key: cord-0859740-cpp0re3c
authors: Janiaud, Perrine; Hemkens, Lars G.; Ioannidis, John P.A.
title: Challenges and lessons learned from Covid-19 trials – should we be doing clinical trials differently?
date: 2021-05-30
journal: Can J Cardiol
DOI: 10.1016/j.cjca.2021.05.009
sha: f28c4f1cc23aa7bb310f1c854180554c24d7bce3
doc_id: 859740
cord_uid: cpp0re3c

The COVID-19 crisis led to a flurry of clinical trials activity. The COVID-Evidence database shows 2,814 COVID-19 randomized trials registered as of February 16, 2021. Most were small (only 18% have a planned sample size >500) and the rare completed ones have not provided published results promptly (only 283 trial publications as of 2/2021). Small randomized trials and observational, non-randomized analyses have not had a successful track record and have generated misleading expectations. Different large trials on the same intervention have generally been far more efficient in producing timely and consistent evidence. The rapid generation of evidence and accelerated dissemination of results have led to new challenges for systematic reviews and meta-analyses (e.g. rapid, living, and scoping reviews). Pressure to regulatory agencies has also mounted with massive emergency authorizations, but some of them have had to be revoked. Pandemic circumstances have disrupted the way trials are conducted; therefore, new methods have been developed and adopted more widely to facilitate recruitment, consent, and overall trial conduct. Based on the COVID-19 experience and its challenges, planning of several large, efficient trials, and wider use of adaptive designs may change the future of clinical research. Pragmatism, integration in clinical care, efficient administration, promotion of collaborative structures, and enhanced integration of existing data and facilities may be several of the legacies of COVID-19 on future randomized trials.

The COVID-19 pandemic has led to an unprecedented volume of clinical trials being initiated. We provide an overview on the wide spectrum of the COVID-19 clinical research agenda, its successes and pitfalls, the lessons learned and their impact on the future of clinical trials beyond COVID-19.

The COVID-19 crisis led to a flurry of clinical trials activity. The COVID-Evidence database shows 2,814 COVID-19 randomized trials registered as of February 16, 2021 . Most were small (only 18% have a planned sample size >500) and the rare completed ones have not provided published results promptly (only 283 trial publications as of 2/2021). Small randomized trials and observational, non-randomized analyses have not had a successful track record and have generated misleading expectations. Different large trials on the same intervention have generally been far more efficient in producing timely and consistent evidence. The rapid generation of evidence and accelerated dissemination of results have led to new challenges for systematic reviews and meta-analyses (e.g. rapid, living, and scoping reviews). Pressure to regulatory agencies has also mounted with massive emergency authorizations, but some of them have had to be revoked. Pandemic circumstances have disrupted the way trials are conducted; therefore, new methods have been developed and adopted more widely to facilitate recruitment, consent, and overall trial conduct. Based on the COVID-19 experience and its challenges, planning of several large, efficient trials, and wider use of adaptive designs may change the future of clinical research. Pragmatism, integration in clinical care, efficient administration, promotion of collaborative structures, and enhanced integration of existing data and facilities may be several of the legacies of COVID-19 on future randomized trials.

The COVID-19 pandemic has required an ultra-urgent response to generate evidence to handle a major public health crisis. Effective treatments, vaccines, and other measures were important to develop, test, and implement as quickly as possible. An unprecedent number of randomized controlled trials (RCTs) assessing therapeutics for COVID-19 were initiated, and to a lesser extent for preventive measures, in particular vaccines (1, 2) . For many other influential decisions, e.g. non-pharmaceutical interventions, evidence sadly depended almost exclusively on precarious modeling and observational data (3) . Here, we review the challenges of and what we have learned from the COVID-19 clinical research agenda in the first 14 months of the pandemic and how we can put this knowledge to good use moving forward. The lessons learned are potentially important not only for COVID-19, but, perhaps most importantly for the future of RCTs in any area.

