A missing clinical trial result was made public the day after the US Food and Drug Administration sent a warning letter to an academic investigator, records show.
The speedy response highlights that action by regulators is key to filling gaps in the medical evidence base.
FDA WARNING HAS IMMEDIATE IMPACT
On 31 August, the FDA sent a letter to the principal investigator of a trial evaluating a novel postoperative pain regimen, giving him 30 days to upload the results of the trial or face a fine of $10,000 for every day the results remained missing from the ClinicalTrials.gov trial registry.
The following day, registry records show, the researcher uploaded the results.
FIRST EVER ACADEMIC TRIAL TARGETED BY FDA
The is the first time that the FDA has issued a “letter of noncompliance” over a missing academic trial result, STAT News reports.
The move is likely to send a shock wave through American universities and research institutions.
While many of the major players have joined a dedicated taskforce and worked hard to achieve legal compliance in recent years, latecomers are now suddenly exposed to considerable legal, financial and reputational risks. Legal reporting requirements do not cover all trials, and a widely used tracking tool only identifies applicable trials completed in recent years, so institutions will have to carefully audit their entire portfolios to identify potential risks.
HOW DOES THE FDA ENFORCEMENT PROCESS WORK?
Thousands of clinical trials are still missing results in violation of the 2007 FDA Amendments Act. It is unclear how the FDA decides which violators to actively pursue, and how many investigators, institutions and companies it has put on notice so far.
The FDA previously told journalists that it “uses a risk-based approach to determine the situations in which Pre-Notices of Noncompliance will be issued,” but did not provide further details.
According to the FDA, “the vast majority of recipients of pre-notices have taken voluntary action to address the issues of noncompliance” after being contacted. This raises the question why the FDA does not scale up its outreach efforts and finally put an end to the long-running scandal of hidden clinical trial results, which have left medical evidence gaps that have harmed patients and taxpayers for many decades.
INDIVIDUAL INVESTIGATOR IN FDA CROSSHAIRS
The subject of the FDA’s warning letter, trial NCT03052816, was completed in 2018, and by law its results should have been uploaded to the registry within a year. The FDA presumably contacted Andrey Petrikovets, the principal investigator, because he is listed in the registry as the “Responsible Party” for the trial even though University Hospitals Cleveland Medical Center had acted as its sponsor.
The FDA’s letter states that:
“[Y]ou responded stating that you were very busy with the ‘Covid surge’ and were short staffed. Although we recognize the unique circumstances that the pandemic presents, we believe we have provided you ample opportunity to submit the required results information. (…)”
“If you do not submit the required clinical trial results information… within 30 calendar days after receiving this Notice, FDA may also seek… a civil monetary penalty of not more than $10,000 for each day of the violation after such period until the violation is corrected.”
While Petrikovets had published the results in a medical journal in 2019, this does not meet the US legal requirement of uploading the results in tabular format onto the publicly managed registry. Trial outcomes published in journals frequently omit important information or even misrepresent outcomes. (Petrikovets himself is not suspected of omitting or misrepresenting any data.)
Approached for comment on Wednesday, Petrikovets – who now runs a private practice – emailed TranspariMED that “I have completed everything as asked already and sent it back last week.”
CLEVELAND MEDICAL CENTER RESPONDS
The trial’s sponsor, University Hospitals Cleveland Medical Center, has hosted numerous trials that violate legal transparency requirements.
According to the FDAAA Trials Tracker, the center has a reporting rate of just 21%, performing far worse than many of its peers. At least ten more of Cleveland-sponsored completed trials are missing results on the registry in apparent violation of the law, including multiple trials of opioids and a trial involving children with Down Syndrome.
University Hospitals Cleveland Medical Center issued the following statement:
“Individual principal investigators are responsible for updating the information. Dr. Andrey Petrikovets reports to have corrected the information last week and FDA has acknowledged receipt of the information. The doctor is no longer affiliated with University Hospitals.”
“We follow-up with researchers if we find that they are out of compliance with reporting data for their studies. We provide detailed instructions on how to correct the records if they are unsure.”
“As an academic medical center with a large research portfolio, we take compliance issues seriously and work with our researchers to have them meet their requirements. UH conducted more than 150 research studies related to COVID-19 during the pandemic, including being selected as trial site #1 for remdesivir as well as trials for the Pfizer vaccine. That the leading pharmaceutical and medical device manufacturers in the world trust UH with their clinical trials testifies to the success of our program in the critical performance areas of quality, documentation and timely completion. To state or imply otherwise would be grossly inaccurate.”
(TranspariMED comment: We expect institutions to ensure that medical research conducted under their auspices complies with the law.)
IMPACT ON EUROPEAN ENFORCEMENT EFFORTS
The FDA’s recent enforcement actions and their positive impact are likely to embolden European medicines agencies to take similar steps.
Comparable clinical trial reporting requirements have long been in place in the European Union, and they will become legally binding in all member states on 31 January 2022. Enforcement rests with national medicines regulators in each country.
Germany’s main regulator BfArM recently disclosed that it contacted over a thousand German trial sponsors about missing results in 2020. (The second German regulator – Paul Ehrlich Institut – appears to still be ignoring the problem.) The Austrian regulator plans to contact sponsors soon. The Danish regulator has announced that it will take persistent violators to court and possibly seek prison sentences in addition to fines.
In June 2021, the umbrella body of national regulators in Europe announced that it will support its members’ efforts to improve compliance with the rules.
Till Bruckner, founder of TranspariMED, said:
“Finally, after decades of dithering by regulators, there is light at the end of the tunnel for patients in America and Europe. The long overdue shift from empty talk about ‘voluntary compliance’ to enforcement action has begun."
"Now, the only open question is how much longer patients will have to wait until regulators shift their pace from crawling to running, and finally get this problem fixed once and for all.”