	In the world of clinical trials, many issues and observations have arisen because of COVID-19. At the top of that list, is the increased talk and implementation around decentralized or hybrid approaches for clinical trials. These approaches appear noticeably more conducive in supporting the challenges that the pandemic has brought to sites and patients. Whether it’s actual trial suspensions, or limited accessibility by monitors, plain fear of

 contracting the virus, or some combination of these or other challenges, it’s clear that COVID is fomenting change in the industry. You can read more about these initiatives, as well as results of investigative sites surveys in our June 

 of public and patients in April around their knowledge or experience of clinical trials in regard to COVID-19 that is notable for exactly that-the audience. This may be a time where, conceivably, more people have heard the term clinical trials regularly mentioned in media coverage. But the CISCRP survey found that awareness of clinical trials remains low, with 58% of respondents having not heard of a COVID-19 research study.

	“Interestingly, among the minority that had recently heard of a COVID-19 clinical research study in the recruitment phase, we learned that a higher proportion (40%) of Europeans are aware than Americans (34%),” said Annick de Bruin, director, research services, CISCRP, in a press release. “This contrasts with our larger baseline 2019 Perceptions & Insights Study where we found that North Americans are more likely to be aware of a current clinical trial in general than any other region. This may partially be due to the fact that the crisis evolved earlier in Europe.”

	In addition, the survey noted misconceptions about the clinical research development process persist. Most (60%) think a treatment or vaccine for the virus will be developed in less than one year. Once developed, the 

majority (64%) think it will be less than a year before people can start receiving it.

	What this, and other reports highlight, is the larger issue around health and/or scientific literacy among the general public, which is clearly lacking and at times, blatantly misguided. For example, while most in our industry understand the value of vaccines, our Washington Correspondent Jill Wechsler reports 

 about the growing anti-vax movement and other vaccination concerns inspired by the pandemic. 

 were hopeful that the pharmaceutical industry’s ability to rise to the challenges of the pandemic, showcasing the positives of scientific innovation, could well prove to be industry’s finest hour. But can that overcome the overall lack of health literacy?

Articles

Recent surveys of the public and patients concerning COVID-19 highlight the larger issue around health and/or scientific literacy among the general public.

A Crisis of Health and Scientific Literacy

 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.

COVID-Sparked Practices Driving New Patient-Centric Behaviors

Home visits have the power to ease the clinical trial process for patients, but complex study design, tight timelines, busy clinical operations teams, and overburdened sites can sometimes make home health feel like yet another moving piece to manage. As COVID-19 restrictions continue to force sponsors and study teams to pivot clinical trials in progress (and consider precautionary adjustments to any new study designs), home visits are being offered as a critical solution for already scheduled drug administration or other types of protocols.

	Sites have expressed concerns in recent surveys that home visits aren’t practical, but fears over widespread site closures may be influencing responses. Sponsors, however, are increasingly concerned about losing their data for ongoing studies. 

	Missed visits can mean starting a clinical trial over despite millions of dollars already sunk into study progress pre-pandemic. 

	Incorporating a home visit component is clearly a viable way to continue additional dosing, blood work collection, or other protocol activities and assessments. Contrary to the concerns of some sites, adding home visits to clinical trials in progress could actually prevent paused studies and resulting site closures from taking place. 

	This article aims to demystify (and de-risk) home visits for sponsors and sites that are considering changing protocols for existing clinical trials and for those interested in including home visits in any new clinical trials. Understanding how to approach home visits will ensure sponsors, sites, and home visit providers are in alignment regarding quality, control, and oversight-and that is the best way to keep studies with a home visit component on target.

	The timeline is always one of the first things sponsors ask about, whether the conversation is taking place prior to the protocol being written, post-study design but pre-first-patient-first-visit, or even mid-study, as is the case with rescues or those threatened by COVID-19 restrictions. And setting realistic timing expectations is critical to making the home visit aspect run smoothly. 

