1. Why Does it Affect Me? Should I Be Concerned?
ClinicalTrials.gov
Why Does it Affect Me? Should I Be Concerned?
Adapted from the work of the Clinical and Translational Science Awards (CTSA) program’s Clinical Trials Registration Workgroup of the Regulatory Knowledge Key Function Committee
2013

2. Be aware that…
Any PowerPoint presentation can only be an introduction to a topic.
This subject is complex – this will point you to many other resources and our office is happy to assist you further.
The points outlined in this presentation are neither the law nor the regulations that apply. 2

3. Learning Objectives
Explain what ClinicalTrials.gov is and what it can do
Explain why you should register your study
FDAAA
ICMJE
Voluntary (Recruitment etc.)
Identify who is responsible for registration
Provide practice examples
Explain how registration works at YOUR INSTITUTION
Help Resources (institutional & national)

4. What is ClinicalTrials.gov?
Why should I be concerned?

6. ClinicalTrials.gov
ClinicalTrials.gov is the national registry of federally and privately supported research studies conducted in the United States and around the world.
The U.S. National Institutes of Health (NIH), through its National Library of Medicine (NLM), has developed this site in collaboration with the Food and Drug Administration (FDA), as a result of the FDA Modernization Act, which was passed into law in November 1997.
The basic rationale for ClinicalTrials.gov is that it can be a tool to improve transparency and reduce duplication of effort.
Over 133,000 studies are registered in all 50 states and in 179 countries. (See current data at
While each study is updated in real time, there is also an archive feature that allows the public to see the history of changes to the record (Note: click on “History of Changes” link towards the bottom of any record).

7. Help for Registering Studies on ClinicalTrials.gov
Login here:
Information on how to submit studies here:

8. ClinicalTrials.gov can be searched in real time to find enrolling and completed studies including:
Conditions
Interventions
Outcome measures
Sponsors/collaborators
Locations
Phases
Dates (Primary completion date, study start date etc.)
Results
Gender-based searches (such as “heart attack and women.”)

9. Rationale Increase research transparency* and public access
For the public:
To know how their money is being spent
To provide quicker and wider access than some publications provide
So that trial results may inform their medical decisions
To help people find trials
For researchers and the research enterprise
To avoid suppression of research results, which impedes the scientific process
To avoid unacknowledged changes being made to the trial protocol (affects interpretation of findings)
Because publications do not always include all pre-specified outcome measures
To provide a place where researchers can see what is going on elsewhere – even before results exist, to avoid duplication of effort
To learn more, visit:
* See detailed explanations of the value of transparency in Dr. Deb Zarin’s presentation
Overview of ClinicalTrials.gov located at

10. Evolution of Clinical Trial Disclosure Requirements: There is a trend – locally and globally – in the direction of more data sharing
1997: FDAMA establishes ClinicalTrials.gov
Law established a registry of clinical trials for both federally and privately funded trials “of experimental treatments for serious or life-threatening diseases or conditions”
2000: ClinicalTrials.gov Database launched
2005: ICMJE requires registration of trials (including at ClinicalTrials.gov)
The International Committee of Medical Journal Editors states that it believes that it is important to foster a comprehensive, publicly available database of clinical trials, broadly defined!
2007: FDAAA expands requirements: (e.g., certain medical device trials); additional trial registration information (e.g., primary outcome measure); and the reporting of summary results, including adverse events, for certain trials. The law also established penalties for non-compliance.
2008: ClinicalTrials.gov adds basic results modules, including adverse events
Source:

11. Updated from D. Zarin, ClinicalTrials. gov, Overview of ClinicalTrials
Updated from D. Zarin, ClinicalTrials.gov, Overview of ClinicalTrials.gov presentation, December 2008,

12. Why should I register a trial in ClinicalTrials.gov?

13. # 1 It’s the law! FDA Amendments Act of 2007 (FDAAA)*
Most prospective clinical trials involving regulated drugs, biological products, and devices must be registered on ClinicalTrials.gov. (The law also requires reporting of results and adverse events for a subset of these studies.)
*The Food and Drug Administration Amendments Act of 2007 (FDAAA or US Public Law ) was passed on September 27, The law requires mandatory registration and results reporting for certain clinical trials of drugs, biologics, and devices.
To learn more about FDAAA 801 Requirements, visit:

14. FDAAA – Registration* Required for “Applicable Clinical Trials”:
Interventional studies (drugs, biologics, devices)
Phase 2 – 4 (not phase 1 drug; not small feasibility device)**
US FDA jurisdiction (e.g., IND/IDE or US site)
Studies initiated after September 27, 2007, or initiated on or before that date and were still ongoing as of December 26, 2007
When:
Within 21 days of enrollment of 1st subject
Update at least every 12 months (30 days for Recruitment Status and Primary Completion Date)
** The following are also not applicable clinical trials: observational studies; single patient expanded access (treatment IND)
* REMEMBER: this is simplification of the law. See

15. FDAAA – Results Submission
Required for:
Applicable Clinical Trials
In which the study product is approved (for any use) by FDA
When:
Within 12 months of Primary Completion Date (final data collection for primary endpoint)
If product not approved by Primary Completion Date but is approved later, then results due 30 days after approval
Note: The Primary Completion Date may be well before you think the study is over. There may be additional follow-up that continues for years, but ClinicalTrials.gov wants results data submitted within a year of the final data collection for the primary endpoint.
That means getting to work on analysis and reporting quickly.

