The US’s Food and Drug Administration has at last published its plan to identify and punish the organisations and people who have broken the law by not reporting clinical trial results. The FDA now wants to hear what we think about the plan.
The FDA Amendment Act 2007 says that lots of clinical trials in the US should be registered on ClinicalTrials.gov and report results information there within 12 months of the end of the trial. AllTrials’s FDAAA TrialsTracker shows that 628 clinical trials have broken this law since the first trials became due in January this year. We have written to the FDA every week to update them on the trials that have breached the law and shared with them a rolling estimation of the amount in fines the Agency could levy on the law breakers. The FDA has the power to fine people up to $10,000 a day and we have assessed that they could have raised $904,499,127 – nearly a billion dollars – but no one has ever been fined. That the FDA is now seriously considering how to start doing this is a long-awaited step forward.
We have analysed the guidance and have written a detailed comment on it which you’ll find below. We think there are a number of areas where the guidelines could be stronger and we suggest some extra elements which would help get old trial results reported and help us all scrutinise the impact of the law.
If you would like the FDA to start fining the people and organisation who break the law on reporting results please tell them here that you welcome the publication of the guidelines and hope they are implemented soon. If you have time to submit a more detailed comment, do read our thoughts below and please feel free to use any of the material here yourself.
Submit comments before November 20 2018 at 11:59 PM ET here: https://www.regulations.gov/document?D=FDA-2018-D-0787-0001
COMMENT FROM ALLTRIALS
We welcome the publication of draft guidance on Civil Money Penalties Relating to the ClinicalTrials.gov Data Bank. Thank you for the opportunity to comment on this draft. This submission is on behalf of the AllTrials Campaign (www.alltrials.net), the global movement for all trials past and present to be registered and their results reported which was founded in 2013 and is backed by more than 700 organizations and 90,000 individuals.
We have included below our comments on specific aspects of the draft guidance and we also suggest additional guidance the Agency should consider adopting. First we want to underline from our experience the importance of effective enforcement of the FDAAA 2007 and its implementing regulations on trial registration and results reporting (42 CFR part 11). Effective enforcement is a vital step to ensuring accurate information about clinical trials is available for public scrutiny and easily discoverable for use by researchers, government officials and clinicians. We are glad the FDA is exploring how to do this. We have launched a number of tools related to transparency in clinical trials, including the FDAAA TrialsTracker (fdaaa.trialstracker.net) which specifically monitors compliance with the results reporting requirements of the FDAAA 2007, to help the public and sponsors discover which clinical trials have adhered to the rules or not and to encourage those responsible to adhere to the law.
This draft guidance on enforcement of the requirements in 42 CFR part 11 is welcome. It focuses on registration and reporting requirements and the processes of submitting information to the ClinicalTials.gov databank. However, we hope that the Agency intends to monitor compliance with the totality of the requirements outlined in 42 CFR part 11 which include not only requirements around initial registration and results reporting but also requirements for the proper maintenance of these records to ensure they contain accurate and up to date information. Enforcement action by the Agency should ensure sponsors are adhering to all of these requirements plus to the statutory timelines set out for required actions such as requesting certificates of delay and resubmitting updated results during quality control.
Comments on the draft guidance
SECTION III B suggests the Agency’s Centers aim to uncover non-compliance with reporting requirements during the Centers’s Bioresearch Monitoring Program inspections. It is useful for sponsors and responsible parties to be aware that registration and reporting will be checked against requirements as part of this established inspection program. Certainty, predictability and a framework for the inspections which includes this assessment will be appreciated by researchers. The FDA should clarify who exactly within BIMO, and the larger Agency, has responsibility for policing breaches once they are uncovered.
However, we wonder whether the Bioresearch Monitoring Program is comprehensive enough to ensure that compliance with the requirements of 402(j) of the PHA is seen as an imperative by all sponsors with non-reporting or otherwise non-compliant trial entries. As of 23 October 2018, our FDAAA TrialsTracker has identified 567 unique sponsors or submitters with either overdue or late-reported trials. This covers only one of the requirements (that applicable trials report within 1 year of their primary completion date) outlined in 42 CFR Part 11. The Agency’s draft guidance states that “Generally, FDA’s BIMO activities are associated with the submission of a research or marketing application or as a part of the Agency’s investigation of a complaint.” It is our concern that large portions of non-compliant sponsors may never or rarely interact with BIMO in a way that would encourage them to ensure they are in compliance with the registration and, especially, the reporting requirements outlined in 42 CFR Part 11.
