to intervention or comparison groups to study the cause- and-effect relationship between a medical intervention and a health outcome.
Registration only – NO results reporting required
Must register before 1st subject is enrolled
ICMJE does NOT consider results data posted on ClinicalTrials.gov as prior publication

12. NIH Policy – Highlights
NIH policy is complementary to the Final Rule.
All NIH defined “clinical trials” funded in whole or in part by NIH must register and post results.
NIH “clinical trial” definition (broad scope): “ A research study  in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.” (NIH Policy, p. 24).

13. NIH Policy – Highlights
If the answer to all four questions below is yes, the study meets the definition of a Clinical Trial:
Does the study involve human participants?
Are the participants prospectively assigned to an intervention?
Is the study designed to evaluate he effect of the intervention on participants?
Is the effect that will be evaluated a health-related, biomedical, or behavioral outcome?
Examples include: drugs/small molecules/compounds; biologics; devices; procedures (e.g., surgical techniques); delivery systems (e.g., telemedicine, face-to-face interviews); strategies to change health-related behavior (e.g., diet, cognitive therapy, exercise, development of new habits); treatment strategies; prevention strategies; and, diagnostic strategies.

14. NIH Policy – Compliance with the Final Rule
The awardee (investigator) is responsible for meeting the expectations of the policy (Responsible Party).
NIH will require dissemination plans (compliance with ClinicalTrials.gov registration and/or reporting requirements) in all new applications and continuing renewals proposals submitted after 1/18/17.
NIH will require certification of the grantee institution’s ClinicalTrials.gov compliance in new applications/proposals and annual Progress Reports of existing awards subject to the new policy.
NIH will not release funding for any new clinical research awards or continuing awards if the grantee institution is not compliant.

15. Final Rule: High Level Overview of New Requirements
Expanded scope of trials needed to register and report results
Clarification of what constitutes an Applicable Clinical Trial (ACT) under Final Rule
Expansion of information submitted to the database
Increased accountability and compliance: clarity on requirements and enforcement of timeline for reporting

16. Final Rule
Applicable Clinical Trial (ACT): Interventional studies (with one or more arms) of FDA-regulated drugs, biological products, or devices that meet one of the following conditions:
The trial has one or more sites in the United States;
The trial is conducted under a Food and Drug Administration (FDA) investigational new drug application (IND) or investigational device exemption (IDE); or
The trial involves a drug, biologic, or device that is manufactured in the United States or its territories and is exported for research.
There are two types of Applicable Clinical Trials:
Applicable Clinical Drug Trial: A controlled clinical investigation, other than a phase 1 clinical investigation, of a drug or biological product subject to FDA regulation.
Applicable Clinical Device Trial: A controlled trial with health outcomes of devices subject to FDA regulation, other than small feasibility studies or pediatric post-market surveillance required by FDA.

17. A Big Game Changer
Upload of IRB-Approved Protocol AND Statistical Analysis Plan
Format: PDF/A
PI may redact sensitive information (i.e. IP, trade secrets….)
Publicly posted for everyone to see……
Changes to QA Review Process (PRS Team)
Previously, ClinicalTrials.gov did not post any submitted information that did not fulfill its quality-control review criteria.
NOW:
ClinicalTrials.gov will post all submitted information on the public database no later than 30 days after receipt even if there are outstanding quality issues.
Responsible Parties will have 15 days to correct registration records and 25 days to correct results information.
Information will be posted publically with a disclaimer that information posted does not meet the quality control review criteria

18. Centers for Medicare & Medicaid Services (CMS)
Mandatory reporting of the NCT# on claims for items and services provided in “qualified clinical trials” for Medicare coverage.
Became effective on January 1, Grace period until January 1, 2015 allowing generic # to be used if NCT# not yet obtained.
Now – you need the actual NCT#!
See
[at Partners, PCRO - Partners Clinical Research Office (PCRO) handles the CMS analysis.
PCRO is is responsible for developing the agreements and budgets for clinical research]

19. CMS What is a “qualifying trial”? *
Purpose of trial must be the evaluation of an item/service that falls within Medicare benefit category (e.g. physicians’ service, durable medical equipment, diagnostic test)
Trial must have therapeutic intent
Trial must enroll patients with diagnosed disease not only healthy volunteers
* This is summary definition. For a complete definition, see Medicare NCD at

20. Who registers the study?
The Responsible Party (RP) defined as:
If IND/IDE: IND/IDE holder
If no IND/IDE:
“The initiator of the study”
The industry, cooperative group, consortium or other external sponsor that initiated the study
If initiated by a Principal Investigator
The grantee institution (e.g. Spaulding)
If no external funding, the PI
At Partners Institutions, the RP is delegated to the PI

21. Overview Regulatory context Requirements Consequences of Noncompliance
ClinicalTrials.gov: 101
Considerations for Implementation at Academic Centers
Resources

22. Consequences of Noncompliance
NIH Policy
Suspension or termination of funding
Considered in future funding decisions for the institution
Record identified as non-compliant in ClinicalTrials.gov
Final Rule (*)
Public notices of noncompliance and violations
Withholding of funds
FDA sanctions
Civil monetary penalties (up to $11,569/day/record)
ICMJE
Cannot publish in journals that follow the ICMJE policy
CMS
Will reject billing claim
*HHS has always has the authority to levy monetary fines under FDAAA, this is unchanged.

