Mike Martin

By now, the pharmaceutical industry knows decentralized clinical trials (DCTs) are here to stay. DCTs offer many benefits, including helping sponsors reach broader and more diverse patient populations. In an article published last year in 

, we noted ZS’s DCT database shows the number of DCTs reported on clinicaltrials.gov increased by 77% between 2019 and 2020—and grew another 34% between 2020 and 2021. We also discussed that multiple studies have demonstrated that DCTs can improve enrollment and retention rates.

While DCT growth accelerated during the pandemic, this trend will outlast COVID-19. ZS’s patient burden collaboration with the Tufts Center for the Study of Drug Development showed that most patients indicated decentralized trial services such as home nurses and home technology will reduce trial burden. And in our March 2021 industry roundtable, most sponsors suggested that decentralized or hybrid clinical trials will become mainstream in three to five years.

clinical trial sites are not expected to fade away

. Rather, they will play a critical role in the decentralization process and are evolving through investment in DCT services such as home health and direct-to-patient investigational products, and in supporting technologies such as eConsent, ePRO, telemedicine platforms and wearables.

Transforming site selection is imperative for successful DCTs

Though sites are adapting to DCTs, the levels of experience and capabilities they offer can vary significantly. A 2021 Society for Clinical Research Sites (SCRS) survey indicated that only approximately one in four sites offered each type of decentralized service. This means there are few one-stop-shop sites for DCTs, and sponsors will need to rely on a robust site selection process to find sites with the right DCT capabilities and experience to meet their needs. Furthermore, they will need to segment sites by capability and experience to understand which sites would need training, resources and additional sponsor support during activation.

Without the ability to identify sites with the right experience, capabilities and willingness to conduct DCTs, studies could be time-consuming, costly or prone to fail. Additionally, sponsors could miss out on partnering with sites that are a good fit for the trial. For example, in our recent analysis of sites suitable for decentralized Parkinson’s disease trials, we identified two institutes that were similar in the traditional sense, each having more than 20 years of clinical trial experience in the disease area. However, only one had participated in trials in which home health, eCOA, ePRO, eConsent or remote monitoring were offered. In a traditional site selection process, sponsors would have similarly ranked both sites, but with additional insight, it’s clear these sites would perform very differently in a DCT.

Unfortunately, some sponsors are experiencing pitfalls. Some do not have visibility into site readiness for DCTs and are taking the same approach to site selection for DCTs as they would for traditional clinical studies. In one case, we saw a major pharma sponsor plan a fully decentralized study but then err by selecting traditional sites without the proper DCT experience. Not surprisingly, this presented major obstacles during the study. The sponsor likely is not alone, making it imperative that sponsors act now to modernize their site selection processes.

Considerations for enhancing DCT site selection processes

For sponsors to identify and select the right sites for their DCTs, a critical first step is to look holistically at how the strategic planning and site selection processes can be “DCT-compatible.”

First, sponsors must layer a DCT readiness analysis into the existing site selection process and include metrics that assess a site’s willingness, experience and capabilities to conduct DCTs. While traditional site selection metrics look mostly at physician and patient access, therapeutic area experience and site enrollment performance, sponsors will need to augment these metrics with ones specific for DCTs.

Sponsors also should update weighting to account for the importance of the new metrics. For example, if emerging sites are heavily equipped for DCTs but have not had a chance to demonstrate their capabilities in trials, they will not receive a fair chance if too much weight is placed on historic indicators. Thus, any DCT metrics added must include the option to put more or less weight on key metrics so that site scoring is aligned with the objective of the analysis.

While we expect there will be “must-partner” sites with both strong DCT and traditional readiness, sponsors will need to determine how to use less-than-optimal sites to meet specific patient population needs and study goals such as improvement in enrollment rates, patient experience, diversity, equity and inclusion.

DCT readiness assessments should help sponsors select the right sites and help them segment sites based on potential experience and capability gaps. During site activation, sponsors will have the opportunity to provide resources and support such as DCT training and relevant technology. This also will accelerate sites’ adoption of decentralized studies.

To further complicate the landscape, sites are partnering with new industry players to adopt novel operating models designed to bridge critical gaps in clinical trial operations. They’re aiming to reach highly qualified patients in a more targeted manner than what is offered by social media and traditional sites. They also want to offer better access to patients in remote areas or underserved populations.

