Ann Neuer

The COVID-19 pandemic has been credited with exposing longstanding challenges in clinical trials,

 including the perpetually inefficient site feasibility process. Finally, this critical step is receiving the attention it deserves, maybe even an overhaul, as the wave of clinical trial decentralization surges on. This effort involves re-thinking the kinds of questions to ask in feasibility questionnaires, now that sites have reopened, and are coping with unprecedented numbers of remote study visits, and increased reliance on digital tools.

Determining a site’s digital readiness is essential, as the pandemic seems to have created the opportunity for access to a broader range of patients, beyond those who live near a site, to include those in rural or in lower income areas, allowing sponsors to meet diversity and geographic targets. Complementing this trend is the growing use of investigator digital platforms designed to eliminate the repetitive nature and drudgery associated with site feasibility.But according to Jeffrey Kingsley, founder and CEO of IACT Health in Columbus, Georgia, there is still a long way to go. “So far, few sponsors and contract research organizations (CROs) are leveraging their databases to eliminate a lot of the questions we get all the time. For example, we are still constantly asked, ‘Do you have a freezer?’ We get this question even from companies we’ve done many clinical trials for. Fortunately, since COVID, this is slowly starting to change,” he explains.

To explore the changes happening to the site feasibility process, 

 interviewed several experts in this field, representing a site, investigator platforms, and vendors. They offer decades of experience and insight into pre- and current COVID efforts to revamp this pivotal first step in increasing the likelihood of a successful trial.

Site feasibility starts by understanding the responsibilities of sponsors and investigators as defined in the International Conference of Harmonisation-Good Clinical Practice (ICH-GCP) Guidelines,

 Notably, these guidelines explain what a qualified investigator is, and the requirement of sponsors to select those investigators to carry out a clinical trial in accordance with a protocol. With this regulatory foundation, the site feasibility process involves choosing sites that not only conform to these requirements, but can also offer the best fit for specific studies, based on past performance, access to a database of appropriate patients, and the bandwidth to perform the study at hand. And with the shift toward decentralized clinical trials (DCTs) or hybrid versions, assessing a site’s familiarity with technology is being added to the process.

It all sounds so simple, but in practice, site feasibility has long been awkward and slow, and often more about checking boxes than turning to sophisticated databases and cloud-based solutions that could eliminate much of the redundancy.

 Today’s thinking suggests that if less time were devoted to repeatedly asking the same questions, more time would be freed up to build relationships and improve communication with sites that have a proven track record in various therapeutic areas.

A recent article by Kurbegov et al. of the American Society of Cancer Oncology (ASCO) describes a Task Force that was convened to evaluate the burdens and challenges of site feasibility, which often lead to delayed study start-up and act as a barrier to site participation.

 With input from sites, sponsors, and CROs in the form of surveys and in-person meetings, the Task Force developed three recommendations for improvement, with a goal of speeding patient access to clinical trial participation, and ultimately, much needed new treatments, as shown in Table 1 below. The third recommendation—leveraging technology to centralize the feasibility assessment—is a nod to performing as much of this process as possible by teleconference due to the pandemic.

The site survey found that the 103 site respondents spent a median of 264 hours annually completing feasibility assessments, with all sites spending a combined 27,192 hours, at a conservatively estimated cost exceeding $1 million for input from the study coordinators alone. Importantly, the stakeholders agreed that standardization will reduce burdens associated with site feasibility, and most thought that sponsors and CROs should use the same set of standardized questions for this process, except for those linked to specific protocols.

These findings align with work from Alliance for Clinical Research Excellence and Safety (ACRES). The organization launched a Site Accreditation & Standards Initiative in 2013, with a goal of addressing the inefficiencies in the clinical trials process, and the lack of uniform standards.

 ACRES promoted the idea that without an accepted, consistent set of standards and accompanying metrics, it is impossible to compare performance across sites, a factor that is critical to site selection. In 2018, ACRES, in collaboration with the British Standards Institution, published its principles for developing standards in 

 with an eye toward site accreditation, and the importance of viewing high performing sites as a critical resource.

At first glance, the changes spawned by the pandemic seem mostly focused on adding questions to the feasibility questionnaire about the status of technology adoption, and whether potential patients are able to participate in televisits, or use apps for patient reported outcomes (ePRO) or eConsent. A closer look, however, reveals those questions as a first step toward using the site feasibility process to expand the geographic area of patients available for study participation.

Mary Costello, head of Site Investigator Network at Medable, a provider of a DCT platform, describes the kinds of pre-qualifying technology questions to be asked for achieving this goal. “These questions might include asking if they have a patient database that tracks details, such as whether patients have smartphones. Do the patients have reliable high-speed internet? If they aren’t comfortable with technology, do they live with someone who can help them log on? We’re in a new era, and you don’t want to leave this information to chance. Successful feasibility is becoming more about anticipating and planning. Anyone who is getting ahead of these questions has a competitive advantage,”
Costello mentions.

