1. ClinicalTrials.gov Jesse S. Reynolds, MS
Yale Center for Analytic Sciences (YCAS) At YSPH
300 George Street, Suite 555
New Haven CT06520  

2. About me… Jesse S. Reynolds, MS
Affiliated with Yale University since 2002
Background in Community Psychology, Public Health and Biostatistics
Includes Peer-reviewed Publications
Worked in the ClinicalTrials.gov arena since 2012
Participant in the CTSA Workgroup since 2013
Collaboration with CTSA institutions on projects and roundtable discussions
Attended the Train-the-Trainer Training at the NIH in 2013
Adjunct professor of biostatistics, industrial/organizational psychology research methods and sociology

3. Agenda
Today’s seminar will provide information on the following topics:
ClinicalTrials.gov registration requirements
What studies need to be registered?
Responsibilities after registering a study
Typical errors in registration
Is Results Reporting is required?
Typical Errors in results reporting
How to stay compliant
How to create the results tables (hands on demo)

4. What is ClinicalTrials.gov REALLY?
ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. (Source:
Brief History
1997: Congress passes first in a series of laws Requiring Trial Registration
2000: National Institutes of Health (NIH) releases ClinicalTrials.gov website
: Guidance for Industry documents are created, approved and released
2005: the International Committee of Medical Journal Editors (ICMJE) began to require trial registration as a condition of publication
2007: Food and Drug Administration Amendments Act of 2007 (FDAAA) Enacted /Expanded Registration Required
2008: “Basic Results” Submission Required
2009: Adverse Events Information Required
2016: Final Rule Published

5. Reason(s) for Registering a Study

6. Reason(s) for Registering a Study
Do I Really Need to Register my Study?
Four Possible Reasons
Federal Law (FDAAA 801)(FINAL RULE)
NIH Funding Requirements
ICMJE Recommendations
CMS Medicare Qualifying Services Billing

7. Reason(s) for Registering a Study
Federal Law (FDAAA 801) (source:
“Old” criteria:
Any “Applicable Clinical Trial" initiated after September 27, 2007, or initiated on or before that date and were still ongoing as of December 26, 2007
Interventional studies (with one or more arms) of FDA-regulated drugs, biological products, or devices
Trials of drugs and biologics. Controlled clinical investigations, other than phase 1 clinical investigations, of drugs or biological products subject to Food and Drug Administration (FDA) regulation
Trials of devices. 1) Controlled trials with health outcomes of devices subject to FDA regulation, other than small feasibility studies, and 2) pediatric postmarket surveillance required by FDA

8. Reason(s) for Registering a Study
Applicable Clinical Trial (Defined in 42 CFR 11.10)
“Applicable drug clinical trial” and “applicable device clinical trial”, for example:
Applicable Drug Clinical Trial means a controlled clinical investigation, other than a phase 1 clinical investigation, of a drug product subject to section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355) or a biological product subject to section 351 of the Public Health Service Act (42 U.S.C. 262), where “clinical investigation” has the meaning given in 21 CFR and “phase 1” has the meaning given in 21 CFR A clinical trial of a combination product with a drug primary mode of action under 21 CFR part 3 is also an applicable drug clinical trial, provided that it meets all other criteria of the definition under this part.
Final Rule, Section IV.A.5. What definitions apply to this part? - § (see 81 FR – 16)

9. Reason(s) for Registering a Study
In Other Words:
Study Type = Interventional*
Studies a U.S. FDA Regulated Drug Product? OR Studies a U.S. FDA Regulated Device Product? = Yes [new data elements]
Study Phase ≠ Phase 1 (drug and biological products) OR Primary Purpose ≠ Device feasibility (device products) [new menu option]
Any of the following apply:
Facility Location: Country = U.S. (or U.S. territory)
U.S. FDA IND or IDE Number = Yes [not made public]
Product Manufactured in and Exported from the U.S. = Yes [new data element]
*42 CFR 11.22(b); If the study is a pediatric postmarket surveillance of a device product as required by FDA under Section 522 of the Federal Food, Drug, and Cosmetic Act, it meets the definition of an applicable device clinical trial 18
IND = Investigational New Drug application; IDE = Investigational Device Exemption  

