Applied Clinical Trials Editorial Staff

Applied Clinical Trials: You are Chief Research Officer at GRYT Health, can you explain what your position entails?

My team and I are responsible for ensuring that the patient experience research projects we take on align with and are conducted in a way that supports GRYT Health’s mission and values. Our patient and caregiver community is at the center of everything that GRYT Health does and, therefore, it is critical to build trust with our community at every step of the research process. We collaborate with research teams that prioritize the patient’s interests—from study design to transparency during participant interactions to engaging with participants beyond data collection.

ACT: Can you tell us more about your move from academia into a more patient-friendly industry?

Early in my career, I struggled with the disconnect between the basic pharmacological research that I was conducting and the end goal of positively impacting the lives of patients through improved health outcomes. I felt that I was too far removed from the end goal and, therefore, made a conscious decision to transition initially to clinical research and then more recently to leading our patient experience research at GRYT Health. This transition was also impacted by my own personal health journey, and the desire to empower others with the information they need to make health-related decisions.

ACT: Your CEO says that everyone at GRYT Health has been personally affected by a cancer diagnosis. Can you share your story?

My closest familial cancer connections are through my paternal bloodline. Around the time I was following the cancer journey of a personal friend, I lost my paternal grandmother to ovarian cancer and my father was diagnosed with prostate cancer. Years later that same personal friend, Shelley Nolden, became one of the founders and the chairwoman of GRYT Health and connected me to the organization.

ACT: What does the pharma industry need to know more about the patients that GRYT Health helps?

GRYT Health helps pharma better understand their end client—the patient. However, it doesn’t end there. We help to build relationships and trust with the patient and advocacy community, and beyond. Our platform provides patients and caregivers connection and education, and empowers them to advocate for themselves and others. GRYT Health also provides opportunities to learn more about research and become involved in it. Because of the services we offer to the patient community and our relationships with advocacy organizations, this allows us to better support our research participants. For example, if a particular need is identified during research participation, we are able to connect that participant to the appropriate resources. We pride ourselves on the humanity and transparency that we bring to research participation. Patient experience research should be neither transactional nor a unidirectional flow of information. Additionally, we provide pharma innovative solutions to patient education through custom virtual platforms that deepen engagement and collaboration.

ACT: How do you view the overall academic/industry/pharma relationship in regard

Drug development is a lengthy, complex process that involves balancing a wide variety of factors and pressures. Collaboration of knowledge, resources, and experience across organizations has the opportunity to accelerate the drug development process. At the core of drug development is identifying and interacting with a drug target to elicit the desired downstream effect; however, this alone will not yield a safe, successful product that is widely adapted by its target population. GRYT Health aids drug development by helping to incorporate patient experience data into the development process. Patient experience data can give insight into patient awareness, experience, goals, perception, and preference, and ultimately provide insight into how a drug might perform within its targeted population pre- and post-approval. Additionally, we help support active clinical trials and the populations they target through our clinical trial awareness services, which utilize our custom virtual platform, relationships within our patient, survivor and caregiver community, and medical, research and marketing expertise. Through this service we are able to directly engage with patients and caregivers through education and resources to increase awareness of clinical trial options and empower them to make informed decisions.

Articles

Darcy Flora, PhD, chief research officer of GRYT Health, a digital oncology company, discusses her career, the company, and drug development.

Building Relationships

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

Elizabeth Rickenbacher, PhD, Director of Strategy for 4G Clinical, has over 15 years of experience in the field of life sciences, and is an eClinical RTSM solutions subject matter expert. In this Q&A, she discusses changes in the IRT and RTSM solutions, their impact on trials during COVID, and the future need for these systems.

Applied Clinical Trials: RTSM (Randomization and Trial Supply Management) can be considered an evolution of traditional IRT (Interactive Response Technology). Is the distinction important?

 Historically, IRT was used primarily for randomization and getting drugs to the site. Over the years, it became apparent that supply management was just as critical as randomization and the combined action of them together elevates the function of this system. They are synergistic and need to coexist. It also helps to bridge the silos between clinical and supply organizations.

The term RTSM has been around since the advent of IRT technologies, but it refers more to the function of the actual system vs. the modality of delivery (voice, web, mobile, etc).

