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The New Normal in Clinical Trials: Decentralized Studies

2020; Wiley; Volume: 88; Issue: 5 Linguagem: Inglês

10.1002/ana.25892

1531-8249

E. Ray Dorsey, Benzi M. Kluger, Craig Lipset,

Biomedical Ethics and Regulation

As with health care delivery, coronavirus disease 2019 (COVID-19) has exposed weaknesses in clinical trials. Around the world, nearly all clinical studies were disrupted, many paused enrollment, and new trials were left on hold.1 Consequently, COVID-19 has postponed the promise of new therapies and cost the life sciences industry millions in additional costs and billions in foregone or delayed revenue. With guidance from the US Food and Drug Administration (FDA)2 and the European Medicines Agency (EMA),3 sponsors have adopted countermeasures to enable trial continuity during the current pandemic. These include in-home visits (eg, for laboratory tests and infusions), direct shipment of study materials to the participant's home, evaluations by video (eg, for rater-dependent outcomes), telephone calls (eg, for safety screening), online assessments (eg, for patient-reported outcomes), and remote patient monitoring. These measures and others mitigate the risk of skipped doses, missing data, and early study termination and have been adopted in clinical trials across disease areas, from cancer to stroke.1, 4, 5 Whereas helpful, these steps are merely temporizing. Current clinical trials have fundamental shortcomings. The cost to develop an approved therapy is between US $1 and 3 billion,6 the industry's productivity continues its decades-long decline,7 and trials only reach a small portion of interested participants.8 The COVID-19 pandemic presents an opportunity to re-envision clinical trials (Table 1), a change that is long overdue.1 Like the clinical care of patients, clinical trials should be designed around the needs and preferences of participants rather than sponsors or site. Technological innovations, such as the internet, social media, video conferencing, and smartphones, which have been long-used in other industries, allow such change. Various terms, including decentralized, direct-to-participant, and virtual studies, are used to describe such a concept.9 In general, all reflect the notion that (1) the focal point of all study activities is no longer the research site, (2) technology has enabled research to migrate toward participants, and (3) participants should have a greater voice in how and where research assessments are conducted.10, 11 These models are not new. Pfizer conducted the first randomized controlled trial of an investigational drug with no in-person site visits in 2011.12 The study used the internet for recruitment, online questionnaires for screening, electronic diaries for outcomes, and home delivery for distribution of the investigational drug. The FDA and public-private partnerships (eg, Clinical Trials Transformation Initiative) have supported or provided guidance on such studies.9 Like telemedicine for patient care, the time for these trials has arrived, and the novel coronavirus may be the forcing mechanism. Such studies offer numerous advantages over current site-based studies. First, because they are not tied to sites, they allow for a much broader pool of potential participants who can be recruited and screened online. Such screening, which can be aided by electronic health records and assess understanding of a study's aims,13 can be more efficient, safer, and ensure that only the most appropriate participants are referred for enrollment. Second, broader geographic participation allows for greater diversity in participation, improves the generalizability of results, and reduces recruitment time. Electronic consent is now increasingly available through multiple modalities (eg, online, telephone, and video) and part of many clinical studies.14, 15 Third, the potential for fewer research sites leads to fewer institutional review boards, reduced regulatory costs, lower training and monitoring expenses, and increased flexibility to make protocol changes. Fourth, a small number of investigators or a centralized group of raters can perform remote assessments leading to reduced variability and smaller studies. Fifth, video conferencing visits allow for more frequent and longer-term safety assessments. Finally, and most importantly, such studies reduce the burden on participants who often are ill, incur time and travel costs to participate, and expose themselves to health risks from investigational therapies. Although such studies will have higher costs for some assessments (eg, visiting nurses), the end result could be smaller, faster, more flexible, and less expensive trials.9 Some outdated end points (eg, certain rating scales) require in-person assessments in the clinic and can slow the adoption of decentralized trials. Digital end points, such as those derived from smartphones or wearable sensors, will enable the shift of studies away from the clinic. Although more trials are using such tools, they have yet to become mainstream. These measures can provide objective, reproducible, real-world evidence on the efficacy and safety of investigational products, are consistent with FDA guidance, and address substantial shortcomings in current clinical measures, such as those for dementia.16 Regulatory acceptance of digital end points, which has already begun,17 and studies that use them as exploratory, secondary, and primary outcome measures will help accelerate their widespread adoption. Digitally powered participant-directed studies are the right direction and may be the new reality. The course of the present pandemic is uncertain, recurrent periods of physical separation are likely, and sites may be periodically closed. Participants in clinical trials frequently have chronic conditions, often have compromised immune, respiratory, or cardiac function, and many are older. In short, they are at high risk for infection and the adverse consequences of COVID-19. Even when clinical sites open, clinical care may be prioritized over research at academic centers, participants may be wary of exposing themselves to COVID-19, and investigators may be reticent to see participants