10. Reason(s) for Registering a Study EXAMPLE
SCENARIO: An investigator initiated study at UC Davis wants to look at whether a drug used to treat depression can be effective in a group of people with PTSD. The primary outcome is relief of anxiety. This is a single arm study that will look at the improvement in anxiety after 3 months. Does this study need to be registered for FDAAA/Final Rule purposes?
ANSWER: Yes, because:
The is study is interventional AND
The study takes place in the United States AND
The study is looking at a change in a health outcome AND
It uses a drug…

11. Reason(s) for Registering a Study
The National Institutes of Health (NIH)*
The NIH requires all funded interventional studies- regardless of phase or type be registered AND report results in ClinicalTrials.gov.
‘The NIH Policy applies to clinical trials which are defined as “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.”’
Applicants for NIH funding are required to submit a plan outlining how they will comply with the clinical trial information dissemination expectations of the policy.
*  

12. Reason(s) for Registering a Study?
NIH has a ‘widget’ to determine if your study is an ACT under FDAAA, but...
s_fdaaa/ACTs_under_FDAAA.htm
Notice the difference between FDAAA Final Rule and NIH Policy

13. Reason(s) for Registering a Study EXAMPLE
SCENARIO: An NIH funded study awarded to UC Davis (as lead site) will look at whether care- coordinated mental health care (compared to routine HIV screening and awareness information) will reduce risky behavior in young, gay/bisexual men. The primary outcome is a specific risk behavior at 1 year. This is a multi-site, randomized, multiple arm study. Does this study need to be registered by UC Davis for NIH purposes?
ANSWER: Yes, because:
The is study is funded by NIH AND
UC Davis is the lead site AND
The study is interventional AND
ALL INTERVENTION TYPES APPLY…

14. Reason(s) for Registering a Study
ICMJE (source:
“Any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes." 
Health-related interventions include any intervention used to modify a biomedical or health- related outcome 
Health outcomes include any biomedical or health-related measures obtained in patients or participants, including pharmacokinetic measures and adverse events

15. Reason(s) for Registering a Study
ICMJE
In other words:
Randomized studies that utilize a control
Health interventions are measured using health related outcomes
You are interested in publishing the findings of your study in medical journals such as:
JAMA (Journal of the American Medical Association)
New England Journal of Medicine
A large number of non-member journals reports that they follow the ICMJE's Uniform Requirements for Manuscripts Submitted to Biomedical Journals (source: membership/)
IMPORTANT: ICMJE and other journals require registration of clinical trials prior to enrollment of the first participant.

16. Reason(s) for Registering a Study EXAMPLE
SCENARIO: An internally funded UC Davis study will look at the efficacy of yoga for stress relief. Participants will be randomized to one of two groups. The intervention group will practice yoga for 12 weeks. The control group will be wait listed for the yoga program to begin in 12 weeks. The primary outcome will be stress relief using a validated instrument. The study PI is really interested in publishing his/her findings. Does this study need to be registered for ICMJE purposes?
ANSWER: Yes, because:
The is study is an intervention AND
It is using randomization and (w control group) AND
Health related outcomes are measured AND
The investigator wants to be able to be able to publish in a top tier journal…

17. Reason(s) for Registering a Study
Medicare Qualifying Services Billing
“Medicare covers clinical research studies, which test different types of medical care, like how well a cancer drug works. These studies help doctors and researchers see if a new treatment works and it's safe.Medicare Part A (Hospital Insurance) and/or Medicare Part B (Medical Insurance) cover some costs, like office visits and tests, and in certain qualifying clinical research studies.” (source:
“Effective January 1, 2014, it will be mandatory to report a clinical trial number on claims for items and services provided in clinical trials that are qualified for coverage as specified in the "Medicare National Coverage Determination (NCD) Manual," Section (source: Education/Medicare-Learning-Network-MLN/MLNMattersArticles/Downloads/MM8401.pdf)

18. Reason(s) for Registering a Study
UC Davis specific language (Policy 2317)
In other words:
If the study has to be registered in the Bridge
a. Does the study utilize a drug or device?
b. Does the study require item(s) or service(s) that result in any charge or billing component (including billing to a third-party insurance, study sponsor, or patient) in the Epic billing system?
c. Does the study include, as part of the protocol, any clinical intervention, including the invasion of any research participant (control or subject) body cavity (e.g. blood draw) when such an intervention takes place within a UC Davis Medical Center (UCDMC) licensed facility?
If the answer “Yes” to at least one of the questions you are required to document your study in the Bridge

