The covid-19 pandemic has caused widescale disruption to global biomedical research activities. These have been acutely felt within clinical trials which were otherwise active, with most research on other conditions stopping. The post-covid-19 research era will entail a very different set of operational restrictions, including significantly reduced funding. Inefficiencies are already considerable within healthcare research, with 85% of money wasted according to a 2009 estimate. [1] The reasons for this are multifactorial, but trial design and methodology limitations, in addition to poor recruitment and retention contribute significantly. [1-3] In our view, virtual trials could help address these problems. A virtual clinical trial is one where patient assessment and data collection do not occur in traditional settings, such as a health centre or hospital, and are instead facilitated via remote interaction.
In response to covid-19, the Food and Drug Administration (FDA), alongside international counterparts, have developed guidance to protect both research participants and trials by advocating for remote data collection supplemented by telemedicine. [4] Before the pandemic, however, virtual integration of clinical trials was already ongoing. Over 1170 studies starting in 2017 and registered on clinicaltrials.gov incorporated connected digital products to facilitate remote data collection. [5] While necessitated by covid-19, incorporating virtual design elements within a clinical trial can provide supplementary benefits beyond the current climate. Stephen Hahn, the FDA commissioner, recently supported retaining aspects of virtual trials post-covid-19: “it could really help us expedite and maybe we get that cycle time even shorter if we use some of these processes moving forward, he said. [6]
Systematic reviews identifying barriers to clinical trials highlight that one factor in poor recruitment and retention rates are the burdens placed on participants through additional on-site appointments or procedures. [7,8] In-person visits may place financial, physical, and time pressures on individuals, leading to reduced participation and greater loss from follow up. [7,8] A feasibility study of remote research visits in Parkinson’s Disease patients demonstrated high satisfaction with participation, and increased reported willingness and ability to participate in trials with remote data collection. [9] Ultimately this may present opportunities to make trial design more patient-centric.
While virtual monitoring through wearable technologies may be a passive process, remote trials may require participants to play an active role in their own data collection. [10] This may not be intuitive for all sections of society, particularly those from a low socioeconomic background, as well as older individuals. These groups commonly have the most complex health needs and barriers to their participation and need to be considered carefully during protocol design to ensure virtual trials remain representative.
Virtual trials confer additional benefits by facilitating recruitment across a greater geographic radius while retaining the investigative team at one site. This can decrease associated administrative burdens and lead to faster initiation of the trial. AT-HOME-PD, a fully-virtual extension of two phase III clinical trials, was able to recruit participants within 6 months of funding. [11] These benefits keep the costs lower than traditional research approaches. In countries with national registries which facilitate patient linkage, such as the Clinical Practice Research Datalink in United Kingdom, the integration of virtual trial data with patient health records would offer a number of advantages, including in trial recruitment and follow-up.
Decentralisation of trial design widens the scope for collecting novel outcomes and biomarkers. These can be defined according to where (healthcare setting/at home) and how (in-person/fully virtual) the data is collected. [10] Moving into the community and reducing researcher input can facilitate near-continuous data collection complementing discrete endpoints traditionally captured through on-site visits. A study incorporating wearable accelerometers, for example, discovered that participants with Huntington’s disease had low activity levels whereby monitoring for effects on activity may be a valuable patient-centric outcome. [12]
Remote data collection has limitations however and can generate its own problems. Arguably the most important aspect of trial design is hypothesis generation and investigators need to ensure that their methodology is hypothesis-driven, rather than by the availability of technology. For some clinical questions, remote data collection may not be appropriate. Furthermore, while it may be acceptable to collect certain endpoints remotely, an appropriately validated instrument may not exist. Trial setting should be thought of as a modular process whereby virtual endpoints can be integrated to reduce patient-burden, but physical aspects retained if required to ensure study validity.
Current disruption to clinical research presents an inflection point, introducing an opportunity to adopt novel technologies and methodological approaches to improve clinical trials. The benefits of virtual trials extend to patient recruitment, engagement, retention, and data collection with favourable effects on trial duration and costs. While covid-19 has resulted in the greatest global disruption to clinical research since the Second World War, the widespread implementation of virtual trial designs may mitigate some of the significant challenges ahead. It is imperative that we embrace some of these unexpected opportunities for innovation as we transition to the new normal.
Simon Erridge, Clinical Research Fellow, Department of Surgery and Cancer, Imperial College London. @Simon_Erridge
Azeem Majeed, Professor of Primary Care and Head of the Department of Primary Care & Public Health, Imperial College London @Azeem_Majeed
Mikael Sodergren, Senior Clinical Lecturer, Department of Surgery and Cancer, Imperial College London @DrMSodergren
Competing interests declaration: We have read and understood BMJ policy on declaration of interests and declare the following interests: SE has performed paid consultancy work for Sapphire Medical Clinics, AM declares no competing interests, MHS has performed paid consultancy work for Verb Surgical and EMMAC Life Sciences and is co-founder of Sapphire Medical Clinics.
References:
(1) Chalmers I, Glasziou P. Avoidable waste in the production and reporting of research evidence. The Lancet. 2009; 374 (9683): 86-89.
(2) Fogel DB. Factors associated with clinical trials that fail and opportunities for improving the likelihood of success: a review. Contemporary clinical trials communications. 2018; 11 156-164.
(3) Heneghan C, Goldacre B, Mahtani KR. Why clinical trial outcomes fail to translate into benefits for patients. Trials. 2017; 18 (1): 122.
(4) de Paula BH, Araújo I, Bandeira L, Barreto NM, Doherty GJ. Recommendations from national regulatory agencies for ongoing cancer trials during the COVID-19 pandemic. The Lancet Oncology. 2020; 21 (5): 624-627.
(5) Marra C, Chen JL, Coravos A, Stern AD. Quantifying the use of connected digital products in clinical research. NPJ Digital Medicine. 2020; 3 (1): 1-5.
(6) Baumann J. Clinical Trial Tweaks Forced by Virus Should Stay, Hahn Says. Available from: https://news.bloomberglaw.com/pharma-and-life-sciences/clinical-trial-tweaks-forced-by-virus-should-stay-hahn-says [Accessed Jun 13, 2020].
(7) Ross S, Grant A, Counsell C, Gillespie W, Russell I, Prescott R. Barriers to participation in randomised controlled trials: a systematic review. Journal of clinical epidemiology. 1999; 52 (12): 1143-1156.
(8) Naidoo N, Ravaud P, Young B, Amiel P, Schanté D, Clarke M, et al. The research burden of randomized controlled trial participation: a systematic thematic synthesis of qualitative evidence. BMC medicine. 2020; 18 (1): 6.
(9) Dorsey E, Wagner JD, Bull MT, Rizzieri A, Grischkan J, Achey MA, et al. Feasibility of virtual research visits in fox trial finder. Journal of Parkinson’s disease. 2015; 5 (3): 505-515.
(10) Coravos A, Goldsack JC, Karlin DR, Nebeker C, Perakslis E, Zimmerman N, et al. Digital medicine: a primer on measurement. Digital Biomarkers. 2019; 3 (2): 31-71.
(11) National Academies of Sciences, Engineering, and Medicine. Virtual Clinical Trials: Challenges and Opportunities: Proceedings of a Workshop. : The National Academies Press, Washington, DC; 2019.
(12) Adams JL, Dinesh K, Xiong M, Tarolli CG, Sharma S, Sheth N, et al. Multiple wearable sensors in Parkinson and Huntington disease individuals: a pilot study in clinic and at home. Digital Biomarkers. 2017; 1 (1): 52-63.