Medical records and interoperability are major issues in countries around the world. Sometimes departments in the same hospital exchange data incorrectly. Sometimes hospitals in the same country exchange data incorrectly. So, expecting international interoperability seems like a dream to many. But that is what we have achieved as a patient-led start up. For the first time, patients using Andaman7 are collecting their health records from both US and EU-based hospitals, at the same time, in the same software and with them in total control. Health data is normalized in their personal health record (PHR) meaning several exchange protocols, formats and interfaces are used to grab the data and store it in a uniform manner inside their smartphones. Storage of the data in a smartphone is key–not only does the patient have instant access to their data but it is more secure than cloud-based systems and under the patient’s total control. For the patients themselves this represents a huge leap forward in health data empowerment.

Andaman7 were encouraged by the patients’ positive feedback: “Navigating the medical system can be a stressful experience over and above the stress related to your own medical condition. It has been a challenge to keep track of accurate and up-to-date health data which has been scattered across several hospitals, and–in the case of my wife and me–across several countries. With the Andaman7 app, my wife and I were able to gather our health data from hospitals in the US and Belgium and manage it in one app in an organized and intuitive way. It feels right to be in charge of our data to ensure a smooth transition of our medical records from the US to Belgium. In addition, we can share our health records with each other and with our doctors if needed. It can only be hoped this becomes a common option.”

The next step, with patient consent, is to send data back to the hospitals–something Andaman7 is ready for. This innovation has far-reaching implications for the collection of real-world data (RWD) and the forming of real-world evidence (RWE). Andaman7 uses FHIR for inbound and outbound health data exchanges (in addition to other, de facto standards). Internally, they also use a very innovative liquid data model and ‘no protocol API,’ and fully support LOINC and SNOMED for high quality structured data. Properly used, RWD could enable us to reach one of the holy grails of medicine–the right treatment, for the right patient, at the right time.

Empowered international patient data access also has implications for tackling global health inequities. Africa bears the world’s greatest disease incidence and has significant healthcare shortages. Yet it has emerged as a new breeding ground for innovative digital health solutions. Our work with African Sustainable Development Advisors (Afrisda, Inc.) leads us to believe Africa can ‘skip one’ in health digitalization. The framework is already in place–large parts of the continent skipped the landline telecommunication stage and went straight to mobile. Now, there is an opportunity to avoid the step of disjointed, physical healthcare and instead embrace teleconsultations, electronic health records (EHRs) and patient empowerment platforms (PEPs). This could benefit local populations and increase RWD and RWE from diverse populations for global therapy developments. However, to truly seize this opportunity patients must be involved in every stage–from development and process to information access and solutions.

The recent controversy in the UK over the GP Data for Planning and Research program shows what happens when patients do not feel informed about how their data will be used. The initial launch was delayed following a public backlash over a lack of patient involvement and awareness. Now, it has been announced the program will not go ahead until key steps are met. Crucially, they include patient ability to opt out and back in and a trusted research environment. However, it is still only focusing on national interoperability.

To truly seize the opportunities of a global health data revolution we must embrace patient empowerment. International interoperability is a huge step forward to achieving that.

Articles

A Closing Thought

Embracing patient empowerment in data collection can lead to new standard of care.

Interoperability Cracked as Patients Collect Health Records from Hospitals

Today’s headlines in clinical development tout the potential of decentralized trials, with some even going so far as to predict that trials of the future will bypass sites through a combination of centralized review, technology, and just-in-time clinical resources. To the contrary, keeping the site at the center of clinical research, even when taking a decentralized approach, is crucial for success and health outcomes.

Clinical trial designs today span a wide continuum, ranging from 100% site-based trials, where all interactions with study participants occur at the site, to 100% decentralized trials, where all interactions are remote and leverage wearable technologies supplemented by occasional visits by trial nurses to the participants’ homes. The latter are often referred to as “siteless” trials.

However, a large majority are a hybrid of the two. This is true even as decentralization, accelerated by the COVID-19 pandemic, jumped to a 77% CAGR between the second halves of 2019 and 2020, according to data from more than 1,000 trials.

Despite our extensive involvement in decentralized clinical trials (DCTs), we agree that “siteless” trials are not optimal. The term itself is counterintuitive. The principal investigator’s site, together with trial coordinators, should remain a key part of the trial ecosystem, whether the trial leverages a single site or a network of coordinated sites, local pharmacies, community clinics, and home health aides supported by wearable devices and platform solutions. Technology simply cannot replace people.

Recent industry experience offers a relevant analogy. Between 2005 and 2015, many pharmaceutical companies rapidly adopted salesforce automation tools for their sales representatives while cutting sales jobs at the same time. From its height at 101,000 sales reps in 2005, the number of reps in the US market dipped to 76,000 by 2010 and hit its lowest level of just 66,000 in 2012. Accenture research showed that one in four pharmaceutical sales rep interactions was replaced by digital alternatives, but it did not achieve the intended effect of improved profitability. The strategy backfired and sales dipped. Now, there are more than 100,000 pharma sales reps in the US, according to various estimates, and overall revenues have been setting records year over year. The ship has righted itself.

Today, we are on the doorstep of a similar technology revolution, largely accelerated by COVID-19 when clinical researchers had no choice but to leverage innovative digital technologies to continue their work. Now, the excitement around technology’s potential is soaring again. The innovative technologies enabling remote or decentralized trials have the potential to dramatically reduce the burden for patient participation in research and for sites who manage studies. Recent data backs this claim, with at least half of the respondents to a recent Association of Clinical Research Professionals’ (ACRP) survey anticipate ‘strong’ use of eConsent (63%), eSource (56%), remote monitoring (55%), and wearables (50%) post pandemic.

Industrywide, there is confusion over terms like “virtual,” “remote,” and “siteless” trials; hybrid trials; and even the DCT concept itself. On the one hand, the Society for Clinical Research Sites (SCRS), in a December 2020 white paper defined its subject thus: “For the purposes of this survey, ‘decentralized or virtual’ referred to studies that are fully virtual, meaning that all study visits are remote.”