19. Maintaining a Record ‘POST’ Registration

20. Maintaining a Record ‘POST’ Registration
For trials initiated before January 18, 2017 (FDAAA)
For trials initiated on or after January 18, 2017 (Final Rule)
In general, must be updated at least once per year
30 calendar day updates
Overall Recruitment Status not later than 30 calendar days after any change
Primary Completion Date (PCD) not later than 30 calendar days after the clinical trial reaches the actual PCD
In general, must be updated at least once per year
15 calendar day update
Device Product Not Approved or Cleared by U.S. FDA must be updated not later than 15 calendar days after a change in approval or clearance status
30 calendar day updates for other elements

21. Maintaining a Record ‘POST’ Registration
If any of these change, you must update the record within 30 Days
Study Start Date (that’s when the first human subject is enrolled)
Intervention Name (after establishment of a non-proprietary name)
Expanded Access Record (after any change in status and type)
Overall Recruitment Status (after any change in status)
If changed to “suspended”; “terminated”; or “withdrawn”; then also must explain “Why Study Stopped”

22. Maintaining a Record ‘POST’ Registration
30 Day Updates – Registration Information
Individual Site Status (after a change in status for any individual site)
Human Subjects Protection Review Board Status (for any status change)
Primary Completion Date (after the trial reaches its actual PCD)
Date is changed to “actual”
Enrollment data element specifying actual number of participants must be submitted
Study Completion Date (after the trial reaches its actual SCD)
Responsible Party, by Official Title (after change in RP or official title)
Responsible Party Contact Information (after change in RP or contact information)

23. Maintaining a Record ‘POST’ Registration EXAMPLE
SCENARIO: Great News! To increase the ability to recruit new participants, a new site has been added to the study. The site’s IRB approved, and they can begin recruiting immediately. What to do?
ANSWER: The site has to be added to the current registration record in the Contacts/Locations section within 30 days.

24. Maintaining a Record ‘POST’ Registration
Other Update Requirements
Record Verification Date
Any time responsible party reviews complete set of submitted clinical trial information for accuracy
And not less than every 12 months, even if no other updated information is submitted at that time
Protocol amendments that impact registration information
If protocol amended with changes communicated to human subjects, then any relevant clinical trial registration information must be submitted not later than 30 calendar days after the protocol amendment is approved by the IRB

25. Maintaining a Record ‘POST’ Registration EXAMPLE
SCENARIO: Despite adding a new site to increase participant recruitment, efforts to recruit participants are still falling short.
Feedback from the people at initial screenings shows that the testing used is time consuming. The study team is also is told that people are reluctant to participate in the study because of the additional testing.
So GOOD NEWS, the study team finds a less time intensive test to screen for eligible participants AND can eliminate some testing at follow up visits. The team amends the study protocol and the IRB approves… What to do?
ANSWER: Because these are protocol amendments, the study record must also be updated in the PRS. If the criteria for eligibility changes- this needs to be addressed. Since it also appears that some data points (outcomes) might not be collected as often- the outcome measures will need to be changed too.
It is sometimes helpful to add when major changes take place in a study in the ‘Detailed Description’ section with a date of change and what was changed added at the bottom.

26. Typical Registration Errors

27. Typical Registration Errors
Most PRS Quality Assurance (QA) rejections are because of the Outcome Measures
ClinicalTrials.gov requires that at least a Primary Outcome be identified in the study record
There are also places for Secondary and Other Outcomes as well
Outcome measures must have the following information:
The name of the instrument/tool/method used
How are you measuring what you are measuring
The range of values the measure can have (1-5, 0-100)
Interpretation of the values (100 = High, NOT GOOD)

28. Typical Registration Errors
Most PRS Quality Assurance (QA) rejections are because of the Outcome Measures
Every timeframe needs to have an outcome measure entry
Every measure needs its own entry
Example: Systolic Blood Pressure at 1, 3, 5, 7, 9 weeks is not acceptable
Instead:
Systolic Blood Pressure at 1 week
Systolic Blood Pressure at 3 weeks
Systolic Blood Pressure at 5 weeks
Systolic Blood Pressure at 7 weeks
Systolic Blood Pressure at 9 weeks

29. Example of a ‘Composite Outcome’ Registration Error
The primary outcome cannot measure multiple things.
‘Symptoms’ is vague
‘GERDQ’ and ‘Eckardt score’ are impossible to report all at once
Time Frame is not mentioned in this reviewer comment- but would likely come back if not specified
Is it between 3-6 months?
Or is it at 3, 4, 5, 6 months…?