In that way, RTSM is an evolution of traditional IRT as it more accurately reflects the functions of the technology, and recognizes the importance of the interaction between clinical operations and supply.

ACT: What can we expect of advancements in RTSMs in the next five years?

 RTSM must continue to evolve to enable new clinical trial designs. Given what we see now, we can expect advancements in RTSMs to handle future iterations of decentralized trial designs, cell and gene therapy trials, digital supply chains as well as much more complexity in terms of adaptive designs, particularly in oncology trials.

From a technical and process point of view, there is a trend toward more self-service components to ease the administrative burden of adapting study parameters such as managing cohorts; enhanced flexibility to the patient level as patient advocacy for their own care continues to increase; as well as functionality to support the protocol designs of tomorrow’s trials.

ACT: How has the COVID-19 pandemic catalyzed a renewed need for RTSMs

 RTSMs are a necessary technology for clinical trials which are too complex for manual trial management. COVID-19 has not changed that. Rather than catalyzing a renewed need for RTSMs, the pandemic has driven innovation in its functionality, for example, the ability to turn direct-to-patient capabilities on and off as needed within a live trial and enable decentralized trial designs with flexibility for patient choice.

RTSMs that have integrated forecasting capabilities also have helped navigate clinical supply challenges. While clinical supply chains were not disrupted as much as originally feared, agility in the supply chain became a necessity during the pandemic and will continue to be the case moving forward.

ACT: What future clinical trial trends will increase the need for RTSM?

 While most Phase I trials are healthy volunteer studies that rarely need the support of an RTSM system, RTSMs are being used more frequently in Phase Ib oncology studies in patients. They have adaptive designs to allow the sponsor to follow different avenues of research–different dose levels, different dosing frequencies, different combination therapies, etc. These more intricate protocol designs and additional data and requirements are expected to move to the next phase.

Ultimately, these trials nearly equate to the completion of multiple early phase trials within a single trial. This complex management requires modern RTSM systems for the flexibility to adapt as these trials evolve.

Another example is handling program level supply management, such as ISTs (Investigator Sponsored Trials). The ability to handle these types of trials in an efficient and cost-effective manner has now become possible.

As for future clinical trial trends, as mentioned before, decentralized trials and increased cell and gene therapy trials, as well as anything that is trending towards therapies for personalized medicine, will require very sophisticated RTSMs to support the multi-faceted logistical requirements of manufacturing and complex supply chains, as well as resource planning 
and allocation.

Elizabeth Rickenbacher, PhD, Director of Strategy for 4G Clinical discusses changes in the IRT and RTSM solutions.

The State of IRT and RTSM Technologies 

At the end of April, The Conference Forum’s Clinical Research as a Care Option, or CRAACO, featured a fireside chat with emerging investigator physicians. These physicians— Ron Blair, MD, President, Forest Lane Pediatrics; Charlotte Grayson, MD, Partner and Internist, First Georgia Physician Group and Tina Kennelly, MD, Director of Tryon Medical Partners—have only been in research for approximately one year. Jennifer Byrne, CEO of Javara, an Integrated Research Organization (IRO) which brings clinical research into healthcare organizations allowing patients and doctors access to trials at the point of care, served as moderator of the discussion. While the physician investigators did partner with Javara to integrate clinical trials into their practices, the insights they shared were specific to their practice’s and patients’ experiences. Byrne acknowledged that their combined efforts led to 2,000 people being enrolled in clinical trials that a year ago would not have had exposure. Byrne also acknowledged that Javara moves “together in partnership with like-minded healthcare organizations, providers, healthcare leaders that actually see the value in research.”

What follows is a summary of their discussion.

Grayson is partner and internist at First Georgia Physician Group located in Fayetteville, Georgia, about 30 miles south of Atlanta. The population around the multi-specialty practice is suburban, somewhat rural, but also draws on the southern Atlanta area. The internal medicine patients start at 18 years of age through end of life and the practice treats many palliative care and hospice patients, as well as complex cases of patients throughout the range of internal medicine. Grayson also noted that the patients were very diverse, with a 90% female base, and a majority of African American, Latino or Southeast Asian descent. “The opportunity to bring research to this population, who tend to be underrepresented in clinical trials, was something I was really excited about. But I also knew that I was going to be facing some challenges with these patients, where many have never heard of research,” Grayson said.