out of concern for their participants' or their own health. Moreover, the first research participant to be hospitalized with COVID-19, regardless of relationship to the clinical study, will cast a large shadow on the study sponsor, investigators, other participants, institutional review boards, and regulators. To avoid a reactive posture requiring constant ad hoc measures, sponsors, investigators, and regulators should commit to fundamental change. Decentralized trials transform not only study operations (eg, procedures, policies, and training) and partner selection (eg, digital monitoring and visiting nurses) but also the overarching clinical development plans for new medicines. These plans should also incorporate feedback from diverse stakeholders, including potential participants, to ensure that these new studies meet their needs. Perhaps most important (and often least appreciated), organizations must address cultural reticence that often creates fictional barriers and reasons to maintain the status quo. Inertia has only increased the cost of trials, excluded many willing participants, led to repeated failures especially for neurodegenerative conditions, and missed the immense benefits of technology that has transformed most other aspects of society.18 The status quo is no longer a viable option. In the near-term, studies may be designed in a site-agnostic, "location-flexible" way that permits options in where and how study assessments are conducted. This approach should leverage robust innovative end points that can be captured regardless of the participants' physical location. Allowing for assessments to be conducted at sites, in homes, or virtually will permit much needed flexibility for clinical trials given uncertainties at both the local and national level. Rapid introduction of digital end points, which are independent of research visit location, and that can be assessed alongside traditional end points, is needed for trials at almost any stage. Decentralized studies have their challenges. Many trials will still require in-person activities (eg, imaging and surgical procedures). Some of these can be conducted locally, but others may require participants to travel to where the investigational drug is delivered or the device implanted. Even for these trials, remote screening and long-term follow-up may be possible and even desirable. Remote monitoring, which can be more frequent than in-clinic assessments, can also help evaluate the safety of research participants, but more research and experience is needed. In some cases, in-person evaluation will be required. Sponsors and investigators will have to become more comfortable with having less control over studies, in part by embracing data capture strategies that maintain high quality regardless of where the data are acquired. Many activities will happen outside research clinics and in environments where they have less control, and participants have more control. Although experience with telemedicine has increased exponentially in the setting of COVID-19,19 many investigators and participants are still not familiar with remote assessments, especially in the setting of research. Additional training may be required for and appreciated by all stakeholders – from sponsors to sites to participants. Finally, a digital divide prevents many from realizing the benefits of telemedicine and is a barrier to participating in remote clinical trials. In the United States, for example, 20% of households do not have a broadband access, and 20% do not have a smartphone.20 COVID-19 is changing our society. We should now re-visit long-held views on how clinical research and trials are conducted, recognize that many of these new changes are irreversible, and embrace clinical trials that meet participants on their terms. The authors thank Emma Waddell, BA, for her assistance in the preparation of this manuscript. This publication was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number P50NS108676. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. E.R.D., B.K., and C.H.L. were responsible for the conception and design of the study. E.R.D., B.K., and C.H.L. were responsible for drafting a significant portion of the manuscript. E.R.D. has served as a consultant to 23andMe, Abbott, Abbvie, Amwell, Biogen, Clintrex, CuraSen, DeciBio, Denali Therapeutics, GlaxoSmithKline, Grand Rounds, Huntington Study Group, Informa Pharma Consulting, medical-legal services, Mednick Associates, Medopad, Olson Research Group, Origent Data Sciences, Inc., Pear Therapeutics, Prilenia, Roche, Sanofi, Shire, Spark Therapeutics, Sunovion Pharmaceuticals, Voyager Therapeutics, and ZS Consulting. He has received honoraria from the Alzheimer's Drug Discovery Foundation, American Academy of Neurology, American Neurological Association, California Pacific Medical Center, Excellus BlueCross BlueShield, Food and Drug Administration, MCM Education, Michael J. Fox Foundation, Stanford University, UC Irvine, and University of Michigan. He has received research support from Abbvie, Acadia Pharmaceuticals, AMC Health, BioSensics, Burroughs Wellcome Fund, Greater Rochester Health Foundation, Huntington Study Group, Michael J. Fox Foundation, National Institutes of Health, Nuredis, Inc., Patient-Centered Outcomes Research Institute, Pfizer, PhotoPharmics, Roche, and the Safra Foundation. Dr. Dorsey provides editorial services for Karger Publications has ownership interests in Grand Rounds, an online second opinion service. B.K. has received research support from the National Institutes of Health, Patient Centered Outcomes Research Institute, Michael J. Fox Foundation and Davis Phinney Foundation. He has received honoraria from the American Academy of Neurology, the Davis Phinney Foundation, the International Parkinson and Movement Disorders Society and the Parkinson Foundation. C.H.L. is the owner of Clinical Innovation Partners LLC, board member at Circuit Clinical and Medstar Health Research Institute, adjunct faculty at Rutgers University, and has served as a consultant to BeaconCure, Castor, Ciitizen Corp., Datavant, Edetek, Gryt Health, Habitu, HiDo, Hu-manity.co, Lokavant, Trials.ai, TrialScope, Unlearn.ai, Virtrial, Withings, and xCures.