The US Food and Drug Administration has dashed patient hopes that it will take rapid and decisive action to force pharmaceutical companies and universities to make the results of their clinical trials public as required by law.
When trial results remain hidden, doctors and patients can get a misleading picture of the safety and effectiveness of medicines and medical devices. In the past, this hidden medical evidence has led to hundreds of thousands of patient deaths in the United States alone.
For this reason, a 2007 piece of legislation called FDAAA made it compulsory for companies and universities running many types of trials to make their results public. During a 2018 consultation, patients, doctors and medical experts had urged the FDA to fully enforce the law.
However, at present, over 2,000 such trials are still missing results. By law, the FDA could by now have collected up to $11 billion in fines for these violations. In reality, the FDA has not collected a single cent. Past pledges to fix the problem, including a promise made by Joe Biden in 2016, have come to nothing.
On Friday, 13 years after the law was passed, the FDA finally set out its plans for collecting fines.
In short, the federal agency may on occasion impose fines, but it will not systematically and routinely go after institutions that flout the law as TranspariMED and other groups had encouraged it to do.
However, the FDA's new plan states that "the Centers may also identify violations based on the evaluation of complaints received by the Agency". Going forward, TranspariMED will explore whether there is a possibility of forcing the FDA's hand by filing complaints about specific companies, universities or trials.
The FDA’s approach appears at odds with the more assertive stance taken by the National Institutes of Health.
The National Institutes of Health recently warned drug and device companies to submit missing data for trials conducted between 2007 and 2017. STAT News called this move “a major win for transparency advocates, who for years have fought to recover the decadelong gap in publicly available clinical trial data,” but cautioned that it remained unclear how many trial sponsors had been warned about noncompliance, “and whether or when they would follow the new rules”.
Dr Karla Soares-Weiser, Editor in Chief of the Cochrane Library, said:
“Failure to register clinical trials and report findings undermines the ability to make truly evidence-informed decisions about healthcare – and can have serious consequences for people’s health if the benefits of an intervention are exaggerated, or the harms underestimated."
"Unfortunately, it is unclear how effective the approach detailed in this new FDA guidance will be in pushing trial sponsors to meet their ethical – and legal – obligations to register and provide results of their research in a timely manner. This is disappointing, especially in the context of the COVID-19 pandemic, which has highlighted the value of clinical trials and the need for relevant trial information to be available as quickly as possible.”
Till Bruckner, founder of TranspariMED, said:
“This is a bitter disappointment for U.S. patients and taxpayers, and runs directly counter to the FDA’s own mission of ‘ensuring the safety, efficacy, and security’ of drugs and medical devices. Failure to make clinical trial results public is not a victimless crime, and the FDA should stop treating it as such."
"The piecemeal approach set out in the new FDA guidance runs directly counter to the letter and the spirit of the law, and the mandate and direction provided by Congress. As a result, American patients will continue to receive treatments whose benefits and harms are not fully publicly documented, and American taxpayers will have to fill in the gap left by uncollected fines. It’s high time for Congress to wake up to this ongoing scandal and tell the FDA to fully implement the law.”
Deborah Zarin, the former director of ClinicalTrials.gov and a current Program Director at the MRCT Center, commented that:
“I am concerned that the FDA plan, as outlined in Guidance, will not serve as a meaningful deterrent to non-compliance with FDAAA reporting requirements."
"Sponsors will have at least two rounds of warnings prior to any possibility of receiving a penalty, allowing those who wish to skirt the law to simply wait to report until they are warned. In addition, BIMO inspections provide an opportunity to identify trials that might not have been registered, but are probably not the most efficient way to identify registered trials that have not reported results within the legally mandated timeframe.”
“The non-reporting of results has serious implications for the integrity of the medical evidence base. ClinicalTrials.gov data can be used to identify such trials in an efficient manner. External groups use publicly available information to do this (e.g., FDAAA Trials Tracker), but NIH or FDA could do this even more accurately using non-public information as well (such as IND/IDE status). The flagging of non-compliant studies identified in this manner could have a major deterrent effect.”
Erick Turner, a former FDA drug reviewer, said:
"Call me skeptical, but considering that the FDA has failed to enforce these delinquency fees after being told so many times to do so, I'll believe it when I see it. The FDA has left nearly $12 billion uncollected for the past two years. If they were to collect that, perhaps they could forego collecting user fees, thus making the FDA less dependent on industry and more accountable to the taxpayer."
Other transparency advocates also expressed their disappointment.
Nicholas DeVito of EBM Data Lab, which runs a tracking platform that flags clinical trials in breach of the law, said:
"The new FDA enforcement guidance leaves much to be desired. The risk-based assessment of enforcement strategy, and primary enforcement being housed under BIMO, would seem to severely limit when and where the FDA plans to actually try and enforce the law."
"The FDAAA TrialsTracker we built has shown that large-scale monitoring is possible at minimal cost. The FDA could implement similar automated monitoring across all trials, while also incorporating information that is not publicly available. We are sceptical that the FDA will consider referrals of unreported trials after our prior efforts to share our FDAAA TrialsTracker data were dismissed by the FDA."