 On the other hand, even a cursory review of current literature on DCTs will demonstrate phrases like “decentralized or hybrid,” blurring the distinction between trials with or without patient site visits.

The DCT concept traces back to the 2018 Clinical Trials Transformation Initiative (CTTI) white paper that specifies that “DCTs can be conducted as 100% decentralized or as a hybrid study in which the DCT offers the additional flexibility of incorporating both in-person visits and virtual visits into the study as appropriate.”

 Although the intent, was to standardize terminologies, this definition proposes that “decentralized” and “hybrid” are synonymous.

There is also some evidence of the impact of the COVID-19 pandemic changing perspectives on “siteless” or fully virtual trials, and hybrid DCTs. A July 2020 SCRS survey found that a mere 3% of clinicians “had participated in a completely virtual trial, where all visits are conducted remotely.”

 But the December 2020 SCRS white paper, based on a May-to-July survey, found that use of “the fully virtual approach” had risen to 15.46%. More recent data found that 22% of respondents conducted “siteless” trials pre-pandemic; 17% had done so during the pandemic “but not because of it,” and an additional 12% had done so “because of COVID-19.”

The clinical trial lexicon will continue to evolve, but “siteless” should not receive a dictionary reference.

Rather than a “siteless” trial, the better approach is to build fit-for-purpose clinical research with a next-generation site at its center. Some trials might be, in fact, wholly decentralized, but even those should incorporate a site whose role may be a different iteration of what a traditional site looks like today. The best-performing trials will continue to have human interactions between physicians and patients. They will not be without sites but, rather, be technology-enabled to reduce burdens and improve efficiency. That is what well-designed technology should do, for both patients and for trial administrators.

Among other benefits, DCTs promise to 1) improve the recruitment and retention of trial participants and 2) increase diversity in trial populations. Given that only seven of 100 enrolled patients complete trials

, ensuring patient retention through all means is vital to trial execution and research efficiency. Interactions with trial physicians, care coordinators, and operational staff are vital to these goals.

People are foundational to clinical research, and the physician/patient relationship is the building block for long-term participation in a trial. It also builds trust, something that is especially critical today as public confidence among minority communities has eroded dramatically since the start of the pandemic. Patients develop close relationships with their study coordinators, who spend time engaging on a very personal level and deliver tender care. Coordinators and site staff give hugs, call patients by their first names, and nurture the relationship. In fact, this is the number one determinant of a patient’s completion of a trial. A “siteless” experience takes this away.

DCT technology should assist site administrators in fostering a trusted patient relationship, while at the same time provide improvements in data quality, data collection, study startup speed, informed consent, regulatory compliance, and all the other goals of a well-run trial. In the aforementioned 2021 Avoca survey, respondents report the two most substantial benefits of DCT technologies are: retention of study participants (with a mean score of 4.2 on a 1-5 scale); and diversity of study participants (3.9). Technology along with real-life patient engagement are the one-two punch to overcoming two of our greatest trial obstacles.

Besides the obvious obstacle to better patient recruitment and retention of travel to and from trial sites, patients can also suffer from limitations in handling modern technologies, ranging from lack of familiarity with smartphones to poor WiFi connections in their homes. In these cases, site-driven, hands-on guidance is paramount to the success of a DCT–and is another instance where the personal touch provided by a trial site is important.

Another aspect of patient retention in clinical trials is the health of the patients themselves. Rochester Clinical has had direct experience with assisting trial participants in getting necessary (in some cases, lifesaving) medical attention to patients that was unrelated to the trial itself. Some of this diagnosis was captured in the initial intake of the patient, where gentle probing helped get closer to the root of illness or personal insights on the patient’s health. In other cases, trial managers uncovered new health problems that cropped up during the trial because of close monitoring. Maybe some of these cases would have been recognized even with a “siteless” trial leveraging wearable technology; maybe not.

While technology can make the process of getting patients signed up for a trial easier, thanks to eSource, eConsent, and remote monitoring tools, there’s a misconception that it reduces the need for a site and its people. On the contrary, these new technologies open the door for new expertise, including more technology support but do not change the fact that there needs to be a centralized location for research and the back-end aspects of a well-executed trial.

The life sciences industry is having the wrong conversation about DCTs. Rather than talking about how DCT technology can replace sites, the conversation should shift to how to better support sites with technology. Technology companies and site managers should not be at odds with each other. Instead, they should be collaborators in providing the best patient experience and enabling successful trials.

, “Why Decentralized Trials are the Way of the Future,” by Fan Gao, Maurice Solomon, Arnab Roy, and William Chaplain (April 5, 2021).

Association of Clinical Research Professionals, 

, “Delving into eConsent: An Industry Survey,” (January 14, 2020) by Neetu Pundir; Mika Lindroos; Jenna McDonnell; Bill Byrom; Spencer Egan.

“Patient Centricity and Virtualizing Technologies in a COVID-19 World.”

Clinical Trials Transformation Initiative (CTTI), “CTTI Recommendations: Decentralized Clinical Trials (September 2018).

Society of Clinical Research Sites, “Impact Assessment of Decentralized Clinical Trials (DCT) Awareness in the Clinical Research Industry,” (2018).

WCG Avoca Group, “2020 State of the Industry Report” (June 2021).

Advarra Report, “Retention in Clinical Trials: Keeping Patients on Protocols,” (March 23, 2021).

Feature Articles

Has technology taken the industry too far?

Sites Still Necessary for Decentralized Trials

means examining a specimen where it is naturally found, or where an event has occurred. These days, in situ could also define the preferred spot for a clinical trial.

Whether it was recognition, for a very long time pre-pandemic, that industry needed new ways to recruit and retain patients, or the success realized last year during the global SARS-CoV-2 vaccine trials, when pharma said we have no choice but to adopt 

–or both reasons–the clinical trial industry is doing a 180, site-selection speaking.

 is in; it guarantees real world evidence because in situ naturally leads to where patients live, are treated, and immortalized, to whatever extent, via their health system’s EHR and other data sources.