16. FDAAA – Results Submission cont’d
Delays are possible, primarily for manufacturer or under limited special circumstances:
Acceptable delays MAY (but will not automatically) be granted:
If you are the manufacturer seeking initial approval
If you are the manufacturer seeking approval for a new use
If you request an extensions for “good cause”
Pending publication is NOT considered good cause for delay

17. International Committee of Medical Journal Editors (ICMJE)
#2 You Want to Publish!
International Committee of Medical Journal Editors (ICMJE)
Requires registration in a publicly available, searchable system.
ICMJE doesn’t require registration in ClinicalTrials.gov, but in any of several international registries, WHO, or European Studies registry. ClinicalTrials.gov is just the most obvious, easy and logical for our researchers, since they may have to post there for government reasons anyway.
Scope is broader than FDAAA
Includes journals that have adopted the ICMJE policy, such as BMJ, JAMA, and NEJM
Source:
The list of journals following ICMJE’s Uniform Requirements for Manuscripts Submitted to Biomedical Journals (URM) is available on the ICMJE website. The URM includes the obligation to register clinical trials. There may be some journals that follow the ICMJE recommendations, but have never requested a listing on the ICMJE webpage. There may be some listed journals that do not follow all of the many recommendations and policies in the document. Authors and others with questions about the processes or policies of a specific journal should consult that journal directly.

18. ICMJE – Registration: Which studies?
Required for prospective studies that:
Assign subjects to one or more health related interventions to evaluate the effects on health outcomes.
ICMJE scope is much broader than the scope of FDAAA:
Interventions include any intervention used to modify a biomedical or health related outcome (e.g. drugs, devices, surgical procedures, behavioral treatments, dietary interventions).
Health outcomes include any biomedical or health-related measure obtained in participants including pharmacokinetic measures and adverse events.
Source:

19. ICMJE - Registration When to register:
Prior to enrollment of 1st subject
ICMJE doesn’t require results submission
ICMJE will not consider results data posted in the tabular format required by ClinicalTrials.gov to be prior publication
Source:
There are several databases that one can use to comply with ICMJE. Other acceptable databases are listed at the ICMJE FAQs:

20. FDAAA and FDAMA Registration
Policy Requirements – Recap (Relative numbers of trials subject to policy)
FDAAA Results & AE
Reporting
FDAAA and FDAMA Registration
ICMJE Registration
Note: NIH policy encourages registration and reporting, whether required by law or not.
Some institutes have their own policy requiring registration; check your institution’s policies.

22. Who is responsible for registering the trial?
ICMJE:
Anyone can register, but the author is responsible for ensuring complete registration
FDAAA:
The Responsible Party (RP) is defined as:
The IND/IDE holder, OR
If no IND/IDE:
The industry, cooperative group, consortium or other external sponsor that initiated the study, OR
If initiated by a principal investigator
The grantee institution OR
If no external funding, the PI

23. FDAAA: Designation of Responsible Party
RP can be designated by the sponsor to a PI who:
Is responsible for conducting the study
Has access to and control over the data
Has the right to publish the trial results, AND
Has the ability to meet the requirements
Example of RP designation
PI initiated study at Institution X* funded by NHLBI
Institution X is the sponsor (grant funding recipient)
Institution X can be the RP or designate the PI as the RP
Note: even if not designated as RP, the PI can still enter data into ClinicalTrials.gov
* e.g., Harvard Medical School, Massachusetts General Hospital, Boston Children’s Hospital, etc.

24. Let’s Practice: Assuming that FDAAA applies… Who is the responsible party in charge of registering the following studies?
Department funded/ PI initiated research
NIH funded research/ Institution X is the grantee institution
Pharmaceutical company initiated research/ multi-center study including site at Institution X
Device company funded research/ Institution X PI is the IDE holder
Cooperative Group study
See the next slide for answers…

25. Who is the responsible party in charge of registering the following studies? (Answers)
Department funded/ PI initiated research
The PI
NIH funded research/ Institution X is the grantee institution
Institution X, BUT the institution may use the right to designate to appropriate PI. Make sure you understand your institution’s policy.
Pharmaceutical company initiated research/ multi-center study including site at Institution X
The pharmaceutical company
Device company funded research/ Institution X PI is the IDE holder
PI as IDE holder
Cooperative Group study
Stay tuned; This is still unclear. The law and guidance currently available don’t have all possible scenarios spelled out.

