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Global landscape of randomized controlled trials responding to the COVID-19 pandemic: a literature review protocol

[version 1; peer review: awaiting peer review]
Mai Inada
https://orcid.org/0000-0001-9694-5284
1, Naoaki Ichihara2, Hiroki Saito3,4
Mai Inada
https://orcid.org/0000-0001-9694-5284
1, Naoaki Ichihara2, Hiroki Saito3,4
PUBLISHED 03 Feb 2023
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REVIEWER STATUS AWAITING PEER REVIEW

This article is included in the Emerging Diseases and Outbreaks gateway.

Abstract

Introduction: Evidence-based care is challenging during public health crisis. During the COVID-19 pandemic, although the tremendous number of clinical trials were conducted, small trials were prevalent, which posed the risk of duplication, heterogeneity, underreporting and limited applicability of the trial results to patients in the clinical setting. These factors are known to potentially jeopardize the efficient production of scientific data for evidence-based care. The objective of this review is to critically appraise the characteristics of randomized controlled trials related to COVID-19 therapeutics and vaccines. This article is a protocol for literature review. 
Methods: This review will include randomized controlled trials (RCTs) on therapeutics and vaccines for COVID-19. Therapeutics include a single drug or a combination of multiple drugs for COVID-19. Non-human trials will be excluded. The search strategy is designed for identifying publication of study results in peer-review journals. Databases to be searched include MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Web of science and CINAHL. Two or more independent reviewers will screen identified publications for inclusion/exclusion and retrieve data including standard information of studies and specific details about RCT designs as well as reporting, for which we will follow the set of information in international trial registries and the CONSORT statement. 
Discussion: It remains unclear what should be improved or strengthened for ecosystems of clinical trials for future pandemics. This review is expected to provide a landscape of RCTs related to COVID-19 therapeutics and vaccines and to explicitly show successful factors for evidence generation in response to pandemics.

Keywords

COVID-19, evidence-based medicine, infectious disease, pandemic response, randomized controlled trials

Corresponding author: Mai Inada
Competing interests: Mai Inada is currently employed by Novo Nordisk A/S.
Grant information: This research is funded by the Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (Kakenhi) (C) (Project Number 22K10382).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Copyright:  © 2023 Inada M et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
How to cite: Inada M, Ichihara N and Saito H. Global landscape of randomized controlled trials responding to the COVID-19 pandemic: a literature review protocol [version 1; peer review: awaiting peer review]. F1000Research 2023, 12:133 (https://doi.org/10.12688/f1000research.129241.1) First published: 03 Feb 2023, 12:133 (https://doi.org/10.12688/f1000research.129241.1) Latest published: 03 Feb 2023, 12:133 (https://doi.org/10.12688/f1000research.129241.1)

Introduction

Evidence-based care is challenging during public health crisis. Looking back at the Ebola outbreak in West Africa in 2014-2016, there was only one randomized clinical trial (RCT) conducted in 2015, which did not reach the target enrollment in the dynamic epidemic situation.1 This study was followed by a multi-armed RCT during another wave of the Ebola outbreak from 2018 to 2019, which finally yielded evidence for treatment of Ebola virus disease.2

In the midst of the COVID-19 pandemic, it is recognized that clinical trials play a critical role to inform public health and clinical decisions and that rigorous RCTs of high quality provide actionable information based on timely availability of valid and comparable data from multiple countries.3 Albeit the health systems have been stretched along with frontline health facilities overwhelmed with a surge of patients, the tremendous number of clinical trials have been conducted for COVID-19 therapeutics and vaccines.

However, only limited number of clinical trials for COVID-19 therapeutics and vaccines were considered to be RCTs with adequate power.4 The prevalence of small trials cause inefficiency and heterogeneity. Eligibility criteria differ amongst COVID-19-related clinical trials.5 This contains the risk of duplication, heterogeneity, underreporting and limited applicability of the trial results to patients in the clinical setting.