She adds further that the pandemic has provided sites with a unique opportunity to expand their outreach beyond patients who live close to a site. “This is a turning point for the industry. Sites have existed on single digit margins for years, and have been limited to a drivable catchment area. Now, a patient might do a one to two-hour drive to an appointment if the rest of the visits can mostly be done remotely. I would suggest enhancing marketing efforts to broader, more diverse communities, as DCT imagines that we can bring in a whole new crop of clinical trial participants,” explains Costello.

Similarly, Diane Carozza, VP, clinical strategic solutions, study planning & site optimization at WCG, comments on how for the first time, site feasibility strategies are having to consider ethnic diversity and inclusiveness for patient recruitment. “We’re on the cusp of a big shift in diversity inclusion that the pandemic is fueling. It’s turning into something that isn’t just a ‘nice to have’. The FDA is calling out sponsors who are submitting applications for indications that have proven epidemiological prevalence data that certain ethnicities have a higher prevalence than others. Carozza explains they are asking, “What are you doing from the beginning to ensure that you include those groups in your trial?”

Attempts to improve site feasibility efficiency have been underway for several years among a handful of organizations, as shown in Table 2 below. Generally, uptake of these efforts was slow,

One of the most visible initiatives is the Shared Investigator Platform (SIP), which was created by TransCelerate BioPharma as an industry-wide solution to the problem of sites having to learn, access, and maintain excessive numbers of portals. SIP was designed with and for sites so they would have a centralized platform for providing information that would be available to multiple sponsors, and would eliminate the burden of repeated duplication of responses. In 2019, TransCelerate considered their SIP project to have met its initial objective, and as originally agreed, ownership of the platform and the intellectual property transitioned to Cognizant. Since then, the company has made significant progress towards establishing SIP as a core platform for clinical operations teams.

Larissa Comis, product owner of the SIP at Cognizant, explains that with the permanent changes to clinical trials brought on by the pandemic, sponsors are keenly interested in sites’ technological abilities to enable virtual collaboration and communication through SIP. As evidence, platform use has grown substantially in the past year, as shown in Chart 1 below. According to Comis, “We now have 146,000 users of SIP, which represents 125,000 site researchers. The rest are sponsors, including 21,000 study teams. SIP is used in 98 countries, in about 25,500 different locations.”

Comis explains that Cognizant was already seeing an uptick in adoption before the pandemic that extended into the early months of 2020. “What was interesting was that other than the first few weeks of the lockdown in March 2020, we did not see a huge fallout of adoption, which amazed us. We were expecting the activity to significantly drop, but it picked right back up really quickly. Now, we see 2021 as totally taking off on the site side and on the sponsor side. We attribute this to the growing use of decentralized clinical trials,” she says.

Jeffrey Kingsley explains that IACT Health is part of an investigator platform through hyperCORE International, a legal partnership of 10 high performing companies. IACT is a founding partner of hyperCORE, which started in 2019, and has evolved into a large, global clinical research site organization with more than 90 sites. To improve efficiency in site feasibility, all of the companies are mandated to use Devana Solutions, a site feasibility technology built on the Salesforce platform. Devana can instantly display and report trial performance metrics on all historic and currently running studies captured in the system. Kingsley remarks, “Within that software, we know everyone’s performance on specific types of trials, and with that transparency of the data, sponsors and CROs can easily see the best sites for their studies.”

Looking forward, Kingsley comments, “It’s about data, data, data.My wish for the industry is that we use data to eliminate all of the waste in the feasibility process. Stop wasting our time asking if we have a freezer. Let’s take steps to address all of the barriers from the site side, such as listening to our input as to how protocol design will impact recruitment and enrollment.”

To secure overall improvement to site feasibility in the long term, stakeholders are focusing on asking the right questions once, rather than repeatedly, all in an effort to speed the finding of the right sites with the right patients and digital readiness for DCTs. Technologies such as electronic health records, internal databases, and investigator platforms will be key as sites use this opportunity to meet enrollment goals by expanding their outreach to patients in underserved and more distant communities.

Henderson L. COVID Exposes the Cracks in Trial Problems. 

https://www.appliedclinicaltrialsonline.com/view/covid-exposes-the-cracks-in-trial-problems

Cotliar J. How a Pandemic Accelerated the Adoption of Virtual Trials. 

https://globalforum.diaglobal.org/issue/may-2020/how-a-pandemic-accelerated-the-adoption-of-virtual-trials/

ICH Harmonised Guideline: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice ICH E6(R2). International Conference on Harmonisation. Available at: 

https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf

Code of Federal Regulations. Subpart D—

Responsibilities of Sponsors and Investigators Electronic Code of Federal Regulations

. Section 312. March 2021. Available at: 

https://ecfr.federalregister.gov/current/title-21/chapter-I/subchapter-D/part-312

Barrett J. Choosing The Right Solution: Improving the Clinical Trial Site Feasibility Process. 

https://www.pharmavoice.com/wp-content/uploads/wp-WCG-03122019.pdf?tracker

Kurbegov D, Hurley P, Waterhouse D, et al. Recommendations to Streamline and Standardize Clinical Trial Site Feasibility Assessments: An ASCO Research Statement.

https://ascopubs.org/doi/full/10.1200/OP.20.00821

Site Accreditation & Standards Initiative (SASI). 

