November 17, 2022 PAO-11-022-CL-05
Decentralized clinical trials (DCTs) currently span a broad range of possible designs that deconstruct the traditional trial layout — in which all assessments are performed on-site — across a spectrum where assessments are increasingly performed off-site. Most DCT designs are hybrid trials that include some aspects of both digitally enabled and decentralized approaches.
In hybrid trials, some activities take place at brick-and-mortar sites, while others are performed remotely at the patient’s home, at local facilities (e.g., local laboratory/imaging centers, mobile clinics, or local doctors’ offices), or through the use of digital technology. Fully decentralized trial designs include no on-site visits at brick-and-mortar sites. The level of decentralization that is possible or practical depends on the:
The healthcare industry is undergoing a paradigm shift across several areas, placing more emphasis on patient centricity. Just as with precision medicine — an innovative approach to tailoring disease prevention and treatment that considers differences in people’s genes, environments, and lifestyles — DCTs are similarly trying to tailor the trial more around the patient’s profile and lifestyle where possible, bringing trial opportunities to the patient while improving retention opportunities.
From the perspectives of the sponsor and the contract research organization (CRO), the greater range of DCT options provides opportunities for selecting the optimum protocol for the specific patient population and the treatment and testing requirements. Different levels of decentralization can be incorporated in different regions or countries to accommodate varying regulatory requirements, to leverage existing healthcare infrastructure, and to best meet patient needs. However, the wide range of possible DCT trial designs can add new complexities for trials sites.
DCTs require new ways of working for everyone across the clinical research industry. Most stakeholders have been party to co-creating or voicing their expectations about the designs and technology of tomorrow’s trials, apart from sites.
When sponsors and CROs build a DCT strategy, it is important to consider patient care, what is allowed in a specific country or region, and what is feasible at a given site. For example, what does a normal workday look like on an oncology ward for staff when the site is participating in clinical research? How are they impacted by the additional technology and remote solutions being added to support the trial?
In addition to mapping out the patient and data journeys, it is critical to plan the site journey and the potential impact it will have on the daily trial delivery on-site. Factors to take into account include site resources, technology, administrative burden, and oversight, without losing focus on the core considerations in clinical research: patient rights, safety, and well-being and data integrity. Sites expect that these issues will be considered, and that extra support will be provided for DCT trials.
Among site staff, nurses are expected to be able to navigate various research technology systems and platforms and to provide a level of technological support to patients. The research technology deployed for the DCT may be different from the systems the site staff use in their daily practice and, if it is not well integrated, can further increase site burden.
Site staff already spend time manually transcribing data from their medical records to electronic data capture (EDC). When adding more technology or requiring home healthcare providers to complete paper worksheets on top of standard site practice, the administrative work burden rises and risks blurring the investigator’s oversight across all the various systems and documents. Changing technology, protocols, or methods is always difficult, and for DCTs this challenge may be exacerbated by a lack of sufficient resources at the site level.
Sponsors and CROs can take steps to support site staff and to overcome these issues. That can take the form of :
To address site resource challenges, sponsors and CROs can provide staff with an appropriate level of training. It is crucial to budget time and funding for the work that still must be completed with respect to checking data and compliance. It is equally important to minimize the number of different technology systems used at a given site and develop application programming interfaces (APIs) to ensure connections between technologies. The more decentralized the trial, the more digital technology is necessary to collect and organize patient data. Technologies that are designed, implemented, and interfaced correctly result in simplified data integration, sharing, and assessment, which ease the burden on site staff.
Overall, it is important to consider the resources available at a site. Some questions to ask include:
Similarly, it is important to look at end-to-end delivery at the study level. Government-funded hospitals and academic sites, for instance, are seeing regular patients in addition to clinical research patients and have established ways of working in line with national guidelines and implemented technology. Commercial sites have different operating procedures. It is important to remember that the patient journey occurs through the investigator site to some degree — even for fully decentralized trials — because the investigator is fully responsible for the patient’s care, and site staff collect and manage the data. The site journey must therefore also be considered, but it can be challenging to prioritize without the proper support and guidance.
The further that the industry moves along the DCT spectrum toward fully decentralized trials, the more it becomes essential to evaluate the existing technology infrastructure. With respect to performance, the use of electronic medical records (EMRs) is fundamental to maximizing the benefits of virtual trials. Data integration is also important, as it eliminates the need to transcribe data between locations. From a security perspective, the appropriate firewalls must be in place to protect patient data from cyberattacks and data breaches. The site staff must be relatively tech-savvy and have the appropriate skills and expertise to implement and manage the digital technologies leveraged for DCTs at the site.