In addition, there have been substantial duplications among trials in terms of interventions and comparisons.6 Small trials are affected by the results from larger trials, which may result in early termination. Such studies may not bring any benefit unless they share the trial data.7 The results of clinical trials, especially industry-funded studies in early phase, are not always reported in a timely manner.8 This is also the case for COVID-19-related trials. More than 90% of registry entries was not published any study results by 15 July 2020.9

The specific objectives of this literature review are to comprehensively review RCTs related to COVID-19, especially with focus on therapeutics and vaccines; and to map out the characteristics of the above-mentioned clinical trials.

Protocol

The proposed literature review will be conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR).10

Eligibility criteria

Types of study

This review will include RCTs. For the purpose of the literature review, we will consider original manuscripts published in peer-review journals that reported results from RCTs.

Types of participants

We will include RCTs regardless of any types of study participants, unless they are animal studies. Non-human trials will be excluded.

Types of interventions

This review will consider RCTs on therapeutics and vaccines for COVID-19. Therapeutics include a single drug or combination of multiple drugs as well as newly developed drugs and existing drugs repurposed for COVID-19.

We will exclude other interventions listed below.

  • • Physical therapy

  • • Preventive and therapeutic interventions for mental health

  • • Interventions aimed at behavior change

  • • Traditional and complimentary medicines (e.g., herbs, propolis, yoga)

  • • Preventive measures and drugs other than vaccines

  • • Medical examination (online consultation etc.),

  • • Diagnostic method, biomarker

  • • Medical device development

Types of outcomes

Neither primary nor secondary outcomes will be considered as inclusion/exclusion criteria for this literature review.

Search strategy

The search strategy will aim to locate manuscripts published in peer-review journal. An initial limited search of Embase was undertaken to identify articles on the topic. The text words contained in the titles and abstracts of relevant articles, and the index terms used to describe the articles were used to develop a full search strategy for MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Web of science and CINAHL (see Table 1). The search strategy, including all identified keywords and index terms, will be adapted for each included information source.

Table 1. Search strategy in EMBASE conducted in November 2021.

SearchQueryRecords retrieved
#1'covid 19'/exp160,317
#2'sars cov 2'/exp47,538
#3'2019 ncov':ti,ab,kw OR 2019ncov:ti,ab,kw OR 'ncov 2019':ti,ab,kw OR ncov2019:ti,ab,kw OR ncov:ti,ab,kw2,431
#4covid:ti,ab,kw OR covid19:ti,ab,kw OR 'covid 19':ti,ab,kw176,176
#5'sars cov2':ti,ab,kw OR 'sars cov-2':ti,ab,kw OR sarscov2:ti,ab,kw OR 'sarscov 2':ti,ab,kw OR 'sars cov 2':ti,ab,kw OR 'severe acute respiratory syndrome coronavirus 2':ti,ab,kw67,512
#6'corona virus':ti,ab,kw OR 'corona viruses':ti,ab,kw OR coronavirus:ti,ab,kw OR coronaviruses:ti,ab,kw OR 'coronavirus'/exp OR cov:ti,ab,kw137,989
#7'covid-19 vaccines'/exp8,475
#8#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7230,509
#9'clinical trial':it OR 'clinical trials as topic'/exp OR 'controlled clinical trials as topic'/exp OR 'clinical trial' OR 'clinical trials' OR 'randomized controlled trial':it OR 'randomized controlled trials as topic'/exp OR 'randomized controlled trial' OR 'randomized controlled trials' OR 'randomised controlled trial' OR 'randomised controlled trials'2,280,420
#10randomized:ti,ab,kw OR randomised:ti,ab,kw OR placebo:ti,ab,kw OR randomly:ti,ab,kw OR trial:ti1,607,911
#11#9 OR #102,912,484
#12#8 AND #1115,915
#13#8 AND #11 AND [1-11-2019]/sd NOT [28-10-2021]/sd14,614

Articles published in English will be included. Articles published from 1 November 2019 to 30 November 2021 will be included because of the first report of COVID-19 case in December 2019.

