Date: May 19, 2022
Decentralized Clinical Trials: Here to Stay?
The COVID-19 pandemic instigated many changes in the clinical research enterprise. Among them was the need to quickly pivot to remote and digital methods for human subjects research in order to reduce exposure to the virus for both researchers and study participants. For clinical trials, this shift to less face-to-face contact during COVID reignited interest in decentralized clinical trials (DCTs). Even as the pandemic wanes, the use of decentralized approaches continues to grow because of the increase in related technology and the benefits DCTs may offer over standard clinical trials. To fully realize the promise of this approach, however, there are challenges that must be addressed to ensure that full or partial DCTs produce scientifically rigorous data while appropriately protecting participants.
What is a Decentralized Clinical Trial (DCT)?
Traditional randomized controlled trials (RCTs) are “site-centric,” i.e., designed so that research activities such as enrollment, intervention administration, and follow-up testing and monitoring happen at selected study sites that are often connected with major medical centers. Participation in these trials often requires frequent travel to the study sites for enrolled patients.
While being site-centric may make it easier to standardize key study procedures in RCTs, being tied to specific geographic sites limits the feasibility of trial participation for many potential participants which, in turn, results in less participant diversity, more time required to meet enrollment goals, and increased participant attrition. A 2020 survey estimated that only about 5 percent of adults in the U.S. had ever participated in a clinical trial (1). In addition, despite efforts to diversify trial participants, standard trials continue to underrepresent women, the elderly, persons from racial and ethnic minority groups, and those with disabilities (2,3). This makes it difficult to generalize trial results and to translate findings into clinical practice. From an ethical perspective, this also means that the benefits of participating in clinical trials are not being made widely available.
By contrast, DCTs do not operate through specific research sites. Instead, they conduct research activities directly with participants through electronic methods augmented, when necessary, by the use of local health care facilities and laboratories. While interest in DCTs has been growing over the past decade, they remained less common in practice than traditional trials. However, this changed during the COVID pandemic. A recent analysis estimated that the percentage of clinical drug trials worldwide using at least some virtual methods increased almost 70 percent between 2019 and 2021 (4).
A DCT can be completely virtual or it can be hybrid with features of both a traditional and decentralized trial. For example, a trial may require that subjects be screened and enrolled at a traditional study site but allow participants to provide patient data electronically throughout the trial and to receive follow-up evaluations through a local physician.
What Are Some Examples of Decentralized Trials?
Research on Electronic Monitoring of Overactive Bladder Treatment Experience (REMOTE), a Pfizer study launched in 2011, is widely viewed as the first DCT in the U.S. (5). The study demonstrated the feasibility of enrolling and managing trial subjects remotely. Another early remote clinical study was SAGE Bionetwork’s observational study of Parkinson’s Disease symptoms that collected data via smart phones (6). In a more recent example, a team from Washington University in St. Louis successfully completed a small, placebo-controlled DCT demonstrating the potential for the anti-depressant fluvoxamine to prevent clinical deterioration in outpatients with acute COVID. Potential participants in this study were screened by email and telephone, provided informed consent electronically, received medication and self-monitoring equipment (for oxygen saturation, blood pressure, and temperature) in a package left at their door, and reported their self-monitored data back to the study team by email and phone (7).
Opportunities and Challenges for DCTs:
DCTs hold the promise of improving clinical trial performance in several key ways:
- By not restricting trials to specific geographic sites, a wider variety of patients may be encouraged to enroll. For example, reducing the need to travel to a distant site may make it more feasible for patients in rural or medically underserved areas or those with mobility issues to participate in clinical research. Not only could this change generate a more diverse group of participants, it could also lead to faster recruitment and improved participant retention.
- Collecting study data remotely, especially through digital or wearable devices, may reduce the amount of missing data because of incomplete follow-up. These methods may also increase the amount of study data, leading to a better understanding of study outcomes.
Electronic data collection technologies may also provide higher quality data.
- DCTs may more closely mimic the eventual use of the study intervention in medical care and may reduce the need to conduct pragmatic trials often used to verify efficacy in real-world medical practice settings following completion of RCTs. This may make promising treatments available more quickly.
Despite the potential of DCTs, challenges remain:
Participants in DCT’s are not as connected to investigators as those in traditional site-based trials. This may require different approaches to building and maintaining trust between participants and the research team.
Clear lines of communication and new approaches to trial monitoring will be needed to ensure on-going adherence to protocols by research team members, including local health care and laboratory personnel, all of whom may be geographically dispersed.
Ensuring subject compliance with study requirements may be more difficult to manage remotely.
Technology gaps due to uneven availability of broadband or smart devices could limit enrollment. Even with the increasing availability of the internet, lack of familiarity with technology among some populations, such as the elderly, will require the availability of strong technical assistance to educate and assist participants.
New ways to ensure appropriate management controls for study drugs will be needed as distribution and oversight will be less centralized.
With increasing electronic transmission of study information, strong data security measures will be needed to protect data at collection during storage and transmission.
