1. Clinical Trial Registration: Requirements and Responsibilities
Kate Scarff
Clinical Research Development Office
Melbourne Childrens Trials Centre

2. Outline What is clinical trial registration?
Why register clinical trials?
Who is responsible for registration?
Which registry should I use?
When should trials be registered?
How do I register?
Maintaining records
Submitting results – when and what

3. What is clinical trial registration?

4. What is clinical trial registration?
WHO regards trial registration as the publication of an internationally-agreed upon set of information about the design, conduct and administration of clinical trials. These details are published on a publicly-accessible website managed by a registry conforming to WHO standards.
What is the purpose of clinical trial registration?
“..to prevent selective publication and selective reporting of research outcomes, to prevent unnecessary duplication of research effort, to help patients and the public know what trials are planned or ongoing into which they might want to enroll, and to help give ethics review boards considering approval of new studies a view of similar work and data relevant to the research they are considering.”  - ICMJE

5. Why register clinical trials?

6. So you can publish your work
ICMJE Requirements
The *ICMJE requires, and recommends that all medical journal editors require, registration of clinical trials in a public trials registry at or before the time of first patient enrolment as a condition of consideration for publication. The ICMJE does not define the timing of first participant enrolment, but best practice requires registration by the time of first participant consent
Editors may consider whether the circumstances involved in a failure to appropriately register a clinical trial were likely to have been intended to or resulted in biased reporting.
Exceptions to policy should be rare, and that authors failing to prospectively register a trial risk its inadmissibility to ICMJE journals.
If an exception is made:
trial must be registered and the authors should indicate in the publication when registration was completed and why it was delayed.
Editors should publish a statement indicating why an exception was allowed.
*ICMJE is a group of medical journal editors who work on Recommendations for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals
ICMJE includes editors from the following journals:
Annals of Internal Medicine
BMJ (British Medical Journal)
JAMA (Journal of the American Medical Association
New England Journal of Medicine
New Zealand Medical Journal
PLOS Medicine
The Lancet
the U.S. National Library of Medicine
and the World Association of Medical Editors.
***************
Initially, the ICMJE required registration of all clinically directive trials, which it defined as "any 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" (1).
In May 2005, the ICMJE clarified this definition to exclude preliminary trials designed to study pharmacokinetics or major unknown toxicity (phase I trials) (5). However, the ICMJE recognizes the potential benefit of having information about preliminary trials in the public domain, because these studies can guide future research or signal safety concerns. Consequently, in 2007 the ICMJE expanded the definition of the types of trials that must be registered to include these preliminary trials and adopts the WHO's definition of clinical trial: "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" (4).
Health-related interventions include any intervention used to modify a biomedical or health-related outcome (for example, drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and process-of-care changes). Health outcomes include any biomedical or health-related measures obtained in patients or participants, including pharmacokinetic measures and adverse events.
As previously, purely observational studies (those in which the assignment of the medical intervention is not at the discretion of the investigator) will not require registration. The ICMJE member journals implemented the expanded definition of clinically directive trials for all trials that began enrollment on or after 1 July 2008.

7. Publication ICMJE Requirements for Registries
You must use a primary register of the WHO International Clinical Trials Registry Platform (ICTRP) or  ClinicalTrials.gov, which is a data provider to the WHO ICTRP.
Currently 17 registries endorsed by ICMJE, including ANZCTR, ISCTRN and ClinicalTrials.gov
The ICMJE endorses registries that meet the following criteria:
Freely accessible to the public
open to all prospective registrants
managed by a not-for-profit organization
have a mechanism to ensure the validity of the registration data
electronically searchable
include the minimum 20-item trial registration dataset ( at the time of registration and before enrolment of the first participant. 
What is difference in requirements to be a primary register of WHO and a register endorsed by ICMJE?

8. Ethical Reasons for Trial Registration
The Declaration of Helsinki explicitly states that "every clinical trial must be registered in a publicly accessible database before recruitment of the first subject". The Declaration is the cornerstone document guiding the ethical conduct of research in humans by physicians.
The World Health Organization (WHO) considers the registration of all interventional trials to be "a scientific, ethical and moral responsibility"
Australia has also endorsed trial registration in two key documents which guide the conduct of Human Research Ethics Committees and the conduct of Australians undertaking research in humans.
National Statement on Ethical Conduct in Human Research (NHMRC)
Australian Code for the Responsible Conduct of Research (jointly authored by NHMRC, the Australian Research Council and Universities Australia)
Ethics committees are increasingly requiring prospective registration as a requirement of ethical approval.
RCH HREC requires prospective registration for clinical trials as outlined in SOP RCH0498: Investigators Responsibilities in Research, dated 08 September 2017