What’s remarkable here is how varied are the business models that have evolved to find sites and patients. The sources are extensive–pharmacies, patients’ homes, community hospitals, physicians’ offices. Further, the attempt to include people who are not white, male or of comfortable means, seems real.

What is not varied, said those interviewed, is the goal–consistently but speedily finding and enrolling the right patients, and retaining them in the trial. However, discovering whether the clinical trial services industry is successful with these strategies so far has yet to show up in a peer-reviewed study. Anecdotally, it appears so.

Labeling the clinical trials support industry as ‘niche’ works. Most rely on other niche businesses to help fill a software or service gap if it lacks what a client wants. Elligo Health Research, an IRO, and Syneos Health, a CRO, have a four-year collaboration. Syneos has the clinical trial networks; Elligo has access to Cerner and other EHR systems, said Maria Fotiu, executive vice president, decentralized solutions, Syneos Health.

Healthcare, said Keith Fern, vice president, corporate development, Elligo, has become a heterogenous business. “Partnering with different companies with access to patients in a variety of healthcare settings is very important to [the Elligo] model.” The sophisticated protocols, the move toward personalized medicine, have made eligible patients harder to find, he said via e-mail. Its patient network, he said, surpasses the 100-million mark.

The pandemic’s effect on ongoing and new studies was unprecedented, said Suzanne Caruso, SVP, clinical solutions, insights and analytics, WCG, in a statement. “It led to an environment unlike any we have seen previously. With the increased competition for patients due to the number of new trials, and the struggle hospitals are having finding the staff and time to run trials, the speed of recruitment has slowed significantly.”

In February, Circuit Clinical and LabCorp announced its collaboration. LabCorp, which is also an investor, said Irfan Khan, Circuit’s CEO and founder, allows Circuit to access LabCorp’s network of healthcare systems and centers.

Almost every company interviewed for this story has received private equity support. Trial-support investment, said a consultant, is a safer bet because no risk is involved.

Other trial-support businesses, like Curebase and Reify Health, have designed cloud-based platforms with the primary intent to speed up the site selection, patient enrollment processes, and if the client desires, help with certain elements of the trial itself, like specimen collection. They are neither CRO nor IRO–Reify’s co-founder Ralph Passarella said Reify isn’t interested in labels, but clearly the company is in the trial-support business with its StudyTeam patient recruitment and enrollment technology platform, and its Care Access decentralized research organization that brings clinical trial infrastructure directly to patients, healthcare providers, and communities.

The speculation as to why this find-your-niche trend developed is multi-pronged.

Craig Lipset, founder, Clinical Innovation Partners, told a story in response to the why question.

He was attending the 2020 Summit for Clinical Ops Executives—pre-COVID—when he saw a friend in a hallway. The friend worked at a top five pharma. What’s going on?, Lipset asked. Well, says the friend, we are pulling back from the CROs; we have assembled 100 trial site pros and data analysts. A few minutes later, Lipset met another friend, who worked at another top five company. He asked the same question and received the same answer.

“Before COVID, most [large pharma] had already pulled back site selection in-house,” Lipset said, including those involved in the COVID-19 vaccine trials. It was not a question of saving money, at least immediately, but the need to show that yes, we can find the right sites and assess our own data.

Will more pharma follow? “They tend to move in packs,” he said. “A good idea tends to move quickly.”

Two questions to ponder: Is this new model sustainable? Or will this model, borne out of pandemic-response necessity, revert due to atrophy? Without a concerted, dedicated commitment, to maintain flexibility in trial site selection and enrollment, Lipset said, atrophy will prevail.

As to the other plausible reasons this find-your-niche industry developed:

In the mid-2010s, various studies found that more than half of new investigators would not partake again.

 But the need for more sites, as more trials were going global, was approaching the critical point.

 The amount of time to run a trial, soup to nuts, was getting longer.

It’s hard to speak to an overall trend, said Passarella, noting that the integrated research industry came to be between 2015 and 2019. While CROs and sponsors partnered for decades for the patient identification and recruitment processes, Passarella said people began to realize that to improve study outcomes they had “to really innovate at the site level.”

The trend of the “last half decade is kind of a push in that direction,” he said.

Lipset also had another suggestion. Asking physicians to become investigators is a tall order, just consider the dropout rate of first-time investigators. Without the proper structure, running a trial while running a practice wasn’t worth the physician’s investment, from every point of view. But to have trained trial professionals drop into a “setting and support doctors as investigators,” that provides that needed structure.

And that is where IROs came into being, Lipset said. IROs offer healthcare sites something more sustainable and scalable. Khan calls it the ecosystem of running a trial—from administrative help to training staff on technology to offering data assessment.

Curebase designed software to make trial participation easier for the patient. “Instead of driving to one site to collect vitals, they can see a PCP in town, they can get a blood draw with a mobile phlebotomist at home, an x-ray at a local imaging center, and complete patient surveys on their phone,” said Tom Lemberg, founder and CEO of Curebase via correspondence. Patients have even gotten swabbed in pop-up drive-through centers.

The tech involved includes mobile provider calendars and workflows, along with the healthcare’s own EHR system. According to the Curebase website, its technology propelled the start of a COVID trial in two weeks. It used drive-through testing centers, where patients gave consent and provided samples. The sponsor used its own technology to do the testing.

Jennifer Byrne, CEO of Javara, said its goal is to run trials as a clinical care option. Say a patient learns she has diabetes, Byrne gave as an example. “Her doctor says, ‘here is your treatment regimen. But, if you are interested, we can offer you more. Our healthcare system is running a trial on diabetes that could help you. You can learn more about your disease.’” The patient now becomes a healthcare consumer, and clinical trials become an option with more patient touch points for the patient and trial staff.

“WCG works with all types of investigational sites, including academic centers, integrated health systems, large site networks and independent sites, as well as part-time investigators,” said Jill Johnston, president, WCG Clinical, study planning and site optimization, in a statement. WCG has agreements with over 3,300 institutions, in addition to more than 5,000 biopharma and CRO clients.