SECTION III B also indicates that “In general, the Centers may also identify violations as a result of complaints received by the agency.” We welcome this. The FDAAA TrialsTracker automatically identifies applicable and probable applicable clinical trials, as defined statutorily and by ClinicalTrials.gov, and assesses which of these have reported results according to the law. The data is updated every working day. Trials are displayed on the website and those which have breached the rules are flagged as overdue. Trials can also be aggregated by sponsor. It is therefore possible to see which sponsors are repeatedly breaching the reporting requirements based on data directly from ClinicalTrials.gov. AllTrials encourages the Agency to use this tool to complement their own monitoring.
In addition, it would be helpful for individuals and external bodies to understand the procedure for submitting complaints to the agency and how these complaints will be handled. Will there be a sole channel for these complaints or will they be accepted through various means on an ad-hoc basis? Will the complaints be made public? Will the agency commit to respond to complaints and explain the actions taken or not taken as a result of the complaint? Clarity around the submission and handling of complaints would be a useful addition to the guidance.
SECTION III C suggests that the “FDA intends to utilize a risk-based approach to determine the situations in which Pre-Notice Letters will be issued consistent with FDA’s public health mission and how the Agency approaches its other compliance programs” and that the Agency will focus on higher risk applicable clinical trials or applicable clinical trials of public health importance. Prioritization is important. However it is concerning that the FDA would not endeavor to reach out to all violating sponsors. Our FDAAA TrialsTracker suggests that, as of 21 October 2018, there are 631 trials identified as being in breach of reporting requirements since the first trials covered under 42 CFR Part 11 became due in January 2018. While this number is high, the FDAAA TrialsTracker shows that the process of identifying clinical trials breaching the reporting law can be automated. The process of notifying sponsors of these trials can be done at very little cost too especially as the Agency should have access to sponsor contact information for all trials via ClinicalTrials.gov. We strongly encourage the Agency to ensure that no sponsor or responsible party feels they will not be at risk of being sanctioned for non-compliance because the trial or trials they are responsible for do not align with the Agency’s priorities and consider at least some measures that would lead to contact with all or most trials in breach of the law.
SECTION III C also indicates that the Agency will focus efforts to send pre-notice letters of non-compliance to trials with “responsible parties or submitters for which there is a pattern of previous noncompliance” including noncompliance with other statutory requirements outside of 402(j) of the PHA. We applaud this. We believe making past compliance behaviour relevant to a researchers’ current and future risk of being identified for sanctions is an effective way to get past trials registered and results information reported. This focus is also to be welcomed as it aligns with the recently reported statement from Dr Jodi Black, NIH Deputy Director of the Office of Extramural Research, that the NIH would not award research grants if it is unable to validate that the applicant registers trials and publicly reports their results, suggesting that NIH plans to consider applicants’ track record on complying with transparency rules when deciding whether to award further research grant.
Suggested additional guidance
Make notices public
The Agency should place all pre-notice letters of non-compliance and notices of non-compliance it issues immediately into the public domain to ensure full accountability for the offending sponsors. It would be useful to publish information on the numbers and specifics of pre-notice letters, notices of non-compliance and fines issued. As well as making these noticies public, summary reports should be made available on a quarterly or annual basis, identifying:
(i) the clinical trials identified to be in breach of the requirements in the previous quarter or year
(ii) the sponsors and PIs responsible for them
(iii) when the trial became compliant
(iv) what action was taken by the Agency, if any, before the trial became compliant.
Send email reminders
We ask the FDA to consider adding a step to the notification process – a prior step of sending an email or letter to the responsible party for applicable clinical trials that haven’t yet submitted results information, but before they are in violation of the law, to warn them that the reporting deadline is approaching. We suggest this step should happen three months before the deadline. This is a function that can be set up automatically with little resource and evidence from a randomised controlled trial has shown that this simple approach increases the amount of required information that ends up being shared (https://www.bmj.com/content/349/bmj.g5579). We believe this additional step, prior to the deadline, will increase the proportion of accurately reported trials and will reduce the burden of pre-notice letters etc. We understand that the ClinicalTrials.gov PRS does automatically notify sponsors of issues regarding their registered trials, however additional targeted notifications from the agency with the statutory authority to seek civil monetary penalty for noncompliance may better encourage sponsors’ adherence to their legal responsibilities.
Investigate what works
We would also be interested to know if the agency plans on conducting, funding, or collaborating with outside groups on research informing the best ways to increase compliance with the FDAAA 2007. There may be considerable variability in the success and cost-effectiveness of various methods of bringing sponsors into compliance. Conducting or supporting research designed to address this question could aid in facilitating efficient and effective enforcement action by the agency.