Researchers will need to be aware of state laws that could impact the use of telemedicine for follow-up.
In terms of research oversight:
- It may be difficult for Institutional Review Boards (IRBs) to consider local context for DCTs that are taking place in many different locales.
- IRBs will need to consider risks associated with wearing or using digital devices, the reliability of digital data if it is used to adjust clinical care in participants, and additional privacy and confidentiality considerations related to the collection, storage, and transmission of data from remote sources. They will also need to ensure that applicable information on these risks is appropriately described during informed consent.
Current Activities and Resources:
The Food and Drug Administration (FDA) has issued three guidance documents relevant to DCTs and virtual methods:
- Use of Electronic Records and Electronic Signatures in Clinical Investigations Under 21 CFR Part 1- Questions and Answers. (Draft guidance, issued June 2017)
- Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency: Guidance for Industry, Investigators, and IRBs (Final guidance; issued March 2020, updated August 30, 2021). While primarily published as an aid to those doing clinical investigations when the pandemic started, it includes guidance on topics relevant to DCTs in the Q & A section including conducting remote clinic visits, delivering Investigational Products (Ips)) to homes, and remote clinical outcome assessments.
- Digital Health Technologies (DHT) for Remote Data Acquisition in Clinical Investigations: Guidance for Industry, Investigators, and Other Stakeholders (Draft guidance; issued December 2021).
The Clinical Trial Transformative Initiative (CTTI) is a public-private partnership established in 2007 by the FDA and Duke University that focuses on improving clinical trial quality and efficiencies. It has held meetings and published recommendations on DCTs and other trial innovations. It recently launched an online Digital Health Trials Hub with updated resources and recommendations.
The Decentralized Trials and Research Alliance (DTRA) is a newer collaborative effort between research industry, regulatory agencies, patient advocates, and clinical research site networks to accelerate the adoption of patient-focused, decentralized clinical trials and research within life sciences and healthcare. DTRA is focusing on 12 initiatives in four priority areas (Definitions, Best Practices, Education, and Removing Barriers) and held its first annual conference in December 2021.
Common recommendations from various groups engaged in DCT’s include:
- Early planning and broad engagement of all stakeholders is critical.
- Early consideration of the appropriateness of DCT or digital methods for a particular study, such as:
- Study population – are they willing and able to reliably use virtual methods?
- Can inclusion and exclusion criteria be accurately determined remotely?
- Can the Intervention be administered in a decentralized model?
- For drug trials:
- Can the investigational drug be safely and reliably delivered remotely? Are there supply chain issues to consider?
Drugs that are prone to misuse, need special handling, or are difficult to administer may be less appropriate for DCTs.
- Research procedures – can they be done correctly and safely in a remote manner?
- Risks – does a DCT approach potentially increase risks and are these balanced by the trial’s benefits? Can the risks be mitigated?
- What is the availability of local laboratories proficient in the tests needed and of local health care professionals to provide appropriate clinical follow-up?
- Data security – are the methods to remotely collect, store and transmit data appropriate and secure?
- Are there any relevant state telemedicine laws where the trial will enroll subjects?
- Even trials that cannot be fully decentralized may benefit from using some remote components and/or digital technologies.
- Existing standards for data and safety monitoring with clear plans for reporting and escalation must be maintained.
- Managing a research team that is very dispersed geographically will require explicit and transparent procedures for staff training, communication, record keeping, and data security practices.
What Does the Future Hold for DCTs?
Given their possible benefits along with increasing availability of digital technologies, it is likely that DCT’s will continue to increase, along with the use of virtual methods generally in clinical studies. Thus, it will be important to continue efforts to document the impact of DCTs on key trial performance measures and to develop and evaluate solutions to barriers.
- Shaohai, J. and Hong, Y.A. Clinical trial participation in America: The roles of eHealth engagement and patient–provider communication. Digital Health. Published online December 14, 2021.
- Global Participation in Clinical Trials, 2015-2016. FDA Report, July 2017.
- Singh H, Kanapuru B, Smith C, et al. FDA analysis of enrollment of older adults in clinical trials for cancer drug registration: a 10-year experience by the US Food and Drug Administration. J Clin Oncol. 2017;35(15 suppl):10009.
- Parker, K .and Hillman, A. 2022 Forecast: Decentralized Trials to Reach New Heights with 28% jump. Clinical Trials ARENA. Published online December 14, 2021.
- Orri, M., et.al., Web-based trial to evaluate the efficacy and safety of tolterodine ER 4 mg in participants with overactive bladder: REMOTE trial. Contemp Clin Trials 2014 Jul;38(2):190-7. Epub 2014 May 2.
- Bot, B. M. et al. The mPower Study, Parkinson Disease Mobile Data Collected Using ResearchKit. Sci. Data 3:160011(2016).
- Lenze, E.J., et. al. Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients with Symptomatic COVID-19: A Randomized Clinical Trial. JAMA. 2020;324(22):2292-2300. doi:10.1001/jama.2020.22760