Orchestrating Collaborative Research and Clinical Trials during COVID-19 Pandemic – A New Normal

The advent of the COVID-19 has indeed sent waves through the global research community. The relentless generation of reports, studies, and trials has contributed to the ever-changing and constantly evolving literature, albeit critically important, but sometimes lack precision and practicality. In light of the retraction of numerous COVID-related articles and a halt in many randomized controlled trials (RCTs), we present some reflections on lessons learnt from pandemic response research, propose solutions, and highlight some important considerations.

RCTs are known to be the ‘gold-standard’ design for evidence-based medicine. However, its applicability in the COVID-19 pandemic has been rather controversial. In context of the perspective by Bauchner and Fontanarosa’s (2020) “Randomized Clinical Trials and COVID-19 - Managing Expectations”¹, many trials lack rigorous design, fail to address heterogenicity of the disease and may lead to difficulty in interpretation of results. The authorities and media rely heavily on these reports; hence, scientists must remain prudent in the conduct of such trials.

Collaborative work

Firstly, there is strength in numbers. The heterogeneity in various randomized clinical trials often yields uncertain results. A multi-center, multi-country collaboration led by a central data and safety monitoring committee can address this issue with standardization of methodology, intervention, and interpretation of results. Using the appropriate statistical techniques, pooled data increases the precision of results, identifies safety concerns, and allows for subgroup analyses for which individual trials may be underpowered. One clear consequence of not having a mechanism in place for pooling of data from RCTs with an independent data and safety monitoring board is that observational evidence is available more quickly, hampering the efforts to get clinical trials started successfully. Hydroxychloroquine is a case in point where reports of use among possibly sicker patients with poorer outcomes hampered two RCTs from starting and others from enrolling, despite the call from scientists for rigorous evidence from randomized clinical trials to guide hydroxychloroquine use.

Utilizing data and technology

Secondly, in this age of data and information technology, a trans-disciplinary collaboration beyond the medical community is a must for the effective conduct of trials. Leaders in the various fields of technology, data analytics, science, and policy can all contribute to the implementation of robust technology platforms and prognostic models utilizing digital tools, big data, and machine learning to aid the conduct of the trial, prognostication, selection, and follow-up of patients for treatment or intervention. Specifically for clinical trials, secure transfer of clean, individual-level participant data into a confidential data management system with clear statistical analysis plans would facilitate timely results for efficacy and safety.

Ethical and safe administration of clinical trials

Thirdly, it is crucial for the implementation of studies in accordance with Good Clinical Practice (GCP) guidelines to ensure quality research and safety to affected but ‘vulnerable’ subjects.² There should be no compromise as digital solutions may now play a big role in ensuring informed consent and proper implementation of the intervention with real-time monitoring and without subjecting trial administrators to the risk of transmission. Conducting participant visits via telemonitoring and allowing self-collection of specimens (nasal swabs and blood) and self-monitoring (oxygen saturation and electrocardiogram monitoring) reduces risks to participants and study staff (Figures 1–3).

Figure 1. Schematics for conducting a clinical trial using digital tools during global crisis situation like COVID-19 pandemic. Functional Architecture - These high level requirements form the basis of key capabilities that are desired by a platform and the need for digital tools that would deliver these capabilities. Depending on the scope of services these capabilities should be added or removed from the overall system architecture

Figure 2. Schematics of a proposed trial illustrating digital interactions for patient recruitment and follow-up during time of circuit breaker and with social distancing measures. A Digital Interaction model (like the example above) helps in defining the interactions between the actors of the system, the tools in context of the overall study process

Figure 3. Schematics of a proposed trial illustrating for deployment for secure and isolated infrastructure for conducting a research study. The architecture view shows how the secure and connected services and web applications will be deployed on hospital infrastructure while providing connectivity and collaboration services with other geo distributed study teams DMZ - Demilitarized Zone between external and internal firewall to guard against security threats from unwanted traffic; SSL - Secure Sockets Layer that encrypts the traffic between user machine and server Encrypted Disk for ensuring securing data at rest; Raid 10- Fault tolerant to guard against disk failures and Reverse proxy - to allow only the application traffic from the DMZ

Pandemic preparedness and response – WHO should take the lead?

Based on the perspective from Bill Gates (2020) letter entitled “Responding to Covid-19 — A Once-in-a-Century Pandemic?” world leaders are indeed in the position to improve population health, implement strategies to prevent disease and to gear up for future pandemics.³ Trans-disciplinary collaboration can conceive efficient and robust disease models with machine learning constructs to aid the conduct of trials, research, and development. However, little progress has been made in pandemic preparedness despite past incidents foreshadowing the current crisis. Collaboration, although ideal, may sometimes stifle competition, creativity, and innovation. The highest bidder often wins and the first in the race tends to put their interests before others. Striking a balance between practicality and equity is a big hurdle we have to overcome. This mammoth task will only be possible with a strong intergovernmental body, specifically the World Health Organization (WHO), and its associated governmental and non-governmental partners. The world appreciates the efforts already put in by various organizations, but we need to empower those who can truly make that ideal into reality, saving millions of lives in the future.

In conclusion, instead of focusing solely on trial results, we need to address the practical goal of population health, the prevention of the disease. World leaders need to take action and improve our response to such a crisis.³ The ball is now in our court to develop a more efficient, effective, and innovative strategy for the future, to be better equipped when the next wave hits. We as researchers and scientists need to set a ‘new normal’ for conducting clinical trials with optimal utilization of the limited resources.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.