Definitions of digital biomarkers: a systematic mapping of the biomedical literature.

BACKGROUND: Technological devices such as smartphones, wearables and virtual assistants enable health data collection, serving as digital alternatives to conventional biomarkers. We aimed to provide a systematic overview of emerging literature on 'digital biomarkers,' covering definitions, features and citations in biomedical research. METHODS: We analysed all articles in PubMed that used 'digital biomarker(s)' in title or abstract, considering any study involving humans and any review, editorial, perspective or opinion-based articles up to 8 March 2023. We systematically extracted characteristics of publications and research studies, and any definitions and features of 'digital biomarkers' mentioned. We described the most influential literature on digital biomarkers and their definitions using thematic categorisations of definitions considering the Food and Drug Administration Biomarkers, EndpointS and other Tools framework (ie, data type, data collection method, purpose of biomarker), analysing structural similarity of definitions by performing text and citation analyses. RESULTS: We identified 415 articles using 'digital biomarker' between 2014 and 2023 (median 2021). The majority (283 articles; 68%) were primary research. Notably, 287 articles (69%) did not provide a definition of digital biomarkers. Among the 128 articles with definitions, there were 127 different ones. Of these, 78 considered data collection, 56 data type, 50 purpose and 23 included all three components. Those 128 articles with a definition had a median of 6 citations, with the top 10 each presenting distinct definitions. CONCLUSIONS: The definitions of digital biomarkers vary significantly, indicating a lack of consensus in this emerging field. Our overview highlights key defining characteristics, which could guide the development of a more harmonised accepted definition.

[Registration of national health registry-based research]. / Registrering av forskning baserad på nationella hälsoregister.

In medical research as a whole, frequent inaccurate or biased findings are of international concern. One measure against reporting biases is study registration before the start of data collection (preregistration), preferably together with the statistical analysis plan. This meta-research study systematically evaluated registration of Swedish observational research based on national health registries. In a random sample of registry-based observational studies published 2010-2022, very few were preregistered with a publicly available analysis plan (<1 procent). Ideas from the meta-research literature can be leveraged to strengthen the brand of Swedish registry-based observational studies and counteract reporting bias.

Clinical trial evidence of quality-of-life effects of disease-modifying therapies for multiple sclerosis: a systematic analysis.

BACKGROUND: Increasingly, patients, clinicians, and regulators call for more evidence on the impact of innovative medicines on quality of life (QoL). We assessed the effects of disease-modifying therapies (DMTs) on QoL in people with multiple sclerosis (PwMS). METHODS: Randomized trials assessing approved DMTs in PwMS with results for at least one outcome referred to as "quality of life" were searched in PubMed and ClinicalTrials.gov. RESULTS: We identified 38 trials published between 1999 and 2023 with a median of 531 participants (interquartile range (IQR) 202 to 941; total 23,225). The evaluated DMTs were mostly interferon-beta (n = 10; 26%), fingolimod (n = 7; 18%), natalizumab (n = 5; 13%), and glatiramer acetate (n = 4; 11%). The 38 trials used 18 different QoL instruments, with up to 11 QoL subscale measures per trial (median 2; IQR 1-3). QoL was never the single primary outcome. We identified quantitative QoL results in 24 trials (63%), and narrative statements in 15 trials (39%). In 16 trials (42%), at least one of the multiple QoL results was statistically significant. The effect sizes of the significant quantitative QoL results were large (median Cohen's d 1.02; IQR 0.3-1.7; median Hedges' g 1.01; IQR 0.3-1.69) and ranged between d 0.14 and 2.91. CONCLUSIONS: Certain DMTs have the potential to positively impact QoL of PwMS, and the assessment and reporting of QoL is suboptimal with a multitude of diverse instruments being used. There is an urgent need that design and reporting of clinical trials reflect the critical importance of QoL for PwMS.

Characteristics, Progression, and Output of Randomized Platform Trials: A Systematic Review.