	Today, there is a completely understandable desire to start up home health services very quickly. Starting from zero, however, still typically takes several weeks at minimum and requires candid communication between the sponsor and home visit service provider. Establishing timing should never be one-sided, and anything less than a partnership from day one will increase the likelihood of issues later on.

	The key point to remember is there is tremendous variability. Individual variables that play a large role in establishing timelines can include factors like:

		Amount of protocol-specific training required.

	Very simple studies can be up and running in a month or two, and incredibly complex studies can take six months or more. If the protocol consists of patients taking a simple dose of pills, that will obviously require a completely different timeline than a daily infusion. The former would require very little training and a few weeks of preparation, and the latter several weeks just for training alone.

	In the current climate, especially, sponsors should be wary of overly aggressive timeline claims that don’t also come with a thorough project plan. The project plan should link directly to the associated timeline and consider all the potential weak links or pitfalls that could arise.

	Understand what a home visit can and cannot do

	While having a home visit option can improve how patients feel about trial participation, home visits are not ideal for every clinical trial. Protocols that require imaging equipment or a sliding scale only a board-certified neurologist can apply can only be done at a site. Additionally, some countries restrict certain medical procedures from being performed in a home setting. That said, many sponsors are surprised to learn the depth and breadth of procedures that can be handled at a home visit, especially as it relates to blood samples and investigational product. 

	In addition to simple procedures like physical exams, blood draws, and collection of vital signs, a high-quality home visit team can perform post-blood-draw preparation such as centrifuging or aliquoting. Home visit nurses can also perform intraperitoneal (IP) injection, including working with carefully temperature-controlled medications or those that have to be reconstituted right before application. 

	Home visits can even be combined with existing telemedicine technology, allowing a hybrid virtual home visit. A physician or site study staff could conduct a telemedicine assessment while other data is collected concurrently by the in-home nurse. 

	Almost anything that can be taught in a straightforward training session with a nurse is possible. What can and cannot be done during a home visit often comes down to balancing a reasonable level of training and equipment within budget. If the protocol would require an in-home nurse to attend weeks of training to support a visit or the equipment required is not portable, that would have a significant impact on the cost of implementation. 

	Home visits, by their very nature, help ensure protocol compliance. Visits need to happen within a specified time frame, and it is much easier for patients to maintain the right number of visits within the right time frame when the visits come to them. Take away the reliance on study participants to make site appointments and you take away a common compliance pitfall. 

	Fully assessing the training program of your home visit provider is also a critical step for sponsors and investigators. While home healthcare nurses are already skilled at administering typical procedures such as physical exams and vital signs, the protocol-specific training should include everything from the procedures that need to be completed, to being sensitive to participants’ physical or mental state, to good clinical practice (GCP) guidelines. And all training should be to the full satisfaction of the principal investigator overseeing the study. 

	Since sites are still responsible for the conduct of home visits from a regulatory perspective, there is often a concern about how they can remain in control of the progress without overwhelming the already busy study team and staff. 

	Approaching home visits as an extension of the site gives the entire engagement critical context. The home visit provider and nurses should understand they are working on behalf of the site but are also accountable for the role they fulfill. 

	From there, it is a matter of confirming the following:

		The home visit provider has a well-established method for opening candid lines of communication between the site, the home healthcare nurse, and the home visit provider’s project coordinator.

		Expectations are clear and there are quality-based key performance indicators (KPIs) in place.

		All data will flow quickly, efficiently, and accurately to the site. 

		The home visit provider has tools and resources in place that guarantee that visits go smoothly.

	Sites should not feel the need to micromanage the home visit details to ensure protocol compliance, and they should sacrifice nothing in terms of control, quality, or oversight. When home visits are done right, they augment the site’s reach and enhance the study participants’ relationship with the site, making the clinical trial easier and more convenient.

	When deployed with thoughtful planning, communication, and partnership, the home visit component should not be difficult to keep on target at all. In addition to the approaches already outlined, the most important key to making home visits work is listening to the needs of the patients. That requires engaging with participants

 and a home visit provider early and including them as stakeholders in the study design so protocols can be crafted to deliver research insights in a way that is as patient-centric as possible.

