The 3 Big Downsides To DCTs

By James Gillespie, Ph.D., and Gregory Privitera, Ph.D.

Decentralized clinical trials (DCTs) are increasingly used by sponsors and CROs, with the COVID-19 pandemic having rapidly accelerated that trend. In fact, hybrid or fully virtual modalities are now becoming the norm rather than a crisis-driven exception. DCTs offer several potential benefits. However, the industry should be thoughtful as it embraces decentralization. We discuss three overlapping categories of concern: (i) consent and selection, (ii) user experience, and (iii) comfort and privacy. Without disputing their many conceptual and practical advantages, we believe the potential downsides of DCTs merit consideration by sponsors, CROs, investigators, patients, and communities. Addressing these concerns will allow us to move toward an environment where DCTs even more strongly promote effectiveness, efficiency, and equity in clinical trials.

Growth In Decentralized Clinical Trials

DCTs are increasingly popular in medical scientific research, and there are four overall drivers. First, beginning with the COVID-19 crisis, sponsors were compelled to adopt virtual versions of consent agreements, data collection, and patient monitoring. Up to that point, electronic data capture (EDC), electronic clinical outcome assessments (eCOA), and electronic informed consent (eConsent) all paved the way for DCTs. Second, regulatory authorities have encouraged experimentation with DCTs. Third, patients and providers today are now considerably more comfortable using technology, including telemedicine. Fourth, there has been a remarkable advance in the available hardware, software, and systems, with the proliferation of cloud computing, highspeed home internet, home delivery services, and the Internet of Things (IoT). As a result, use of DCTs is increasingly normalized. Sponsors and CROs are now conducting more hybrid trials than traditional site-based trials, with over 1,300 trials having a substantial virtual component.¹ In this paradigm change, the industry shifted from asking, “Can we decentralize?” to “How do we best decentralize?”

To answer the latter, it helps to understand that the FDA defines DCTs as trials conducted via telemedicine and by mobile/local healthcare providers, using processes and technologies differing from the traditional clinical trial model.² Decentralization does not necessarily mean site-less. Instead, it means localization, with the trial “site” being closer to the patient. DCTs can leverage private homes/residences, as well as community-based providers, including ambulatory clinics, imaging facilities, laboratory centers, and neighborhood pharmacies. In a completely decentralized trial, all steps (including identification, recruitment, treatment, data retrieval, and analysis) are done remotely. In a hybrid trial, there is a mix of in-person and virtual. DCTs typically fall along a continuum rather than being completely virtual.

Globally, regulatory authorities have been supportive of DCTs. In the U.S., the FDA has developed resources for sponsors, investigators, and patients regarding DCTs, including regulatory guidance on the deployment of digital tools for informed consent, monitoring safety remotely, and clinical endpoint assessment.³ FDA Commissioner Robert M. Califf, MD, has said, “Decentralized clinical trials may enhance convenience for trial participants, reduce the burden on caregivers, expand access to more diverse populations, improve trial efficiencies, and facilitate research on rare diseases and diseases affecting populations with limited mobility.”⁴  The European Medicines Agency (EMA), European Commission (EC), and Heads of Medicines Agencies (HMA) have also issued a series of recommendations regarding decentralized clinical trials, providing guidance on data integrity, patient safety, and key subjects.

Despite the growth trends and regulatory support, decentralized trials do have potential downsides.

Consent And Selection Challenges

With regard to enrollment consent, it is essential to establish the conditions for autonomous decision-making. In the traditional clinical trial, the opportunity to participate is usually presented and explained in person by the healthcare provider or study coordinator. Consent is then typically obtained at that time or in a subsequent face-to-face meeting. The trial process would then involve researchers testing a new drug on a group of people traveling to a single location such as an academic medical center, hospital, or research center. Given the absence of direct human contact in a DCT, consent via electronic means must guard against three heightened dangers of (i) the person giving consent does not match the identity of the participant (i.e., consent by imposter), (ii) the participant provides consent that is impacted by undue influence (i.e., consent by coercion), and (iii) the participant provides consent but lacks a full understanding of what they are agreeing to (i.e., consent by ignorance).

