A Note From the ClinicalTrials.gov PRS Administrator, Brian Brotzman
ClinicalTrials.gov - Why It Matters
As a concept, ClinicalTrials.gov - a public database of clinical trial information - is an idea most would agree has value. The idea was introduced by the Food and Drug Administration (FDA) in 1997 and was officially launched in 2000. Now, several years later, ClinicalTrials.gov has become a platform with mixed opinion. On one hand, it is a public database of invaluable information that benefits researchers, journal editors, administrative bodies, and the public. On the other hand, it is a platform of various regulations, policies, and expectations that have left many investigators feeling confused and overwhelmed. To many, these requirements mean little more than extra work and additional burden, which begs the question - "Is it worth it?"
As a public database, ClinicalTrials.gov possesses a wide variety of benefits. For the public, it provides information on various diseases, including current research examining those diseases. For research participants, the site shows recognition and value for the time they have invested and the risk they have taken in participating in greater than minimal risk research. Journal reviewers, editors, and administrative bodies (e.g. NIH, IRBs) all benefit from the database which houses detailed information on the research they review and/or support, in a standardized format. Finally, for researchers and investigators the database can be an invaluable tool. It is a source of information on all clinical trials, and not just favorable results, as we see reported in many academic journals. The site can serve as a recruitment tool with nation-wide access, can be a platform with which to plan funding opportunities, and can be utilized as a large database for research purposes.
The benefits of ClinicalTrials.gov are numerous, but what about the deterrents? It requires extra work. Registration can take several hours, and maintaining the record requires attention through the life of the study. Reporting results can be time consuming and frustrating, as well, and using the Protocol Registration and Results System (PRS) can be a time consuming and frustrating process to become efficient. It should be pointed out at this point that the information required to be included on ClinicalTrials.gov, whether in the registration or results reporting, is not anything researchers would not already plan to do as part of their research study. A protocol, or study plan, is drafted for all clinical trials and the registration portion of a record seeks only to have this information described. Results are always reported and broken down to indicate information about the subjects involved, just as requested in the 4 results modules on ClinicalTrials.gov. So then, it seems plausible that primary burden is the extra work of presenting this information on a new platform. At the University of Iowa, we offer numerous ways to learn the system and assure that these needs are being met. For more information, check out our ClinicalTrials.gov webpage
You're Being Tracked
Did you know? There are sites dedicated to tracking compliance with ClinicalTrials.gov regulations. Both the Protocol Registration and Results System (PRS) reviewers, and NIH track compliance regularly, as well.
A recent announcement in the publication STAT reported on the current status of compliance with the Food and Drug Association Amendments Act (FDAAA 801), for both industry and academic institutions who conduct clinical trials. The article, a follow up to a 2015 article indicating that compliance with FDAAA 801 was sub-par (Piller 2015), indicates that compliance has improved, but not yet to the level required by law. According to the authors, only 77% of required trial results were reported at academic institutions; an increase from 58% just 2 years earlier (Piller & Bronshtein, 2018). This increase in reporting is most likely do to the revised reporting requirement, 42 CFR 11, which took effect January 2017. In this report, the University of Iowa was ranked among the top 5 most improved institutions.
In addition to the article, STAT released an interactive diagram that allows visitors to the site to view their findings, specific to each institution or industry sponsor. Shortly after the release of this article, an editorial published by investigators at the University of Oxford was released calling for more accountability from clinical trial investigators (DeVito, Bacon, Goldacre, 2018). The article also presented a new tool, the FDAAA Trials Tracker website, which readily displays up to date information on an institution’s compliance (fdaaa.TrialsTracker.net). Further, the website mirrors an article published in STAT this year which puts out a call to the FDA to take action and levy penalties to investigators in non-compliance (Fernandez Lynch, 2018). According to the website, the FDA has missed out on $498,427,227 which could have been levied against investigators and institutions for non-compliance, as of the writing of this article.