The databases to be searched include MEDLINE, Pubmed, Cochrane Central Register of Controlled Trials (CENTRAL), Web of science and CINAHL.

Study/Source of evidence selection

After electronic searching, we will download all titles and abstracts retrieved to a reference management database, EndNote 20.1, and remove duplicates. We will upload titles and abstracts to COVIDENCE online software for screening. At least two reviewers will independently screen titles and abstracts for assessment against the inclusion criteria for the review. Next, we will retrieve the full-text study reports/publication, and at least two reviewers will independently screen the full-text and identify studies for inclusion and record reasons for exclusion of the ineligible studies. Any disagreement that arises between the reviewers at each stage of the selection process will be resolved through discussion or with an additional reviewer/s. We will record the selection process in sufficient detail to complete a PRISMA flow diagram.11

Data extraction

Data will be extracted from papers included in the literature review by two or more independent reviewers using Covidence online software (covidence.org). The data extracted will include standard information of studies and specific details about RCT designs as well as reporting, for which we will follow the set of information in international trial registries and the CONSORT statement. The CONSORT statement is an evidence-based, minimum set of recommendations for reporting randomized trials which allows structured reporting of RCTs.12 When there is a protocol available for RCTs, we will also refer to it and extract the same data set to assess what are/are not reported against the protocol. The draft framework of data extraction is shown in Table 2.

Table 2. Example of data extraction instrument.

Bibliometrics
Study titleAuthor(s)SourceYear and month of publicationDOI
Study data
Study design
Ex. Cluster randomization, adaptive design, clinical trial platform/master protocol, mixed studies including qualitative studies, decentralization, multiple arms		Study phase

  • • Phase 1

  • • Phase 2

  • • Phase 3

  • • Phase 4

Funding

  • • industry sponsoring

Multi country participations

  • • participations from LMICs

Data sourceSponsor
(e.g. academic, commercial, government)
Interventions and comparisons
Ex. Repurposed drugs, investigational new drugs, comparison with standard care, existing drugs or placebo		Target populations

  • • Severity

  • • Age eligibility

Study size

  • • Efficacy measure used for sample size calculation

  • • Target and actual enrollment

Study period
Ex. first recruitment, recruitment closed, completion		Outcome measured

  • • Positive results

  • • Negative results

  • • Safety events

  • • Study Completion with planned enrollment volume

  • • Early termination with positive results

  • • Early termination due to safety concerns

  • • Early termination due to any other reasons

Risk of bias*

  • • Bias arising from the randomization process

  • • Bias due to deviations from intended interventions

  • • Bias due to missing outcome data

  • • Bias in measurement of the outcome

  • • Bias in selection of the reported result

  • • (For cluster-randomized trials) Identification/recruitment bias

Ethics

  • • Informed consent procedures

  • • GCP compliance

Information sharing

  • • Registration in global clinical trial registries

  • • Published full protocol

  • • Open access to study data

Influence

  • • Number of citations

Reporting style (CONSORT statement)
Title and abstractIntroductionMethodsResultsDiscussionOther information

* (ref) Higgins JPT SJ, Page MJ, Elbers RG, Sterne JAC. Chapter 8: Assessing risk of bias in a randomized trial. 2021. In: Cochrane Handbook for Systematic Reviews of Interventions version 62 (updated February 2021) [Internet]. Cochrane. Available from: www.training.cochrane.org/handbook.

The draft framework of data extraction will be modified and revised as necessary during the process of extracting data from each included evidence source. Modifications will be detailed in the literature review. Any disagreements that arise between the reviewers will be resolved through discussion, or with an additional reviewer/s. If appropriate, authors of papers will be contacted to request missing or additional data, where required.

