Guest blog: Regular audit cycles could improve data on European clinical trials
Note: The following is adapted, with editing from TranspariMED, from the Discussion in Chapter 6 of Nicholas DeVito’s doctoral thesis. This chapter includes original research assessing the quality and availability of data on the EU Clinical Trials Register.
Providing accurate data to the European Clinical Trial Register (EUCTR) fulfils both ethical and legal obligations.
As a primary member of the WHO International Clinical Trial Registration Platform, the EUCTR commits to “make all reasonable efforts to ensure that the data registered is complete, meaningful, and accurate.”
Chaos on the European trial registry
Sadly, the actual performance of the European trial registry falls short of this commitment.
Conflicting information on trial completion and over three thousand missing results create additional burden for users in analysing, interpreting, and acting on data from the registry.
Missing public registrations may also complicate publication for researchers who rely on the EUCTR to satisfy journal requirements for prospective registration, further undermining confidence in its use.
When regulators cannot ensure basic record-keeping requirements are fulfilled, it undermines trust in their other capacities.
The information pipeline between trial sponsors, national regulators, and the EUCTR appears to have been disrupted across multiple countries including the Netherlands, which is now home to the European Medicines Agency.
It is unclear whether these issues originate with the regulators, sponsors, or some combination of both.
Other anomalies exist, for instance, it would appear impossible that Romania - the 6th most populous country in the EU - only approved 239 clinical trials through 2020 since entering the Union in 2007. A search of ClinicalTrials.gov for interventional drug trials in Romania first registered over the same period returns >1900 records as of March 2022.
End of trial documentation is required as part of the EU regulatory process, but it is difficult to know whether the gaps I documented originate with sponsors failing to submit the necessary paperwork or regulators failing to act on paperwork after it is provided – either would be concerning.
In the best-case scenario, the proper paperwork is archived with regulators but has simply not been acted upon.
Need for regular audit cycles
Addressing these issues could be rectified through improved record-keeping efforts.
Regular audit cycles from both national regulators and the EMA, like the analyses presented here, would allow for timelier follow-up of missing information from either sponsors or national regulators.
While failure to provide results information ultimately falls to trial sponsors, since they upload results directly to the EUCTR, regulators can play a more active role in promoting and following-up on reporting as envisioned by the guidelines.
Extrapolating the rates of non-compliance found through manual searches to the entire population of trials that either are, or are very likely to be, completed suggests thousands of additional trials may be unreported beyond those already documented on the EU TrialsTracker.
For many of these trials, the EUCTR would represent the first, and often only, place that results would appear.
Improving results reporting
While the European Medicines Agency has conducted some outreach on reporting, national regulators may be better positioned to act within the local regulatory context.
The Austrian regulator conducted sponsor outreach concerning the results reporting requirements and has seen subsequent increases in results submissions. The UK regulator’s work to address issues has been documented and could aid other national authorities in understanding how their processes could be improved.
Ultimately, flexibility in working with sponsors outside rigid bureaucratic rules, especially in rectifying data from very old trials, may be warranted to improve data quality on the EUCTR.
To date, the pre-Brexit UK parliament has been the only government to directly pressure sponsors to report results under EU guidelines, with notable success.
This may change as new EU regulations are phased into effect through 2025. The new regulations include provisions that specifically empower EU member states to implement sanctions for non-compliance.
Denmark and Belgium have already implemented policies targeting non-reporting sponsors under these provisions.
EUCTR remains relevant
The new CTIS trial portal launched in January 2022, but the EUCTR should not be neglected as an important source of clinical trial information.
The corpus of registered trials from 2004 through the phasing out of new EUCTR registrations in 2023 contains information on thousands of trials of treatments in wide use today.
The EUCTR is, and will long continue to be, an important source of information about clinical trials.
In one recent example, two controversial Phase 3 trials for the Alzheimer's treatment aducanumab did not have to be reported under the FDAAA 2007 until after they received their approval in June 2021.
The drug’s maker, Biogen, submitted results to ClinicalTrials.gov that month but they did not become public until September 2021. Results were published in the literature in March 2022.
However, both trials had detailed results available on the EUCTR (2015-000966-72, 2015-000967-15) by November 2020 since no delays for results of unapproved therapies exist under EU regulations.
The guest blog above was contributed by the creator of the EU 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 6.7.4: Implications for Policy and Practice). Please refer to the original thesis for references.