Alliance for Clinical Research Excellence and Safety (ACRES)

http://www.acresglobal.net/about-us/initiatives/site-accreditation-and-standards-initiative-sasi/

Koski G, Kennedy L, Tobin MF, et al. Accreditation of Clinical Research Sites—Moving Forward. 

MBA, President, Medical deScriptions, LLC

Articles

How asking better questions and leveraging site databases can expand access to more patients.

Revamping Site Feasibility as Trials Become Decentralized

, when the impact of the COVID-19 pandemic was in its early stages. Voices from stakeholders, including vendors and other organizations are presented, along with data from recent surveys. They provide insight into how the industry is adapting to new approaches to clinical trial conduct during the COVID-19 era, largely with the aid of virtualizing tools, strong partnerships, and regulatory guidance. Despite the upheaval in the past year, they share a sense of optimism that at least some of the systemic changes leading to the remarkably quick development of several vaccines will remain. This could involve expanded use of already popular technologies, which according to a new survey by the Society for Clinical Research Sites (SCRS) and Medidata, includes electronic clinical outcomes assessment (eCOA) (used by 72.9% of respondents), email notification (64.3%), online recruitment (63.3%), and more.

 But, for an industry that is notoriously slow-moving, not enough time has passed to determine which process changes will ultimately become standard practice post-COVID.

One key finding from the interviews was that hybrid models, as compared to fully virtual or traditional trials, are widely expected to assume a prominent role in the clinical trials landscape, as they facilitate the growing emphasis on patient centricity. There are also lessons learned, mainly involving the realization that stakeholders need a strong foundation to transition to decentralized clinical trials (DCTs), whether they are fully virtual or a hybrid of remote, in-home, and onsite visits. The foundation is rooted in strategic partnerships with contract research organizations (CROs), vendors, and associations who share collective wisdom to develop best practices or apply knowledge acquired from clinical care to the clinical trial realm. Stakeholders weigh in on the critical importance of building this foundation in order to move ahead with revamping clinical trial operations.

 presents current thinking on how sites are becoming more comfortable with an evolving industry. Jim Kremidas, Executive Director of the Association of Clinical Research Professionals (ACRP) comments, “Sites recognize that things are changing, and they have to be looking for people with new skill sets or developing people within their organizations to leverage these new skill sets.”

So, the sector is in flux, as evidenced by the rising use of technology, greater reliance on remote visits and partnerships, and a work force that is a better fit to the new reality of conducting clinical trials during a pandemic and beyond.

Status of decentralized clinical trials (DCTs)

When the pandemic first hit, there was a sudden awareness across the industry that if existing clinical trials were to resume, and if there was any hope of a vaccine being quickly developed, processes had to be adopted that would allow the safety of patients and site staff to remain top priority. With patients increasingly reluctant to visit sites, “safety” meant instituting at least some remote or “televisits”, a key aspect of DCTs. In the last few months, DCT uptake has grown dramatically, and is slated to continue. A recent analysis suggests that the global market for DCTs is expected to reach $10 billion by 2026, rising at a 6.5% compound annual growth rate between 2020–2026.

 As evidence of this growth, the SCRS/Medidata survey found that televisits, already used in the past two years by 45.1% of the 204 respondents, are likely to be adopted by an additional 39.2% of respondents in the next two years.

 The survey also reported that only 15.5% of respondents participated in decentralized or completely virtual trials in the past two years. But, 42.1% stated that they expect to implement them in the next two years–nearly a three-fold increase.

Research from the Tufts Center for the Study of Drug Development (CSDD) indicates that during the pandemic, telemedicine has become the most frequently used approach for supporting DCTs.

 Its use by more than 80% of companies reviewed for a recent 

 suggests that its growth is due mostly to the relative speed and ease of implementation. This was the finding of a CSDD analysis of the 50 largest pharmaceutical companies, based on published information, virtual conferences, and detailed interviews with 23 pharmaceutical companies conducted in August and September 2020.

Melissa Nezos, Vice President of Clinical Operations at Firma Clinical Research, a provider of in-home health services, comments on the ongoing shift toward DCTs. “What I’m hearing from big pharma is that they are setting corporate goals going forward to have a decentralized clinical trial component. Many of the large companies have innovation groups where DCT is a focus for the future. Before the pandemic, they were slowly inching toward the goal of performing more DCTs, but the pandemic has forced these innovation groups to immediately become engaged. They’re now working with partners like Firma on how to pivot their ongoing trials, and how to strategize on incorporating DCTs into their future trials,” Nezos explains.

Regarding the use of more home-based visits, Rasmus Hogreffe, Vice President of Decentralized Clinical Trial Innovation at Medable, a provider of a DCT platform, says, “We are seeing rising decentralized trial adoption in the industry on a daily basis, including home visits. Before, patients were going to the site, and now, we are seeing sites going to the patient. It’s a patient-centered approach, rather than a site-centered approach.”