Importance: Platform trials have become increasingly common, and evidence is needed to determine how this trial design is actually applied in current research practice. Objective: To determine the characteristics, progression, and output of randomized platform trials. Evidence Review: In this systematic review of randomized platform trials, Medline, Embase, Scopus, trial registries, gray literature, and preprint servers were searched, and citation tracking was performed in July 2022. Investigators were contacted in February 2023 to confirm data accuracy and to provide updated information on the status of platform trial arms. Randomized platform trials were eligible if they explicitly planned to add or drop arms. Data were extracted in duplicate from protocols, publications, websites, and registry entries. For each platform trial, design features such as the use of a common control arm, use of nonconcurrent control data, statistical framework, adjustment for multiplicity, and use of additional adaptive design features were collected. Progression and output of each platform trial were determined by the recruitment status of individual arms, the number of arms added or dropped, and the availability of results for each intervention arm. Findings: The search identified 127 randomized platform trials with a total of 823 arms; most trials were conducted in the field of oncology (57 [44.9%]) and COVID-19 (45 [35.4%]). After a more than twofold increase in the initiation of new platform trials at the beginning of the COVID-19 pandemic, the number of platform trials has since declined. Platform trial features were often not reported (not reported: nonconcurrent control, 61 of 127 [48.0%]; multiplicity adjustment for arms, 98 of 127 [77.2%]; statistical framework, 37 of 127 [29.1%]). Adaptive design features were only used by half the studies (63 of 127 [49.6%]). Results were available for 65.2% of closed arms (230 of 353). Premature closure of platform trial arms due to recruitment problems was infrequent (5 of 353 [1.4%]). Conclusions and Relevance: This systematic review found that platform trials were initiated most frequently during the COVID-19 pandemic and declined thereafter. The reporting of platform features and the availability of results were insufficient. Premature arm closure for poor recruitment was rare.

Use of pragmatic randomized trials in multiple sclerosis: A systematic overview.

BACKGROUND: Pragmatic trials are increasingly recognized for providing real-world evidence on treatment choices. OBJECTIVE: The objective of this study is to investigate the use and characteristics of pragmatic trials in multiple sclerosis (MS). METHODS: Systematic literature search and analysis of pragmatic trials on any intervention published up to 2022. The assessment of pragmatism with PRECIS-2 (PRagmatic Explanatory Continuum Indicator Summary-2) is performed. RESULTS: We identified 48 pragmatic trials published 1967-2022 that included a median of 82 participants (interquartile range (IQR) = 42-160) to assess typically supportive care interventions (n = 41; 85%). Only seven trials assessed drugs (15%). Only three trials (6%) included >500 participants. Trials were mostly from the United Kingdom (n = 18; 38%), Italy (n = 6; 13%), the United States and Denmark (each n = 5; 10%). Primary outcomes were diverse, for example, quality-of-life, physical functioning, or disease activity. Only 1 trial (2%) used routinely collected data for outcome ascertainment. No trial was very pragmatic in all design aspects, but 14 trials (29%) were widely pragmatic (i.e. PRECIS-2 score ⩾ 4/5 in all domains). CONCLUSION: Only few and mostly small pragmatic trials exist in MS which rarely assess drugs. Despite the widely available routine data infrastructures, very few trials utilize them. There is an urgent need to leverage the potential of this pioneering study design to provide useful randomized real-world evidence.

Meta-research on pragmatism of randomized trials: rationale and design of the PragMeta database.

BACKGROUND: Pragmatic trials provide decision-oriented, real-world evidence that is highly applicable and generalizable. The interest in real-world evidence is fueled by the assumption that effects in the "real-world" are different to effects obtained under artificial, controlled, research conditions as often used for traditional explanatory trials. However, it is unknown which features of pragmatism, generalizability, and applicability would be responsible for such differences. There is a need to provide empirical evidence and promote meta-research to answer these fundamental questions on the pragmatism of randomized trials and real-world evidence. Here, we describe the rationale and design of the PragMeta database which pursues this goal ( www.PragMeta.org ). METHODS: PragMeta is a non-commercial, open data platform and infrastructure to facilitate research on pragmatic trials. It collects and shares data from published randomized trials that either have a specific design feature or other characteristic related to pragmatism or they form clusters of trials addressing the same research question but having different aspects of pragmatism. This lays the foundation to determine the relationship of various features of pragmatism, generalizability, and applicability with intervention effects or other trial characteristics. The database contains trial data actively collected for PragMeta but also allows to import and link existing datasets of trials collected for other purposes, forming a large-scale meta-database. PragMeta captures data on (1) trial and design characteristics (e.g., sample size, population, intervention/comparison, outcome, longitudinal structure, blinding), (2) effects estimates, and (3) various determinants of pragmatism (e.g., the use of routinely collected data) and ratings from established tools used to determine pragmatism (e.g., the PRagmatic-Explanatory Continuum Indicator Summary 2; PRECIS-2). PragMeta is continuously provided online, inviting the meta-research community to collaborate, contribute, and/or use the database. As of April 2023, PragMeta contains data from > 700 trials, mostly with assessments on pragmatism. CONCLUSIONS: PragMeta will inform a better understanding of pragmatism and the generation and interpretation of real-world evidence.