	Home visits are not a panacea. Not everyone wants a nurse coming into their home. However, when home visits are applied appropriately and incorporated intelligently and with flexibility, they can leave study participants with a more positive impression of the research being conducted-and enhance the successful completion of the clinical trial. 

Aligning approaches in quality, control, and oversight to get the most out of including home visits in clinical trial protocols. 

How to Keep Home Healthcare on Target

The terms “personalized medicine” and “precision medicine” have been in common use for more than 20 years. In 2005, personalized medicines only represented 5% of new molecular entities (NME) approved by the FDA, but in 2015 that number had increased to 42%, with most occurring in oncology.

 By 2018, more than 55% of all oncology clinical trials involved the use of a precision medicine biomarker, compared to 15% in 2000.

 The therapeutic benefit of these medicines is now clear, and the economic benefits are also becoming evident. However, significant challenges remain in bringing these precision medicines to the right patients at the right time.

	Academic medical centers and large cancer centers have traditionally been best equipped and have administered the bulk of oncology clinical trials.

 Hence, oncology studies are most often run within large institutions, often urban settings, even though it is estimated that 85% of patients are treated in the community oncology setting, found in suburban or rural areas.

 This is partially due to the infrastructure required to successfully execute a cancer study. This creates a clear misalignment, hampering the ability of oncologists and clinical research coordinators (CRCs) to find enough qualified patients to effectively triage, enroll, and matriculate through the clinical trial process. 

	As such, oncologists and CRCs struggle to recruit patients for oncology studies. Less than 5% of eligible adult cancer patients enroll in clinical trials.

 As CRCs must sort through extensive treatment options, specific requirements for type, stage and grade of tumor, lab test results, specific treatment histories, recurrence of disease, or failure of a prior line of therapy (all of which require longitudinal tracking), finding patients for enrollment is laborious. Increased dependency on molecular and pathological diagnosis, including stain-based pathology, as well as molecular assays, such as next-generation sequencing, nCounter, and quantitative polymerase chain reaction (qPCR), places further burdens on the care team of oncologists, nurses, research coordinators, pathologists, and others who

 strive to match eligible patients to clinical trials. A lack of information about the specific activities required prior to enrolling patients in a study contributes to sluggish, ineffectual oncology trial recruitment, especially against a backdrop of rapidly changing study parameters with new trials launching, study arms opening and closing, and trials completing enrollment. In addition, the emergence of basket studies, umbrella studies, and multi-arm study designs adds even more complexity and forces the care team to consider a much broader set of treatment options than ever before. Presently, it is an overwhelming task to educate care teams, provide adequate training and sourcing for test requirements, and manage the vast number of patients who are interested in participating in clinical studies as a treatment option.

	Thus, it’s clear that the current patient recruitment process is inefficient, inadequate, and warrants improvement, particularly if it is to continue to extend opportunities for trials in the community setting. This article will showcase how rich data and workflow technologies built to help integrate early diagnostic data and centralize information can help reduce the burden on care team members, allowing for improved management of clinical trial prescreening activities and increase patient enrollment. Technology systems can open up the patient recruitment bottleneck and let the right patients and their care teams flow into the right trials more quickly. Specifically, artificial intelligence (AI)-based technologies are now being deployed for quick, efficient identification of eligible patients for oncology clinical trials.  

	With personalized medicine for oncology comes data complexity

	Patient recruitment represents a major bottleneck for oncology trials due to four main reasons: 

		Incomplete connectivity between care teams and the data.

		Ineffective prescreening data management tools. 

	Integrated patient-data platforms, such as Deep Lens’ VIPER platform, which combines AI-based trial matching with CRC workflow support, can offer solutions for all four issues. 