To make this happen, site staff need to be trained in how to conduct a DCT. A 2019 survey of 340 site professionals conducted by SCRS in collaboration with VirTrial revealed that 60% of respondents had no experience in remote trials or any type of virtual processes, 37% claimed to have conducted a hybrid trial, and only 3% had participated in a completely virtual trial.

 With protocols embracing more virtual components, these statistics are concerning, but they were collected pre-COVID, and since then, site professionals have gained exposure to virtualizing tools and are incorporating them into ongoing studies. Kremidas of ACRP remarks, “Now that people have been forced into using virtual technologies, they’re realizing that it’s not as scary as they thought. They’ve become accustomed to using these tools, and that’s half the battle. The analogy is—when you get a new computer with unfamiliar software, you first move a little slower than you’d like, but as time passes, you get used to it, then you start to like it, and finally you can’t live without it. That’s where we are now.”

Our research shows a consensus that as the pandemic rages on, DCTs are clearly trending toward the hybrid model. While some trials may be fully virtual, and some may remain traditional, many more will be hybrid, as they are well-suited to a customizable patient-centric mix of on-site and remote visits. Ken Getz, Executive Director and Professor, at CSDD, explains, “About 55% of all trials moved to remote or a model with support from virtual technologies during the pandemic. I think once the pandemic is behind us, and there is more familiarity with these approaches, the hybrid approach is the most likely model because it’s defined by patient preferences. We are giving patients the option to come into the center or have virtual visits. Why wouldn’t we offer that for any trial?”

Similarly, Nezos of Firma comments, “Most of our current studies are hybrid. We aren’t seeing or working with companies performing fully virtual trials yet. A lot of technology would have to be in place for studies to be fully virtual and that’s something that most stakeholders don’t have. As for hybrid, sponsors are asking us to look at the protocol to see what they can do to bring in more virtual elements, so they can maximize the amount of visits that can be done in the home.” As part of this effort, she points out that many protocols include assessments and items that could be performed in the home with the help of home health practitioners, such as sample collection, blood draw, and EKG.

But there is still a vital role for site visits. For example, the first and last study visits may be more extensive, and may involve imaging, which would require visits to the site or to an imaging facility. Also, patients may want to have at least some face-to-face visits with the principal investigator and study coordinator, so to enable this, the protocol could be designed to move items originally planned for a remote second visit into an on-site first visit.

Amy (Nordo) Cramer, Global Product Development Operations Strategic Partnerships at Pfizer, sees the movement toward DCTs as operating along a spectrum, reflecting the specifics of various therapeutic areas and patient populations. “On one end is the fully virtual, completely decentralized trial, and at the other end is a study with maybe just one virtual tool, such as ePRO, with hybrid in the middle. Out of cautiousness, portions of the research community will opt to move slowly from one end of the spectrum, maybe starting with one functionality of a DCT, and as they become more comfortable, they’ll start moving across. I think other companies, like Pfizer, will be innovative and lead the industry by utilizing the full spectrum of DCT,” Cramer says.

The discussion about DCTs is also a discussion about patient centricity. DCT momentum was fueled by the COVID crisis, but their growing acceptance suggests that they are offering solutions to long standing challenges for the clinical trials sector, such as patient recruitment, enrollment, retention, and compliance. Current thinking indicates that if potential subjects could more easily enroll and participate in study visits from the convenience of home, retention and compliance might improve.

Getz from Tufts CSDD remarks, “I think the term ‘DCT’ does not go far enough in conveying what we need to do as an industry. Calling studies ‘decentralized’ is still putting the site at the center of the trial. We should be thinking about this as patient-centric. This would mean that patients who are more anxious may want to have at least some in-person visits, whereas others may want to mostly interact using a hand-held device.”

Jeremy Price, Director, Clinical Innovation & Strategic Partnerships at Pfizer, says, “We are proactively meeting with study teams and reviewing their protocols with them to see if including remote visits makes sense. If we can add some remote visits, even one or two over the duration of the study, it’s a huge win from the patients’ perspective, and they are more likely to stay in the study. It can also be a win for diversity and inclusion, as we can increase access for participants from a variety of backgrounds and locations that may be further from study centers.”

To boost patient centricity in clinical trials, Medable launched its Patient Advisory Council (PAC) in February 2020.

 It is a nationwide network of advocates who are advising the company and its biopharma customers on how to improve patient access, experience, and outcomes in clinical trials. The PAC is a network of patient advocates, advisors, and caregivers with diverse backgrounds in patient engagement and a strong understanding of patient preferences. The goal is to improve clinical trial access and efficiency by embedding patient voices and perspectives into aspects of clinical trials, and identifying and prioritizing potential hurdles that patients face. Medable is incorporating those perspectives into its DCT platform.

As greater use of DCTs unfolds, the logical next question is—which of the current changes will remain once the pandemic winds down? It is fair to say that no one knows for sure, but there are smart initiatives underway that are looking at the infrastructure and partnerships needed to make some of the changes stick.