Inherent to e-consenting is the understanding that a key reason DCTs can be so effective is that tablets, as well as smartphones, wearables, and other ubiquitous devices can be used to transmit information. But, because DCTs necessarily rely on technology, the clinical trial participants may skew more technology savvy (often meaning younger) than the actual patient population. Some potential participants might be discouraged to enroll if they are not familiar with digital tools or have internet connectivity issues, thus exposing a systematic exclusion of certain demographic groups. This multi-fold digital divide also can be geography-based because of insufficient high-speed internet in rural areas and demographic-based, with those who are elderly, less educated, and in a lower socioeconomic status tending to be less tech savvy.

Technological advancement also can skew site selection. We have to protect against DCTs generating a race to develop and implement the most advanced technology, which makes integration, standardization, and user understanding even more challenging. Also, DCT technology can change from trial to trial. Because of the extra initial startup costs and time commitments required for DCTs, including extra investments in personnel training, software/hardware infrastructure, data privacy/security measures, and data processing/storage requirements, smaller sponsors and research sites with less robust resources may be unable to participate. They are essentially “priced out” of DCTs.

Because of these skews, we should not assume that DCTs will automatically increase access to clinical research for all, especially minority and underserved populations. Instead, the methods, procedures, and processes need to be critically examined to see whether DCTs help address the long-standing structural issues regarding lack of inclusivity in clinical trials. The evidence remains inconclusive.⁵ In fact, because of the reduced face-to-face human interaction, the shifting of some logistical burdens from investigators to participants, and the typically more frequent monitoring/self-reporting, DCTs hold the potential to increase rather than decrease mistrust of clinical trials and scientific experimentation held by many communities.

User Experience Challenges

Participants must learn how to use technologies properly and safely. Traditional clinical trial systems can be difficult to understand even for highly trained health professionals. Some potential participants may also be uncomfortable with using new technologies, such as wearable sensors. Devices can present obstacles to those with mental or physical impairments, and elderly participants may have dexterity or perceptual challenges (e.g., hearing or vision impairment). Depending on the quality of external connections, patients may not be able to easily enter or upload data, and if patients cannot see the data via a dashboard or other effective summary, they may not feel as engaged.

Participants may also prefer face-to-face interactions with clinical professionals, as they can provide comfort and reassurance, but DCTs provide reduced opportunities for direct interaction between participants and healthcare professionals. This limited physical contact has the potential to negatively impact the robustness of safety monitoring and overall patient engagement. Although study participants may be motivated to enroll in DCTs, it can be a potentially greater challenge regarding motivation, engagement, and retention, given the reduced direct contact with healthcare personnel.

With DCTs, we have to carefully monitor unintended use of medicinal products. For example, as is usual, if an investigational drug is being taken by the patient as part of a clinical trial, the drug is traditionally administered during the participant’s visit to the clinic, hospital, lab, pharmacy, or other facility. A skilled health professional can ensure that the dosage, timing, and administration modality are all correct. In the case of a home-based study where the drug is shipped to the patient and self-administered, the potential for unintended error increases. It also can be more difficult for patients to get medical advice and attention in real time. Thus, it is important to carefully track patient conditions for adverse reactions. This risk rises if a procedure is more complex or invasive, so there should be convenient, timely medical consultations and other online help available for participants.

Comfort And Privacy Challenges

Some elements of a DCT would require a healthcare professional to visit a participant’s home. But often, trial participants prefer that the clinical trial process not come into their home, as it’s often the primary emotionally/psychologically safe space to retreat from healthcare problems. Also, there are often other people closely interacting with and even living with participants; for example, a friend or family member might be present while study-related activities are occurring. Given certain stigmatized health conditions, some participants face increased privacy-related risks as they may not want family, friends, or neighbors to know about a sensitive medical condition.

