correspondence COVID-19 clinical trials: learning from exceptions in the research chaos

To the Editor — Jeremy Farrar, Director of RECOVERY timeline SOLIDARITY timeline

Wellcome and Chair of the World Health Jan Remdesivir and lopinavir trials in China Jan– WHO Working Group requests core international Organization R&D Blueprint Scientific Jan stalled by epidemic’s ending Feb protocol for therapeutics against COVID-19 Advisory Group, has said “It’s critical that the global research effort is rapid, robust WHO Global Forum prioritizes therapeutic Feb 12 and is conducted at scale and co-ordinated questions to be addressed initially Funding for a trial from the WHO R&D Blueprint Scientific Advisory Group across multiple countries.” UKRI 2019-nCoV Rapid Response Call 1 recommends simplicity of trial protocol Of the >2,000 planned drug studies 5 First protocol written 9–10 March; WHO announces SOLIDARITY trial examining COVID-19 treatments (https:// 13 March, submitted to ethics review board 13 19 Mar 18 www.covid-trials.org), most have delivered 22 First patient recruited in the DisCoVeRy trial in France 1 First patient enrolled at 26 little or no directly useful information . 29 John Radcliffe Hospital in Oxford 3 First patient recruited to Nordic countries’ Exceptions include two large, adaptive, 7 add-on study (Oslo University Hospital) 132 UK hospitals with almost pragmatic trials, RECOVERY and WHO and INSERM agree DisCoVeRy will 1,000 patients randomized when the Apr SOLIDARITY, which combined have UK had the world's highest deaths be an add-on of SOLIDARITY randomized >20,000 patients to assess the First hospitals in Iran enroll patients effects of several treatments on mortality2, (with 17 more centers within two weeks) and the US National Institutes of Health 10,000 patients randomized

14 May ACTT trial, which randomized 1,059 Convalescent plasma arm added patients to assess the effect of remdesivir on 23 With 11,000 patients randomized, announces 3 5 time to disease resolution . hydroxychloroquine “has no clinical benefit” The speed of the RECOVERY trial WHO Global Forum reviews the trials of

Announces low-cost dexamethasone 16 Jun hydroxychloroquine and lopinavir–ritonavir (https://www.recoverytrial.net/files/ “reduces death by 1/3 in hospitalised patients”; recovery-protocol-v7-0-2020-06-18.pdf) adopted as NHS practice the same day 29 was record-breaking: the period from 1 Discontinuation of hydroxychloroquine and Announces lopinavir–ritonavir has 8 4 lopinavir–ritonavir arms due to futility protocol to first patient recruitment was “no clinical benefit” Jul nine days, with the 176 UK hospitals 12,000 patients enrolled Remdesivir and interferon arms continue, Jul recruiting >12,000 hospitalized to assess any effects on mortality Azithromycin, tocilizumab and convalescent Jul– patients (15% UK COVID-19 cases), plasma continue, plan to add a monoclonal Aug and it provided clear answers within antibody cocktail in October Aug a few months on the effectiveness of NHS announces RECOVERY as the principal More than 9,000 patients in 30 countries; 2 18 dexamethasone and the ineffectiveness national clinical trial platform for COVID-19 27 highest in Iran (>2,000) of hydroxychloroquine and lopinavir– phase 2 and 3 therapeutics trials ritonavir (Fig. 1). Notably, it sought to achieve reliability and quality by design rather than by compliance with good clinical practice or site monitors, relying Fig. 1 | RECOVERY and SOLIDARITY timelines. NHS, National Health Service; WHO, World Health instead on centralized computer checks on Organization. site behavior and patient compliance, and utilizing central National Health Service medical records of treatment and outcome. Also, it did not necessarily require written survival. SOLIDARITY also includes add-on central randomization; no additional consent where the medical emergency sub-studies (Nordic and Canadian arms and biological samples or extraneous data rendered this inappropriate. the European DisCoVeRy trial; https:// collection; and the simple, unambiguous The World Health Organization–led presse.inserm.fr/en/launch-of-a-european- primary outcome of all-cause mortality. SOLIDARITY trial (https://www.who.int/ clinical-trial-against-covid-19/38737/) that RECOVERY benefited from the willingness emergencies/diseases/novel-coronavirus- provide more-detailed data on safety and of UK doctors to randomize unproven 2019/global-research-on-novel-coronavirus- clinical and laboratory surrogates. treatments (rather than, as in many other 2019-ncov/solidarity-clinical-trial-for-covid- Both trials have common origins in the countries, obstructing randomization by 19-treatments) has recruited >9,000 international collaborative work enabled incorporating unproven drugs into local patients across 30 countries and is by the World Health Organization R&D practices and guidelines); strong national currently recruiting about 2,000 patients Blueprint (Fig. 1). The RECOVERY support from funders and the National a month. SOLIDARITY has also provided protocol, written in only two days, was Health Service; and the pre-existing UK important evidence on the ineffectiveness heavily influenced by the 1980s ideas of clinical-trials network, which provided of hydroxychloroquine and lopinavir– large, simple, pragmatic trials4, exemplified research nurses at recruiting centers6. ritonavir and is the largest trial examining by the International Studies of Infarct RECOVERY’s streamlined trial conduct the effects of remdesivir and interferon on Survival5: broad, simple inclusion criteria; and data collection7 — including foregoing