9. Funder Requirements for Trial Registration
NHMRC
According to a statement released by NHMRC’s CEO Professor Warwick Anderson in 2015, “All NHMRC-funded researchers are required to register clinical trials with a recognised clinical trials register prior to the commencement of the clinical phase of the trial. This helps to meet the requirements of NHMRC’s Australian Code for the Responsible Conduct of Research and the National Statement on Ethical Conduct in Human Research, 2007 which applies to all Australian researchers.”
NIH
All NIH funded trials must be registered with ClinicalTrials.gov

10. Legal Reasons for Trial Registration
Registration of clinical trials is not legally required in Australia or New Zealand.
There is a legal requirement to register FDA-regulated clinical trials that meet the FDAAA 801 definition of an *applicable clinical trial (ACT) 
Sponsors of ACTs must register their trial and report summary results to ClinicalTrials.gov in accordance with 42 CFR Part 11 Clinical Trials Registration and Results Information Submission: Final Rule that was published on September 16, 2016.
Your study is an ACT if:
Study type is interventional
Study phase/primary purpose is NOT phase 1/device feasibility
Studies an FDA-regulated drug product (including biologic product)/device
One or more of the following:
At least one U.S. facility location
Product manufactured in and exported from the United States
Conducted under an FDA Investigational New Drug (IND) application /Investigational Device Exemption (IDE)
 * and were either initiated after September 27, 2007 or initiated on or before that date and were still ongoing as of December 26, 2007.
Have some MCRI studies that meet the definition of an ACT because they use FDA-regulated products and either:
US sites
Product manufactured in and exported from the US
So important that you are aware when your trial meets the definition of an ACT as you must use ClinicalTrials.gov.

11. Which registry should I use?

12. MCTC recommends ClinicalTrials.gov or ANZCTR
Established by the US National Library of Medicine of the NIH in response to The Food and Drug Modernization Act (*FDAMA) that was signed into law in 1997.
Must be used for all studies that meet definition of an Applicable Clinical Trial.
Has some additional data elements that are required for ACTs
ANZCTR
The Australian New Zealand Clinical Trials Registry (ANZCTR) is an online register of clinical trials based at the NHMRC Clinical Trials Centre in Sydney.
The ANZCTR contributes data to the International Clinical Trials Registry Platform (ICTRP), which was developed by the World Health Organization (WHO).
Imports and displays ClinicalTrials.gov records that lists Australian or New Zealand sites
*Section 113 of the Act required the NIH to establish a registry of clinical trials for both federally and privately funded trials of experimental treatments for serious and life-threatening diseases

13. Using ClinicalTrials.gov vs ANZCTR
The Melbourne Children’s Trials Centre’s (MCTC’s) registry of choice is ClinicalTrials.gov. The reasons for this preference are highlighted below:
Attribute
ClinicalTrials.gov
ANZCTR
Endorsed by ICMJE 
Oversight by MCTC? 
Registry QA Review?
Permits summary results to be posted?
Fulfills FDA requirements for ACT registration?
Includes *data sharing plan?
Permits registration of observational research
Data sharing
Authors of secondary analyses using shared data must attest that their use was in accordance with the terms (if any) agreed to upon their receipt.
They must also reference the source of the data using its unique, persistent identifier to provide appropriate credit to those who generated it and allow searching for the studies it has supported.
Authors of secondary analyses must explain completely how theirs differ from previous analyses.
Those using data collected by others should seek collaboration with those who collected the data. As collaboration will not always be possible, practical, or desired, the efforts of those who generated the data must be recognized.
*ICJME requirement for clinical trials that begin enrolling participants on/after 1 January 2019

14. Who is responsible for trial registration?

15. Sponsor is responsible for Trial Registration
The trial's sponsor or an appropriate representative is responsible for registering a trial.
The sponsor is defined by the NHMRC and Therapeutic Goods Administration (TGA) as "an individual, company or institution or organisation which takes responsibility for the initiation, management and/or financing of a clinical trial”.
Sponsors include Coordinating Principal Investigators (Lead PIs) who are responsible for conducting and coordinating investigator-initiated clinical trials (IITs). To recognise the dual role of the CPI in IITs, CRDO and MCTC have adopted the term Sponsor- Investigator.
MCRI will usually be the Sponsor for IITs led by campus staff but many responsibilities of the Sponsor, including trial registration and undertaking the design, conduct and reporting of the trial are delegated to the Sponsor-Investigator.