	First, many clinical sites administer dozens of trials across different disease types simultaneously, which quickly leads to data from thousands of patients. Each of those trials has different inclusion and exclusion criteria. With precision therapies and complex study designs (umbrella, basket, and multi-arm), the criteria list gets longer and more complex. Data that is needed to find these patients early and track them during their disease to find the appropriate windows when they qualify for a trial (e.g., during a change from one line of therapy to another) come from different sources. 

	These sources include the electronic medical record (EMR), the laboratory information system (LIS), molecular data from vendors, and interviews with the patient. Identifying, tracking, and monitoring patients via these various data elements is a painstaking process. Studies show that enrolling a single patient can take nine or more hours of screening time.

	Secondly, patient recruitment suffers from limited connectivity of the entire care team. Historically, pathology sat outside of the designated care team. In fact, the oncology care model does not account for pathology in the care paradigm for value-based care in cancer. This is a mistake, as the pathologist is the first step in reaching an effective treatment for a patient-in most cases, they are the source of initial diagnosis. Patient health data is initially captured in a pathology report that designates the type, location, and severity of disease. This information eventually comes to the oncologist via a PDF report and ultimately gets housed in the EMR, but other sources for data are also critical in making the appropriate decisions for a patient’s care. This includes additional EMR data, LIS data, and genomic and other screening data that come from third-party diagnostic labs. Ideally, all of that data should be stored in one master EMR, but it is rarely seamlessly integrated as such. For example, a third-party report might be scanned in as a PDF image or an attached document that is not text-searchable, and, therefore, requires a person to open and read the entire report.

	 At some institutions, CRCs rely heavily on physician referrals, while at others it is up to them to scour patient records to find those that meet the specific trial criteria. During initial recruitment screening, which can start as early as a patient’s initial diagnosis, a CRC may need to pull one piece of data out of the EMR layers contributed by multiple care team members to check for inclusion criteria. 

	Finding a way to connect all these different data elements in a way that’s meaningful and easily searchable is key. Another challenge is maintaining the connections between principal investigators (PIs) and healthcare teams, especially when a study is recruiting across multiple locations. A multi-site investigator may not be able to see all patients throughout all parts of the enrollment process, but he or she needs to know when a patient is being enrolled, has given consent, and if the care team needs their input on a potential patient. 

	The third significant challenge for trial recruiters is reaching patients during the narrow enrollment windows available to them. Many studies require that a patient has failed a specific prior therapy, has a recurrent disease, or shows laboratory results in a narrow range in order to qualify. 

	Even a seemingly good candidate must sometimes be placed into a “watchful waiting” queue based on their current course of treatment. CRCs typically manage this triage through spreadsheets (or even sticky notes) that remind them to return to a particular patient, pull up their EMR, dig out specific data points, and then physically track down the patient to inform them about a trial. A CRC can easily miss that patient during the narrow window between a first and second, or second and third, line of therapy to approach them for consent and eventual enrollment on a study.  

	Lastly, there are not enough effective tools that allow CRCs and care team members to recruit patients efficiently and get them to the point of enrollment. Once a patient is enrolled, there are many more tools to see them through the trial process, such as a clinical trial management system (CTMS). But prior to enrollment, better tools are needed to manage the multiple layers of moving parts: from the complex criteria and patient data, to tracking patients’ care trajectories, and staying in communication with their care teams as a trial progresses.

	Technology tools can help patients find clinical trials, allowing participants themselves to query clinicaltrials.gov (directly or indirectly) for trials that match their cancer diagnosis, location, and are currently enrolling. Several tools have been built over the years to assist patients (e.g., Corengi.com, TrialX.com, eTACTS, Patientslikeme.com, and TrialReach).

 These tools are helpful, but are not typically geared toward the clinical care team and don’t take advantage of patient data to help with the triage process. Some larger institutions have developed their own, internal tools to assist with this issue, however, they are often customized and are not easily scalable to other institutions. 