In March 2020, the COVID-evidence database (www.covid-evidence.org) was launched with the aim to gain insight on the COVID-19 clinical research agenda (4) . Using a multi-method approach combining peer-reviewed search strategies of study registries and publication databases, continuous automated extraction of search results, automated classifications combined with manual screening and data extraction, and quality control through expert review, it provides information about worldwide planned, ongoing, and completed RCTs on any intervention to treat or prevent SARS-CoV-2-infection. In the first 100 days of the pandemic, over 500 RCTs had already been registered on ClinicalTrials.gov and the World Health Organization International Clinical Registry Platform. The vast majority assessed interventions for treating patients with COVID-19; conversely only 11% focused on interventions to prevent COVID-19 and none assessed social distancing or lockdown measures. RCTs were mostly small and often investigated the same interventions (1) . Similar observations were made in other reviews of early registered COVID-19 RCTs (5-10). While these clinical research efforts were much needed, the excessive duplication of efforts and lack of collaboration in the early COVID-19 clinical research agenda was putting it at risk of creating research waste (11) characterized by unnecessary duplication of trials, poor study designs, and insufficient reporting of results.

The cumulative number of RCTs registered has steadily increased ( Figure 1A) , with a total of 2,814 RCTs included in COVID-evidence as of February 16, 2021. Of note, the monthly number of RCTs registered has been slowly decreasing after a peak in the number of registrations in April 2020 (n=592, Figure 1A ). Although the clinical research agenda was initially largely dominated by trials conducted in Asia (mostly China), by March 2020 the number of trials registered in the rest of the world quickly increased following the spread of the pandemic ( Figure 1B ). Most trials have continued to be small ( Figure 2 ) with only 18% of the RCTs planned to include over 500 participants. Treatment with hydroxychloroquine was explored by a total of 304 RCTs out of 2,814 RCTs (in the first 100 days, every 1 in 6 RCTs looked at this intervention). The results from RECOVERY showed no clinical benefit (12) and a meta-analysis showed an association of hydroxychloroquine with increased mortality (13) . However, an additional 60 RCTs were registered after the RECOVERY trial press release (14) . Overall, as of 2 March 2021, there are 6 drug treatments (remdesivir, COVID-19 convalescent plasma, bamlanivimab, baricitinib in combination with remdesivir, casirivimab and imdevimab, and bamlanivimab and etesevimab) with Emergency Use Authorizations (EUAs) by the Food and Drug Administration (FDA) (15) and only 1 (remdesivir) with a conditional marketing authorization by the European Medicine Agency (EMA) (16) .

Drug development is a long and costly endeavour, antinomic to the urgent need of finding therapeutics for an acute pandemic. Therefore, the vast majority of RCTs focused on testing the repurposing of already existing drugs that had been already approved or had been under investigation for other indications(17) ( Table 1 ). This is based on the assumptions that there is substantial evidence on the efficacy and safety of these drugs (18) . However, a review focusing on the reporting of clinical results for 19 potential COVID-19 drugs showed that 40% of the completed trials assessing those drugs, prior to the pandemic, did not report their results on ClinicalTrials.gov or in the scientific literature (18) . For hydroxychloroquine, 37% of the trials were unreported.

Since the beginning of the pandemic, the most pressing clinical question has been -'how do we prevent deaths?'. However, it has been previously shown that only 15.8% of registered RCTs assessing a treatment intended to use mortality as a primary endpoint (1). A commonly reported endpoint identified is the use of ordinal scales (19) ; the most common one being a 7-point ordinal scale (1.Death, 2.Hospitalized on invasive mechanical ventilation or Extracorporeal Membrane Oxygenation, 3.Hospitalized,on non-invasive ventilation or high flow oxygen 4.Hospitalized requiring low flow supplemental oxygen, 5.Hospitalized not requiring supplemental oxygen requiring ongoing medical care(COVID-19 related or otherwise), 6.Hospitalized not requiring supplemental oxygen no longer requiring ongoing medical care, and 7.Not hospitalized). Although ordinal scales have the advantages to be able to capture multiple clinical states ranging from cure to death and to gain in statistical power, (20) there is a substantial lack of harmonization in the usage of ordinal scales in COVID-19 trials with heterogenous point systems and definitions (21) . Several initiatives have been implemented to develop core outcome sets but their impact have yet to be assessed (22) .

Another predominant issue is the representativeness of the patients included in the COVID-19 clinical research agenda. An early review assessing 12 published RCTs showed that the median age of the included patients was 56.3 years and most exclusions were based on comorbidities significantly more prevalent in patients  65 years old, highlighting the under-representation of the elderly (23) although they are 30-100 times more likely to die (24) . Of note, the extraordinary role of RECOVERY is reflected also by its representativeness with about 20% of the patients aged 80 and older (12, 25, 26) . Elderly people have always been less likely to be included in RCTs of diverse conditions (27,28) and it is unlikely to be different in the COVID-19 era. The issue is more severe for COVID-19 trials and the under-representation may be worse for elderly who are also frail. Frail nursing home residents accounted for large proportion of deaths in most European countries and the USA (29), but were not represented properly in either therapeutic or vaccine trials. Other reviews have highlighted the lack of inclusion of pregnant and lactating women, and children (30). In addition, the fatality rate is higher in males compared with females (31), yet early publications did not consistently report results stratified by sex (32).

