Note: The following is adapted, with editing from TranspariMED, from the Discussion in Chapter 5 of Nicholas DeVito’s doctoral thesis. This chapter covers original research examining gaps in the implementation and enforcement of the FDA Amendments Act 2007.
Clinical trials are not abstract research projects: they are large, expensive, practical, and necessary evaluations that aim to directly inform clinical practice. Ensuring that sponsors are meeting their legal and ethical responsibilities is of paramount importance.
The FDA Amendments Act, which requires results of trials to be reported, has been US law for well over a decade and its Final Rule was implemented in 2017.
Each trial sponsor has had ample time to prepare to meet the requirements and yet over 24% of applicable clinical trials, 3,500 trials total, are currently still missing results.
Regulatory inertia at the FDA
The lack of any regulatory momentum around the enforcement of FDAAA has been an ongoing issue.
The delay in the final rulemaking can be seen as a symptom of an overall institutional lethargy in ensuring the transparency goals of the FDAAA were being met.
Even after the Final Rule finally came into effect it took over three years for the FDA to announce an official enforcement strategy. The proposed process required multiple rounds of notifications before sanctions are considered.
The FDA claims they monitor compliance through the Bioresearch Monitoring Program. This links enforcement of FDAAA to a program described in the guidance as “associated with the submission of a research or marketing application or…the Agency’s investigation of a complaint.”
This process has been slow and ad hoc, with no comprehensive strategy for compliance monitoring across all sponsors.
Impact of past FDA enforcement
In April 2021, the first official “Notice of Noncompliance”, the final warning for sponsors to comply within 30 days or face potential monetary sanctions, was sent to Acceleron, a small biotech company, for their failure to report a drug trial that was nearly three years overdue.
In the FDA’s statement about the letter they divulged publicly, for the first time, that only ~40 pre-notices of non-compliance have been sent over the life of the FDAAA despite thousands of overdue trials appearing just since the advent of the Final Rule.
The trial in question was already two years past due at the time of Acceleron’s pre-notice and the FDA waited an additional eight months to send the Notice of Non-compliance.
Acceleron quickly complied by submitting results the very next day.
I downloaded TrialsTracker data in June 2021 following the Acceleron letter and in the week following the Notice of Noncompliance, 91 trials newly reported results representing the highest weekly total ever. This began a sudden surge in reporting, as four straight weeks reached the level of ≥70 trials reports submitted, a level only rarely seen prior to the Acceleron letter.
Though the reporting levels quickly returned to normal, the burst in reporting around discrete enforcement activity, combined with the rapid reporting of all sponsors receiving a letter, shows the promise of more active enforcement.
However, to date, the FDA has issued a total of only four “Notices of Noncompliance”.
Additional research on the FDA’s actions under FDAAA is currently underway alongside calls for increased enforcement activity for non-compliant sponsors.
FDA options for strengthening compliance
The entire FDAAA TrialsTracker project is proof-of-concept that comprehensive monitoring can be established as a means to provide early warning to potential non-compliant sponsors.
This system can also aid in prioritising enforcement better than seemingly random and inconsistent inspections based on unrelated complaints or issues.
While the FDA treats the question of applicable trial status as a “complex legal question” requiring individual consideration, compliance can be encouraged even before investigation into individual trials.
The probable impact of more proactive and widespread FDA enforcement cannot be understated.
Even a decade after FDAAA, some institutions remain unclear about their responsibilities under the law.
Rapidly encouraging voluntary compliance at scale, perhaps first through preliminary reminder letters prior to any official notification, could be a powerful proactive tool to improve reporting in the hands of the FDA.
This is consistent with prior work showing that reminders can increase reporting. This would also meet the FDA’s stated goals to improve voluntary compliance with the law without resorting to enforcement action.
The guest blog above was contributed by the creator of the FDAAA Trials Tracker, Nicholas DeVito from the University of Oxford. It is an edited and updated extract from his PhD thesis on “Trial Registries for Transparency and Accountability in Clinical Research” (section 5.7.4: Implications for Policy and Practice). Please refer to the original thesis for references.