Effects of remdesivir in patients hospitalised with COVID-19: a systematic review and individual patient data meta-analysis of randomised controlled trials.

BACKGROUND: Interpretation of the evidence from randomised controlled trials (RCTs) of remdesivir in patients treated in hospital for COVID-19 is conflicting. We aimed to assess the benefits and harms of remdesivir compared with placebo or usual care in these patients, and whether treatment effects differed between prespecified patient subgroups. METHODS: For this systematic review and meta-analysis, we searched PubMed, Embase, the Cochrane COVID-19 trial registry, ClinicalTrials.gov, the International Clinical Trials Registry Platform, and preprint servers from Jan 1, 2020, until April 11, 2022, for RCTs of remdesivir in adult patients hospitalised with COVID-19, and contacted the authors of eligible trials to request individual patient data. The primary outcome was all-cause mortality at day 28 after randomisation. We used multivariable hierarchical regression-adjusting for respiratory support, age, and enrollment period-to investigate effect modifiers. This study was registered with PROSPERO, CRD42021257134. FINDINGS: Our search identified 857 records, yielding nine RCTs eligible for inclusion. Of these nine eligible RCTs, individual data were provided for eight, covering 10 480 patients hospitalised with COVID-19 (99% of such patients included in such RCTs worldwide) recruited between Feb 6, 2020, and April 1, 2021. Within 28 days of randomisation, 662 (12·5%) of 5317 patients assigned to remdesivir and 706 (14·1%) of 5005 patients assigned to no remdesivir died (adjusted odds ratio [aOR] 0·88, 95% CI 0·78-1·00, p=0·045). We found evidence for a credible subgroup effect according to respiratory support at baseline (pinteraction=0·019). Of patients who were ventilated-including those who received high-flow oxygen-253 (30·0%) of 844 patients assigned to remdesivir died compared with 241 (28·5%) of 846 patients assigned to no remdesivir (aOR 1·10 [0·88-1·38]; low-certainty evidence). Of patients who received no oxygen or low-flow oxygen, 409 (9·1%) of 4473 patients assigned to remdesivir died compared with 465 (11·2%) of 4159 patients assigned to no remdesivir (0·80 [0·70-0·93]; high-certainty evidence). No credible subgroup effect was found for time to start of remdesivir after symptom onset, age, presence of comorbidities, enrolment period, or corticosteroid use. Remdesivir did not increase the frequency of severe or serious adverse events. INTERPRETATION: This individual patient data meta-analysis showed that remdesivir reduced mortality in patients hospitalised with COVID-19 who required no or conventional oxygen support, but was underpowered to evaluate patients who were ventilated when receiving remdesivir. The effect size of remdesivir in patients with more respiratory support or acquired immunity and the cost-effectiveness of remdesivir remain to be further elucidated. FUNDING: EU-RESPONSE.

Robustness of reported postacute health outcomes in children with SARS-CoV-2 infection: a systematic review.

OBJECTIVE: To systematically assess the robustness of reported postacute SARS-CoV-2 infection health outcomes in children. METHODS: A search on PubMed and Web of Science was conducted to identify studies published up to 22 January 2022 that reported on postacute SARS-CoV-2 infection health outcomes in children (<18 years) with follow-up of ≥2 months since detection of infection or ≥1 month since recovery from acute illness. We assessed the consideration of confounding bias and causality, as well as the risk of bias. RESULTS: 21 studies including 81 896 children reported up to 97 symptoms with follow-up periods of 2.0-11.5 months. Fifteen studies had no control group. The reported proportion of children with post-COVID syndrome was between 0% and 66.5% in children with SARS-CoV-2 infection (n=16 986) and between 2.0% and 53.3% in children without SARS-CoV-2 infection (n=64 910). Only two studies made a clear causal interpretation of an association between SARS-CoV-2 infection and the main outcome of 'post-COVID syndrome' and provided recommendations regarding prevention measures. The robustness of all 21 studies was seriously limited due to an overall critical risk of bias. CONCLUSIONS: The robustness of reported postacute SARS-CoV-2 infection health outcomes in children is seriously limited, at least in all the published articles we could identify. None of the studies provided evidence with reasonable certainty on whether SARS-CoV-2 infection has an impact on postacute health outcomes, let alone to what extent. Children and their families urgently need much more reliable and methodologically robust evidence to address their concerns and improve care.