Nature Medicine | VOL 26 | November 2020 | 1671–1673 | www.nature.com/naturemedicine 1671 correspondence

formulaic training on good clinical large, simple, core studies should be national Technical University of Munich School of Medicine, practice — enabled the participation of priorities, with coordinated support from Munich, Germany. 5Department of Internal hospitals already stretched by patients chief medical officers, healthcare providers, Medicine, Tampere University Hospital, Tampere, with COVID-19, with many of the funders and regulators to expedite set-up Finland. 6Institute for Evidence-Based Healthcare, less-research-experienced hospitals being processes and promote rapid recruitment. Bond University, Robina, Australia. among the best recruiters. Finally, a strong Rapid clear answers to treatment ✉e-mail: [email protected] letter of support from the Chief Medical questions have the potential to save Officers of England, Wales, Scotland and hundreds of thousands of lives during the Published online: 22 September 2020 Northern Ireland emphasized that the trial course of the COVID-19 pandemic. In https://doi.org/10.1038/s41591-020-1077-z was to be seen as part of clinical care and previous pandemics, large-scale randomized 8,9 References stated that “Use of treatments outside of a trials were generally not set up in time . 1. Glasziou, P. P., Sanders, S. & Hofmann, T. Br. Med. J. 369, trial, where participation was possible, is a However, RECOVERY and SOLIDARITY m1847 (2020). wasted opportunity to create information have set new standards and have shown 2. Te RECOVERY Collaborative Group. N. Engl. J. Med. https:// doi.org/10.1056/NEJMoa2021436 (2020). that will benefit others.” that a combination of old-fashioned 3. Beigel, J.H. et al. N. Engl. J. Med. https://doi.org/10.1056/ The SOLIDARITY protocol was randomization, established clinical-trials NEJMoa2007764 (2020). also a simple, pragmatic design adapted networks and imaginative use of modern 4. Yusuf, S., Collins, R. & Peto, R. Stat. Med. 3, 409–422 (1984). 5. ISIS Collaborative Group. Lancet 2, 349–360 (1988). rapidly from a pre-existing core pandemic information technology can provide many 6. Wise, J. & Coombes, R. Br. Med. J. https://doi.org/10.1136/bmj. protocol. Multi-country involvement rapid and reliable therapeutic answers, m2670 (2020). allowed recruitment to shift with disease following the recently published rationale 7. Tenaerts, P., Madre, L. & Landray, M. Clin. Trials 15, 5–12 (2018). 8. Muller, M. P., McGeer, A., Straus, S. E., Hawryluck, L. & incidence. A few countries, such as France for pursuing the magic of randomization Gold, W. L. Emerg. Infect. Dis. 10, 389–394 (2004). (DisCoVeRy) — aided by the pre-existing rather than the myth of real-world 9. Tansey, C. M., Herridge, M. S., Heslegrave, R. J. & Lavery, J. V. REACTing network — started recruiting evidence10. Throughout the world, however, CMAJ 182, 1533–1537 (2010). quickly, and within four weeks, seven over-regulation and the lack of national 10. Collins, R., Bowman, L., Landray, M. & Peto, R. N. Engl. J. Med. 382, 674–678 (2020). countries were randomizing. Unfortunately, and international efforts to facilitate many others were delayed by approvals from appropriately large trials represent a missed Acknowledgements national drug regulators, ethics committees opportunity to improve care. During the We thank P. Horby and M. Landray (of RECOVERY), or health ministries and missed the first COVID-19 pandemic, several false claims of A.M. Henao-Restrepo, M.