	Open avenues for information to flow freely

	Another example of an emerging solution is a cloud-based platform like VIPER. The platform ingests trial protocols and uses complex logic engines to break down the inclusion and exclusion criteria and to access data at the earliest point in a patient’s journey, the time of diagnosis, in order to find appropriate patients for trials. Data is analyzed from various sources, including pathology, EMR, LIS, and third-party genomic laboratory data, and processed via AI. The patients who fit the appropriate inclusion and exclusion criteria are flagged for CRCs. Then the platform pushes notifications to the patients’ care team, which includes the CRC, oncologist, and/or nurses, to alert them about the patient’s eligibility for all nearby, ongoing clinical trials (see Figure 1 below). The system accesses data to ensure that patients, their care teams, and clinical trial sponsors are connected and educated at every step of patient treatment. VIPER’s complete digital pathology workflow system also keeps a broad array of pathology image and annotation data organized alongside other more traditional health data.

	At the recent ASCO 2020 Annual Meeting, it was shown that a single CRC using VIPER was able to manage prescreening activities for 20 different oncology studies at a cancer center serving the community setting, across 11 different cancer types that included 12 biomarkers and three basket studies. During a four-month research initiative, more than 5,700 patients were prescreened, resulting in the identification of about 150 patients as potential candidates for studies who had previously been undetected.

	Just as traffic bottlenecks improve when more lanes open up to let cars flow freely, so too can the recruitment and enrollment bottlenecks be opened up using integrated patient data platforms. These platforms also allow information to flow freely in both directions and give more complete data integration from pathology through treatment.  

	Beyond linking previously ignored data from pathology, such as tumor biology, integrated data platforms allow PIs to understand where there may be snags in the enrollment processes. They also give clinical research managers performance metrics and audit capabilities, and they empower CRCs and care team members to track patient prescreening activity via a real-time screening log. This eliminates the need for manually transcribing notes into a separate system, reducing double entry and errors. 

	Time-sensitive alerts through these platforms remind CRCs when a patient might need revisiting or has become available to enroll. In this way, ideally, fewer potentially eligible patients slip through the cracks.

	Recruitment traditionally comes through the large academic research institutions where studies are conducted. However, about 85% of patients are actually treated for their cancers in the much smaller community clinics where, currently, nearly two-thirds of those patients don’t have local study options.

	Until recently, there has not been a good way to connect patients in community settings to oncology clinical trials being run nearby. Often, by the time a community physician realizes that their patient could be eligible for a particular study, the enrollment window may have already closed. For instance, a patient that has failed a first-line treatment may become eligible for trials nearby, and at the same time their physician is trying to make other care decisions that may affect their future eligibility for studies. If the patient and their physician are simply unaware of the options for participating in a clinical trial, those opportunities that could potentially benefit the patient can be easily missed.

	Technology solutions are essential to closing the community gap. These solutions are being developed in-house at some institutions and are also available commercially. Typically, they are championed by the PIs and clinical trial program management at adopting institutions. When these tools are deployed, they can help to connect community clinics, physicians, and patients across community care organizations and also to nearby affiliated research centers that are running studies. 

	Moving cancer care forward during a pandemic  

	The global COVID-19 pandemic has burdened healthcare facilities like never before, and it will continue to do so in the coming months, if not years. The shutdown of nonessential medical care and the repositioning of staff and resources to care for the critically ill has already negatively impacted patient enrollment in clinical trials for diseases beyond COVID-19. 

	The barriers to recruitment are even higher than usual as patients who are immunocompromised (including oncology patients) will want to limit their contact with healthcare facilities and professionals. 

	While some sponsors have publicly acknowledged that their trial programs have slowed down since April 1, many cancer clinical trials, even in New York City, are still going forward with hospitals taking extra precautions for those patients and their exposure risks. FDA has released modified guidelines allowing for more flexibility during the COVID-19 outbreak.

calling for the adoption of new tools and innovation in clinical trials, including telemedicine and virtual, cloud-based technologies that can help minimize disruption in cancer care.  