The CRO or sponsor is responsible for setting up the digital technologies and data management systems for sites. The platforms are built by the CRO or — more often — technology vendors and include modules such as:
The patient-facing screenshots are submitted and approved by institutional review boards or ethics committees before activation at investigator sites. The site staff is then provided with logins and trained on the various technologies. In most cases, where there is no single-sign-on (SSO), the site staff needs to remember and use multiple username and passwords across one trial. Having an authentication scheme as a SSO allows site staff to log in with a single ID to several related, yet independent, software systems deployed on a trial.
As trials have evolved, sites have voiced concerns about the increasing number of communication channels. In a traditional trial, the touchpoints throughout the trial for one site may include more than 10 different roles at the CRO and the sponsor. Adding digital and decentralized solutions further increases the number.
With the addition of digital technologies and decentralized solutions to study designs, it is important to consider the communication pathways. If a site is working with eight different technology systems supporting eight different trials, should there be eight different IT help desks, or could they possibly be batched? For one trial, site staff may even be navigating three or more technology systems with the same amount of technology helpdesk, home healthcare, and training resources.
Remote source data verification (SDV) has been reported to create more work for sites compared with on-site clinical research associate (CRA) visits, largely because most sites work with multiple CROs and sponsors that use different methodologies. There is significant variance in how DCTs are structured and, with differing remote SDV systems and guidance, more administrative work is placed on site staff.
This issue illustrates the reality that many DCT activities are currently evolving, and standardization has not yet been achieved. The study team must work with the site from the outset to ensure clear communication pathways and limit the number of touchpoints required for the study coordinator and PI to get answers to their questions.
The CRA should engage with the site from early onset on the trial. Pre-study site visits provide the opportunity to assess the site’s experience, limitations, and concerns with technology and home healthcare. Those insights can be used to tailor the site’s communication, support, and training to ensure successful DCT implementation. The CRA needs to provide training to the investigator concerning oversight, helping to develop a PI oversight plan that outlines the process by which the PI will maintain oversight of:
Oversight is critical, regardless of the type of trial. Investigators need to log in and check patient safety data and self-reported outcomes and interact with patients who are not coming in for on-site visits. Study coordinators are also responsible for performing the same compliance assessments whether trials are traditional, hybrid, or fully decentralized.
The nomenclature of investigator oversight and responsibility for a DCT needs to be addressed from a regulatory perspective. There can be different definitions or understandings by CROs, sponsors, and ethics-/regulatory- competent authorities. Harmonization will be essential to resolve PI concerns in this regard.
With fully decentralized trials, patient interaction is reduced for investigators, and consequently they are not as close to the patient and investigation intelligence as they are with traditional trials. As a result, because the investigator is not seeing patients in person, some have expressed concerns regarding responsibility for patients. A home healthcare professional — not hired by the investigator — may be seeing the patients, but the investigator is ultimately responsible for the care given.
At the same time, there is a greater burden with respect to technology training, data administration, and handling of deviations generated by home healthcare professionals. Research income is diverted, with fewer on-site patient visits and less of the revenue they generate, as traditional on-site visits are replaced with more remote solutions. A reduction of research income may have further consequences, including the inability of sites to retain research staff.
Over the past few years, most sites have become engaged with or interested in DCTs as the implementation of new health technologies and decentralizing treatments has become part of the standard of care. However, successful adoption requires that:
Because sites largely continue to work in the same way that they have for traditional trials, CROs and sponsors must respect their level of expertise and resources while the transition to fully decentralized trials is underway.
For example, several sites would like to see the return of in-person attendance at investigator meetings and conferences. There is an appreciation of the value of digitalizing trial activities that bring direct benefits to patients, but many believe that it’s more effective to share knowledge and network in person.
As many as 10 technologies and decentralized solutions may be in use in today’s DCTs. It will become easier for investigator sites to plug in and understand the different methodologies that are being adopted as the industry gains experience with digital decentralized solutions, regulations evolve to better support them, and more harmonization is achieved.
It is imperative that sponsors and CROs engage with sites about both patient benefits and the benefits that DCTs bring to the sites themselves. Decentralized solutions should be seen as strengthening the recruitment and retention potential for the sites for the benefit of their patients — and improved recruitment and retention will ultimately accelerate the time needed to bring the investigational medicinal product to market. With DCTs set up seamlessly and with the right support systems, trial burden is reduced.
As more digital technology and decentralized solutions are being used, it is essential to not overlook the patient and site experiences. Sponsors, CROs, and technology and home healthcare providers must consider what makes sense for both patients and sites. The success of DCTs is heavily impacted by site adoption. For sites to successfully embrace DCTs, the industry needs to improve site engagement in DCT setup and delivery and listen to the challenges that sites face.