With these extensive connections, Caruso observes there’s no one-size-fits-all approach for clinical trial recruitment. “It’s not only that the diseases are so different, so too are the specific patient segments.” She noted that these include people with physical limitations or those struggling with day-to-day issues. If the needs of these patient segments aren’t recognized early and addressed at each site, meeting recruitment goals may not happen.

Very often, said Passarella, recruitment will be hospital dependent. A heat map of a particular disease presence might indicate a heavy concentration in a large city, but it also might pick up a smaller hospital or center that is three hours away that is a better fit for the study. “It matters which hospital or clinic you are talking to.”

Elligo’s Fern described the process for finding patients for a possible migraine trial. The Elligo investigators “searched across disparate data sources, normalizing them for a clinical protocol.” The result: patient level data “that will allow the sponsor to identify highly likely participants for their trial.”

Circuit Clinical, which has a presence in 34 states, approaches mid-size, research-naïve healthcare centers, said Khan. These include the federally qualified health centers, which have large minority patient populations, Khan said. “It is our job to pull as much friction out of the process” as possible for healthcare administrators and physicians.

When it comes to training support, the Circuit ecosystem includes training the investigator’s staff on those technologies that Circuit will use to run the trial.

Oftentimes, said those interviewed, smaller providers do not have the up-to-date tech training needed to run a trial. Staff training is on the menu if staff wants it. “It depends on their appetite for engaging,” said Passarella.

Curebase offers virtual support, especially for research-naïve clinics. Principal investigators get help to oversee the study, while virtual research coordinators help the patients with e-consent, scheduling visits, and so on. The software also automates other processes like payments and data entry, Lemberg said.

 in their own homes; vans take trial personnel to patients’ homes for sample taking, collection, medical checks, and so on. Reify works with research-naïve institutions as well, these healthcare providers might not have the up-to-date software, so staff needs to learn how to use them. “When we go to certain settings that don’t have cutting edge technology, part of what we do is bring it in and make it accessible to staff.”

Byrne addressed another important point. Even though the investigators can unload administrative and clerical tasks, the physician still is responsible for the medical and clinical decisions regarding the patient.

Since 2018, said Byrne, the company has built partnerships with major healthcare organizations, like Atrium Wake Forest Baptist Health, allowing the company a patient base of more than 6 million. Collaboration, she said, is key from a healthcare standpoint.

Khan said Circuit’s diversity numbers are two times higher than the average seen in clinical trials, according to figures gathered between May 2019 through May 2021. “This is not because we targeted certain ethnicities—it is because we operate within healthcare and, therefore, see the populations that represent all of the US.”

Circuit also offers its clients a real-time method to improve if and where it needs to. The Trial Journey platform lets patients go online, discuss their experiences, and rank their treatments and physician encounters, from a scale of 1 to 5. The platform is also open to doctors and the healthcare system itself.

At first, he said, the physicians and healthcare systems were “worried that [patients] will trash them. On Trial Journey, the average rank is 4.2. How do the physicians or health systems react when they see less than a 5? They work to improve it, Khan said.

Many of the IROs use existing health system EMRs, to find patients, but, to be kind, the process is incomplete.

“EMR is the best tool we have, but only 50% of it is useful,” said Khan. “It doesn’t have data that helps determine if a patient is right for a trial. People need to understand how limiting it is.”

There are different approaches to how existing EMR data are used. Elligo, for example, extracts the data needed, then transforms it to become standardized. “We build it as we go,” said Fern.

Byrne said Javara hasn’t come up with a universal language; her team works with the client to standardize its EHR language. “We can pinpoint and ID patients through large data sets.” Which Javara did in a COVID vaccine trial. Of the 100-plus sites, Javara performed in the top 5%. While artificial intelligence can help enhance protocol matching tools, pinpointing the right patient takes a human touch. “It is still not widely appreciated that tech is an enabler.” These tech tools are just that: they supplement the human experience.

Taking into account the in situ trial support options and the IRO/DRO models, is there evidence that the industry is showing demonstrable, trial performance results?

When asked that question, Lipset looked down at his desk, made some rustling noises, and then held up a piece of paper to the Zoom screen: He had drawn a large circle with a line through it. A line of anecdotes, he said, is not evidence. “I haven’t seen this taken on by anybody.

Corneli A, Pierre C, Hinkley T, et al. One and done: Reasons principal investigators conduct only one FDA-regulated drug trial. Cornell Contemporary Clinical Trials Communications. 2017; 6:pp 31

Craig Morgan. 10 Tips for Selecting High Performing Clinical Sites. Oracle Health Sciences. Health Sciences, Study Startup . September 3, 2019.

New support models range from flexible software platforms, IROs, and DROs.

The Evolution of Site Selection

Clinical stage biopharma InterveXion Therapeutics is developing novel products for the treatment of addiction disorders. In this 

, the outline of how the company used Emergency Medical Services (EMS) data to identify sites for a Phase II clinical trial. In this Q&A, InterveXion CEO Keith Ward and Andrew Schafer, vice president of strategy for Biospatial discuss the details of this study.

Applied Clinical Trials: This is an interesting case study. How did the three

companies—InterveXion, Syneos Health, and Biospatial—come together?

 InterveXion had contracted with Syneos Health to support our Phase II study for acute methamphetamine intoxication (Meth-OD) and we thought site selection might be especially difficult for this trial. Syneos Health was already working with Biospatial, and they suggested the Biospatial data might be a good way to identify sites. We looked into it, and it fit our needs, the data were coming in near real-time and that was important for us because a lot of the epidemiology data we could find were out of date and were not compiled nationally using similar collection methods.

 All three companies working together was a great experience. Biospatial was able to help InterveXion, not only identify high-prevalence sites, but we were able to provide demographic information on potential patient pools to help ensure a diverse patient population for the study.

 has covered the clinical development industry for a long time, and we have never heard of using EMS data. Where does it come from and how is it being used?

 As we continue to talk with pharmaceutical companies, CROs, patient recruitment companies, hospitals, and substance abuse centers, we hear the same thing: “I had no idea these data existed.” Biospatial has spent years signing data use agreements with EMS offices at the state level, which allows us to access EMS ePCR (electronic Patient Care Report) data. Think of our data products as EMR-like for an ambulance transport and it comes to us in near real-time, making it especially valuable for studies where patient consent needs to occur in a short timeframe—for example, with stroke, cardiovascular events or trauma—or where healthcare trends change quickly, such as drug use or overdose, COVID-19 infections or other infectious diseases.

We had the same thoughts as well. In our case, we were doing our first study in an emergency medicine setting, so we were delighted to have such an on-target dataset. After diving into the platform, we found it easy to navigate and could use our inclusion/exclusion criteria to help refine our site selection search. The data elements contained in the data set were quite robust.

ACT: How was the ePCR data used specifically for this clinical study?

 As Keith mentioned, we were able to take the study characteristics and the inclusion/exclusion criteria and develop a search of which hospitals have access to the patient population. After that list of approximately 200 was created, we overlayed patient demographic information to help provide a diverse set of sites for InterveXion to consider.

ACT: What were the results and any next steps?

 We’re still a little early to have hard enrollment results as some of the sites are in the process of being initiated. In our early going, however, the patient flow we are seeing definitely matches our expectations based on the Biospatial data. So far, we are happy with the process and the outcomes as we continue to track potential patient volume at each site. We are also currently considering using Biospatial’s ability to notify the project manager and site coordinators, via text and email, as to when a potential patient has entered the hospital.

InterveXion CEO Keith Ward and Andrew Schafer, vice president of strategy for Biospatial discuss the details of a study which utilizes EMS data to identify sites for a Phase II clinical trial.

Utilization of EMS Data in Site Selection

This month’s phrase to watch: “warm and ready” or “ever-warm.” Clearly lacking in business-speak, I found this term repeated at least three times in the past week, so for me, that speaks to a trend. Two instances were in regard to clinical trials sites, and one in regard to vaccine and therapeutics
production capabilities.

Warm and ready is a comforting term. Of course, because its opposite is cold and unprepared, or frigid and inaccessible. In the world of clinical trials, it is coming to the fore in response to future pandemic readiness. That is, in order for sites to be able to pivot quickly to clinical trials in the face of a crisis, those sites would need to be up-to-speed with capabilities and scale. What one person described as a “ready-made pandemic clinical trial network.”

That description came during the Reagan Udall Foundation’s Public 

 titled COVID-19 Lessons Learned: Clinical Evaluation of Therapeutics. There were three panels, all of them interrelated, however, the first recommendation from this panel was stated: Identify and leverage existing clinical trial network infrastructure (incl. NIH-funded networks, nonprofit & industry/CRO sites networks) and public-private partnerships (e.g., ACTIV) to maintain a ‘warm base’ for public health emergencies (PHEs) and that can be deployed against high priority unmet needs.” Out of this need to increase the number of sites, additional recommendations such as engaging more community-based institutions and networks, increasing diverse populations in clinical trials, and best practices for increasing participations from those communities.

These are not new ideas. Warm and ready sites, maybe, but embedding trials in the healthcare setting? Increasing diverse trial participation at the site level? No. The problem is how to keep sites monetized at a warm and ready level. The panel recommended a blend of industry and government monies, but that’s for another day. This day is to review our feature article on page 10 and discover that there are a number of new industry business models that are working to get more diverse populations, closer to the point of care into clinical trials.

 doesn’t use the term warm and ready, but it succinctly outlines what the Reagan Udall workshop brought to light: “the need to to support the development and long-term sustainability of an infrastructure that unites clinical research with clinical care.”

 is Editor-in-Chief of Applied Clinical Trials. She can be reached at 

From the Editor

Industry-wide unity paves path for preparedness.

“Warm and Ready” Clinical Trial Sites

Issue PDF

Click the title above for a link to open the Applied Clinical Trials October 2021 issue in an interactive PDF format.

Applied Clinical Trials October 2021 Issue (PDF)

Despite the agency’s remarkable success in speeding vital new vaccines and therapies to patients to combat the COVID-19 pandemic, while also continuing to advise on and approve a broad range of vital medicines, FDA officials have been under attack. The regulators either are acting too fast and risking public safety—or too slow, mired in rules while ignoring important scientific findings.

A main difficulty is that the agency has lacked a confirmed leader for the past 10 months, making it difficult to set priorities and explain actions within the Biden administration and to the public and policymakers. As acting commissioner, Janet Woodcock has maintained a steady hand on this diverse agency that oversees a vast range of products vital to public health. In addition to vaccines and new drugs, FDA has been in the spotlight recently over its efforts to limit marketing of e-cigarettes to halt the dangerous vaping epidemic among young people. The agency is responsible for assuring the safety of much of the nation’s food supply, veterinary medicines and dietary supplements. Plus its regulation of cannabis products and cosmetics are under debate. FDA’s oversight of medical devices and diagnostics has put it in the hot seat for shortages of critical products for protecting medical personnel and for providing fast and accurate public testing for COVID infection. And there’s the continuing wave of false claims about popular treatments to combat the pandemic, some dangerous and most ineffective.

Earlier in the year, it looked likely that Woodcock would become FDA’s permanent commissioner, but that was sidelined by some Democrats and public health officials upset by the agency’s earlier approval of what turned out to be deadly opioid pain killers that are easily abused. As the long-time head of drug development and approval at the Center for Drug Evaluation and Research (CDER), Woodcock also was accused of working too closely with biopharma companies in accelerating the development and marketing of important new therapies, some turning out to have limited long-term benefits — and many posting high price tags. Although patient advocates and research groups have championed Woodcock for providing strong leadership in shifting FDA away from a more risk-averse stance, that approach has been challenged. The result is that the White House has delayed in selecting an FDA commissioner, even though federal rules require Woodcock to vacate her acting position by mid-November unless the administration nominates a new commissioner, permitting her to continue on during the Senate confirmation process.

The situation has hampered FDA in articulating future priorities and pushing back against miscommunications and outside complaints. The recent debate over approval of booster shots for anti-COVID vaccines is a case in point, with FDA compelled to manage President Biden’s promise to provide third shots by late September amidst highly publicized internal agency dissension on the issue. Leading FDA vaccine officials contended that the agency was ignoring the scientific evidence in authorizing booster shots and that such a policy was inappropriate when initial vaccines were desperately needed by much of the third world.

That dispute over vaccines followed an even more blistering debate over FDA approval of a costly new treatment for Alzheimer’s disease, Biogen’s Aduhelm, based on questionable and very limited clinical evidence. The approval decision by CDER officials was blasted by members of Congress, the medical community and even some patient groups, but justified by the reviewers as likely to provide some benefit to some patients who lacked any alternative treatment for this devastating disease. Continued charges of FDA officials caving to industry pressures, though, prompted Woodcock to seek an independent review of the approval process for the drug from the HHS Inspector General.

These developments have generated media reports on tumult and dissension at FDA and continued criticism about the agency putting industry interests above the needs of public health. The Aduhelm decision was blamed for undermining FDA’s “gold standard” for ensuring drug safety and efficacy and linked to the agency’s dependence on industry-paid user fees for shifting the balance away from careful oversight and toward too-speedy approvals.

Such charges gain support from several departures of long-term agency. Most visible was the recent announcement of retirement by top vaccine approval officials, Marion Gruber and Phillip Krause, director and deputy director of the Office of Vaccine Research & Review (OVRR) in the Center for Biologics Evaluation and Research (CBER). At the same time, many leading staffers who have been at FDA for decades have announced retirement plans, such as Theresa Toigo, CDER associate director for drug safety operations.More departures are expected, as many FDA officials past retirement age are exhausted from the pressures of the past year and now seek to move on after postponing their departures during the height of the public health emergency. Public scorn for the agency’s efforts to evaluate reams of data as fast as possible has tipped the balance in favor of leaving the public spotlight.

Meanwhile, agency veteran Woodcock has worked with her staff to keep review and regulatory decisions on track. Industry leaders have supported her for the top job, but went quiet as the administration signaled that would not occur. Woodcock opened the recent annual “Convergence” conference sponsored by the Regulatory Affairs Professionals Society (RAPS) by citing FDA’s efforts to ensure access to needed diagnostics, vaccines and therapeutics during the health emergency, and in meeting the challenges in conducting clinical trials, inspecting drug and food facilities, and issuing “reams of guidances” to facilitate emergency use authorizations for vital vaccines, drugs and diagnostics—while also keeping up with the usual volume of premarket reviews of innovative products.

Woodcock concluded by expressing hope that these efforts in dealing with the pandemic will create “at least among some people” a “renewed appreciation for the importance of science, technology, and data.” She said she looks forward to a greater understanding of the “essential role play by the FDA and other public health agencies” in responding to this crisis and in protecting and promoting public health.

View from Washington

Critics say FDA is either acting too fast and risking public safety—or too slow—mired in rules while ignoring important scientific findings.

FDA Officials Caught in Political Crossfire

Even before COVID stimulated renewed urgency in mechanisms to promote rapid and efficient product development, the drive for innovative–and more complex–clinical trials was already well underway in Europe and beyond. The response to the pandemic has, however, given new momentum to many ongoing reflections on getting a better– and faster–bang from the bucks (or more elegantly, more patient benefit from platform trials) in clinical development.

While the classic RCT may remain the preferred approach for many regulators, there is growing concern over its costs and delays, and a reinforced appetite to overcome the associated challenges in subject recruitment, and in patients finding the right trial for their needs. One of the key tasks of HERA, the European Union's newly-announced strategy for tackling health risks, is to work with the European Medicines Agency "to create a long-term and large-scale EU platform for multi-center clinical trials and corresponding data platforms." This 'European Health Emergency preparedness and Response Authority', unveiled in mid-September, will incentivize "advanced research, innovation and development of relevant technologies and countermeasures–including diagnostics, therapeutics, and vaccines," says the official announcement, and will promote data sharing arrangements that "can lead to breakthrough discoveries and accelerate the development of health solutions." It will, it says, rely heavily on European clinical trial networks and platforms "to accelerate trials and connect all development stakeholders for designing and conducting trials." These platforms should, it adds, be easily adjustable to respond to a broad range of potential threats, and should reduce current lead times.

EU officials acknowledge that the trial landscape in response to the pandemic has been fragmented, with a multitude of small, national trials, struggling to generate robust and actionable clinical data, with great duplication of efforts and direct competition for shared resources and participant populations. Action has already been taken to build a COVID therapeutics network, based on three large-scale multi-center, adaptive platform trials– REMAPCAP, EU-SolidAct and DisCoVeRy. When these are combined, they will encompass around 200 trial sites across half of the EU member states. Another early initiative in this context is VACCELERATE–the first EU-wide network for COVID vaccine trials, which is collaborating with EMA to ensure these trials provide relevant evidence fast for a marketing authorization assessment, and is currently designing three trials that aim to inform future COVID vaccination strategies. HERA envisages that all these networks will be brought together into "a large-scale EU platform for multi-center clinical trials to avoid fragmentation."

But as officials also acknowledge, these trials are demonstrating yet again how hurdles relating to innovative trial designs, long regulatory approval processes and complex site administration lead to delays and underachievement. These must be tackled at European and national level to guarantee the availability of the best clinical management options, they recognize. "Efforts are needed to better address identified barriers and challenges, to ensure the necessary agility and speed of large-scale multi-country trials across the EU," according to an invitation to an official EU meeting planned for October to seek solutions and to build "increased and mutual trust with regard to the implementation of adaptive platform trials."