	For both oncology and COVID-19 patients, it’s imperative to find ways to compress clinical trial timelines so that efficacious drugs get to the market as soon as possible. Technologies like VIPER are positioned to help through two major routes: by accelerating the remote/virtual screening process, and by matching the right patient with the right treatment at the right time.

	It’s never been more exciting to be in a position to usher in the era of precision medicine. But clinical trial sponsors face a steep challenge in patient recruitment: in the decade ending in 2015, clinical trial countries and investigative sites rose 63%, while the mean number of patients involved in trials declined by 18%.

	To break up recruitment bottlenecks so that cancer patients get the treatments they need, we must harness and integrate scientific knowledge with individualized patient data. New technologies that incorporate the latest advances in AI and natural language processing, will give clinical trial leaders a better, more efficient way to cut through the vast amounts of data required to match a patient with a therapy. By doing so, these platforms will play a critical role in shortening the drug development lifecycle.

	1. “The Personalized Medicine Report.” Personalized Medicine Coalition. 2017.

	2. “The Evolution of Biomarker Use In Clinical Trials For Cancer Research.” Personalized Medicine Coalition. 2020.

	3. Copur (2018). “How to Build a Clinical Trial Infrastructure in the Community Oncology Setting.”  The ASCO Post.

	4. Copur (2019).  Inadequate Awareness of and Participation in Cancer Clinical Trials in the Community Oncology Setting.  

	5. Murthy VH, Krumholz HM, Gross CP. Participation in cancer clinical trials: race-, sex-, and age-based disparities. 

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	6. Tejeda HA, Green SB, Trimble EL, Ford L, High JL, Ungerleider RS, Friedman MA, Brawley OW. Representation of African-Americans, Hispanics, and whites in National Cancer Institute cancer treatment trials. 

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	7. Penberthy et al. (2012). “Effort Required in Eligibility Screening for Clinical Trials.” 

	8. Chen et al. (2013). “Screening Intervention to Identify Eligible Patients and Improve Accrual to Phase II-IV Oncology Clinical Trials”.  

	9. Cross-system Evaluation Of Clinical Trial Search Engines, 

	8. Novel Artificial Intelligence (AI)-based technology to improve oncology clinical trial fulfillment.  ASCO 2020 Annual Conference Poster.

	9. Murthy (2004) Participation in Cancer Clinical Trials. 

	10. Copur (2019).  Inadequate Awareness of and Participation in Cancer Clinical Trials in the Community Oncology Setting.  

. Ken Getz, Tufts CSDD Impact Report July/August 2018, Vol. 20 No.4

How integrated data platforms can help find the best-suited patients for cancer studies and reduce the burden on care teams.

Busting Patient Recruitment Bottlenecks in Oncology Trials

COVID-19 has dramatically impacted clinical trials in high-income countries because of site closures, stay-at-home orders, supply chain issues, and participant reluctance to visit doctors’ offices and hospitals, among other barriers. Many of these difficulties have been exacerbated-and accompanied by new ones-in low- and middle-income countries (LMICs). COVID-19 also is amplifying some of the difficulties that are always present in clinical trials in LMICs.

	While the substantial majority of clinical trials still take place in countries classified by the World Bank as high income, a review of clinical trial registrations on the World Health Organization (WHO) International Clinical Trials Registry Platform and clinicaltrials.gov shows that a significant and growing number are being conducted in LMICs, with major centers in Eastern Europe, the Middle East, Brazil, China, India, and South Africa. Even very low-income LMICs without large numbers of investigators and sites trained in International Conference on Harmonization (ICH) good clinical practice (GCP) have dozens or hundreds of trials.

	Five critical challenges faced by researchers conducting clinical trials in LMICs are examined ahead.