23. Overview Regulatory context Requirements Consequences of Noncompliance
ClinicalTrials.gov: 101
Considerations for Implementation at Academic Centers
Resources

24. ClinicalTrials.gov
Database operated by the National Library of Medicine (NLM)
Every organization (e.g. MGH) has an institutional account
Individual investigators/employees are given user profiles on that account
One record per trial
Many records/trials under a user profile
Type of information in ClinicalTrials.gov
Registration
Results Reporting (Outcome Measures/Adverse Events)
**ClinicalTrials.gov database can be used to satisfy FDAAA, ICMJE & CMS**

25. Public view of study registration
Public website:

26. Protocol Registration System (PRS) System Login
This is different from Public website! This is the backend. Where you enter you study information and data
Each institution has a PRS Adminisator. They can provide you will a username….
Can obtain your Org name from PRS Adm. PRS Admin can request a username/password for you…
The PRS System is where you create & edit the record for your study
PRS System:

27. How is information provided to CT.gov?
Tables are constructed by data providers
“Stand alone” tables - must be meaningful to people who are not already familiar with the study.
No Narratives
Columns are study arms
Rows are measures
Type of measure determines specific design of cells
Content is similar to what is in your journal article or what you submit to the IRB at continue review. However the format is likely different – CT.gov focuses on raw data, it purposefully stays away from narrative.

28. Registration Content Description of study Recruitment information
Study Type, Phase, Design, Outcome measures
Recruitment information
Eligibility criteria, locations, recruitment status
Administrative and other information
Key dates and contact information
Helpful links
Medline publications, Consumer health information, FDA information

29. Results Reporting content
4 Modules
Participant Flow
Baseline Characteristics
Outcome Measures (and Statistical Analysis)
Adverse Events
Results and Adverse events are:
Entered once
Aggregate
Information you should already be collecting…in a different format

30. Snapshot: Study Arms

31. ClinicalTrials.gov Review Process
Data Provider Inputs Registration or Results Data. RP “approves”& “releases” data to CT.gov.
CT.gov conducts QA review of data (Registration (5-7 days) & Results ( 30 days).
APPROVES: CT.gov posts data on public website.
RESETS to “in-progress”: CT.gov provides QA comments to Data Provider.
What happens once you “release” registration or results to ClinicalTrials.gov….

32. Overview Regulatory context Requirements Consequences of Noncompliance
ClinicalTrials.gov: 101
Considerations for Implementation at Academic Centers
Resources

33. Issues to Consider Policy considerations:
Obtaining institutional support
Determining appropriate scope for the institution
Determination of responsible party
Identifying who will be the CT.gov expert in-house
Process considerations:
Identifying studies that need registration
Providing education to researchers
Identifying who will input the data
Designing internal compliance plan
Each institution should implement a registration policy.

34. Strategies for Registration
Full Service
Self Service
Automated System
Incorporate into hybrid system
Investigators are mostly on their own
Greatly bases on size of institution and resources
Automated System:
eIRB system identifies applicable trials
Mapping to ClinicalTrials.gov fields
System notifies Investigators of applicable trials
System s ClinicalTrials.gov to obtain user account
Sends reminders via automatic compliance monitoring
Add on to existing system:
eIRB application includes CT.gov module
- identifies applicable trials
- identifies the RP
- directs PIs to appropriate resources if questions
Continuing review eIRB application
- Update reminders
- Tracks primary endpoint completion
Compliance also monitored via PRS
administrators
This can vary greatly based on
available resources and size of institution

35. Define scope of system for the Institution
Founded by Massachusetts General Hospital and Brigham & Women’s Hospital
Network of 11 hospitals in Massachusetts
Partners Human Research Affairs overseas IRB and other systems that support regulatory oversight at MGH & BWH & McLean
Over 7000 ongoing protocols at MGH, BWH, SRH & McLean
Define scope of system for the Institution
FDAAA? ICMJE? CMS?
Who will be the Responsible Party?
Institution or Principal Investigator?
Determine Institutional leverage
E.g. Require National Clinical Trials (NCT) number before IRB approval
System for identifying which clinical trials need registration
FDAAA, ICMJE, CMS
Automated, centralized process, decentralized process
Supporting the investigators through the registration & results reporting process
Guidance, in-house resources, tools, technology
Education and on-going communication
Tracking and addressing noncompliance
Manage transfer of ClinicalTrials.gov records before Investigators relocate

36. Centralized Process at Partners: MGH, BWH, McL, NWH, NSMC, SRH
Utilizes IRB submission to identify relevant studies to register and report results per FDAAA
Initial & Continuing review eIRB submission
IRB approval conditioned on receipt of NCT#
Modifications/Deferral letters include language regarding trial registration
Designation of Responsible Party to Investigator in all cases
Designates registration/reporting to the PI who best knows the study
PI is required to sign an appropriate Clinical Trials Designation Letter
Required prior to IRB approval
PRS Administrators
Create profiles on Organizational accounts
Provide support regarding requirements and mechanics of database
Internal compliance activities to ensure FDAAA, NIH & ICMJE requirements are met

37. Overview Regulatory context Requirements Consequences of Noncompliance
ClinicalTrials.gov: 101
Considerations for Implementation at Academic Centers
Resources

38. Resources Public website: https://clinicaltrials.gov/
PRS system:
Registration resources:
Results resources: :
More questions? Contact the ClinicalTrials.gov staff at

39. Additional Resources FDAAA
FDAAA related information:
Office of Extramural Research (OER):
ICMJE
ICMJE Clinical Trial Registration Requirements: l
CMS
Mandatory Reporting of NCT# Requirement:
Qualifying Trial information: