Implementation Challenges for Hybrid and Decentralized Clinical Trials

Abstract: The transition toward decentralized clinical trials marks a paradigm shift in medical research, propelled by a commitment to innovation and patient accessibility. These models, emerging from a need to diversify participant demographics and enhance engagement, have faced challenges like industry conservatism and technology integration. Innovative blood collection solutions have emerged as a pivotal component, enabling frequent and less invasive data capture, pivotal to the success of DCTs. The future promises an increase in these patient-focused trials, driven by regulatory guidance and technological advancement, including increasingly transformative contributions from artificial intelligence (AI).

Introduction

The recent and ongoing evolution of clinical trial models over the past few decades ––particularly in the last few years –– has been a testament to the commitments to innovation and adaptability on the part of the pharmaceutical industry and the medical community. While the premise of clinical research has remained consistent — to evaluate the safety and efficacy of new treatments — its execution has undergone significant optimization as new technologies and approaches have emerged and been embraced. The most notable recent paradigm shift to transform the conduct of clinical trials was the arrival of decentralized clinical trials (DCTs). Although DCTs have received far greater attention and wider adoption of late, the underlying concept is not new, having emerged from the need to make clinical studies more patient-centric and accessible, thus improving participation rates and the diversity of patient populations, as well as reducing patient dropouts and trial failures.

In traditional clinical trial models, participants are required to frequently travel to central sites, a process that can disrupt their schedules and presents accessibility challenges.  This is especially cumbersome for trials investigating rare diseases with geographically dispersed patient populations. In addition, such barriers can lead to a lack of diversity among study participants, potentially affecting the understanding of a therapy’s varied impacts across different population groups. DCTs, by contrast, harness patient-centric methods like direct-to-patient (DTP) supply of drugs and ancillary supplies and direct-from-patient (DFP) delivery of samples, home healthcare services, and digital technologies, such as mobile health apps, wearable devices, telemedicine, and remote monitoring tools, to bring the trial directly to participants, irrespective of their location. This methodology is not just a patient-centric advancement that can reduce the burdens of clinical trial participation; it is transforming how clinical data is collected, with real-time data offering a more dynamic and accurate reflection of a treatment’s performance in diverse, real-world settings.

The roots of DCTs lie in earlier efforts to incorporate electronic data capture and telehealth components into trial design. However, the widespread adoption of DCTs, as well as hybrid clinical trials, which combine aspects of centralized and decentralized models, was propelled by the exigencies of the COVID-19 pandemic, which drove a rapid reimagining of clinical research methodologies. During this period, even industry stakeholders who previously had reservations about the shift witnessed the resilience of decentralized approaches, which allowed for the continuation of trials that would have otherwise been paused or canceled during the global crisis. The learning curve was steep, but the eventual success stories have made a compelling case for the broader adoption of DCTs.

The advantages of DCTs extend beyond mere convenience. They embody a more inclusive approach to clinical research by enabling individuals from a variety of demographic backgrounds, including those from remote or underserved regions who have traditionally been underrepresented in clinical research, to participate. Additionally, DCTs can lead to more efficient enrollment and higher retention rates and may contribute to cost reductions associated with site infrastructure and participant travel reimbursements.¹ The rich, diverse data sets derived from these trials can enhance the understanding of a treatment’s effectiveness across different populations, leading to more robust and generalized findings. This panoply of benefits has led to enthusiasm for DCTs among regulators like the U.S. Food and Drug Administration (FDA). In May 2023, the FDA’s guidance on decentralized clinical trials became a beacon for the industry, signaling a clear commitment to support this innovative approach.²

Despite the promise and potential of DCTs, their adoption has not come without challenges. Industry conservatism, coupled with a learning curve associated with new digital tools and methodologies, still tempers wider implementation, as does challenges associated with remote sampling and monitoring for which novel solutions have yet to emerge. However, continued encouragement from regulatory authorities, concerted educational efforts from clinical research organizations and digital solution providers, and the growing evidence of successful DCT outcomes are collectively driving the clinical trial landscape toward a more decentralized future.

Challenges of Decentralization

The first roadblock in the transition from traditional trials to DCTs –– which is still a work in progress –– was overcoming the inertia associated with a well-established model in a traditionally conservative sector. Concerns over data integrity, patient safety, and aligning with regulators posed significant barriers. The validation of remote monitoring tools and the development of robust electronic data capture systems has driven significant progress in alleviating some of these early concerns. These tools have become integral in ensuring that remote data collection adheres to regulatory standards for clinical practice and in navigating the complex web of international regulations for trials spanning regions and regulatory agencies.

The emergence of electronic consent (eConsent) has significantly streamlined the enrollment process, and telehealth services have expanded the potential patient base, allowing participants from remote locations to contribute valuable data. Mobile healthcare and home visits, along with improvements in DTP/DFP infrastructure and the optimization of remote clinical trials kits, have addressed logistical hurdles by reducing the necessity for in-person visits at trial sites. However, these solutions come with a fresh set of challenges that require persistent attention and innovation.

Ensuring data quality and integrity remains a core focus for all stakeholders. The technology underpinning DCTs must not only be reliable but must also produce clinically meaningful outcomes that are accepted by the medical community and regulatory authorities. As clinical trials incorporate increasingly sophisticated technology, such as wearable devices and electronic clinical outcome assessments (eCOAs) and patient-reported outcomes (ePROs), the imperative to validate these tools becomes even more critical.

Artificial intelligence (AI) has emerged as a potentially transformative solution to address the new challenges resulting from increasingly decentralized and digitalized clinical trials. AI can enhance data management through sophisticated algorithms capable of analyzing complex data sets from wearables and other remote monitoring tools, ensuring data integrity and regulatory compliance. Furthermore, AI can significantly improve participant monitoring by predicting potential compliance issues or health risks, enabling preemptive interventions. Such capabilities not only streamline trial operations but also foster a proactive approach to patient safety. As AI continues to evolve, its integration into decentralized trials could greatly enhance operational efficiency and patient engagement, thereby reinforcing the foundations of patient-centric clinical research.

Ultimately, patient centricity is at the heart of DCTs. Tailoring trial designs to meet the needs and preferences of patients — whether that means the choice between the convenience of decentralization and the focused care of physician visits or different cohorts’ comfort levels with digital technologies — plays a crucial role in enhancing patient engagement and compliance. As clinical trials transition to a more virtual nature, maintaining patient engagement and providing adequate support become paramount. The experience of participating in a trial must be as intuitive and reassuring as the more familiar traditional methods, if not more so.

Amid these technological and patient-focused innovations, the industry continues to grapple with the need for sophisticated logistical solutions, particularly those involving cold-chain management for the transport of sensitive materials and samples. The increased burden on clinical research professionals, who are expected to adapt to these new technologies and methodologies, also calls for comprehensive training and support systems.

The ABCs of DCTs

The implementation of DCTs brings forth a multitude of benefits, which can be easily remembered using a ABCDE framework:

• Access: DCTs expand access to clinical trials by removing geographical barriers and logistical constraints associated with traditional centralized models. Participants can engage in trials from the comfort of their homes, regardless of their location, thereby broadening the reach of research studies and enabling a more diverse participant pool.

• Benefits for participants: By shifting the trial activities to the patient’s environment, DCTs alleviate the burden of frequent travel and site visits, enhancing the overall participant experience. Patients experience greater convenience and flexibility, leading to higher satisfaction levels and increased willingness to participate in future studies.

• Costs: DCTs offer potential cost savings by minimizing expenses related to site infrastructure, participant travel reimbursements, and on-site staffing. The elimination of the need for physical trial sites and centralized monitoring can result in more efficient resource utilization and overall cost reductions.

• Data: DCTs enable the collection of richer and more comprehensive data sets by leveraging digital technologies for real-time, real-world data capture. This approach results in a higher frequency of data points, providing researchers with a more nuanced understanding of treatment effects across diverse patient populations. Moreover, the ability to engage participants from various demographic backgrounds –– with recruitment efforts supported by real-world data –– enhances the representativeness of study findings, while the improved patient experience reduces the likelihood of study drop-outs that represent losses of data.

• Efficiency: The streamlined processes inherent in DCTs lead to increased operational efficiency and accelerated trial timelines. By leveraging digital platforms for patient recruitment, consent, and data collection, researchers can expedite study start-up and execution, ultimately bringing new therapies to market faster.

As the adoption of DCTs continues to grow, stakeholders across the healthcare ecosystem stand to benefit from improved accessibility, efficiency, and data quality in clinical research endeavors.

Need for Novel Sample Collection Solutions

One notable challenge associated with the DFP side of DCTs is the need for novel sample collection solutions that are patient-friendly and can be used remotely. Traditional methods of blood collection typically involve venipuncture at a clinical site, which does not align with DCT models. Even with the expansion of local testing labs that can collect samples and distribute them to sites, venipuncture can cause anxiety and discomfort to patients, which can have consequences on enrollment and retention of certain types of patients, potentially preventing the trials from meeting the industry’s and regulators’ diversity and representation goals for such studies.

Novel patient-centric sampling methods can not only improve patient convenience and the sampling experience but also enable more frequent testing, which could enable the capture of data that was previously impossible and unlock new possibilities in clinical trial protocols. Moreover, there’s a financial aspect to consider: while some patient-centric technologies might present higher initial costs compared with traditional methods, the overall societal cost could be lower due to improved health outcomes and broader access​​.

When it comes to home-based blood collection, finger-stick methods for collecting dried blood spots are suitable for small sample volumes. For larger volumes, conventional phlebotomy had long been necessary often used, despite its associated challenges, including discomfort and the logistical complexity of transporting samples from remote locations. However, innovations in self-collection devices, like the Touch Activated Phlebotomy (TAP^®) Micro Select device, allow patients to collect their own samples with less discomfort and without the need for a trained professional. The challenge lies in ensuring that these devices are validated to deliver data that can be reliably used for clinical analysis, which has traditionally been based on venous blood.

The use of such devices in clinical trials requires careful consideration during protocol design, considering the regulatory status of these devices, the most appropriate applications, and the patient’s ability to use the device correctly. Assay development and validation is another significant aspect, as most laboratory tests approved by regulatory authorities are based on venous blood, not capillary blood, which may necessitate the development of specific reference ranges for capillary blood​​.

Logistical considerations are equally critical, from kit building to ensuring proper centrifugation of samples, which might be required before shipment. Direct-to-patient kit delivery and the logistics of sample pick-up and return are also key factors, with patient preferences for pick-up times and the need for expedited return of samples to ensure sample integrity. Supporting patients with these new sampling techniques will be essential and could include video training, live support, and rapid resupply if an adequate sample is not obtained on the first attempt.

However, any novel challenges associated with self-collection are a small price to pay for a solution that allows fully decentralized, remote sample collection that maximizes patient convenience and comfort, and the path toward optimization is clear.

Sidebar: The TAP^® Micro Select

The TAP^® Micro Select device from YourBio Health produces high-quality blood samples at high volumes, making it ideal for DCTs, wellness testing, and clinical-grade blood sampling. The device leverages YourBio Health’s HALO™ technology, a bladeless microneedle array consisting of 30 microneedles thinner than eyelashes placed in a circle. The needles only pierce the skin to a depth of approximately 1 millimeter, remaining above where nerve endings are located and eliminating the major source of pain during blood draws. This microneedle technology is the primary differentiator of the TAP^® devices from other upper-arm blood collection devices because it has been specifically designed to address the pain-point component of blood collection.