Trials assessing drugs for treating COVID-19 have clearly dominated the clinical research agenda since the beginning of the pandemic (1, (5) (6) (7) 9, 10) . Conversely, very little to no data exist regarding non-pharmaceutical measures to help prevent COVID-19, such as for example the use of masks (33) or school closures (34).

The search for a vaccine was another cornerstone of the strategy against COVID-19. As of mid-February 2021, there were 175 vaccine RCTs registered planning to include 899,808 participants (Table 1) . Vaccines trials represented 6.2% of the clinical research agenda compared with 10.8% for hydroxychloroquine trials but included twice as much participants (899,808 versus 436,403 participants, respectively). Nineteen of the registered RCTs had a publication. Despite the unprecedented speed of the clinical research agenda, it resulted in only very few authorized vaccines: Pfizer-BioNTech, Janssen and Moderna vaccines obtained EUAs by the FDA (15) and by the EMA (16) while the AstraZeneca vaccine was authorized only by the EMA.

Poorly designed and reported studies have always been symptomatic of research waste (35) but with the duplication of many small studies during the pandemic the phenomenon has aggravated.

Based on the information in clinical trial registries, as of mid-February 2021, 168 of 2,814 registered RCTs (6%) were listed as being completed and 41 (1%) as terminated early. Of note, only 14 RCTs had results posted in the registry. Delays in the research agenda have been observed impacting its potential to deliver much needed evidence (2). Since registries may be not consistently updated, it is important to acknowledge that some more trials have been completed.

The COVID-evidence database also contains 283 publications of RCTs reporting results; 171, of which were linked to a registered RCT. In-depth evaluation was conducted for 50% of them (141/283), randomly selected: 73% (103/141) seemed to have completed the planned protocol, 19% (27/141) were terminated early , and 8% (11/141) were ongoing and presenting preliminary or arm-specific results. Out of the 27 trials terminated early, the most common reasons, among others, were enrollment difficulties with a decrease in number of cases (n=13), futility (n=5) and emergence of new evidence (n=5).

The COVID-19 experience has informed some of the long-standing debates about the optimal design and conduct of an RCT agenda. The key lessons learned are summarized in Box 1.

Traditionally, most medical decisions in the past have been informed from results of mostly small trials. Large trials have been uncommon. While large trials were deemed desirable, and calls for large, simple trials were made decades ago (36), their conduct has been increasingly perceived to be difficult, requiring a long time to recruit and achieve sufficient follow-up. The choice of small trials has also generated high dependence on surrogate and composite outcomes rather than on simple, clinical endpoints that truly matter. During the COVID-19 pandemic, however, our cumulative experience shows that the paradigm of large, definitive trials can work and can provide rapid evidence on outcomes that matter.

Conversely, it is questionable whether much was learned from the many hundreds of small trials that were initiated. Most of these small trials are underpowered to generate any results in a time frame that would be deemed useful for dealing with the pandemic, and many may never generate any worthwhile results or may even be abandoned because of futility. Small trials seem to have disadvantages at multiple fronts, including those previously perceived as potential advantages. Not only is their outcome selection and pragmatism questioned, but also the timing for accumulating robust evidence from multiple small trials can be actually slower than the timing of a large trial. Small trials and their meta-analyses have led to misleading inferences in the past in fields that had the benefit of conducting also large trials, e.g. cardiovascular medicine. Interventions like magnesium in myocardial infarction offer cautionary tales (37). The COVID-19 experience reinforced the need for timely, large trials.

In the last decade, there has been a major push to promote the use of observational data for obtaining large-scale, so-called real-world evidence in a timely fashion for comparative effectiveness questions. This trend has been questioned as to its validity by some methodologists and some empirical data (38) , but has been heavily endorsed by many proponents. The track record of non-randomized clinical trials and of observational datasets analyses of effectiveness during the pandemic has been rather disappointing with regard to providing reliable evidence. This is reminiscent of past disappointments with high-profile observational data refuted by mega-trials in cardiovascular medicine and other fields (e.g. hormone replacement or vitamin E) (39) .