16. Sponsor-Investigator responsibilities
The Sponsor-Investigator is responsible for:
registering the trial
the accuracy and completeness of registered data
ensuring that information on any one trial is submitted only once
communicating with trial collaborators regarding the registration status of the trial, and the registration number
ensuring information is kept up-to-date

17. When should trials be registered?

18. Prospective registration is vital!
The ICMJE requires that trials be registered before enrolment of the first participant in order to be considered for publication.
Clinicaltrials.gov requires registration within 21 days of the first participant being enrolled in order to comply with US law
Hence follow the shortest timeframe requirement = before first participant enrolled
Important:
Recommend you commence process once you submit your study for initial ethics approval. You can prospectively register a study before you receive ethics approval as long as recruitment has not started.
ClininicalTrials.gov and ANZCTR must review all registrations prior to making them viewable to the public. 
The review process usually takes 2-5 business days and may result in comments that must be reviewed and responded to.  Can take up to 4 weeks!
Your trial has not been fully registered until you receive an from registry indicating your trial record has been approved and providing your registration number.

19. How do I register my trial?

20. Entering data into the record
ANZCTR
Follow instructions on the website at mailto:
Includes how to apply for a user account.
ClinicalTrials.gov
Contact MCTC at to request a PRS User account so you can create and modify your own record
Create a new record in the PRS and enter information about the trial
Help entering data:
ClinicalTrials.gov help tools
MCTC SOP, “Clinical Trial Registration of Investigator-initiated Trials (IITs)”
MCRI’s PRS Administrator – MCTC
Review the record for accuracy, completeness, errors and system validation messages
Make changes, approve and release record to ClinicalTrials.gov for review
The process for registering trials takes some time. It is therefore recommended that the trial registration is submitted to the registry at least 21 days before the anticipated date of first participant enrolled.

21. Registry Review and Addressing Issues
Before the record becomes public it must undergo a review by registry staff
Review usually takes 2-5 business days
The registry staff may request changes before the record is registered.
ANZCTR timelines – ask that you are prompt but no specific timeframe
ClinicalTrials.gov timelines
Major comments – within 15 calendar days
Advisory comments – should be addressed to improve clarity of the record
Once record meets review criteria it will be posted on the registry website and considered registered.  

22. My trial is registered, so what next?

23. Notify Stakeholders
Once study is registered, provide approving HREC and local Principal Investigators at Participating sites with evidence of registration that includes the date of registration and the trial registration ID
E.g. NCT number (ClinicalTrials.gov) or ACTRN (ANZCTR)
File your registration receipt in your Trial Master File.

24. Keep the record up-to-date
The record needs to be updated if any of the following change:
Recruitment status - individual sites, overall recruitment status and completion date
Protocol, e.g. outcome measures, data collection time points
Contact details
ANZCTR records will be marked “Not up to date” if they have not been updated in the previous 12 months.
ClinicalTrials.gov
Changes in recruitment status must be provided as soon as possible, but no later than 30 days after such changes. This includes changes to individual site status, overall recruitment status and completion date.
All other data must be reviewed, verified, and updated as necessary and no less than every 12 months.
Recommends that the Record Verification Date be updated at least every 6 months for studies that are not yet completed, even if there were no changes to the record.

25. Requirement to submit results – Applicable Clinical Trials Only
Results to be submitted depend on whether or not the investigational product is approved, licensed or cleared by the FDA
AND
If the primary completion date is before or on/after January
Results to be submitted include participant flow, demographic and baseline characteristics, primary and secondary outcomes and AE information
Results must be submitted no later than one year after the primary completion date
(Can apply for delayed submission or waiver but conditions apply)
Supporting documents that must be submitted – full version of the protocol and Statistical Analysis Plan, including all amendments

26. Resources

27. Where can I get further information?
MCTC SOP: Clinical Trial Registration of Investigator Initiated Trials (IITs) available at mailto: oct2017.pdf
ClinicalTrials.gov help guides available at
ANZCTR FAQs available at mailto:
ICMJE website at mailto: issues/clinical-trial-registration.html
Publications
Final Rule for Clinical Trials Registration and Results Information Submission (42 CFR Part 11) available at trials-registration-and-results-information-submission
Taichman DB et al. Data sharing statements for clinical trials: A requirement of the International Committee of Medical Journal Editors [Editorial]. New Engl J Med 2017; 376:
Final Rule clarifies and expands requirements for submitting clinical trial registration and results information to ClinicalTrials.gov in accordance with Section 801 of the Food and Drug Administration Amendments Act of 2007 (FDAAA 801)

28. THANK YOU