In parallel to these specifically COVID-related activities, there are plenty of moves within the European clinical trials community to explore and expand understanding of the challenges of matching clinical trials design to the exigencies and opportunities of scientific advances. The European drug industry worked on complex clinical trials in 2020 with researchers in the European Organization for Research into Treatments for Cancer and specialists in the Association of Clinical Research Organizations, as well as with the European Union's Clinical Trial Expert Group, composed of national health ministry officials. This built-in part upon the 2019 recommendation paper on the initiation and conduct of complex clinical trials from the Clinical Trial Facilitation and Coordination Group, a working group of the EU Heads of Medicines Agencies, which covered enrichment designs, adaptive designs, master protocols, and use of historical controls in clinical trials. The EMA Regulatory Science Strategy to 2025 finalized in March 2020 also recognized the need to foster innovation in clinical trials as a priority focus area–a position supported further by Europe's national medicines agencies' network in their strategy to 2025.

Meanwhile, an EU-funded research project with industry input–EU-PEARL–is one of several aiming to make clinical trials more efficient and patient friendly, through adaptive platforms which allow multiple companies to test their candidate drugs simultaneously against a shared placebo group. It is exploring how an adaptive platform trial with a single master protocol can allow new treatment groups to be added at any time, and candidate drugs that prove ineffective to be dropped. Other similarly-funded EU projects include ADAPT SMART, looking at evidence generation throughout the product life cycle and making best use of real world/registry data, GetReal, which is focused on including RWE in drug development using innovative trial designs, and EPAD, which is pioneering a flexible adaptive design for Alzheimer’s disease treatments.

On a broader geographic scale, the US FDA Complex Innovative Trial Design Pilot Program was set up in 2018, and in 2019 FDA released final guidance on Adaptive Designs for Clinical Trials of Drugs and Biologics. The US-based Clinical Trials Transformation Initiative is developing resources that will guide the appropriate use of the master protocols on which complex trials depend. And the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) is developing guidelines on Adaptive Clinical Trials with a timeline of 2023, and on Good Clinical Practice Renovation to address the increasing diversity of clinical trial designs and data sources. And in September the University of Maryland Center of Excellence in Regulatory Science and Innovation organized a workshop on Complex Innovative Trial Design in Advancing the Development of Pediatric Therapeutics to discuss opportunities for leveraging complex and innovative trial designs, and to develop solutions on overcoming challenges, particularly in the use of bridging biomarkers in extrapolation and of Bayesian techniques in pediatric studies.

It is against this background that the European drug industry is sponsoring a multi-stakeholder workshop in October to develop shared solutions for the use of complex clinical trials to optimize drug development in Europe. As the industry grouping EFPIA says, "Complex clinical trials have the potential to accelerate drug development and enable patients to get timely access to transformative therapies." Its workshop is aiming to develop shared solutions in terms of simplified and standardized definitions, and in agreed responses to the challenges faced by regulators, health technology assessment bodies and payers, academia, patients’ organizations and industry. It hopes to define action plans to gain acceptance of complex trials supporting regulatory decision-making. The need may be obvious, but the sempiternal diversity of approaches to health–and particularly to medicines–in Europe may make achieving the objective more elusive than merely agreeing the agenda.

View from Brussels

Pandemic sparks new advancements in clinical trial development.

Europe Seeking Clarity in Complex Clinical Trials

It is widely accepted that electronic clinical outcome assessments (eCOA) are the preferred means of collecting participant data. In traditionally designed, site-based studies, eCOA has proven to be an effective method for capturing high-quality data while meeting all necessary regulatory requirements. Today, the use of electronic patient-reported outcomes (ePROs) and electronic clinician-reported outcomes (eClinROs), two of the most utilized eCOAs across all studies and all therapeutic areas, are commonplace.

While many eCOAs are still taken during in-person clinic visits, the flexibility of the electronic platforms proves valuable. This allows study teams to gather participant data, including regular quality-of-life measures, more frequently and cost effectively while maintaining compliance.

Digital collection and submission of outcome assessments are a natural fit for today’s decentralized clinical trials (DCTs). One of the key advantages of DCTs is the ability to expand participant recruitment beyond the geographical limitations common in site-based clinical studies. This allows sponsors to reach a much wider range of participants, including those living in rural areas located great distances from study center hospitals. This is significant, with more than 70% of clinical trial participants living two or more hours away from a study center. This is obviously beneficial for those seeking to conduct large, global studies while finding the most inclusive group of participants possible and is particularly useful for recruiting and enrolling optimized participant groups for rare disease trials. With DCTs, eCOA is useful in monitoring and managing participants spread out over great distances, as remote assessments help to minimize the number of in-person visits.

That said, global DCTs also present specific challenges for eCOA that should be considered and addressed to ensure study success. This article will discuss learnings and insights for sponsors conducting global DCTs

 Data security is a challenge for all industries that process and store data digitally. A recent poll taken of stakeholders in the clinical trials industry showed that 32% of respondents reported that concerns about data security was their primary barrier to using more digital technologies in clinical research. For DCTs and hybrid studies to work efficiently, data needs to be captured remotely from participants and other users, increasing both the risk of data incidents and the need for effective controls to maintain data integrity.

To keep data secure, numerous regulations and laws exist around the world that spell out the various approaches that need to be taken and safeguards that need to be in place. In healthcare, where data including personal health information is particularly sensitive, strict regulations must be acknowledged and followed. These regulations vary from country to country.

This can be a challenge for global trials, as the regulations for each country in which a participant lives must be adhered to. For example, in trials where participants live exclusively in the United States, all eCOA activity—ranging from participant-entered data to assessments recorded during telehealth visits, must be compliant with patient privacy regulations such as HIPAA (Health Insurance Portability and Accountability Act). For trials that involve participants living in the European Union and United Kingdom, GDPR (The General Data Protection Regulation) is an even more strict set of regulations designed to keep all personal data (not only health-related information) of EU citizens private and secure. GDPR equivalent regulations are now in place within Asia-Pacific countries as well.