For example, in August 2020, the FDA issued an EUA for convalescent plasma for the treatment of hospitalized patients with COVID-19 in a situation without sound randomized trial evidence (40) but with observational data from over 35000 patients published as a preprint (41) . Interestingly, within 5 months, large-scale randomized evidence contradicted not only the beneficial results of this analysis but also many of the perceived limitations made in the preprint against conducting RCTs in the pandemic situation to assess plasma. The large RECOVERY trial published results for the convalescent plasma arm in January 2021, showing the clear feasibility to randomize 10,406 patients and showing no benefit on mortality (42) .

Similarly for hydroxychloroquine, numerous very large observational studies contributed to high expectations but were contradicted by subsequent randomized evidence. The lowest point was the rapid publication and retraction of data from a largescale observational analysis (43) that apparently was entirely fake (44) . Faking large-scale observational data is "easier" than faking an equivalent-size RCT, as illustrated by the former example and the fact that large-scale clinical trials have typically much stronger oversight, by regulators and independent monitoring committees.

Of note, some very small randomized trials also suggested potential benefits, e.g. for convalescent plasma. It is unknown whether this may reflect chance findings, especially with surrogate outcomes and superimposed selective reporting or publication. Sadly, there is some evidence from the pre-COVID-19 era that a large share of small RCTs, perhaps the majority, from some jurisdictions may be "zombie trials" as their data suggest fraud and/or are implausible (45, 46) . With an increasing number of RCTs done in jurisdictions without strong clinical research tradition and with weak oversight, these problems may become more prominent.

At the same time, non-randomized evidence is likely to continue to be extremely important for mapping adverse events for licensed interventions when these are applied widely in the community, outside a trial setting and when long-term follow-up is afforded. This is particularly relevant for urgently authorized vaccines. A challenge with emerging observational data on harms is that the evidence-base is often fluid, changing, and open to different interpretation by regulatory agencies, as in the case of adverse events from the Astra-Zeneca (47) and Janssen vaccines (48) . Uncertainty and lack of harmonization may contribute to skepticism and vaccine hesitancy. Now, with the approval of the first vaccines, placebo-controlled trials are considered unethical (49) and alternative designs using sound causal inference methods are required such as for example non-inferiority randomized trials (50) or randomized vaccination rollout (similar to an individual stepped wedge design) once vaccines have been approved (51) . However, placebo-controlled trials may become again possible or even necessary in the future, if new, relevant questions arise, e.g. the speculated need for a third dose of vaccination.

While large RCTs seem to be the solution in the COVID-19 pandemic, we have to be cautious to avoid claiming that they are always correct. Large RCTs can have their own shortfalls. For example, they may include multiple sites, some of which are inexperienced and thus get unreliable results impacting the final result for the entire trial (52) . Moreover, they may not be able to examine sources of potential heterogeneity (e.g. different dose or timing of the intervention) that would be provided when the same sample size comes from several trials that are combined in a meta-analysis.

It is thus useful to have more than just one large trial. For COVID-19, this was the case in many circumstances. COVID-19 has also led to rethinking the role, conduct and dissemination of systematic reviews and meta-analyses. With the rapid evolution of the emerging evidence, many traditional systematic reviews and meta-analyses are at risk of being outdated before being published. Rapid reviews, scoping reviews, and living reviews are becoming increasingly popular (53) (54) (55) (56) , very large numbers of such evidence syntheses were undertaken and published very quickly.

In addition, many systematic reviews have been conducted on observational studies often concluding that RCTs are needed to confirm the observed results. Such as, for example, the systematic reviews on physical distancing, face masks, and eye protection to prevent COVID-19 which provided evidence graded as "moderate certainty" for social distancing and "low certainty" for the others (57). More robust randomized evidence is still lacking and is needed to confirm the observed associations.

The COVID-19 clinical research agenda was triggered by the urgent need to determine effective therapies; nevertheless, most potential therapies were evaluated in small two-arms trials rendering the process extremely inefficient. Adaptive platform trials give the opportunity to simultaneously assess multiple interventions all the while allowing to drop or include new interventions as new evidence emerges (58) . Such designs aim to maximize flexibility in the trial without compromising its integrity and validity. By analyzing accumulating data through pre-specified interim analyses, prompt adaptations can be made such as, for example, stopping early a treatment arm for superiority or futility and changing the randomization allocation ratio, in favor of the most promising treatment arms. The RECOVERY platform trial is probably the most illustrative example of a successful adaptive design(59) ( Table 2 and Box 2) .

