Why did clinical trial registries fail to prevent Covid research chaos?
During the pandemic, trial registries completely failed to deliver on their promise of supporting effective global research coordination.
When the pandemic struck, researchers around the world looking for effective treatments for Covid rapidly launched hundreds of small, weakly designed, and badly aligned trials.
Most Covid drug trials did nothing to advance patient care and eventually ended up as costly research waste.
Note: This blog is part of a series presenting findings of a recent report by Health Action International and TranspariMED. A previous blog discussed Covid research waste. Future blogs will discuss the transparency of Covid trials, and the paucity of trials of non-pharmaceutical interventions. The full report can be downloaded below.
Why did trial registries fail to deliver?
In theory, a key benefit of trial registries is their potential to prevent exactly the kind of research chaos that ensued during the pandemic.
There is a long-standing global ethical obligation to register all trials before they start, shored up by regulatory requirements in some jurisdictions. Data from 18 registries worldwide feed into the WHO-managed International Clinical Trials Registry Platform (ICTRP), providing a continuously updated overview of who is researching what, when, where and how – at least in theory.
If the registry infrastructure had worked and been used as intended, much of the COVID-19 research chaos would have been avoided.
For example, researchers considering launching a hydroxychloroquine trial could have searched ICTRP and discovered that the drug was already being investigated by numerous other trials. Those researchers could accordingly have focused on investigating other treatment options instead, or aligned their outcome measures with existing trials.
Trial registries also offer the option of rapidly uploading summary results once a trial has been completed, offering the opportunity to make outcome data public at speed, open access and easy to find.
So what went wrong?
The global registry infrastructure has long been inadequately supported by legislators and regulators, and is woefully underfunded.
This persistent neglect of the world’s only comprehensive directory of medical research led to costly research waste on an incredible scale during the pandemic.
The WHO recommends that member states should by law require every interventional trial to be registered and reported. In addition, WHO recommends that all trial results should be made public specifically on a registry within 12 months, and that registry data should be kept up to date.
By enforcing these three simple rules, regulators would ensure that there is a comprehensive, up-to-date global database of all trials and their results.
In reality, existing laws in the EU and the US only cover a small minority of trials and are not being effectively enforced, while many other jurisdictions have no relevant laws at all.
(The UK is the only country worldwide that currently has comprehensive legislation in the pipeline.)
Much registry data continues to be entered by untrained individual researchers with no effective institutional or regulatory oversight.
Due to this long-standing legislative and regulatory neglect, many trials are never registered, around half of all trials never make their results public in any form (let alone on a trial registry), and registry data are often incomplete, inconsistent and out of date.
Gaining a comprehensive, reliable, and up-to-date overview of all clinical trials and their results is thus impossible.
For example, out of 3,754 pre-pandemic trials of 19 potential COVID-19 (repurposed) drugs, 40% had never made their results public in any form when the pandemic hit.
Underfunding of the WHO data hub
During the early days of the pandemic, the WHO’s perennially underfunded ICTRP registry hub crashed due to its inability to handle the massive increase in traffic - at the very moment when real-time access to the only available map of global research efforts was most important.
ICTRP for several months was unable to provide users with real-time access to its data, instead making weekly updates available for download.
More broadly, the world’s only global trial registry hub should be expected to contain a management information system and dashboard that synthesises actionable ‘big picture’ information that is vital to aligning global research efforts. For example, such a dashboard should have included breakdowns of the status, outcome measures, and inclusion- and exclusion criteria used by every hydroxychloroquine trial involving Covid patients.
In reality, ICTRP only has basic search and filter functions, making it necessary to aggregate such data manually, which cannot be done in real time. It required the combined efforts of 19 researchers just to compile a basic overview of the key features of all trials launched during the first hundred days of the pandemic because the process was so laborious and time-consuming.
Underfunding of trial registries
The global ICTRP hub can only be as good as the data it receives from its 18 contributing registries.
Some of those registries are perennially underfunded, have a dismal infrastructure and extremely limited IT support, and appear to lack even basic quality control mechanisms.
For example, the Dutch registry’s design is extremely basic, the Indian registry reportedly only receives IT support once a year, and the European EudraCT and CTIS registries and the German DRKS registry sometimes include entries that are not in English, making systematic searches using key terms difficult.
Frequently, these registries feed incomplete registrations into the global system that lack even basic data, such as the identity of a trial’s sponsor or the treatment being investigated.
Research has repeatedly documented widespread inconsistencies between data for identical trials listed in two or more different registries.
The American ClinicalTrials.gov registry alone seems to meet high quality standards, combining a structured tabular summary result function with quality assurance through manual expert review of results submitted.
The adoption of simple features such as automated emails to remind researchers to upload their trial results could significantly improve the global medical evidence base.
Underuse of registry reporting
Due to lack of legal requirements and regulatory engagement and enforcement, researchers still do not habitually upload or link all trial results on registries.
Thus, locating the results of all relevant clinical trials requires time-consuming manual literature searches that sometimes miss relevant publications, undermining rapid evidence syntheses.
There were some cases during the pandemic where researchers – apparently unaware of the option of sharing results through trial registries – complained about difficulties in rapidly getting their results published in journals and instead took to social media.
Policy initiatives
The urgent need to strengthen the global registry system and its 18 constituent registries has so far not made it onto the wider policy agenda.
However, there are currently several developments within the European Union – a major data contributor to ICTRP – that will influence the completeness and robustness of medical evidence on trial registries for many years to come.
EudraCT registry
The Heads of [National] Medicines Agencies in Europe appear to have walked back on a 2021 commitment to encourage and support the reporting of over 3,400 overdue trial results on EudraCT.
While the European Medicines Agency itself and several national regulators have made significant efforts to address this issue, often with considerable success, some regulators (notably in France and Italy) have yet to take action. Unless action on these data gaps is taken soon, the results of many clinical trials will be lost forever.
Clinical Trial Information System registry (CTIS)
The new European trial registry CTIS, launched in February 2022, has additional functionalities and transparency features. The EU Clinical Trial Regulation, which also became applicable in February 2022, gives legal force to a maximum 12 month reporting timeframe for all new clinical trials of investigative medicinal products registered on CTIS.
In the runup to the launch, the EMA put considerable effort into preparing trial sponsors for the new registry, which will hopefully improve voluntary compliance. However, if and when violations occur, it remains to be seen whether EU Member States will enforce their national laws effectively.
Medical device trials
The EU Medical Device Regulation, incoming in May 2022, does not require clinical trials of medical devices to be registered on an ICTRP-linked registry, and does not require the results of all medical device trials to be made public on an ICTRP-linked registry.
While some medical device trials will have to be entered into the new European EUDAMED database, EUDAMED is not linked to the WHO’s global trial registry network; this could lead to a fragmentation of the global evidence base for medical devices.
Recommendations
The European Commission can and should address these problems:
Clearly communicate to the Heads of Medicines Agencies and the governments of EU Member States the expectation that national regulators will initiate efforts to address the backlog of missing drug trial results on EudraCT (as recently demanded by Members of the European Parliament and civil society), and going forward will effectively enforce drug trial reporting timeframes on CTIS.
Install automated safeguards in the EUDAMED medical device database to ensure that clinical trials of medical devices can only be entered into EUDAMED once they have obtained a registration number from an ICTRP-linked global trial registry, and explore options for using EUDAMED functionalities to encourage – and ideally de facto necessitate – the reporting of trial results on an ICTRP-linked registry.
Download the full report
The full report by Health Action International and TranspariMED from which this blog was extracted can be downloaded below.
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