From the perspective of the investigational site, the key to successful DCT design is examining the end-user experiences — both patient and site user — together with the visit methodology, which in turn determines whether it is practical for the site. For instance, an eConsent application on a small tablet may take longer for a patient to review than a printed copy and, because there is a screen between them, limits the rapport building between investigator and patient. eConsent itself is not the problem, but its setup and deployment are not fully optimized.
Change management is also necessary. Home healthcare is a process that has been well mapped out, but uptake is not as high as expected given the level of patient flexibility it offers. A better understanding is needed of how processes like home healthcare are set up and how to better communicate the benefits. Indeed, most home healthcare providers create paper worksheets, and sites must transfer those data manually into their EDC systems. CROs and sponsors need to be more proactive, specifically in delineating expectations for technology vendors regarding coherence, integration, and data sharing.
It is also critical to select DCT vendors that:
Building the DCT strategy should include the full data journey, as this will often reveal the interface gaps that lead to increased site burden, redundant data entry, and the risk of poor data collection.
Failure to select the right vendors risks placing more work on the site to deal with protocol deviations, extra reporting, and manual data transcription, which will trickle through to frustrated site staff, as well as patients, and subsequently low adoption. Sites will need to be paid for the extra efforts working on DCTs and resolving issues caused by DCT providers.
More studies are leveraging digital and decentralized solutions. Many of PPD’s trials globally have some decentralized components, and, as a result, most trial sites are starting to explore opportunities, particularly with respect to learning about standardized eCOA. As regulations become more harmonized, it is expected that more sites will leverage DCT solutions. There is appetite on the sponsor side, and a growing number of sites — having recognized that the standard of care is moving in the digital direction — are also eager to adopt DCTs.
PPD designs DCTs that meet site and patient needs by tapping into country-level initiatives to gain better understanding of regulations, healthcare systems, standards of care, and technology use. Through this, it is possible to see how we as a CRO can fit in and potentially help guide how clinical research might be performed in the future.
PPD also has ongoing interactions with a global network of investigator sites through the Society for Clinical Research Sites (SCRS) and can gain their feedback regarding DCTs and their implementation. For decentralized trials to be effective, sites must fully buy into the concept, and a CRO like PPD must build studies using technologies that sites can understand and practically implement. If sites perceive digital technologies to be too much of a burden and that they take time away from finding and supporting the right patients, they will not opt in to DCT trials anywhere on the DCT spectrum.
With this insight, PPD has established a PPD DCT network, which engages with traditional sites to leverage their trial knowledge and combine it with our DCT expertise while establishing an advocacy group for sites to share their DCT experiences, successes, and challenges. The network makes it easier to tap into and select the right sites for DCT trials and to continue to improve DCT offerings, technology setup, and designs to benefit patients and sites.
By tapping into the experience of our own sites, we gain insights into what works for them within the DCT trial continuum. We continue learning from these sites as technology is created, adapted, or changed within hybrid and fully virtual trials, gaining a better understanding of both the pain points and successes. PPD also gathers feedback from CRAs, country heads, and other stakeholders involved in DCTs. All that information is used to move trial designs forward, support study teams, and provide updates on what is developing from a digital decentralized perspective.
As an advocate for trial sites — in addition to gathering and responding to site feedback — PPD provides an ecosystem of tools to sites conducting trials along the DCT spectrum. Our white-glove service ensures that sites implementing digital technologies have a high level of support as they start their DCT journeys. PPD is currently developing a DCT certification program, which will be accredited by SCRS. Where appropriate, we also offer patient concierge services and support site staff to reduce the administrative burden through our virtual research coordination center for virtual study support.
All efforts around DCTs are coordinated with PPD’s Digital and Decentralized group, which is staffed with experts knowledgeable in all aspects of DCTs. Our digital implementation managers and digital strategy directors fit into the clinical team and provide guidance on study design and directly support sites with setup, implementation, and daily trial operations — support that is a gamechanger for sites.
Learn more about PPD’s digital and decentralized solutions: https://www.ppd.com/how-we-help/decentralized-clinical-trials/
Kamilla Posselt is a Senior Director in the Digital & Decentralized Solutions consultancy, innovation, and strategy group. Her role is focused on driving DCT initiatives as well as providing consultancy to help sponsors realize the potential of decentralized trials by developing strategies and trial designs focused on reducing patient burden and enhancing trial participation. Kamilla has more than 22+ years in experience working within clinical research mainly for Top 5 CROs and in early days for clinical research sites. She has been engaged in various roles within DCT, clinical operations, as well as in strategic partnerships and alliance management, leading the development of operational strategy and framework solutions between CRO and several Top 50 Pharma clients. She has a proven ability to lead, develop and achieve successful operational business delivery and growth. She is passionate about streamlining and simplifying clinical research and identifying bespoke strategies and solutions that will suit patients, sites, study teams and bring benefits to clients.