Pfizer has been active in the DCT space for a long time, according to Price. He says the company has strong strategic partnerships with many types of clinical research community members, including those with telehealth capabilities. “Early in 2020, adoption of telehealth for clinical care increased exponentially, so we were able to jump on that and utilize those tools for visits in our trials.” Cramer adds, “We had already done a significant piece of work in trying to form a better bridge between clinical care with clinical research, so when we got into the COVID situation, and needed to find alternatives, we knew the options clinical care was using, and our strategic partnerships helped us understand how we could use existing functionality in clinical care in clinical research. Our partnerships were a large part of our ability to pivot so quickly.”

For Pfizer, the importance of partnerships is being played out in a new initiative called Vulcan. Launched in August 2020 by Health Level Seven International (HL7), Vulcan seeks to use a model for collaboration among diverse stakeholders in the translational and clinical research space to define a common set of standards that can be implemented globally, using the HL7 Fast Healthcare Interoperability (FHIR) standard for data exchange.

 The intent is to optimize the design, conduct, and reporting of clinical studies. Cramer, the group’s co-chair, mentions, “We have this opportunity as a collective group of the entire research community to work on solutions together. No longer does clinical research sit at its own table. We’ve joined a table of all of healthcare, and the benefits of this collaboration are exciting. We are actually working together in a way that I haven’t seen in my career. This is a game changer for clinical research.”

In December 2020, the formation of another alliance—Decentralized Trials & Research Alliance (DTRA)—was announced.

 The goal of DTRA is to unite a wide range of stakeholders, namely healthcare companies, regulators, patient groups and research organizations to enhance patient-focused trials and remove barriers to participation by advancing practices and technologies for decentralized studies. According to a recent DTRA press release, there hasn’t been a forum in which a diverse group of stakeholders could collaborate on this subject.

 As evidence of the strong interest in this initiative, there were 50 founding members, growing to nearly 70 members by early January 2021, just weeks after the organization’s launch.

The movement toward greater patient centricity and the adoption of decentralizing tools that enable it has been brewing for a while, but in recent months of the pandemic, there has been a dramatic uptick. So, the tide is clearly turning, and the industry’s embracing of DCTs is a silver lining. But will this momentum last?

Getz comments, “It’s hard to envision how it will play out because the pandemic forced a very abrupt change in design. Regulatory guidance has accommodated that abrupt shift. Basically, the door has been opened, and a lot of patients are going to say now that they’ve seen the light, why would they revert to only having in-person visits?”

He expects the path to a DCT world to be far from smooth, as most everything that’s been done in response to the pandemic has added more complexity and customization to clinical trials. This in turn increases cycle time, inefficiency, and cost, and the industry needs to figure out how to
manage this.

Because of the unsettled landscape, CSDD is more cautious about making statements about process change being sustainable. “We aren’t convinced of that. Historical precedent would suggest that the speed and incredible collaborations and success we’ve had in developing COVID-19 vaccines may be more of a one-time occurrence unless there are a whole host of fundamental areas that are addressed,” Getz warns.

Still, this is an amazing time for the clinical trials sector, as recent success in developing several vaccines is a testament to what this industry can accomplish. But, it is shifting, so it will be critical to re-visit this subject periodically to determine which changes become permanent.

Neuer A. Patient Centricity and Virtualizing Technologies in a COVID-19 World. Society for Clinical Research Sites and Medidata. December 2020. Available at: 

https://myscrs.org/learning-campus/white-papers/

Global Virtual Clinical Trials Market By Study Type, By Indication, By Region, Industry Analysis and Forecast, 2020–2026. KBV Research. December 2020. Available at: 

https://www.reportlinker.com/p05999876/Global-Virtual-Clinical-Trials-Market-By-Study-Type-By-Indication-By-Region-Industry-Analysis-and-Forecast.html?utm_source=GNW

Lamberti MJ, Smith Z, Wilkinson M, et al. Impact Report. Global Clinical Trials Transition to Decentralized Models Abruptly, in Nuanced Ways. Tufts Center for the Study of Drug Development. November/December 2020.

Impact Assessment of Decentralized Clinical Trials (DCT) Awareness in the Clinical Research Industry.Society for Clinical Research Sites and VirTrial. May 2020. Available at 

Marklein T. Medable Forms Patient Advisory Council to Advocate for Patient Access, Experience, and Outcomes in Clinical Trials. Medable Press Release. February 19, 2020. Available at: 

https://www.businesswire.com/news/home/20200219005346/en/Medable-Forms-Patient-Advisory-Council-Advocate-Patient. Accessed December 31, 2020

Ribick A. HL7 Starts Project Vulcan FHIR Accelerator Program. HL7. Press Release. August 11, 2020. Available at: 

http://www.hl7.org/documentcenter/public/pressreleases/HL7_PRESS_20200811.pdf. Accessed January 3, 2021

Decentralized Trials & Research Alliance (DTRA) Launches to Democratize and Accelerate Clinical Trials. Decentralized Trials & Research Alliance. Press Release. December 10, 2020. Available at: 

https://dtra.org/dtra-launches-to-democratize-and-accelerate-clinical-trials/

Hybrid studies, patient-centric tools, and collaborations create big changes for clinical trials and stakeholders during COVID-19.