	Several LMICs, including India, South Africa, Kenya, Brazil, Mexico, and Peru,

 have issued guidance or directives pertaining to clinical research during the pandemic. These guidance documents often mirror the content of similar documents from the FDA, the European Medicines Agency (EMA), and the U.K.’s Medicines and Healthcare Products Regulatory Agency (MHRA). Typically, these agencies urge those conducting trials to take steps to protect participants; allow flexible amendments to protocols for participant safety, remote study visits, and monitoring; and in some cases, such as in Colombia, explicitly prioritize COVID-19 trials. Argentinian regulators are recommending postponement of any recruitment of healthy participants except in COVID-19 studies, for example. 

	The vast majority of LMICs, however, have not issued specific COVID-19 guidance for clinical trials, which creates uncertainty around study protocol changes that may be needed in light of the pandemic (such as whether telemedicine, electronic acceptance of informed consent documents, or shipping investigational product to a patient are acceptable). This uncertainty is in addition to the normal delays often associated with regulatory approvals in LMICs.

	Quarantines and internal travel restrictions will impact the ability of clinical trial participants and research staff to go to investigative sites. Both the International Monetary Fund

 are monitoring government responses in each country. Oxford’s heat map

 provides a good visualization of how restrictive a national government’s restrictions are (keeping in mind that many countries also have state, provincial, or local restrictions as well). 

	In addition, law enforcement and military in LMICs have been more likely than high-income countries to enforce quarantines with violent acts, as has happened in Kenya, Paraguay, and India, among other places. Fear of police action or illness may reduce participants’ willingness to travel to trial sites even if they are not legally prevented from getting there. Participants are also likely to be lost to follow-up as migrant workers throughout South Asia, India, and the Middle East return home; in India, for example, out-of-work laborers are leaving cities in large numbers and returning to rural villages to live with family members.

	While remote trial monitoring is an important way to continue research during the pandemic, as the FDA has noted, there are often components of an on-site monitoring visit that cannot be completed remotely. External travel restrictions, which are in place almost everywhere as of this writing, are limiting in-person monitoring of studies that have monitors from outside the country. Some countries, such as Vietnam, are requiring “immunity passports” for foreigners entering the country, or are requiring long quarantines of international arrivals.

	These requirements make in-person monitoring impractical even if contract research organizations (CROs) and other key vendors believe it safe for their monitoring personnel to travel. Medical professionals in several countries, including Mexico, Colombia, and the Philippines, have been attacked by individuals concerned about contracting COVID-19. In addition, there has been a documented increase in anti-foreigner sentiment worldwide, including in West Africa, China, and Ethiopia, which may impact foreign monitoring and any foreign staff operating at a clinical trial site or central lab. Even in-person monitoring by in-country monitors may be prevented by trial site policy or safety.

	The availability of necessary supplies and disruptions to supply chains as a result of the pandemic will, in general, impact LMICs more than high-income countries. COVID-19 will likely have a long-lasting effect on global supply chains.

 The U.S. and more than 50 other countries are restricting or considering restrictions on exports of supplies that are needed to mitigate the effects of COVID-19 locally.

 Internationally, the World Trade Organization and the World Customs Organization issued a joint statement noting the disruptive impact of the virus on global supply chains and pledged to cooperate to facilitate trade in essential goods.

	LMICs are struggling to obtain limited hospital supplies in the global market in competition with the U.S., the European Union, Japan, and similar high-income buyers, as recent reporting about the COVID-19 outbreak in Nigeria shows.

 Clinical trial sites in LMICs that cannot obtain needed supplies in-country could obtain them from a study sponsor, assuming the products can be legally imported and shipments to that country are not cost-prohibitive in light of global freight and logistic disruptions.

	Protocol changes and other circumstances that may impact the risks and benefits of a clinical trial have implications for the participants’ ongoing informed consent and the ethics oversight of the trial. In-person study visits may be riskier in some LMICs than in high-income countries during the pandemic as a result of personal protective equipment (PPE) and eventually vaccine, antibody, or other preventative availability. 