 When conducting global clinical trials, there is no such thing as one-size-fits-all eCOA. For each country represented by participants in a study, eCOA must be available in the appropriate languages and dialects. To maintain content validity, there needs to be a consistent presentation for all languages. Simply translating from one language to another is not realistic—validated eCOA has approved translations for use which have gone through rigorous equivalence testing. Thought must be given to how each language will reflect in the presentation of the eCOA instrument and how this will be impacted on screens ranging in size from smartphone screens to laptop and desktop monitors. Each language must be presented in a way that maintains the validity and intuitiveness and ease-of-use of eCOA applications. At the same time, content needs to mirror how the user actually speaks while avoiding terms or words that might be offensive in certain regions of specific countries. In any case where a translation does not exist, and where approval of the new language is not required by the scale author (e.g., questionnaires, surveys, eDiaries, etc.), it is useful to seek out translation vendors who can provide linguistic validation to ensure that the proper meaning and intent of the content is in place.

The translation process should not be underestimated; such processes can be complex. Choosing experienced vendors to manage this process on your behalf can simplify the experience for you and reduce or eliminate any potential language-specific user issues. Following is an example of a translation workflow for eCOA:

 The source content and, more importantly, the context around the intent of how the content will be used is shared with the translator, who then translates the content (preserving meaning and intent) into the desired language.

 Localized dialect experts ensure that the translation is optimized for the intended target population.

 The forward translation is reviewed and edited (as necessary) by a different translator.

 The forward version is translated back into the source language and checked to ensure that the original intent and meaning of the content are preserved.

 The final version is submitted for review to all relevant parties, including sponsor and clinical team members

These steps will need to be repeated for every language—and dialect of each language—involved in the study. For large, widespread global studies, this is quite an undertaking. The right translation vendor, again, can help manage and simplify this process.

Despite the previously mentioned challenges, eCOA is an accepted interface for global data collection and is a standard feature within DCT. eCOA can be conducted in a variety of ways while maintaining the “fit-for-purpose” validation requirements set by regulators. For example, a majority of eCOA can be conducted via virtual telehealth visits that are device agnostic, do not require provisioned devices, and allow the users (participants, caregivers, home health nurse, etc.) to be anywhere while conducting the assessment. This adds flexibility to the process while meeting all eCOA license holder requirements such as user interface specifications, form factor restrictions, and process steps.

eCOA, combined with specialized telehealth platforms, can digitally recreate much of the in-person visit experience. Using the video and audio recording capabilities of a standard handheld device, for example, assessments of participant movement and vocal characteristics can be made remotely.

To realize the benefits of eCOA in global decentralized and hybrid trials, we must overcome the security, privacy and user-related challenges discussed earlier. Having helped sponsors and CROs (contract research organizations) perform hundreds of DCTs over the years, THREAD has developed some best practices for how to optimize eCOA in these studies.

Seek out systems with built-in privacy and security: 

Countries around the world present different sets of regulations regarding data security and privacy. Some are more stringent than others, so it is important to ensure that any software or platform vendors adhere to the most stringent regulations across your trial portfolio, irrespective of where any one single study is being conducted. eCOA platforms that are designed from the ground up with this in mind can help to address these differences. For example, GDPR is one of the strictest sets of restrictions regarding personal data in the world. By developing an eCOA platform that meets the strict standards of GDPR, a vendor will also meet or exceed any other sets of less-stringent regulations used in other parts of world. An example would be a vendor who utilizes advanced tokenization strategies to effectively mask all personally identifiable information (PII). Tokenization is a process by which PII is collected, only when necessary, directly from the participant and then immediately tokenized—or masked—and encrypted. In this way, all participant identification data is obscured immediately and completely.

Going digital also raises concerns around what security standards are applied to your data sets and what measures need to be taken to minimize data incidents. Choosing platforms built from the beginning with a cloud infrastructure can protect data from breaches.

Provide localized expertise and support to help global DCT eCOA run smoothly, study leaders should involve local experts and support in the regions of the world where participants are located. This helps to mitigate regional challenges like navigating country-specific regulations, different languages and dialects, and cultural norms.

Local knowledge enables sponsors—and any vendors helping them to conduct studies—to be aware of any changes in the regulatory landscape before they occur. This is essential to keeping each region involved in a global trial running smoothly.

Language translation and use of correct regional dialects are much easier to achieve if you have native speakers on the ground in those areas. These professionals—who can be employees or contractors—can help to confirm that the language has been accurately translated in a way that preserves the intent and meaning of the eCOA application while respecting any and all relevant cultural idiosyncrasies of the participant population. This is true for eCOA application content, of course, but also is necessary for all participant/user study materials including training manuals, interface user guides, process walkthroughs and more.

Region-based support is critical for participants and other users (caregivers, clinicians, etc.) who may need assistance with the applications, the devices, or other challenges associated with their eCOA responsibilities. Providing access to expert support in the native language and dialect helps to solve issues quickly and keep participants on track.

Use participant-friendly, intuitive technologies:

 Easy-to-use technologies are a must for successful eCOA in any type of study. For global studies, intuitive interfaces are critical to keeping the stream of eCOA data flowing. Comprehensive applications anticipate the most common needs of users and offer a focused user interface similar to those found in the kinds of consumer applications that the study population is already familiar and comfortable with. Intuitive interfaces reduce the need for user training and minimize the potential for human error. Structured screen presentation helps to onboard new users, guiding them through instructional screens that serve to educate them on what is required for study participation. Moving later into the study, the same kind of screen flow and support functions help guide the eCOA process itself.

 Another advantage of electronic assessment applications is their ability to house a wealth of easily accessible support content. Users can access content like videos, diagrams, or text on a variety of topics, such as:

Answers to frequently encountered questions

Education on their condition and symptoms

When and how to schedule a telehealth visit

Handheld devices, such as smartphones and tablets, are particularly useful at providing bite-sized content. This utility is a perfect fit for providing clinical trial participants and other users of eCOA applications, quick, image-heavy resources to support them over the course of a study. This helps them to address potential issues before they become problems and can help reduce the need for clinical team outreach, saving time and cost.

Guidance on the unique challenges presented by electronic outcomes.

Applied Clinical Trials-10-01-2021