Recent STAT article URL - https://www.statnews.com/2018/01/09/clinical-trials-reporting-nih/
First STAT article URL - https://www.statnews.com/2015/12/13/clinical-trials-investigation/
Trials Tracker URL - http://fdaaa.trialstracker.net/
The National Institute of Health (NIH) has revised its definition of a clinical trial. The new definition, which consist of 4 criteria which must all be met to be considered a clinical trial, encompasses a wider-range of research under the term 'clinical trial' than traditionally considered. The new criteria are:
- Does the study involve human participants?
- Are the participants prospectively assigned to an intervention?
- Is the study designed to evaluate the effect of the intervention on the participants?
- Is the effect being evaluated a health-related biomedical or behavioral outcome?
Many investigators are already aware that the landscape for clinical trials is changing. As the above criteria point out, behavioral interventions are now considered clinical trials in some circumstances. Likewise, some basic science studies now fall under NIH's definition. With these changes, there has been much debate with NIH from researchers, and others, who argue that the revised definition is too broad, and that ClinicalTrials.gov is not set up to accommodate all types of trials that are being asked to register. In 2017, shortly after NIH published several case examples on its website showing how they intended to apply their new definition, there was a large amount of debate in the research community about the appropriateness of the applicability of this broad definition. Shortly thereafter, a petition began circulating among institutions that culminated in an open petition to the Director of the NIH with 2,837 signatures, including 27 from the University of Iowa.
The open petition highlighted several concerns, but most notable was the concern about the registration requirement for basic science involving human subjects. On July 20, 2018 NIH announced a delay in the enforcement of the regulation for basic science studies until September 24, 2019. In the announcement, NIH agreed that these studies may register and report results on a more appropriate site for basic science information. However, they noted an expectation that studies registered on these sites would be moved to ClinicalTrials.gov at a later time, although they did not specify a mechanism for this to occur.
On August 10, 2018 NIH released a Request for Information (RFI) asking for comment and examples relating to difficulties and concerns of reporting on basic science studies. Comment for this request ended November 12, 2018, and University of Iowa contributed comment and support in a joint letter from the Council on Government Relations (COGR). NIH provided a response to the RFI, indicating that they plan to make updates to the existing content on ClinicalTrials.gov, making registration of basic science studies easier. Additionally, they intend to grant leniency to existing basic science studies that meet the ACT definition by delaying the enforcement of penalties on these types of records for at least one year, until the updates to the system are made. Further, exceptions will be granted to basic science studies wishing to publish on a database other than ClinicalTrials.gov.
Finally, on top of these indications, NIH implemented a new Funding Opportunity Announcement (FOA) specific to 'Basic Experimental Studies Involving Humans.' Researchers who receive this type of funding will not be immediately subject to the NIH clinical trials reporting policy, as enforcement of the policy is being postponed. This change in expectations allows for NIH to further evaluate how to meet the needs of researchers, and for researchers continue their basic science work without fear of being penalized. Remember, there are many regulations and policies regarding clinical trials. It is important to remember that these concerns only apply to studies utilizing NIH funding.
FDA Releases Draft Guidance on Civil Monetary Penalties for ClinicalTrials.gov Non-Compliance
Published in September 2018, the FDA has provided guidance regarding the enforcement of penalties described in 42 CFR 11. Penalties include:
-Fines of $10,000 that rise yearly with inflation. The current fine amount is $11,805. These fines can be granted for an initial infraction, and if not resolved within 30 days, the same amount can be incurred per day until the issue is resolved.
-Withholding or removal of funding
-Potential loss of future funding
-Potential criminal penalties
-A notice of non-compliance in the public record on ClinicalTrials.gov
An important note is that both the investigator and the institution can be penalized under this regulation. In the event that a penalty were levied against an investigator and the institution, it is likely that both the investigator and their department would be required to make amends. Therefore, both parties have a shared interest in remaining in compliance with this regulation.