	Virtual/remote visits could be riskier, where they are allowed, because living arrangements may not facilitate privacy, and internet cost and speed will often prevent video conferencing. Participation in general may be riskier in LMICs because of the capability of the health system to treat COVID-19 or study injuries during the pandemic and because of the privacy concerns government anti-COVID-19 measures may create, such as China’s QR health code system

 and India’s Aarogya Setu app16, both of which are generally mandatory.

	In addition, the Declaration of Helsinki, FDA regulations, ICH GCP E6, and influential U.S.

 ethical reports on research in developing countries all recognize the special considerations that are involved in researching these populations. 

	The populations in LMICs are more likely to be vulnerable already because of poverty, lack of education, underlying disease (e.g., malaria, HIV/AIDS, and tuberculosis), and in some areas, heightened familial coercion. The United Nations has also produced a working paper containing estimates of the impact of COVID-19 on global poverty as of April.

	Many will not have access to clean drinking water or running water in their homes to wash their hands to prevent COVID-19. Many also will be food insecure; the Famine Early Warning System is an excellent way to determine whether there are food security issues in a country or region.

 Most will have come under some additional stress as a result of losing loved ones or jobs. 

	The U.S. National Institute of Mental Health has issued “Ethical Issues to Consider in Developing, Evaluating, and Conducting Research Post-Disaster,”21 which will be useful for researchers confronting these issues. 

	In addition, it would be prudent for drug researchers to plan to address cases of participants facing domestic violence

 even if that is not explicitly the subject of the research, by determining what resources might be available for them in their communities.

	As clinical trial sponsors work with their CROs and sites to address the challenges posed by COVID-19 in their LMIC-based studies, they should be sure to follow any regulatory guidance available in the countries where the sites are located, either specific to clinical trials or those that generally pertain to the healthcare sector. For those LMICs without regulatory guidance, following the general principles articulated in FDA’s guidance is advisable 

to the extent possible. Participant safety must be the priority, so when trials are started or ongoing during the pandemic, decreased in-person study visits and monitoring should be implemented wherever possible. Every protocol deviation and missing data element should be documented. 

	Finally, informed consent forms and study institutional review board (IRB) and independent ethics committee (IEC) approvals may need to be revisited in light of local conditions.

 is an attorney at Bass, Berry & Sims. He can be reached at 

http://www.sahpra.org.za/wp-content/uploads/2020/03/SAHPRA-Communication_COVID_19-Final-25032020.pdf

https://pharmacyboardkenya.org/files/?file=Clinical_Trials_During_COVID-19_Pandemic.pdf

http://portal.anvisa.gov.br/documents/219201/4340788/SEI_ANVISA+-+0989653+-+Nota+Técnica14.pdf/6b48273f-550f-4761-8ba1-4e731a87b526

https://www.gob.mx/cofepris/articulos/medidas-extraordinarias-en-relacion-a-estudios-clinicos-ante-la-pandemia-de-covid-19

https://ensayosclinicos-repec.ins.gob.pe/images/Nueva_actualización_12.12.19/Actualización_2020/Comunicado_N_002-2020.pdf

https://www.imf.org/en/Topics/imf-and-covid19/Policy-Responses-to-COVID-19

Outlining the five critical hurdles faced by clinical teams conducting studies in these nations amid quarantine and other restrictions.

Applied Clinical Trials-06-01-2020

A Crisis of Health and Scientific Literacy

COVID-Sparked Practices Driving New Patient-Centric Behaviors

How to Keep Home Healthcare on Target

Busting Patient Recruitment Bottlenecks in Oncology Trials

COVID Challenges for Trials in Low-to-Middle-Income Countries

Drug Development in Wartime: Driving Tomorrow's R&D Decisions with Today's COVID-19 Data

Taking Stock of Intentional Dose Non-Adherence

COVID Vaccine Clinical Trials Require Fast Decisions, But No Shortcuts

Save Sites Now to Preserve the Future of Clinical Trials

Germany’s HTA Agency Seeks Support on Transparency About COVID-19 Agents

News Notes

Applied Clinical Trials, June 2020 Issue (PDF)