New report documents rampant research waste in Covid trials
Most clinical trials of potential Covid drugs have ended up as research waste, with delays in identifying effective treatments causing many patient deaths, a new report by Health Action International and TranspariMED concludes.
The report also warns that:
Some Covid vaccine trials run outside Europe and the United States had substantial transparency gaps
There is a lack of robust evidence on the benefits and harms of many non-pharmaceutical interventions such as school closures because of a lack of relevant trials
TranspariMED will serialise the report’s findings over the coming days. Today’s blog focuses on Covid drug trials only. Over the coming days we will cover trials of vaccines and non-pharmaceutical interventions, and the failure of trial registries to prevent research waste.
Early warnings about research waste
Experts have long warned that many clinical trials fail to meet basic quality standards and are therefore doomed to become research waste before they even begin.
These warnings were fully borne out during the ‘research chaos’ that erupted in the early months of the pandemic when hundreds of trials were hastily launched to evaluate whether existing drugs might be effective at treating patients with COVID-19, often by non-commercial sponsors with no prior experience of running trials of investigative medicinal products.
Experts warned at an early stage that rampant duplication of research efforts and weak trial designs doomed the overwhelming majority of Covid trials to end up as research waste before they had even started.
Drug regulators and the wider medical research community now concur that this proliferation of uncoordinated, unaligned, underpowered, and often badly designed trials of repurposed drugs constitutes a major collective failure of the global medical research enterprise during the pandemic.
Covid research chaos
The most notorious failure in this regard involved the drug hydroxychloroquine (HCQ). Early research (later criticised as flawed) indicated that HCQ might be an effective COVID-19 treatment. HCQ was already widely used for other indications, so many clinicians had access to the drug and promptly started administering it. During the first hundred days of the pandemic, 84 separate HCQ trials were registered worldwide.
Long before most of those small trials had been completed, strong evidence from two large high-quality trials showed that HCQ provided no benefit to COVID-19 patients. These HCQ trials were not an isolated case.
Overall, most COVID-19 drug trials focused on only a small number of treatment options, and many eventually ground to a standstill.
By October 2020, nearly a third of the 516 trials registered during the first hundred days of the pandemic had not recruited a single patient, and only 10% had made their results public. The limited outcome data that small single-center trials did generate could not easily be pooled for meta-analyses because of widely divergent standards of care, inclusion criteria, dosages, and outcome measures.
Role of regulators
Regulators worldwide failed to ensure that trials of potential repurposed drugs for the treatment of COVID-19 were adequately coordinated and well designed.
Notably, in some EU Member States, national drug regulators appear to have uncritically greenlighted multiple small COVID-19 drug trials without considering their potential to add scientific value.
During the first three months of the pandemic alone, 118 separate investigative drug trials testing potential COVID-19 treatments were registered across 14 EU Member States, each of them authorised by the national drug regulator of that country. A third of those trials were run by sponsors that had never before run an investigative drug trial, and nearly all of the remainder were run by sponsors with a track record of violating European trial reporting guidelines.
It appears likely that most investigative COVID-19 drug trials registered in the EU (and in virtually all other jurisdictions) eventually ended up as research waste.
Research into repurposed drugs appears to have been highly successful only in the UK (see the full report for a detailed discussion).
Global health impacts
The uncoordinated ‘research chaos’ surrounding potential COVID-19 treatments had a substantial negative impact on global health.
Many patients died because of delays in identifying effective treatments; only the UK’s RECOVERY trial (and to a lesser degree WHO’s Solidarity trial) prevented that death toll from becoming far worse. Also, considerable resources were wasted on ineffective treatments, and millions of patients were exposed to treatments whose benefit-harm balance was unclear.
For example, convalescent blood plasma, a treatment whose administration requires substantial human resources and entails significant costs, was given to an estimated 500,000 U.S. patients during the first year of the pandemic based on weak evidence. Due to lack of robust evidence from large trials, it long remained unclear to regulators and clinicians whether the treatment on balance benefited or harmed patients.
In December 2021, the WHO recommended against giving plasma to patients in standard care, while calling for plasma trials involving patients with severe Covid to continue. As of April 2022, more than two years since the start of the pandemic, plasma trials have still not delivered sufficient evidence for the WHO to come to a definite conclusion on the treatment’s merits for severely ill patients.
Impact on regulatory agenda
A journal article written by European regulatory staff in October 2021 illustrates that regulators are highly aware of the problems caused by “the fragmented nature of clinical trials [of repurposed drugs which were] often small, underpowered or with suboptimal design”. The paper concludes that:
“There is a need to support and enable rapid advice and approval of large, well-designed trials, including platform trials, that can provide the robust data needed to support decision making and demonstrate that new or repurposed medicines are safe and effective, whilst also refuting as early as possible those [trials] which are ineffective and or unsafe.”
“It is also key to establish the research investigator networks on a large, pan European scale with effective infrastructural support, to enable such large trials, whether private or publicly sponsored.”
Policy initiatives
There is now positive momentum towards strengthening the coordination of clinical research efforts and improving the quality of trials.
Within the EU, the recently launched multiyear ACT-EU initiative aims to improve trial coordination, promote better and larger multinational trials, streamline trial approval processes, and support academia with training. On a national level, the UK is currently reviewing its entire national trial portfolio to winnow out studies that are “struggling to deliver” and refocus resources on trials that are likely to add value.
Relevant global initiatives include the 2021 G7 ‘Clinical Trials Charter’. A draft proposal recently put forward by the UK and Argentina ahead of the 75th Global Heath Assembly on 22-28 May urges countries to improve the coordination of clinical trials, strengthen trial quality, avoid duplication of research, and take steps to promote trial registration and rapid results reporting. The proposal also requests the Director-General of the WHO to develop a corresponding draft action plan by 2023.
Recommendations
European Medicines Agency: Identify the gatekeeper responsible for preventing futile drug trials from being launched.
European Commission: Set up a working group to identify ways to curb research waste in clinical trials of medical devices and other non-drug trials.
Download the full report
Today’s report by Health Action International and TranspariMED can be read online or downloaded below.
For further reading, see the COVID-evidence team’s excellent studies on Covid trials and research waste.