Where data are missing, we will refer to separate data source (trial protocol etc.) or contact authors of included studies to request additional information where possible.

Data analysis and presentation

The results will be presented in a descriptive and narrative form, using tables showing the main characteristics of the studies. The review will illustrate the trends observed in published RCTs over the time of COVID-19 pandemic and inform policy makers, trialists and other stakeholders of the baseline information on countries’ capacities to conduct RCTs in response to pandemics.

Dissemination

We intend to write a manuscript for peer-review publication to disseminate our findings.

Study status

The full-text screening is currently being conducted at the time of manuscript submission.

Discussion

It remains unclear what successful factors are missing in the majority of RCTs conducted during the COVID-19 pandemic and what should be improved or strengthened to effectively and efficiently generate scientific evidence in response to pandemics. This literature review is expected to inform policy makers and academic leaders of how to strengthen ecosystems of clinical trials for future pandemics.

Ethical consideration

Ethical approval is considered not required for this research as this research does not directly involve human subjects.

Data availability

No data is associated with this article.

References

  • 1.  Davey RT Jr, Dodd L, Proschan MA, et al.: A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection. N. Engl. J. Med. 2016; 375(15): 1448–1456. PubMed Abstract
  • 2.  Mulangu S, Dodd LE, Davey RT Jr, et al.: A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics. N. Engl. J. Med. 2019; 381(24): 2293–2303. Publisher Full Text
  • 3.  G7: G7 Therapeutics and vaccines clinical trials charter.2021.
  • 4.  Woodcock KBJ: Trends in COVID-19 therapeutic clinical trials. Nat. Rev. Drug Discov. 2021; 20: 254–255. Publisher Full Text
  • 5.  Abi Jaoude J, Kouzy R, El Alam MB, et al.: Exclusion of Older Adults in COVID-19 Clinical Trials. Mayo Clin. Proc. 2020; 95(10): 2293–2294. PubMed Abstract | Publisher Full Text | Free Full Text
  • 6.  Thorlund K, Dron L, Park J, et al.: A real-time dashboard of clinical trials for COVID-19. Lancet Digital Health. 2020; 2(6): e286–e287. PubMed Abstract | Publisher Full Text | Free Full Text
  • 7.  Dal-Ré R, Porcher R, Gluud C: COVID-19 clinical trials: Ethical and scientific consequences of the RECOVERY trial results. Basic Clin. Pharmacol. Toxicol. 2020; 127(6): 445–447. PubMed Abstract | Publisher Full Text
  • 8.  Saito H, Gill CJ: How Frequently Do the Results from Completed US Clinical Trials Enter the Public Domain? - A Statistical Analysis of the ClinicalTrials.gov Database. PLoS One. 2014; 9(7): e101826. PubMed Abstract | Publisher Full Text | Free Full Text
  • 9.  Dillman A, Park JJH, Zoratti MJ, et al.: Reporting and design of randomized controlled trials for COVID-19: A systematic review. Contemp. Clin. Trials. 2021; 101: 106239. PubMed Abstract | Publisher Full Text | Free Full Text
  • 10.  Tricco AC, Lillie E, Zarin W, et al.: PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation. Ann. Intern. Med. 2018; 169(7): 467–473. PubMed Abstract | Publisher Full Text
  • 11.  Moher D, Liberati A, Tetzlaff J, et al.: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann. Intern. Med. 2009; 151(4): 264–269, w64. Publisher Full Text
  • 12.  Schulz KF, Altman DG, Moher D: CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. Ann. Intern. Med. 2010; 152(11): 726–732. Publisher Full Text

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Inada M, Ichihara N and Saito H. Global landscape of randomized controlled trials responding to the COVID-19 pandemic: a literature review protocol [version 1; peer review: awaiting peer review]. F1000Research 2023, 12:133 (https://doi.org/10.12688/f1000research.129241.1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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