-P. Preziosi, J.-A. Røttingen wave’s peak. Furthermore, countries lacked efficacy have emerged from non-randomized and V. Sathiyamoorthy (of SOLIDARITY) and N. Peiffer-Smadja and Y. Yazdanpanah (of DisCoVeRy) for clear processes for prioritizing around larger comparisons (often misleadingly referred insightful advice. K.A.O.T. is supported by the Academy of pandemic trials, with many small trials to as ‘real-world evidence’), and it has Finland, Competitive Research Funding of the Helsinki and hindering progress of the global mega-trial. been refreshing to see how perfectly such Uusimaa Hospital District and Sigrid Jusélius Foundation. Over-optimistic claims that fueled off-label weakly founded claims can be swept aside The sponsors had no role in the analysis and interpretation of the data or the manuscript preparation, review, or use of drugs, such as hydroxychloroquine, by evidence from properly conducted, approval. also hindered recruitment. large-scale, randomized trials. ❐ While both trials’ results are clinically Author contributions important, the global research community Kari A. O. Tikkinen1,2, Reza Malekzadeh3, K.A.O.T. and P.G. conceived of and drafted this can learn much from examining their Martin Schlegel4, Jarno Rutanen5 and Correspondence on the basis of interviews with trial Paul Glasziou6 ✉ investigators; all authors provided comments on the draft processes. Countries should support and approved the final version. clinical-trial networks that can quickly 1Departments of Urology and Public Health, activate and adapt to contribute to large, University of Helsinki and Helsinki University Competing interests simple multi-center trials that can study Hospital, Helsinki, Finland. 2Department of Surgery, K.A.O.T. is the national principal investigator of the both older drugs and (if not unduly South Karelian Central Hospital, Lappeenranta, SOLIDARITY trial in Finland; R.M. is the national 3 principal investigator of the SOLIDARITY trial in Iran; over-burdened with safety monitoring) new Finland. Digestive Disease Research Institute, M.S. is a steering committee member of the SOLIDARITY drugs, complementing more-detailed trials by Tehran University of Medical Sciences, Tehran, Iran. trial in Germany; and J.R. is a steering committee member helping assess any effects on mortality. Such 4Department of Anesthesiology and Intensive Care, of the SOLIDARITY trial in Finland.

COVID-19 puts the Sustainable Development Goals center stage

To the Editor — A recent Comment1 and targets will not be met by 2030” and that effectively unveiled the inequities and accompanying Editorial2 in Nature have ”some could even be counterproductive”1. governance dysfunctions that the SDGs raised the question of whether it is time to We argue for a more optimistic view and are poised to rectify3,4. By its very nature, revise the United Nations (UN) Sustainable hold that the COVID-19 pandemic may help a pandemic teaches that no one should be Development Goals (SDGs) and their spur efforts to realize the UN’s 2030 Agenda. left behind and that no one is safe until various targets in the wake of the COVID-19 Rather than calling for a revision of everyone is safe. crisis. In their Comment, Naidoo and Fisher the SDGs, COVID-19 should be seen as Indeed, COVID-19 makes extant argue that it is ”likely that many of the 169 a catalyst for progress. COVID-19 has challenges impossible to ignore. It brings

1672 Nature Medicine | VOL 26 | November 2020 | 1671–1673 | www.nature.com/naturemedicine