One noteworthy model is the integrated research organization (IRO), which involves patients’ regular physicians in all stages of clinical research. This enables more targeted recruitment and retention of patients who are highly qualified for the trial. Furthermore, the IRO model also can lead to better patient diversity by leveraging the relationship between the physician and the patient if the IRO has a strong presence in institutions and community clinics in underserved areas. In our recent article, “

How to recruit more diverse clinical trial participants

,” more than half of underrepresented patients surveyed indicated they would be more comfortable if the trial principal investigators were the doctor they see regularly.

A decentralized research organization (DRO)—such as Care Access or Emvenio Research (previously Matrix Medical Network)—is another model that can improve recruitment, retention and diversity by bringing trials closer to target patients who were once considered inaccessible. This can be accomplished by using “sites on wheels,” which include mobile investigation teams, on-demand sites and local clinics and pharmacies.

While emerging site operating models are vastly different, one similarity is that most sponsors are not assessing the benefit-to-cost ratios of partnering with these organizations for a trial. This could lead to two scenarios, neither of which are optimal. The first is underusing these new site models, which could possibly cause enrollment, retention and diversity metrics to fall short and bring about less effective patient targeting. The second is overusing trials that do not necessitate these services to meet their recruitment needs, which could lead to unnecessary cost increases.

Sponsor considerations for site selection

While we expect most clinical trial sites will continue to be chosen through a site selection process adapted for DCTs and hybrids, we also anticipate a growing percentage of sites will come from partnerships with organizations such as IROs and DROs. Sponsors will need to keep important considerations in mind as they navigate this more complex site landscape.

The first is site strategy. Sponsors must look holistically at their strategic planning processes and site strategy frameworks to ensure they are current and able to assess if novel services should be utilized. It’s critical for sponsors to cover both of the following scenarios as part of their assessment:

Sponsors should explore partnerships with new organizations such as IROs and DROs to recruit and enroll patients as a supplement to enrollment from the sites identified in traditional site selection analyses.

 Sponsors should think about reducing the number of traditional sites needed and replacing them with sites provided by DRO and IRO services.

For each scenario of the site strategy, sponsors must assess the benefit-to-cost ratio of increasing the percentage of sites chosen through IRO and DRO partnerships for trials. For example, through correlations of how IROs and DROs quantitatively benefit enrollment, retention and diversity, estimate the ratio of quantifiable benefit against any cost premiums.

With DCTs and emerging operating models such as IROs and DROs, the future of clinical trials is here. Now is the time for sponsors to update their site selection strategies to realize the benefits of these new site offerings. For sponsors wondering where to begin and how to ensure success in modernizing site strategies, the following considerations are critical to success.

First, a good starting point is to understand what data is available to provide the insights needed for transformation. For example, does in-house and third-party public data exist to identify trials and sites that have leveraged DCT technologies? What pricing information and correlations between new site operating models and patient recruitment, retention and diversity are available?

Another consideration is how this data will inform budgets and resourcing for DCTs and hybrid trials. It is common for sponsors to assume that both patient facing and non-patient facing hours for sites will decrease with DCTs and hybrid trials, but this is not always the case. According to the 2021 SCRS site survey, sites cited adverse event reporting, screening failures and start-up costs as the top underfunded areas in the trial budget. This data would be critical, for example, to accurately assess the benefit-to-cost ratios of DCTs and hybrid trials, and to inform the trial budget.

It’s also important to understand how can sponsors use that data to improve their site selection decision-making. For example, what analytics and key performance indicators are needed to reveal the best sites for a sponsor’s trials? Is it easy to provide sound justification for partnerships with new research organizations? It’s critical to define study execution expectations and to identify and address potential risks for monitoring and capability gaps, so that sponsors can adequately support the sites with needed technologies and services to execute DCTs and hybrid trials.

Sponsors and sites are driven to improve the patient experience, operational efficiency and patient diversity in clinical trials. For these commitments to materialize, sponsors must enhance their approaches to site selection, engagement and partnerships. Let’s work together to enable a future where clinical trials include the right patients, and let’s meet them where they are.

, PhD, MS, is part of the ZS R&D excellence leadership team. She leads the digital and DCT vertical in clinical development.

 leads ZS’s global clinical development practice area.

 is a leader in ZS’s R&D excellence practice area and leads the development and global commercialization of ZS's DCT strategy and analytics solutions.

 is a leader in ZS’s R&D excellence practice area and leads strategy and analytics work in the areas of DCT and clinical feasibility.

 are consultants for ZS's R&D excellence team and members of the digital and DCT vertical in clinical development.