The needles are attached to a proprietary spring mechanism and can only be activated by pressing a plunger on the device, which actuates the needles at the right velocity and angle to pierce the skin. When ready to be used, the TAP^® Micro Select is placed against clean skin, and the plunger is pressed. The needles retract after about 3 milliseconds, creating a vacuum into which capillary blood is drawn. Over 90% of users can successfully draw 200 µL blood in under two minutes, while 75% will collect 500 µL. 

Along with the device, YourBio Health offers customizable sample management services, including kitting, fulfillment, and sample tracking from the end user to any central lab. The standard kit contains items to produce whole capillary blood samples from any remote location, including the TAP^® Micro Select device, instructions for use, a warming pack, alcohol wipe, gauze, bandage, and return bag and box. The kit design can be customized to meet the specific needs of different clinical trial protocols, with varying imagery, layouts, and other components. 

Use of the TAP^® Micro Select device helps to reduce barriers to blood collection and enables high success rates. The devices are end-user preferred, virtually painless, and yield a 99% collection success rate in several trials and commercial products. In clinical trials, a 200% increase in patient retention and completion rates has been observed when TAP^® technologies, rather than a fingerstick approach, have been employed. In addition, 98% of patients report they would repeat self-collection using TAP^® devices. By leveraging patient blood collection in the home with TAP^® technologies, it is possible to increase trial diversity, collect more representative data, and reduce DCT completion times and failures.

Enhancing Patient-Centricity in Clinical Trials

The TAP^® Micro Select device has proven to be an invaluable tool for patient-centric sample collection in decentralized and hybrid clinical trials, as exemplified by the studies below.

Assessment of immune responses post-booster during the Omicron wave: A decentralized, real-world study centered on evaluating the antibody response following COVID-19 boosters during the Omicron wave employed TAP^® devices to enable participants to self-collect blood samples. This approach facilitated a digitally supported DCT model, where individuals, without the need for professional medical assistance, could contribute data from any location, highlighting the device’s versatility in supporting public health research.

Antibody monitoring in COVID-19 vaccine trials: Researchers in a study investigating the longevity and efficacy of maternal antibodies against SARS-CoV-2 were able to conveniently collect blood samples from infants at key developmental stages using TAP^® devices. The non-intrusive nature of the device facilitated adherence to the study protocol and ensured robust data collection, which was vital in reaching the conclusion that maternal antibodies provided protection, but that protection waned after six months.

Both trials underscore the TAP^® device’s contribution to streamlining the blood collection process, making it possible to reach a wider participant base, including diverse demographics and geographically dispersed individuals, with high participant retention and satisfaction rates. While both studies underscore the TAP device’s role in reducing patient burden (particularly for infants), enhancing participant compliance, and broadening the potential for diverse data collection, they also demonstrate its adaptability across different research contexts—be it monitoring long-term vaccine-induced immunity in adults or providing insights into maternal-fetal antibody transfer.

Conclusion and Outlook

Innovative solutions have been crucial in facilitating DCTs and further advancing patient centricity and accessibility. As new solutions are widely adopted, focus will shift to other pain points in an ongoing effort to decrease patient burden, maximize enrollment and retention, and enhance data security and robustness, which is likely to increasingly involve AI, machine learning, and related technologies. The development of novel, less invasive blood collection methods and devices is a representative example of a conceptually simple but technically challenging solution that resolves a significant challenge in remote sampling and patient compliance and comfort, with wider ramifications for the success and representation of clinical trials. 

As these technologies and a range of digital health tools mature, they will continue to enhance the execution of DCTs. However, challenges persist, such as the high cost of logistics and the need for standardization in data collection. Looking forward, continuous improvement in these areas, coupled with growing regulatory support and technological adoption, suggests a promising trajectory for DCTs, aiming for a more inclusive and efficient future for clinical research.