30. Typical Registration Errors
Other areas where error(s) can occur:
Outcome measures are missing key information or are vague
Descriptions of study arms and descriptions of study interventions do not overlap
Drugs as part of a study should be identified- even if ‘usual care’
Recruitment status cannot be ‘recruiting’ for studies with study start dates in the future
The record should function like a ‘living document’

31. Typical Registration Errors: EXAMPLE
Here the secondary outcome is collecting 2 things.
There is also no explanation as to how the info will be collected and reported.
“Obtaining” is a verb but they are measuring rates here.
To fix this, there will need to be 2 outcomes created (1 additional).

32. Typical Registration Errors: EXAMPLE
Here the same intervention is assigned to both groups.
One is placebo
One is active comparator
In theory, they should both not receive study drug- only the experimental group should.
To fix this, a ‘placebo’ intervention needs to be created.

33. Does the Study NEED to Report Results?

34. Does the Study NEED to Report Results?
Think back to “Do I Really Need to Register my Study?”
Four Possible Reasons
Federal Law (FDAAA 801)(FINAL RULE) - YES
NIH Funding Requirements - YES
ICMJE Recommendations – NO – unless FDAAA/NIH
CMS Medicare Qualifying Services Billing – NO – unless FDAAA/NIH

35. Does the Study NEED to Report Results?
Older studies would not have to report results if any of the following were true:
The study was only intended to be a phase 1 drug or device feasibility study and was wrongly entered…
The primary completion date of the study was prior to December 2007…
The study was terminated with 0 subjects enrolled…
All else… then likely, yes, results will need to be entered.

36. Does the Study NEED to Report Results? EXAMPLE
Example: A study, funded internally by UC Davis, looks at the effect of a new behavioral intervention on the rates of quitting smoking. Participants are enrolled and then randomized to 1 of 2 arms. One arm will use meditation (which has been shown to be effective and is standard of care) and the other arm will use a new method of cognitive behavioral therapy. Should it report results?
No, by law it does not require results reporting- FDAAA does not cover behavioral interventions.
No, because NIH is not the funding source it is not required under NIH Policy.
BUT Maybe… ICMJE (which would cover this study for registration) likes studies to voluntarily report results for registered studies.
This is left to the discretion of the study team (PI).

37. Does the Study NEED to Report Results?
ClinicalTrials.gov provides the following tool to determine if your study applies.
If all 4 = yes – then register before the 21 day limit after first subject enrollment.
CT_Checklist.pdf

38. Does the Study NEED to Report Results?
NIH has a ‘widget’ to determine if your study is an ACT under FDAAA, but... It can be confusing.
s_fdaaa/ACTs_under_FDAAA.htm
So, notice the differences between FDAAA Final Rule and NIH Policy.
This table is more helpful.

39. Typical Errors in Results Reporting
MISSING DATA: Here we see how a study that collected data on 3 subjects did not analyze these data. The reasons for not analyzing data should be specified as to why OR every effort should be made to summarize what was collected.

40. Typical Errors in Results Reporting
VAGUE OUTCOMES: Sometimes it isn’t the results entered BUT the way that the record was set up to begin with. Here, reviewers have no issue with what was entered but rather the description of what was measured.

41. Typical Errors in Results Reporting
INCONSISTENCIES: Here we can see that the manner in which the data were entered in the participant flow, demographics and outcomes sections do not match. The key is to try and be clear from the beginning.
Start at the ‘flow’, be clear on the groups ‘n’ in demographics and then move to the outcomes.

42. How to stay compliant Be sure that the Protocol is up to date AND…
Changes in protocol are reflected in CT.gov.
Be proactive when study closes to make sure that ‘anticipated’ dates are changed to ‘actual’.
Try to create a plan for how results are going to be entered.
Coordinate with the study analyst/statistician/biostatistician
Create templates/spreadsheets for how CTgov – Adverse Events reporting can be tricky!
If a paper is published include the citation (for transparency) in the record.
NCT numbers are searchable in PubMed.
PubMed ID’s appear in CTgov.

43. Training Demo for Results Entry
NCT