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Sites not expected to fade away even as DCTs continue to grow past COVID-19.

Adapting Site Selection for Clinical Trial Decentralization and the Future Landscape

	In accordance with recommendations from the FDA, there are four key actions that biopharmaceutical sponsors can take immediately to offset disruptions:

For clinical studies currently in flight, sponsors need to virtualize their trial operations

to avoid jeopardizing the safety of patients as well as site staff. In a purely virtual setting, patients are in contact with study teams and trial physicians through smartphone technologies

, and investigational products are shipped directly to patients’ homes. Patients can self-administer therapies if feasible. For more complex procedures and interventions, sponsors can collaborate with third-party home-trial vendors

or incorporate at-home nurse visits. Obviously, the feasibility and logistics of this approach need to be analyzed thoroughly. For example, does a protocol involve procedures that cannot be conducted outside of a hospital setting? 
		 

If clinical research associates are unable to access sites because of global travel restrictions or local quarantines, sponsors should enable remote monitoring and oversight as the FDA recommends. If not already in place, sponsors may need to enable virtual workspaces for sites to upload the necessary documents for centralized monitoring. The Association of Clinical Research Organizations (ACRO) recently laid out emergency guidelines

for sponsors, clinical research organizations and sites on conducting trial oversight during the pandemic. 
		 

Engage patients and investigators through proactive communication.

Developing a communication and remote engagement strategy with patients and investigators that can be sustained throughout the pandemic is vital to ensure motivation and reduce burden. Virtualizingtrials or monitoring sites will only be successful if sponsors frequently engage and empathize with patients and sites in order to assuage concerns caused by COVID-19.
		 

Assess the overall clinical portfolio and evaluate study design, feasibility and operations as the pandemic evolves. 

For each clinical trial in the portfolio, sponsors need to conduct a thorough assessment exercise aimed at answering key questions related to design, feasibility and operations in the immediate term, short term and long term. For example, in the immediate term, sponsors should determine which of their in-flight trials need to pause enrollment and which of their new planned trials need delayed starts. In the short and long term, sponsors should think through: 

		Protocol modifications to incorporate remote patient and site assessments or other virtual elements

		Patient visit requirements and anticipated data collection challenges

		Effective resumption of activities when the pandemic situation improves

		Improvements to risk management planning

		Overall impact on clinical trial and clinical program timelines (including time to approval) 

	These are just a few questions among many that need to be sorted out. To plan for the short- and long-term scenarios, sponsors should go back to the drawing board and reevaluate overall clinical study design, including patient eligibility, feasibility, enrollment, timelines and budgets against the evolving global landscape.

	Sponsors should note that these strategies may require amendments to study protocols, and the FDA guidelines urge sponsors to engage with institutional review boards (IRBs) as soon as possible. However, in cases where protocol changes are made to directly eliminate hazards to patients, these may be implemented

without IRB approval. Finally, alarming projections indicate that social distancing countermeasures may need to be in place well into 2021

, which means that biopharmaceutical sponsors should make urgent decisions now to plan for continued clinical research in the coming months.

 is a manager in ZS’s San Francisco office. 

 is a manager in ZS’s Los Angeles office. 

 is ZS’s global clinical lead, based out of ZS’s Princeton office. 

 is an associate consultant in ZS’s San Francisco office. 

	Editor’s Note: The full version of this article will be available in our April digital edition on April 13. 

https://www.science37.com/wp-content/uploads/2020/03/12161417/Navigating-Clinical-Trials-in-the-Coronavirus-Era_Science37.pdf

https://www.science37.com/blog/siteless-clinical-trials-changing-the-game-for-patients/

https://www.clinicalleader.com/doc/the-benefits-and-challenges-of-siteless-clinical-trials-0001

https://www.acrohealth.org/wp-content/uploads/2020/03/ACRO-Statement-on-Monitoring-Oversight-FINAL-3.13.20.pdf

https://info.zs.com/activeingredient/clinical-development-risks-and-issues-in-a-covid-19-world

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-guidance-conduct-clinical-trials-medical-products-during-covid-19-pandemic

https://www.washingtonpost.com/health/2020/03/19/coronavirus-projections-us/

Biopharmaceutical sponsors should make urgent decisions now to plan for continued clinical research in the coming months.

Mike Martin

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