Clinical trial research agenda on COVID-19 - the first two years in Germany and beyond.

BACKGROUND: We have followed the COVID-19 clinical trial research agenda from the beginning using the COVID-evidence.org platform. Now, two years after the COVID-19 pandemic started, our aim was to re-examine this research agenda with the latest data to provide a global perspective on the research landscape with a focus on Germany. METHODS: We reviewed and updated previously published data on the COVID-19 clinical research agenda as of 28February 2022 focusing on randomized trials. We used the COVID-evidence.org platform including registry entries from ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform as well as publications from the Living OVerview of Evidence platform for COVID-19 (L·OVE). RESULTS: Two years on from the pandemic outbreak, there were 4,673 registered trials. The majority of these trials have remained small with a median of 120 planned participants (IQR 60-320). In the first hundred days of the pandemic most of them (50%) had been registered in China. More than two years later, the five countries with the most registered trials (alone or within a framework of international collaborations) were the USA (825 trials; 18%), Iran (619 trials; 13%), India (566 trials; 12%), China (353 trials; 8%), and Spain (309 trials; 7%). Only 119 trials were reported to have a study site in Germany (2.5% of the registered trials). Of the 4,673 trials registered, 15% (694 trials) had published their results by February 2022. The clinical research agenda has been marked by both successes, such as the large RECOVERY trial providing evidence on 10 treatments for COVID-19 including over 45,000 patients as of February 2022, and failures: worldwide only 57 randomized trials have been registered over two years that aimed to assess non-pharmaceutical interventions (e.g., face mask policies and lockdown measures) to prevent COVID-19, and only 11 of them had published results informing decisions that have an impact on the life of billions of people worldwide. CONCLUSIONS: The COVID-19 clinical research agenda has highlighted the substantial effort of the research community but also the challenges of the clinical research ecosystem. Most importantly, it has shed light on the ability to circumvent traditional barriers and to make trials more useful even under extraordinary conditions. The time to learn our lessons and apply them is now, and the time to demonstrate how we have improved the system is before the next pandemic.

Randomized trials on non-pharmaceutical interventions for COVID-19: a scoping review.

OBJECTIVE: We aimed at providing a systematic overview of randomised trials assessing non-pharmaceutical interventions (NPIs) to prevent COVID-19. DESIGN: Scoping review. METHODS: We included all randomised trials assessing NPIs to prevent COVID-19 in any country and setting registered in ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform using the COVID-evidence platform (until 17 August 2021). We searched for corresponding publications in MEDLINE/PubMed, Google Scholar, the Living Overview of Evidence platform, and the Cochrane COVID-19 registry as well as for results posted in registries (until 14 November 2021). Descriptive statistics using numbers and percentages were used in the narrative synthesis of the results. RESULTS: We identified 41 randomised trials. Of them, 12 were completed (29.3%) including 9 with published results. The 41 trials planned to recruit a median of 1700 participants (IQR 588-9500, range 30-35 256 399) with a median planned duration of 8 months (IQR 3-14, range 1-24). Most came from the USA (n=11, 26.8%). The trials mostly assessed protective equipment (n=11, 26.8%), COVID-19-related information and education programmes (n=9, 22.0%), access to mass events under specific safety measures (n=5, 12.2%), testing and screening strategies (n=5, 12.2%) and hygiene management (n=5, 12.2%). CONCLUSIONS: Worldwide, 41 randomised trials assessing NPIs have been initiated with published results available to inform policy decisions for only 9 of them. A long-term research agenda including behavioural, environmental, social and systems level interventions is urgently needed to guide policies and practices in the current and future public health emergencies.

Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX ). METHODS: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. RESULTS: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. CONCLUSIONS: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.

U.S. Food and Drug Administration Reasoning in Approval Decisions When Efficacy Evidence Is Borderline, 2013-2018.