Sharpening the Focus on Patient-Centricity as Pandemic Continues

 became a runaway bestseller by describing the factors that fuel an epidemic, and how the world suddenly becomes a different place as it reaches the inflection point. He discusses epidemics as spreading quickly like a virus, causing people to start behaving differently, triggering contagiousness, whether it applies to fashion trends, the uptake of cell phones, or the spread of disease. Gladwell’s explanation of how epidemics occur bears an uncanny resemblance to what is happening in the clinical trials sector as stakeholders are abruptly changing entrenched study behaviors due to the impact of the COVID-19 pandemic, raising questions as to whether these changes will persist once it subsides. 

	This article takes a look at an industry in flux, with the pandemic driving a long-awaited trend away from the traditional site-based study model toward one that is more patient-centric, meaning that decentralized and hybrid approaches may finally be taking hold. These newer methods, which include home study visits, telemedicine, and remote monitoring, have been happening over the past few years, but uptake has been slow, reflecting the clinical trials industry’s renowned conservative view of change, often citing regulatory concerns, and clinging to an “if it ain’t broke, don’t fix it” attitude. This resistance has stubbornly persisted despite sobering statistics. A recent study from the Tufts Center for the Study of Drug Development (CSDD) found no significant differences in the mean number of patients enrolled per site or by therapeutic area in 2019 versus 2012.

 The study also showed that late development studies had a higher average drop-out rate in 2019 (19.1%) than in 2012 (15.3%).

	This may all be about to change, and fast, due to the COVID-19 pandemic. Suddenly, with participants unable to get to the site, or unwilling to travel for fear of contracting the virus, sponsors and contract research organizations (CROs) are anxious to embrace patient-friendly decentralized practices in a big way, hoping to curb the number of studies that are shutting down or not starting at all. Darcy Forman, vice president of clinical operations for Science 37, a provider of virtual clinical trials, comments, “We have been unbelievably busy with this pandemic as sponsors are wanting to transition to a virtual model. It’s really accelerating, and they are finally pushing through their hesitancy.”

	Part of this patient-centric effort includes growing interest in simplifying protocols, and documenting those changes. Michael Cioffi, senior vice president of clinical solutions and strategic partnerships with WCG, 

remarks, “We’re getting lots of questions from stakeholders asking if they should amend the protocol. We’re looking at whether there are visits in the protocol that may not be essential for getting to the primary endpoint.”

	To explore these major shifts, several clinical trial stakeholders were interviewed to gain an understanding of remote processes unfolding in the era of COVID-19, and how smart technologies and mobile health staff are key to sites making this transformation. The larger question is whether their wider acceptance will be the inflection point that truly upends the status quo. In the long term, the intent is to remove some of the barriers of traditional models of study conduct, resulting in faster and more productive clinical trials.

	Starting in March, stories began appearing about sponsors slashing clinical trial activity as the coronavirus was actively spreading across the globe.

 This slow-down reflects an all-out effort to protect the trial participants and site staff, meaning that study visits are being reduced, shifted to tele-visits, or cut entirely. Also, large numbers of healthcare staff are being re-routed to care for patients infected with the coronavirus. A recent webcast by WCG included ethicist Dr. Arthur Caplan, professor of bioethics and founding director, Division of Medical Ethics, NYU Langone Medical Center, who discussed this chaotic activity.

“Morally, we are trying to shift away from autonomy toward protection of the community,” he said. “We want to reduce the impact of the pandemic, so we are trying not to conduct research unless it is absolutely benefiting a person, and taking it away would harm them.”  

	At the same time, a startling number of new trials dedicated to vaccine study, development of therapies, or observational case studies are ramping up. As of May 29, clinicaltrials.gov listed more than 1,800 studies for COVID-19 in various stages being conducted the world over.

 Most-85%-are either recruiting or have not yet started recruiting, but the short descriptions of each trial make it difficult to tease out how many visits will be virtual or will include home visits.

	To minimize confusion and to help stakeholders safely conduct these clinical trials during the era of COVID-19, regulatory agencies have released guidelines

 having put forth guidances in March.  And with the pandemic a changing picture, both guidances have already been updated. 

	The FDA guidance was implemented immediately and without prior public comment due to the urgency of the situation, and its recommendations are intended to remain in effect only for the duration of the COVID-19 public health emergency. This guidance includes a number of bullet points and a Questions and Answers Appendix focused on ensuring the safety of trial participants. Importantly, there is a statement about use of alternative and remote methods for safety assessments, such as phone contact, virtual visits, and alternative locations for assessment, and sponsors should be determining if in-person visits are necessary to assure trial safety. Also, sponsors should consider whether participant safety can be assured through use of remote monitoring. The box below lists a sampling of the bullet points in the FDA guidance.

	Similarly, the EMA guidance states that actions for ongoing clinical trials should be based on benefit-risk considerations from national and local perspectives, with priority given to the impact on the health and safety of the trial participant. This may include conversion of physical visits into phone or video visits, postponement of visits, or complete cancellation to ensure that only strictly necessary visits are performed at sites. Changes to studies should avoid further burdening of sites in terms of time and staffing during the pandemic. As for new trials, the feasibility and immediate necessity of starting them should be critically assessed by sponsors in close collaboration with stakeholders, especially investigators. This guidance includes a section on monitoring methods (see highlights below).