Per the guidance, the FDA has indicted that they are willing to work with investigators before assessing fines. Investigators will be given a Preliminary Notice of Noncompliance (Pre-Notice) and allowed to make updates, in most circumstances. If the issue is not resolve within 30 calendar days from the date of the notice, an FDA-Warning Letter is sent and an initial penalty levied.
The guidance also indicates that penalties will only be assessed when non-compliance is brought to the attention of the FDA. The typical mechanism for this is via an FDA-audit, but could also be identified via other methods such as a complaint. The guidance did not mention the effect websites such as FDAAAtrialstracker.net, which track compliance with this regulation, will have on the enforcement of penalties. Investigators should be wary and avoid non-compliance with ClinicalTrials.gov regulations when possible.
According to the guidance 'Civil money penalties may be assessed for:(1) failing to submit required clinical trial registration and/or results information to the ClinicalTrials.gov data bank, (2) submitting false or misleading information to the ClinicalTrials.gov data bank, (3) failing to submit the required certification to FDA, or (4) knowingly submitting a false certification to FDA. See section 301(jj) of the FD&C Act.22'
ClinicalTrials.gov Working Group
The University of Iowa offers direct assistance with ClinicalTrials.gov-related issues via a ClinicalTrials.gov Working Group consisting of Departmental Liaisons. While not all departments have a liaison, all investigators can receive assistance by a member of this group.
The ClinicalTrials.gov regulations are many, and learning how to use the Protocol Registration and Results System (PRS) can be daunting. Knowing this, members of the Working Group are fully trained to provide direct feedback and assistance to even the most complicated questions.
Departments wishing to have representation on the ClinicalTrials.gov Working Group should contact email@example.com. Our current membership includes:
Member Name Department
Necole Miller - Internal Medicine
Jessica Gallagher - Pediatrics
Kellie Bodeker - Radiation/Oncology
Cena Jones-Bitterman - Cancer Center
Angela Childs - Cancer Center
Jackie Searls - Surgery
Jess Fiedorowicz - ICTS
Patrick Ten Eyck - ICTS
Kimberly Sprenger - ICTS
Debra O'Connell-Moore - ICTS
Zita Sibenaller - Anesthesiology
Brian Brotzman - HSO
Wendy Beaver - DSP
Gen Shinozaki - Psychiatry
Debra Brandt - OB/GYN
Trial Tips to Tout
- NEW! HawkACT Checklist is now available. Investigators can utilize this checklist to receive an ACT determination informally (for funding purposes), or to communicate information to the IRB in their consideration of the ACT determination. More information can be found on the UI ClinicalTrials.gov webpage.
- The ‘Unique Protocol ID’ field in the ClinicalTrials.gov Protocol Registration and Results System (PRS) record should list the HawkIRB number- digits only - (e.g. 123456789). This is institutional policy, and will not appear as an error in the PRS.
- UI investigators who initiate a protocol are considered 'Sponsor-investigators' - they both initiate the protocol and conduct the study. Be sure to correctly identify this in the record by selecting ‘Sponsor-Investigator’ in the ‘Sponsor/Collaborators’ module.
- 'Principal Investigator' is a designation indicating when an outside sponsor delegates responsibility to a PI.
- Keep in mind that ‘Principal Investigator’ and ‘Sponsor’ are almost never appropriate designations for your records, and are used only in special circumstances.
- The University of Iowa should never be listed as the sponsor of a study unless you are notified to do so by a PRS administrator.
- It is very important to keep your record up to date and to avoid being put on the problem list. ACTs on the problem list are in non-compliance with federal regulations and are subject to civil and criminal penalties.
- PRS offers help and advice via the ‘Help’ and ‘Definitions’ links for each section of the record.
- The Human Subjects Office ClinicalTrials.gov page is a great resource
- The PRS Administrator is available to offer assistance by emailing firstname.lastname@example.org, or by calling 319-384-4623.