BACKGROUND: The U.S. Food and Drug Administration (FDA) has substantial flexibility in its approval criteria in the context of life-threatening disease and unmet therapeutic need. OBJECTIVE: To understand the FDA's evidentiary standards when flexible criteria are employed. DESIGN: Case series. SETTING: Applications submitted between 2013 and 2018 that went through multiple review cycles because the evidence for clinical efficacy was initially deemed insufficient. MEASUREMENTS: Information was obtained from the approval package (available on Drugs@FDA), including advisory committee minutes, FDA reviews, and complete response letters. RESULTS: Of 912 applications reviewed, 117 went through multiple review cycles; only 22 of these faced additional review primarily because of issues related to clinical efficacy. Concerns about the end point, the clinical meaningfulness of the observed effect, and inconsistent results were common bases for initial rejection. In 7 of the 22 cases, the approval did not require new evidence but rather new interpretations of the original evidence. No FDA decisions cited reasoning used in previous decisions. LIMITATION: The conclusions rely on the authors' interpretation of the FDA statements and on a series of "close calls." CONCLUSION: The FDA has no mechanism to find or tradition to cite similar cases when weighing evidence for approvals, resulting in standalone, bespoke decisions. These decisions show highly variable criteria for "substantial evidence" when flexible evidential criteria are used, highlighted by the recent approval of aducanumab. A precedential tradition and suitable information system are required for the FDA to improve institutional memory and build upon past decisions. These would increase the FDA's decisional transparency, consistency, and predictability, which are critical to preserving the FDA's most valuable asset, the public's trust. PRIMARY FUNDING SOURCE: U.S. Food and Drug Administration.

Validity of observational evidence on putative risk and protective factors: appraisal of 3744 meta-analyses on 57 topics.

BACKGROUND: The validity of observational studies and their meta-analyses is contested. Here, we aimed to appraise thousands of meta-analyses of observational studies using a pre-specified set of quantitative criteria that assess the significance, amount, consistency, and bias of the evidence. We also aimed to compare results from meta-analyses of observational studies against meta-analyses of randomized controlled trials (RCTs) and Mendelian randomization (MR) studies. METHODS: We retrieved from PubMed (last update, November 19, 2020) umbrella reviews including meta-analyses of observational studies assessing putative risk or protective factors, regardless of the nature of the exposure and health outcome. We extracted information on 7 quantitative criteria that reflect the level of statistical support, the amount of data, the consistency across different studies, and hints pointing to potential bias. These criteria were level of statistical significance (pre-categorized according to 10-6, 0.001, and 0.05 p-value thresholds), sample size, statistical significance for the largest study, 95% prediction intervals, between-study heterogeneity, and the results of tests for small study effects and for excess significance. RESULTS: 3744 associations (in 57 umbrella reviews) assessed by a median number of 7 (interquartile range 4 to 11) observational studies were eligible. Most associations were statistically significant at P < 0.05 (61.1%, 2289/3744). Only 2.6% of associations had P < 10-6, ≥1000 cases (or ≥20,000 participants for continuous factors), P < 0.05 in the largest study, 95% prediction interval excluding the null, and no large between-study heterogeneity, small study effects, or excess significance. Across the 57 topics, large heterogeneity was observed in the proportion of associations fulfilling various quantitative criteria. The quantitative criteria were mostly independent from one another. Across 62 associations assessed in both RCTs and in observational studies, 37.1% had effect estimates in opposite directions and 43.5% had effect estimates differing beyond chance in the two designs. Across 94 comparisons assessed in both MR and observational studies, such discrepancies occurred in 30.8% and 54.7%, respectively. CONCLUSIONS: Acknowledging that no gold-standard exists to judge whether an observational association is genuine, statistically significant results are common in observational studies, but they are rarely convincing or corroborated by randomized evidence.

Challenges and Lessons Learned From COVID-19 Trials: Should We Be Doing Clinical Trials Differently?

The COVID-19 crisis led to a flurry of clinical trials activity. The COVID-evidence database shows 2814 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 February 2021). Small randomized trials and observational, nonrandomized 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 (eg, 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. On the basis of the COVID-19 experience and its challenges, planning of several large, efficient trials, and wider use of adaptive designs might 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 might be several of the legacies of COVID-19 on future randomized trials.

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

Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.