	The sharp turn toward more patient-centric study models is perhaps the single-most dramatic change to the clinical trials landscape. Jim Kremidas, executive director of the Association of Clinical Research Professionals (ACRP), says, “The silver lining in all this is what we might call the COVID Catalyst for decentralized trials.”  

	Finally, the traditional study model, whereby all visits take place at the site, is giving way to a more virtual approach, with technologies and platforms enabling this transition. One example is Science 37’s platform, which brings clinical research into the home, facilitating interactions between participants and study teams by supporting virtual patient recruitment, electronic consent, videoconferencing, and data collection by electronic clinical outcomes assessment (eCOA).  In addition, for some trials, the study product is shipped directly to patient homes. Mobile teams are trained to do home visits, which may include blood draws, and in some instances, home infusion. To ensure the safety of patients and staff, Science 37 has an in-home COVID-19 protocol in place, which conforms to the FDA guidance.

	Megan Liles, executive director, operational strategy and feasibility for clinical trials, at Precision for Medicine, a service provider for biomarker studies, explains that for oncology trials, sponsors are actively seeking a more patient-centric approach. “At this time, sponsors are looking at their protocols to see if there are opportunities to make home-based visits or telemedicine-type visits,” she says. “They are also looking at ways to scale back on the number of procedures, and put flexibility in the protocol. This is an immediate need.”

	As patient visits become more remote, monitoring activity is following suit. The growing interest in remote monitoring capability is evidenced by regulatory input, and the number of articles,

 webinars, or portions of webinars on this subject. WCG’s Cioffi comments that as remote monitoring gains attention, sponsors are concerned about being able to monitor the quality of the data appropriately. “Not every sponsor is comfortable with remote SDV. But if they are, they need to ensure the mechanics of it, such as having the proper monitoring plan in place to allow for this,” he says. “The challenge they have is their concern that protected health information could be transmitted, and a lot of people are very uncomfortable with that. Some companies have secure portals, where the source documents are being redacted and then uploaded.”

	Cioffi adds that sites also have issues with remote monitoring, as source documents cannot leave the site, and any efforts to monitor them remotely must be in accordance with HIPAA guidelines. For many sites, this is new ground.

	With study pipelines being cut, sites are facing very real issues of viability linked to furloughing staff, downsizing, or outright demise of their sites. To quantify the impact of COVID-19 on study activity, ACRP, in partnership with Continuum Clinical, a patient recruitment provider, released results of an online survey for U.S. sites in early April.

 The 297 respondents revealed that sites not actively working on COVID-19-related studies are being heavily impacted by the global pandemic. Nearly one-third (31%) reported fear of total site closure as stay-at-home orders and patient concerns over interacting with healthcare professionals were stepped up. Seventy-seven percent stated that at least one of their current clinical trials had been put on hold or cancelled in recent weeks.

	Also disturbing is the fact that sites are facing serious staffing issues, with 38% claiming that employees are experiencing difficulties working from home, and 33% reporting employees are not fully engaged due to COVID-19-related disruptions.

	These data are telling an important story, and according to Kremidas, “Another U.S.-based survey is scheduled for early May. We’ll be tracking some of these issues longitudinally to see if things have changed. Site closure will be asked about, and if that jumps to 50%, that will be another red flag.”

	ACRP did conduct a follow-up survey in May (n = 274), and while results are still being tallied at the time of this writing, preliminary findings are somewhat encouraging. Importantly, sites are significantly more optimistic that they will not need to close in the coming weeks. Specifically, 75% indicated that site closure is very unlikely.  Also, there was a tremendous increase in the percentage of sites conducting COVID research (from 18% to 43%), and a strong interest in use of telehealth (91%).

	As for trials currently on hold, there was a slight rise in the use of telemedicine to maintain patient engagement.

	Clinical Score, a provider of patient-centric drug development and commercialization services, also conducted a recent online site survey.

 This one, with responses from 363 sites in 42 countries, also highlighted the toll that treating patients with COVID-19 is taking on site staff, including their ability to obtain supplies, equipment, and labs. An impressive 92% claimed that they have attempted to keep trials on schedule, and as evidence of the ongoing shift, 36% of sites responded that virtual site visits is currently their most commonly used approach. But still, the difficulty of modifying protocols because patients are not coming in for study visits was too great for 34% of enrolling sites, so they opted to stop seeing study patients, or moved to virtual trials.

	These findings raise questions as to how ready sites will be able to ramp up as the clinical trials sector eventually attempts to resume studies beyond those for COVID-19 treatments or vaccines. “Investigative sites are the most important piece of the supply chain,” says Kremidas. “When this thing ends, there will be a whole backlog of new trials that sponsors want to do without a workforce to do it. The shortage of sites is going to slow down development of drugs and raise the cost.”

	ACRP is launching an initiative to help sites through this tough time, and is actively seeking partners to assist in this effort.