Christopher Morten of the NYU Law School, who recently won a transparency court case against the FDA on hidden trial data, said:
"While the issuance of guidance is generally promising, we need a more concrete commitment from FDA. The guidance is vague. When will FDA issue its first pre-notice letters? How many will it send? How, exactly, will the FDA define a “pattern of previous noncompliance”? Also, a federal judge recently announced that trial results collected from 2007-2017 on the safety and efficacy of FDA-approved products are important to public health. I'm disappointed that the guidance doesn't make enforcement of reporting these results a clear priority. The FDA seems uninterested in enforcing the court's order."
Charles Seife, a professor at New York University who acted as a plaintiff in the recent court case, said:
“I'm glad that this is happening, and it's a step in the right direction. But given how reluctant FDA has been to exercise its authority in this area, I'm not holding my breath until the agency starts actually enforcing its rules.”
Key takeaways from the new guidance
In an analysis, CenterWatch commented that:
“The guidance also covers those who submit false or misleading information to the database and allows for the possibility of civil injunction and/or criminal prosecution.”
“In addition to enforcing penalties, the FDA says it will post violators’ notices of noncompliance on its website and the National Institutes of Health (NIH) will upload them to CT.gov.”
“The agency began developing an enforcement mechanism for CT.gov noncompliance in 2016, prior to the issuance of a final rule from HHS that authorized monetary penalties, which it tested with a pilot program that notified 15 responsible parties of their violations, the FDA said. To date, all parties have complied.”
“Two weeks ago, the NIH issued a draft policy letter that calls on violators to submit their missing data from the years 2007 to 2017 ‘as soon as possible’ and mentions potential fines, although specific amounts were not addressed."
“The FDA will take a risk-based approach to investigating potential violations, focusing on trials of products that carry a high health risk or are intended to address a significant public health need; trials with a previous pattern of noncompliance; and those that also are in violation of other regulatory requirements for trial conduct.”
“In determining the amount of monetary penalties, the agency will take into account the ‘nature, circumstances, extent and gravity of the violation; the ability of the violator to pay or effect of the penalty on its ability to continue to do business; history of similar violations; and degree of culpability’.”
The FDA will in future take the following steps in issuing financial penalties, according to an analysis circulated to its subscribers by TrialScope, a company specialising in managing clinical trials disclosure for pharmaceutical companies:
1. The Center identifies a violation through the FDA’s Bioresearch Monitoring Program (BIMO) or based on the evaluation of complaints received by the Agency.
2. The Center will send the responsible party a Preliminary Notice of Noncompliance (Pre-Notice) Letter, which describes the potential violation and requests that the responsible party take any necessary actions to address the potential violation within 30 calendar days after receiving the letter.
3. Failure to comply with the requirements relating to applicable clinical trials may result in further regulatory action by the Center, including the issuance of a Notice of Noncompliance, civil money penalties, injunction, and/or criminal.
4. 30 days after issuing a Pre-Notice letter, the Center will follow up on the violation, and if it is determined that a submitter failed to submit the required certification to the FDA or knowingly submitted a false certification, the Agency intends to issue a Notice of Noncompliance to the submitter, giving the sponsor another 30 days to remediate.
5. The Notification of Noncompliance will be made publicly available on the agency’s website and transmit the Notice of Noncompliance to NIH so it can include the notice regarding noncompliance on ClinicalTrials.gov.
6. Failure to remediate the issues identified in the Notification of Noncompliance within 30 days means that the Center intends to seek civil money penalties, taking into account the type of noncompliance and the circumstances associated with the lack of remediation.
Thomas Wicks, Chief Strategy Officer of disclosure company TrialScope, commented:
"While the FDA has issued guidance on assessing civil monetary penalties relating to ClinicalTrials.gov, the emphasis is on encouraging rather than enforcing compliance. Although the regulation mandating clinical trial disclosure has been in effect for 13 years, some organizations continue to withhold data that should be made publicly available by law.
After all this time, everyone conducting clinical trials in the U.S. should be well aware of the regulations and have established the systems to ensure compliance. Perhaps because there are no fines or public notices, the immediate cost of noncompliance remains lower than the investment required to disclose the data, or the concerns about releasing competitive information.
However, being out of compliance with regulations can have long-term consequences. For commercial trial sponsors this can mean red flags for investors and due diligence issues during merger talks, while investigators may be unable to apply for grants. In any case, withholding information that should be made publicly available hurts patients, slows research, and affects the reputation of all organizations that conduct clinical trials.
Raising the cost of noncompliance through fines and public notices may change the calculus for those that are still withholding data in violation of the regulations."
In other news, a new study has found widespread inconsistencies between results reported on the U.S. national trial registry ClinicalTrials.gov and corresponding publications in medical journals.
The authors note that there still seems to be “poor knowledge of FDA and NIH reporting requirements” at many academic institutions and warn that their findings “underscore the necessity for monitoring for concordance of clinical trial information and results reported between these sources.”
The new FDA guidance document can be accessed here.