Basic logistical challenges include the need to store and perhaps even transfer physical outputs (e.g., blood or stool samples). In DCTs, patients take on more responsibility for safe handling, storage, administration, and disposal/return of investigational products, whether devices or drugs. Sponsors, CROs, and investigators need to maintain proper hygienic conditions to minimize the risks to participants’ safety related to a sampling procedure, particularly regarding biological specimens. There are also added data security dimensions. Collecting sensitive medical information from multiple remote sources requires effective data management platforms and skills, as well as the use of digital tools (e.g., apps, web-based interaction, wearables), which have potential to increase cybersecurity risk. Thus, we have to prevent unauthorized data use, and that risk is often greater in the DCT context.

Finally, we have to protect participants against excessive data collection. If cameras, wearables, and other connected devices are being used to “unobtrusively” collect data, we have to guard against the reality or the perception of constant surveillance. In addition, we have to be careful not to overburden participants with virtual notices as a way to compensate (actually overcompensate) for the lack of in-person interaction. Excessive reminders and requests can be intrusive and even harassing, and the burden to continually use their wearables and in-home devices can impose a mental toll on participants. At the start of the trial, participants have to devote extra, uncompensated energy and time to learn DCT systems and technology, and as it continues, they may be asked to complete study procedures that otherwise would have been completed by an in-person healthcare professional. To avoid unintentional exploitation of participants’ energy, time, and other resources, study leaders have to carefully evaluate direct and indirect costs.⁶

Final Thoughts On DCTs

The choice to use a DCT should be subject to careful consideration. Greater vigilance and careful cost-benefit assessments of risk are required to minimize the additional equity, medical, privacy, and security issues posed by DCTs. We also need rigorous randomized controlled trials comparing DCTs to traditional in-person clinical trial methods in terms of convenience, cost, and clinical efficacy. To promote interoperability and user experience, sponsors, CROs, sites, and technology providers should establish standardized platforms and solutions that are flexible, transparent, easy-to-use, and simple-to-deploy. With continued evaluation and optimization, DCTs will continue to have a positive impact on the clinical trial ecosystem.

Resources:

1. https://www.centerwatch.com/articles/25878-hybrid-trials-may-overtake-traditional-studies-in-2022-new-data-show
2. https://www.fda.gov/drugs/news-events-human-drugs/evolving-role-decentralized-clinical trials-and-digital-health-technologies
3. Decentralized Clinical Trials for Drugs, Biological Products, and Devices; Draft Guidance for Industry, Investigators, and Other Stakeholders; Availability https://www.federalregister.gov/documents/2023/05/03/2023-09399/decentralized-clinical trials-for-drugs-biological-products-and-devices-draft-guidance-for-industry A Notice by the Food and Drug Administration on 05/03/2023
4. https://www.fda.gov/news-events/press-announcements/fda-takes-additional-steps-advance-decentralized-clinical trials
5. Dahne J. and Hawk L. Health Equity and Decentralized Trials. JAMA. 2023 Jun 20; 329(23):2013-2014. doi: 10.1001/jama.2023.6982. PMID: 37261810
6. Vayena, E., Blasimme, A., and Sugarman, J. "Decentralised clinical trials: ethical opportunities and challenges." The Lancet Digital Health (2023)

About The Authors

James Gillespie, Ph.D., is a researcher and scholar in healthcare and life sciences, with extensive experience building collaborative stakeholder relationships across the private and public sectors. He is a faculty member in business and management at Saint Mary’s College and cofounder of the nonprofit Center for Healthcare Innovation. His education includes Northwestern University Ph.D., Harvard University JD, and Princeton University MPA.

Gregory Privitera, Ph.D., is a professor at St. Bonaventure University where he teaches interdisciplinary courses across psychology, business, analytics, and public health. He is a recipient of their highest honor for teaching and for scholarship. Privitera is a nationally awarded author, having published over four dozen texts in fields of methodology, analysis, health, and healthcare; his best-selling statistics text is now nominated for the 2024 lifetime achievement “Texty” award. His research is highly collaborative, having received national recognition by the American Psychological Association with two papers also nominated for an Ig Nobel Prize.