	Gladwell says that getting to the so-called tipping point is all about an epidemic spreading in such a way that unexpected behavior becomes expected, and radical change is more than a possibility-it becomes certainty. But, as the clinical trials world is heading toward a more patient-centric model, with redesigned protocols, including a mix of on-site, remote, and home visits made possible with digital tools, it’s not entirely clear what elements of this abrupt change will remain post-COVID, and which will slip back to the old model. Opinions are mostly optimistic, as there is a sense that stakeholders are ready to snap out of perpetual pilot mode, and embrace the technologies needed to conduct more efficient clinical research.

	“Before the pandemic, I heard more interest from sponsors in virtual visits because it’s becoming more important to take the trial to where the patients are,” says Precision for Medicine’s Liles. “Especially since our trials are biomarker-driven, we are dealing with a very small population of patients, so there is going to be more interest in this approach. I hope this is the catalyst we need. On the other hand, some project managers said they’ve heard that after the pandemic, they’ll be going back to 100% SDV rather than moving toward risk-based monitoring.”

	Brian Neman, CEO and founder of Sanguine Biosciences, a provider of mobile health staff for clinical trials, remarks, “Sponsors often perceived home visits as a risk, but now, they are considering it a risk-mitigation strategy. In line with that concept, I think some sponsors will stop over-auditing, meaning an overhaul of the vendor review and qualification process. For example, is it wise for smaller companies, like those with less than 100 employees, to spend precious time and resources auditing global service providers, such as Amazon Web Services or Salesforce.com? That time could be better spent adopting technologies that have entered the space that facilitate patient centricity.”

	Making the changes more likely to stay after the pandemic will involve addressing how a remote model will enable the study drug to get to the patient, how the patient will be monitored, how the data will be analyzed, and which sites are best prepared to go with the new flow. These are long-simmering questions about clinical research that are finally starting to get answered.

, MBA, is President of Medical deScriptions, LLC

	1. Batista G, Lowy P. Tufts CSDD Impact Report January/February 2020, Vol. 22(1). Press Release. January 2020. Available at: 

	2. Lee J. Lilly to Halt Enrollment in Clinical Trials as a Result of COVID-19. MarketWatch. March 23, 2020. Available at: 

https://www.marketwatch.com/story/lilly-to-halt-enrollment-in-clinical-trials-as-a-result-of-covid-19-2020-03-23?siteid=yhoof2&yptr=yahoo

	3. Fidler B. Guide to Clinical Trials Disrupted by the Coronavirus Pandemic. 

https://www.biopharmadive.com/news/coronavirus-clinical-trial-disruption-biotech-pharma/574609/

	4. Part 1: Clinical Trials in the Era of COVID-19: Changes You Need to Make Now. WCG Webinar Series. March 18, 2020. 

https://www.wcgclinical.com/events/covid-19-webinar-series/

	5. Clinicaltrials.gov. COVID-19 Studies. May 29, 2020. Available at: 

https://clinicaltrials.gov/ct2/results?term=COVID-19&Search=Clear&age_v=&gndr=&type=&rslt=

	6. Heelan B. COVID-19 Pandemic and Regulatory Guidelines on Clinical Trial Conduct; Similarities and Differences Between Regions. PAREXEL. March 27, 2020. Available at: 

https://www.parexel.com/news-events-resources/blog/covid-19-pandemic-and-regulatory-guidelines-clinical-trial-conduct-similarities-and-differences-between-regions

	7. FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency. Food and Drug Administration. May 14, 2020. Available at:. 

https://www.fda.gov/media/136238/download

	8. Guidance on the Management of Clinical Trials During the COVID-19 (Coronavirus) Pandemic. European Medicines Agency. April 28, 2020. Available at: 

https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/guidanceclinicaltrials_covid19_en.pdf

	9. Johnson T, Yee H. Adjusting To Clinical Trial Remote Monitoring During COVID-19: Working Smarter & Safer. Halloran Consulting Group. 

https://www.clinicalleader.com/doc/adjusting-to-clinical-trial-remote-monitoring-during-covid-working-smarter-safer-0001

	10. COVID-19 Regulatory Developments Impacting Technology Use in Clinical Trials. Medidata Blog. April 30, 2020. Available at:

	11. Survey Shows One-Third of Clinical Trial Study Sites Fear Total Closure; 77% Indicate at Least Some Ongoing Research Trials Have Been Impacted Due to COVID-19. Association of Clinical Research Professionals. Continuum Clinical. April 8, 2020. Available at: 

https://acrpnet.org/2020/04/08/survey-shows-one-third-of-clinical-trial-study-sites-fear-total-closure-77-indicate-at-least-some-ongoing-research-trials-have-been-impacted-due-to-covid-19/?

	12. Kaplan GA, Weaver R, Cloud B. The Effect of COVID-19 on Clinical Trials: Insights from the Inside. 

http://www.appliedclinicaltrialsonline.com/effect-covid-19-clinical-trials-insights-inside?pageID=1

Clinical trial stakeholders weigh in on the major shifts unfolding in the era of COVID-19, as efforts move away from the traditional site-based model.

Ann Neuer

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