26. What happens if I don’t register?

27. Consequences of Noncompliance
FDAAA
Public notices of noncompliance and violations
Withholding of NIH funds
FDA sanctions
Civil monetary penalties (up to $10,000/day)
ICMJE
Cannot publish in journals
following ICMJE policy, and
other select journals

28. What are my responsibilities for the following studies? Hmmm…
Let’s practice!

29. Study #1
Effectiveness of Bupropion for Treating Nicotine Dependence in Young People
Study Design: multi-center, randomized, efficacy study
Interventions: Bupropion, placebo
Primary Outcome: Smoking behavior over 6 months
Study initiated and funded by Company X
Register? For FDAAA? For ICMJE?
Results?
Responsible Party?

30. Study #1 (Answers)
Effectiveness of Bupropion for Treating Nicotine Dependence in Young People Register? For FDAAA? For ICMJE? Register due to both FDAAA and ICMJE. Results reporting? As this study falls under FDAAA and Bupropion is already an FDA approved drug, results reporting will be needed. Responsible Party? Company X.

31. Study #2
Assess the impact on Quality of Life (QoL) of long term caregivers of patients with multiple sclerosis.
Centers/sample size: Multi-site, 450 subjects
Intervention/method: Caregivers take QoL survey monthly for 2 years
Other fact: NIH funded study and University X is the grant recipient
Register? For FDAAA? For ICMJE?
Results?
Responsible Party?

32. Study #2 (Answers)
Assess the impact on Quality of Life (QoL) of long term caregivers of patients with multiple sclerosis.
Register? For FDAAA? For ICMJE? This study does not have an intervention of a drug, device or biologic; it would not fall under FDAAA. This study appears to be a purely observational study, so registration being required due to ICMJE is unlikely.*
*However, since ICMJE says “when in doubt, register”, some PIs may want to register, to ensure that publication options won’t be curtailed subsequently. Also please remember that one can always voluntarily register their study.
Results Reporting? As this study did not fall under FDAAA and there is no previously FDA approved drug/device/biologic, results reporting is not needed.
Responsible Party? If the PI decided to register due to ICMJE, the responsible party could be anyone. However, it would likely be the PI as he/she would be interested in publishing. There may be an institutional policy that addresses this.

33. Study #3
Implantable device designed to relieve the symptoms of heart failure through counter-pulsation technology.
Study Design: Open label
Intervention: Implantable device (IDE obtained)
Primary outcome: to test the feasibility of the device
8 people enrolled, 6 month study
Register? For FDAAA? For ICMJE?
Results?
Responsible Party?

34. Study #3 (Answers)
Implantable device designed to relieve the symptoms of heart failure through counter-pulsation technology.
Register? For FDAAA? For ICMJE? If this study is only looking at feasibility of the device then it would not need to be registered due to FDAAA. This study may need to be registered due to ICMJE if there is a health-related intervention used to evaluate the effects on health outcomes.
Results Reporting? As this study did not fall under FDAAA and there is no previously FDA approved drug/device/biologic, results reporting is not needed.
Responsible Party? If the PI decided to register due to ICMJE, the responsible party could be anyone. However, it would likely be the PI as he/she would be interested in publishing. Also there could be an institutional policy to address this.
Sidenote: IF this fell under FDAAA, the IDE holder would be the RP.

35. What is the FDAAA requirement for informed consent language?

36. Informed Consent Language
FDA-Mandated Changes in Consent Form Language
The FDA has added a new element of consent that is required for “applicable clinical trials.” All applicable clinical trials are required to include this new element of consent by March 7, 2012.
By federal regulation, the required language must be incorporated verbatim and cannot be altered in any way. “A description of this clinical trial will be available on as required by US law. This website will not include information that can identify you. At most, the website will include a summary of the results. You can search this website at any time.”
Subjects who were consented before March 7, 2012 will NOT have to be re-consented or otherwise sign addendum consent with this language. For more information or questions, contact your institution’s IRB office or office of regulatory affairs.

37. Nonbinding on government!
“As required by law”
Note: you should only include that section if the trial is an “applicable clinical trial” required by law to post in ClinicalTrials.gov.
If not, do not use this language.
Guidance for Sponsors, Investigators, and Institutional Review Boards
Questions and Answers on Informed Consent Elements,
21 CFR § 50.25(c)
(Small Entity Compliance Guide) Feb. 2012
Nonbinding on government!
Guidance:

38. What if I have more questions?

39. Additional Resources
General ClinicalTrials.gov information:
FDAAA related information:
Food and Drug Administration Amendments Act of 2007 Public Law No : 110publ85.pdf
For specific questions or comments:
Office of Extramural Research (OER):
Frequently Asked Questions for NIH Grantees:
ICMJE’s Obligation to Register Clinical Trials:
Contact your institution’s Clinical Trials Registration Administrator via the Harvard Catalyst Regulatory Atlas: Atlas: 50

40. This slide set was made possible by a collaboration of CTSA organizations (Mayo Clinic, Partners, University of Michigan Medical School, University of Rochester) and the National Library of Medicine. The Clinical and Translational Science Awards Program (CTSA) is part of the Roadmap Initiative, Re-Engineering the Clinical Research Enterprise and is funded by the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH).