Clinical Researcher—August 2024 (Volume 38, Issue 4)

PEER REVIEWED

Casey Halle, MCR; Esther Chipps, PhD, RN, NEA-BC, FAONL

 

 

 

Decentralized clinical trials (DCTs) have emerged in popularity in the clinical research industry in recent years. Advantages and disadvantages to this clinical trial operations model are described here through the lens of quality management, participant outcomes, and data management. Furthermore, U.S. Food and Drug Administration (FDA) guidance on DCT operations is summarized as related to each of the corresponding deliverables. DCTs are not intended to replace the traditional site model, but can be used in conjunction with traditional site models to diversify enrollment and data. Overall, this review serves as an observation on decentralized trial impact on industry trends, sustainability, and outcomes.

Background

Traditional clinical research trials are conducted at research sites such as academic hospitals, outpatient research clinics, or private provider offices. This is referred to as the standard “brick and mortar” site model, which has lost popularity in the new age of DCTs. There is no central site or location in the DCT model, allowing subjects to participate from within their own homes. In this model, access to a clinical trial is brought to the participant by way of telehealth, mobile healthcare staff, and shipment of clinical visit supplies and investigational product. The decentralized model increases healthcare access and equity in clinical trials, as it does not discriminate participation based on proximity to an enrolling traditional site location. (Apostolaros et al., 2019)

The decentralized model has existed for slightly more than a decade, with Pfizer sponsoring the first fully decentralized trial in 2011. (Petrini et al., 2022) The model surged in popularity in the wake of the COVID-19 pandemic beginning in 2020, and its success has led to the long-term sustainability of decentralized trials. However, there are advantages and disadvantages to this model of clinical trial delivery, as described in the following sections.

Quality Management

FDA Guidance

Despite such trials being piloted more than a decade earlier, the FDA did not release formal guidance on “[DCTs] for Drugs, Biologic Products, and Devices” until May 2023. This document also serves as a reference for hybrid or partially decentralized trials, where only certain activities are conducted remotely. Primarily, the guidance states that regulatory requirements for decentralized trials are identical to those used for traditional onsite clinical trials. Standard requirements regarding documentation, adverse event management, and licensing of staff and laboratories must be followed. All regulatory documents are required to be in the investigator site file (ISF) and maintained physically and/or electronically. (FDA, 2023)

When deciding if a trial is appropriate for the decentralized model, the FDA recommends considering whether the investigational product or device is simple to administer or use, has a well-characterized safety profile, and does not require complex medical assessments. On the other hand, investigational products with complex administration procedures, high-risk safety profiles, or are in early development may need in-person supervision by investigators at a trial site.

This guidance does not specifically state what phase, indication, or formulation of products are not recommended. However, it can be inferred that Phase I and II trials are not well suited for decentralization, as safety is a main endpoint of consideration in those trials. Phase III and IV trials are more appropriate for use in decentralized trials as safety profiles are better established, and further efficacy or post-marketing surveillance data are being collected. Investigational products such as gene therapy, biologics, and devices that are injected or implanted are not suitable for decentralized trial use. (FDA, 2023)

To assess the appropriateness of decentralized trial utilization, product safety profiles are used to consider the risk of hypersensitivity, abuse potential, and the type of trial (such as dose escalation). Additionally, the FDA only recommends investigational products with high stability through shipment excursion and long shelf lives as suitable for decentralized trial use. Only devices that can be used over the counter are considered suitable for decentralized trial utilization. Devices that would be used in ambulatory or hospital settings are not recommended for decentralized utilization. As required with any trial, accountability and documentation of all investigational products and devices shipped and received are required, and centralized distribution of these products is recommended. (FDA, 2023)

Digital Tools

The execution of successful decentralized trials relies on the use of many digital applications and tools. One of the most popular digital applications, although not exclusive to decentralized trials, is electronic consent (eConsent). eConsent forms are regarded as positive as they are easy to file, retrieve, and reference. (Petrini et al., 2022) However, eConsent forms can also pose challenges to certain populations, including the elderly, those with low technology literacy, or those without a personal device.

The digitization of eConsent can improve the quality of the informed consent process by providing prospective subjects with a user-friendly platform to reference before the consent visit, along with digital education material. (Harmon et al., 2023) Per the FDA guidance, eConsent forms must contain the site investigator’s contact information for research questions and to report any research-related injuries. Furthermore, eConsent forms are also used to notify subjects of all bodies that will have access to their digitized trial data and personal health information. (FDA, 2023)

eConsent forms require institutional review board (IRB) approval, just the same as physical consent forms, and it is essential to ensure the digital modality used is in compliance with the Health Insurance Portability and Accountability Act (HIPAA). (Apostolaros et al., 2019) eConsent platforms must have data security measures and safeguards in place to ensure forms and subject personal health information (PHI) are confidential and secure. (Petrini et al., 2022) Real time date and time stamps can also improve the quality of the informed consent process for accurate signature information. The United States and the FDA consider electronic signatures legally valid, and eConsent signatures are no exception. (Vayena et al., 2023)

Digital clinical trial assessments are commonly known as electronic patient-reported outcomes (ePROs) and electronic clinical outcomes assessments (eCOAs). Active reported outcomes include participants directly entering data into survey forms at scheduled time periods. This improves data quality because participants can truthfully answer questions with no reporting bias or perceived pressure from study staff. This allows participants to take a more active role in the trial while promoting retention. (Petrini et al., 2022) Therefore, ePRO and eCOA can improve quality by allowing participants to take more ownership and authority of their data reporting in an easily accessible digital location.

ePRO and eCOA reports do require review for quality control by study staff to ensure that data collection is accurate and complete. Additionally, the use of digital assessments can increase enrollment retention due to convenience to participants, and can improve compliance and quality of study data collection. (Norman, 2021)

Review Boards

Decentralized trials utilize fewer IRBs because regulatory documents and patient-facing materials are standardized across the study, without site-specific differences. (Noman, 2021) Central IRBs are utilized and can improve data quality with standardized approval processes, communications, and timelines. Central IRBs also reduce redundant resubmissions to multiple IRBs at the site level. This reduces costs while improving the ability for sponsors to pivot based on trial needs, and to submit protocol amendments with streamlined timelines. Overall, central IRBs improve data quality in DCTs with standardized approval, communication, and adaptability to evolving trial needs. (Noman, 2021)

Participant Outcomes

DCTs utilize telehealth, mobile healthcare providers, and central labs to conduct clinical research visits. This method allows subjects to have more flexibility over trial participation schedules to reduce the burden of travel, work, etc. The FDA guidance also praises decentralized trials for the ability to expand access to participation and improve clinical research diversity and robust data collection. Therefore, enrollment and retention in clinical trials can be superior in the decentralized model. (FDA, 2023) In this model, investigational products are shipped to subjects’ homes from central pharmacy or device vendors. Additionally, mobile healthcare providers can travel to participants’ homes to collect and ship labs, perform exams, and complete drug accountability. (Vayena et al., 2023)

While the use of telehealth allows the investigator and the subject to be in different physical locations, the investigator still must be licensed in the states in which the subjects reside. For example, some decentralized clinical research companies will have investigators licensed in several states, including up to all 50 states in the U.S. This allows for subjects to be recruited and enrolled in all states for DCTs in accordance with investigator licensing regulations. However, this also requires close regulatory monitoring of all investigator state licensing and expiration dates in order for renewals to be managed on time and in compliance with legal and regulatory guidelines. (Apostolaros et al., 2019)

Participant experience on a trial can also be improved in more ways than just convenience in the decentralized trial model. For example, comfort levels in the home and investigational product education and adherence training in the environment in which the product will be used can improve subject confidence and adherence. Additionally, DCTs require more subject responsibility with remote reporting of adverse events, with training of methods and technology to report these events. This training for self-advocating can assist with participants feeling more autonomous and comfortable with participating in the decentralized trial. (Apostolaros et al., 2019)

Decentralized trials do come with some drawbacks to participants. Primarily, the remote investigator is likely a provider they have never met and who is not well acquainted with their medical history. Subjects may feel less comfortable sharing their medical history and current condition with a new provider, and the relationship may be limited to medical record review and standard clinical trial outcome reporting. Additionally, there can be limitations based on states where investigational products cannot be shipped directly to subjects. Lastly, subjects may not be able to participate based on investigator licensing limitations and mobile healthcare provider travel restrictions, such as in more remote states with lower populations. (Apostolaros et al., 2019)

Case Study

STOPCoV, a recent study that highlights the successful implementation of the DCT model, was developed to assess the long-term antibody response of preventative COVID-19 vaccines, and to collect data to inform booster decision analysis. This study utilized remote recruitment, eConsent, ePROs, at-home sample collection devices, and satisfaction surveys. Overall, this decentralized study demonstrated the ability to quickly recruit, enroll, and complete the clinical trial with a diverse and satisfied participant pool. The performance metrics of this study included: 95% of the participants were satisfied with their participation in the decentralized trial, 90% of participants viewed the eConsent and ePRO as easy to use, and 37% of participants reported enrolling as a result of the convenience of completion in their home. This study highlights alignment with FDA guidance with post-marketing surveillance data being collected, digital tool utilization, and enhanced recruitment and enrollment performance metrics. (Ravindran et al., 2023)

Data Management

Introduction and Utilization

Clinical trial data are paramount to both the sponsor and the FDA in determining if an investigational product shows statistical significance in terms of safety and efficacy. Important considerations must be made to secure data collection and management to protect the proprietary data for sponsors, and the safety and privacy of the participants in the trial. (Petrini et al., 2022)

With decentralized trials being conducted without a central site or location, the way in which data are collected, integrated, and utilized has been transformed from traditional clinical trial models. DCTs are also referred to as digital trials because they operate with all data collection online throughout recruitment, enrollment, and closure of the clinical trial. (Harmon et al., 2023) The FDA has also provided guidance on software considerations for sponsors in a decentralized trial, in that it can be used on a variety of platforms and support multiple trial operations. The FDA states that tablets, cell phones, and personal computers can be utilized for operations in decentralized trials; however, this must be outlined in the sponsor’s data management plan to account for all methods of data collection and platform utilization. (FDA, 2023)

Beyond the aforementioned eConsent and ePROs, recent digitization processes that are standard in decentralized trial conduct include smartphone applications and wearable technology. (Harmon et al., 2023) Some electronic data collection is active, such as signing consent or completing ePROs where the participant actively answers questions and completes the data collection fields. Other data collection can be passive, including data collected from consented wearables, such as heart monitors. Additionally, participants must be informed of the risks with electronic data collection and management, and details about who will have access to the participants’ data must be disclosed. (Petrini et al., 2022)

HIPAA and the FDA

When participants utilize technology that collects PHI, data security precautions must be in place. (Petrini et al., 2022) The aforementioned HIPAA does not define the terms of decentralized or virtual clinical trials. (National Academy of Sciences, 2019) However, research is defined as a systematic investigation and DCTs can reasonably be categorized under research operations. Additionally, HIPAA regulations do apply to all of the clinical trial data collected by the investigator, regardless of whether they originated from a participant’s smartphone or a study-issued device. (National Academy of Sciences, 2019)

Leonard Sacks, Associate Director for Clinical Methodology with the FDA, has stated that existing regulations need to be applied to the data that remote technology produces in the interest of patient safety, privacy, and data integrity in technology-enabled decentralized trials. (National Academy of Sciences, 2019) It is critical that participants are adequately informed at the time of consent of the intended use and risks associated with their data collection in any clinical trial model. Data integrity and safety must be considered during all phases of the clinical trial. Furthermore, the risk of unintentional data disclosure or breach of privacy are real-world threats to PHI and data. However, training and precautions can be well implemented in attempt to avoid these occurrences, and are equally important among all clinical trial models. (Petrini et al., 2022) 

Monitoring

Monitoring is just as important in decentralized trials as in traditional models, in order to assure complete and quality trial execution. Source data in DCTs, where the clinical trial data are initially recorded, are entered into an online source data collection form. Data are then entered or integrated into larger electronic data capture (EDC) systems where queries can be generated on large datasets. (National Academy of Sciences, 2019)

The FDA requires sponsors to ensure proper monitoring of an investigation, as highlighted in the DCT guidance. (FDA, 2023) With the emergence and popularity of DCTs, a parallel relationship has emerged in decentralized risk-based monitoring. In the FDA guidance for industry, risk-based monitoring with reduced source data verification (SDV) has become more widely acceptable as opposed to conventional 100% SDV requirements. (FDA, 2013) Risk-based monitoring has grown in popularity with DCTs as centralized online source documentation and EDCs allow for large dataset trend analysis. (Williams et al, 2021)

Closing Thoughts

DCTs have gained popularity in the industry with the ability to recruit more participants from diverse geographical areas more quickly and with less burden to participate. This has caused innovation and adjustments in the operations of data, quality, and participant experiences. There are advantages and disadvantages to decentralized trial delivery; consideration of FDA guidance must be taken into account for the suitability of this model based on the clinical trial model, phase, and indication. It is prudent during protocol development and study design for assessment of appropriate use in the decentralized model. This is not an all-encompassing review of DCTs, as new protocols, treatment methods, and delivery models are constantly evolving in the industry. This is an overview of main deliverables and how decentralization impacts those outcomes.

Works Cited

Apostolaros M, Babaian D, Corneli A, Forrest A, Hamre G, Hewett J, Podolsky L, Popat V, Randall P. 2019. Legal, Regulatory, and Practical Issues to Consider When Adopting Decentralized Clinical Trials: Recommendations from the Clinical Trials Transformation Initiative. Therapeutic Innovation & Regulatory Science 54(4):779–87. https://doi.org/10.1007/s43441-019-00006-4

Harmon DM, Noseworthy PA, Yao X. 2023. The Digitization and Decentralization of Clinical Trials. Mayo Clinic Proceedings. https://doi.org/10.1016/j.mayocp.2022.10.001

Mehta P, Zimba O, Gasparyan AY, Seiil B, Yessirkepov M. 2023. Ethics Committees: Structure, Roles, and Issues. Journal of Korean Medical Science 38(25). https://doi.org/10.3346/jkms.2023.38.e198

National Academies of Sciences, Engineering, and Medicine Forum on Drug Discovery, Development, and Translation and Board on Health Sciences Policy, Health and Medicine Division. 2019. Virtual Clinical Trials: Challenges and Opportunities, Proceedings of a Workshop. Edited by Alper J, Khandekar E, Shore C. Washington, D.C.: National Academies Press. https://nap.nationalacademies.org/read/25502/chapter/1

Petrini C, Mannelli C, Riva L, Gainotti S, Gussoni G. 2022. Decentralized Clinical Trials (DCTs): A Few Ethical Considerations. Frontiers in Public Health 10. https://doi.org/10.3389/fpubh.2022.1081150

Ravindran R, Szadkowski L, Lovblom LE, Clarke R, Huang QW, Manase D, Parente L, Walmsley S. 2023. Decentralized Study of COVID Vaccine Antibody Response (STOPCoV): Results of a Participant Satisfaction Survey. PLOS Digital Health 2(5):e0000242. https://doi.org/10.1371/journal.pdig.0000242

U.S. Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Center for Devices and Radiological Health (CDRH), Office of Good Clinical Practice (OGCP), and Office of Regulatory Affairs (ORA). 2013. Guidance for Industry Oversight of Clinical Investigations—a Risk-Based Approach to Monitoring. https://www.fda.gov/media/116754/download

U.S. Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Center for Devices and Radiological Health (CDRH), and Oncology Center of Excellence (OCE). 2023. Decentralized Clinical Trials for Drugs, Biological Products, and Devices Guidance for Industry, Investigators, and Other Stakeholders Draft Guidance. https://www.fda.gov/media/167696/download

Van Norman GA 2021. Decentralized Clinical Trials. JACC: Basic to Translational Science 6(4):384–7. https://doi.org/10.1016/j.jacbts.2021.01.011

Vayena E, Blasimme A, Sugarman J. 2023. Decentralised Clinical Trials: Ethical Opportunities and Challenges. The Lancet Digital Health. https://doi.org/10.1016/s2589-7500(23)00052-3

Williams EL, Pierre DL, Martin ME, Beg MS, Gerber DE. 2021. Taking Tele behind the Scenes: Remote Clinical Trial Monitoring Comes of Age During the COVID-19 Pandemic. JCO Oncology Practice 17(9):577–9. https://doi.org/10.1200/op.21.00524

Casey Halle, MCR, (caseyhalle@gmail.com) is a Clinical Research Associate at Beckman Coulter Diagnostics, and previously worked at Science 37 and Nationwide Children’s Hospital. Earlier this year, she earned her Master of Science degree in Applied Clinical and Preclinical Research from The Ohio State University.

Esther Chipps, PhD, RN, NEA-BC, FAONL, (Chipps.1@osu.edu) is Professor of Clinical Nursing at The Ohio State University College of Nursing and a Clinical Nurse Scientist at The Ohio State University Wexner Medical Center.