Other trials were originally designed for other conditions. For example, the REMAP-CAP trial was designed (60) as an adaptive platform trial assessing interventions for community-acquired pneumonia. As early as March 2020, they adapted their protocol to include patients with COVID-19 and to assess COVID-19 relevant interventions (61) . In the 2,814 registered RCTs in COVID-evidence, 15 were registered before January 2020 but then included patients with COVID-19.

COVID-19 is also characterized by an unprecedented volume of research being quickly disseminated in the scientific literature and preprint servers with over 200,000 items published by early December 2020 (62) . For example, the JAMA Network recorded 53% more submissions in the first quarter of 2020 compared with the year before (63) and MedRxiv saw its median number of daily submission increasing by over 8-fold from before the pandemic (median 6, IQR [4] [5] [6] [7] [8] ) compared with during the pandemic (median 51, IQR [23; 83] ) reaching a total of 7,695 posted articles between July 2019 and June 2020 (64). The publication process was drastically shorter for COVID-related papers ranging from 6 to 20 days from submission to publication versus over 100 days for non-COVID-19 related papers .

This exciting contribution to the scientific literature by the mobilized scientific community has been tarnished by research-publishing scandals (44) with over 70 COVID-19 related-article retractions recorded as of December 2020 on Retraction Watch (68). However, it is too early to assess the true impact of COVID-19 related retractions compared with other scientific research areas (68) .Concerns have been raised regarding the quality of the publications being disseminated with the majority not presenting original data (i.e. expert opinion pieces) and when original data were presented over 80% showed intermediate to high risk of bias and included small number of patients (69) . Many journals have experienced a massive increase in submissions putting heightened pressure upon editors and peer reviewers. Many suboptimal papers may pass through thinned out review filters (70) and/or because they fit favored narratives. In addition, dissemination of misinformation has been exacerbated by media attention and mob behavior in social media platforms (71) relayed by decision-makers and politicians.

The rapidly evolving and fragmented landscape of the COVID-19 pandemic requires good research practice, reproducibility and transparency to ensure informed decision making and maintain public trust (72) . Data sharing allows reanalysis, synthesis and building upon existing evidence increasing the reproducibility and transparency of the scientific method. Although those advantages of data sharing are well known and have been endorsed by the International Committee of Medical Journal Editors, the gap between the intent of sharing data and the actual availability of the data remains wide (73) and is unlikely to be bridged during the COVID-19 pandemic. Several initiatives are underway to provide clinical trial data sharing platforms (74) , prospectively pool individual patient data from trials (75) and conduct collaborative meta-analysis of all available data (76) .

Regulatory authorities throughout the world have been under immense pressure to make decisions as the evidence appeared, sometimes regardless of the source of the evidence and its credibility. For example, press releases of trial results have had substantial impact with the FDA revoking the EUA for hydroxychloroquine just 10 days after or dexamethasone being recommended by the UK authorities just 3 days after the press releases from RECOVERY ( Table 2) .

Up to April 2020, the FDA had issued 174 EUAs; most were for diagnostic tests for various disease outbreaks and only 3 had been issued in the past for therapeutics which were all for the treatment of the 2009 influenza A(H1N1). Currently there are 6 EUAs for therapeutics and 3 EUAs for vaccines for COVID-19 (77) but no COVID-19 therapeutics have yet received a full or accelerated approval from the FDA. EUAs are crucial in a public health crisis but they should not compromise the integrity of the scientific method.

Conducting non-COVID-19 trials during the pandemic has been challenging (78): the lockdown and social distancing measures directly interfere with efficient enrollment and randomization (79) ; and overwhelmed hospitals due to COVID-19 cases may have redirected their resources away from clinical research. As early as March 2020, the FDA had issued a guidance for conducting trials during the pandemic (80) ensuring patients safety all the while minimizing the impact on the conduct of trials not related to COVID-19. Yet, from January to March 2020, an average of 1,147 non-COVID-19 trials were stopped (i.e. recruiting status changed to active, not recruiting, suspended, completed, terminated or withdrawn) per month versus 638 trials per month in 2019 (81) . The peak of suspended trials explicitly due to COVID-19 was reached in April 2020 with 1,021 trials being suspended (82) .

Although the non-COVID-19 clinical research agenda was disrupted, this experience has also emphasised the need to implement innovative solutions such as online recruitment and informed consent (78) , streamlining interactions between stakeholders (funders, site staff, trial manager, and steering and data monitoring committees) including remote monitoring of clinical trials and shorter regulatory processes (detailed below), and remote delivery of interventions using mail drop-off of pills or devices (83) and collection of outcomes using electronic health records. Some of these lessons and gained skills may be useful to implement also in the post-pandemic world and may enhance the efficiency of the clinical research enterprise at large.

The COVID-19 situation highlighted a number of excellent approaches to overcome research challenges in the pandemic. Many of them represent promising solutions for the most common perceived limitations of RCTs in general.

Putting research in context is critical to increase research value and return of investment. Instead of separately planning small trials, joining forces and contributing to large trials is key. This requires that such large trials are identifiable and open for collaboration. As large collaborative studies acquire great prestige, visibility, and citations, they may offer a stronger incentive for investigators to join them rather than perform their own underpowered study.

Platforms such as the COVID-evidence project aim to show the trial research agenda on a website and actively bring together research groups and trial teams to collaborate (4). Such trials need to be expandable, i.e. designed in a way that centers can easily be added, to lower the bar for collaboration and contribution. The RECOVERY trial had such expandability and started with over 130 hospitals recruiting 1000 patients in two weeks, and 176 UK hospitals had then recruited 10000 patients in two months (84). About one year later, in February 2021, it even expanded to a different continent with centers in Nepal and Indonesia, then having recruited more than 36000 patients globally (85) .

A critical issue is the avoidance of creating an environment where trials compete for the same patients (i.e. two trials conducted in the same location with similar eligibility criteria). Trials often use the exclusion criterion "enrolment in another clinical trial". However, this needs to be carefully considered when planning a clinical trial and allowing patients to participate to a second treatment protocol may be desirable when no other treatments are available (86) .

Centers with limited research expertise may not be able to perform rigorous research under acute circumstances when there is limited or no sufficient time and resources for training and for auditing centers performance. Careful planning of centers should be done upstream as inclusion of inexperienced, poorly performing centers may affect the overall trial results, as has been shown in some examples in the pre-COVID era (52) .

The COVID-19 trial research agenda has clearly shown that RCTs can be launched very fast. The setup of novel data infrastructures is time consuming but can often be avoided. Using available infrastructures, either from existing clinical trials, cohorts, registries or from routine care can be extremely helpful to rapidly generate evidence. The REMAP-CAP trial used its existing trial processes and infrastructures (61) and has been expanded for COVID-19 patients. The RECOVERY trial used nationwide EHR data for outcome assessments and combined this with short term active data collection (59) . A trial assessing mental health interventions to cope with COVID-19 has been embedded in a cohort of patients with sclerodermia (87) .

Future pandemic research preparedness may include the setup of very large, nationwide cohorts in which multiple interventions could be tested as Trials Within Cohorts (TWiCs) (88) .

Several trials showed how clinical research can be embedded in routine clinical care, becoming even the standard of care. The RECOVERY trial with its 3 inclusion criteria and streamlined recruitment processes avoided artificial research settings by embedding the trial in routine care and ensuring inclusivity of the recruitment. One in 6 patients hospitalized for COVID-19 in England took part in RECOVERY (89) . This resembled realworld treatment choices and not only boosted trial feasibility -by design, it also maximized the applicability of the results. Similar highly pragmatic trials that are embedded in clinical routine may systematically evaluate treatment strategies, ideally for all relevant healthcare choices also beyond COVID-19.

Funders, Institutional Review Boards (i.e. ethics committee), data monitoring committees (DMC) and regulators have shown remarkable adaptation and flexibility when confronted to the urgency of the pandemic. Many countries have implemented a fast track procedure for the authorization of clinical trials including ethical reviews (90) . In the UK the Health Research Authority reduced the ethic review process from 60 to 10 days (91) . In Switzerland, the Swiss Association of Research Ethics Committees lists all approved and submitted but not yet approved trials, promoting transparency of their processes (92) .

DMCs play a crucial role in the successful conduct of adaptive platform trials by reviewing interim analyses and safety data, and making recommendation on the fate of trials (or treatment specific arms). Trials are often underpowered to assess safety; better coordination is needed between the DMCs of trials addressing similar clinical questions, allowing them to share emerging evidence to better assess the risk and benefit of interventions (93) .

The lack of coordination and collaboration raises important ethical issues to the detriment of patients but also to the medical staff already overwhelmed (94) . Higher authorities such as the WHO with the Solidarity trial (95) or the UK government call to conduct a trial to investigate dosing of alternating vaccines (96) , have shown their ability to set priorities and foster nation-and worldwide collaborations.

The pandemic has shed light on the need and feasibility to streamline the excessively complex administrative procedures that have burdened clinical research. Stakeholders need close interoperability allowing for data and resources flow between stakeholders nationally and internationally (i.e. regulatory authorities, funders, clinical sites, and monitoring committees) (97).

Overall, COVID-19 has clearly challenged the traditional myths that conducting clinical trials must be difficult and time-consuming, resulting in trials that are too small or take too long to be completed. This crisis has clearly magnified those shortcomings but has also shown how to make clinical research more useful -by doing trials with elegant designs reduced to essential elements and prepared to be combined with others, allowing to be performed with speed and flexibility in large collaborations.

Concept and design: All authors. Acquisition, analysis, or interpretation of data: Janiaud. Drafting of the manuscript: All authors. Critical revision of the manuscript for important intellectual content: All authors. Supervision: Ioannidis.

Disclosure of potential conflicts of interest: All authors declare that they have no potential conflicts of interest can receive more than one experimental treatment)  Adaptive design allowing to add or drop intervention arms as evidence emerges  Simplified online randomization easing the work of investigational sites  Pragmatic features with broad eligibility criteria (i.e. hospitalized, confirmed or suspected SARS-CoV-2 infection, and no specific contraindication to their participation)  Primary endpoint, all-cause mortality at 28 days, is collected through a unique online follow-up form filled out at deaths, discharge or at day-28, whichever comes first.  Linkage to national health registries to make use of routinely collected data  As of February 2021, over 36,000 patients have been recruited in over 180 investigational sites (of which 2 are outside of the United Kingdoms) March 2021, several European countries decided to pause the vaccination due to events involving blood clots. The EMA led an investigation and maintained its position that the benefits outweighs the risk of side effects 

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Misinformation Dissemination in Twitter in the COVID-19 Era

Access to data from clinical trials in the COVID-19 crisis: open, flexible, and time-sensitive

Evaluation of Data Sharing After Implementation of the International Committee of Medical Journal Editors Data Sharing Statement Requirement

Timely access to trial data in the context of a pandemic: the time is now

Pooling Data From Individual Clinical Trials in the COVID-19 Era

Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19: an international collaborative meta-analysis of randomized trials. medRxiv

Need for Transparency and Reliable Evidence in Emergency Use Authorizations for Coronavirus Disease 2019 (COVID-19) Therapies

It is unprecedented: trial management during the COVID-19 pandemic and beyond

Preserving Clinical Trial Integrity During the Coronavirus Pandemic

FDA Guidance on Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency

Effects of the COVID-19 Pandemic on Active Non-COVID Clinical Trials

Clinical trial recovery from COVID-19 disruption

Remote Research and Clinical Trial Integrity During and After the Coronavirus Pandemic

Trial rolled out across the UK -RECOVERY Trial

World's largest clinical trial for COVID-19 treatments expands internationally -RECOVERY Trial

COVID-19 trial co-enrolment and subsequent enrolment. The Lancet

Protocol for a partially nested randomised controlled trial to evaluate the effectiveness of the scleroderma patient-centered intervention network COVID-19 home-isolation activities together (SPIN-CHAT) program to reduce anxiety among at-risk scleroderma patients

Ethics and practice of Trials within Cohorts: An emerging pragmatic trial design

Pm 5:30. One U.K. trial is transforming COVID-19 treatment. Why haven't others delivered more results?

Fast track procedure for COVID 19 Clinical trials | ECRIN

How we accelerated clinical trials in the age of coronavirus

Information on the coronavirus: In order to promote transparency and facilitate research coordination, swissethics is now also publishing research projects that have been submitted but not yet approved

Achieving effective informed oversight by DMCs in COVID clinical trials

Ethical rationale for better coordination of clinical research on COVID-19. Research Ethics

Solidarity" clinical trial for COVID-19 treatments

Oxford leads first trial investigating dosing with alternating vaccines | University of Oxford