For the majority of physicians in Grayson’s practice, their exposure to research was limited to their residency and training days. They needed refresher-training, as well as full training for the staff, to learn how to present research to patients and answer questions. “As we started to ramp up clinical trials, we did a kind of bedside education with them so that they understood what these trials were and how to interact with our patients.”

Tryon Medical Partners, based in Charlotte, North Carolina, is a fairly new practice, which broke off from a nearby hospital system approximately three years ago. The multi-specialty group includes cardiology, dermatology, rheumatology, endocrinology, as well as Kennelly’s specialty internal medicine. She says her primary focus is on women’s health and preventative care. The group didn’t have a formal research department and wanted to offer research as an option for patients because of what they felt were the inherent patient benefits. “We thought that it would provide a higher touch option for patients. Maybe patients who weren’t as well controlled in their diabetes could get enrolled in a diabetic study and we could couple them with trainers, as well as clinical trial navigators and get them involved. Again, providing a high touch option that would hopefully improve their care overall.”

Kennelly explained that the group began with smaller trials, an anxiety trial and atrial fibrillation, both device trials. But when they were offered COVID vaccine trials, they had to ramp up research pretty quickly. Of the one hundred physicians in the practice, 50% have been trained as investigators or sub investigators. “It took a lot of support and infrastructure to get our group—who was pretty naive because we are a young practice—where we are today. We’ve done the Moderna COVID vaccine trial, as well as the Janssen ENSEMBLE 3001 trial. So having a lot of support on the ground with Javara integrated into our clinical atmosphere helped us get patients involved and enrolled in these trials.”

Ron Blair has nearly 30 years of experience caring for pediatric patients. His practice in Northern Texas, Forest Lane Pediatrics, has a primary focus on infants to age 19, but also includes a multi-specialty group with internal medicine, family practice, and OB-GYN among other specialties. Blair began working with Javara earlier than the other two practices, and he said the relationship has benefited his patients, in addition to being fun and interesting. “We’ve taken a step-by-step approach with a lot of guidance from Javara because our group didn’t have extensive experience with [clinical trials]. We spent time training our clinical investigators and preparing a nice portfolio of our different specialties,” said Blair.

For the patients, Kennelly thinks they have a better sense of support when they are involved with research. “For some of these trials, we’re seeing patients once every other month, but in between, we’re talking to them on the phone. Sometimes once or twice a week, sometimes every day for a couple of days for short periods of time. That allows them to voice their concerns and ask questions, and it allows more interactions for the physician or the PI or sub investigator. The patients also interact with the clinical trial navigators and assistants. Overall, the patient does enjoy the experience and when integrated with primary care and their own PCPs, I think clinical trial retention rates are higher because of the attention from their provider.”

As predicted, Grayson said their staff spent time with patients helping them understand their clinical research options. “I did notice many patients, in some respects, still have a lot of mistrust for the medical community. But I have found that they actually do trust their provider. And if we come to them and talk to them about the benefits of the research, they trust that coming from their own provider,” she said. Grayson also sees that the patients are excited to participate when asked, and spread the word to friends and family. Because of the practice population, and history of underrepresentation, Grayson believes that the clinical research information and understanding for them is enlightening. And she believes that in the bigger picture, it is important to continue to try to include these populations.

Blair’s practice initially sent queries to patients in the form of a survey asking if they would be interested in participating in relevant clinical trials. The response was more enthusiastic than they predicted. “When we interview people, there are several questions about clinical research. Our patients trust our ongoing focus on their continuum of care and gladly share appropriate information relevant to potential clinical trials. So it’s been very good for the patients and good for my staff and good for the other physicians involved.”

Blair, who did have exposure to clinical research during his residency training, is proud of the number of physicians who signed on for clinical investigator training. “It’s pretty exciting for all of us to be involved in contributing to the fund of knowledge. And also that we’re able to provide services and potential treatments to our patients that we would not have been able to previously.” Blair credits Javara for opening doors to research for practicing physicians that previously was just in the domain of academic institutions.

Physicians share their experiences integrating research into practice.

Bringing Clinical Trials to the Point of Care

Trialcome is a software development company focused on the development and launch of an artificial intelligence (AI) driven medication non-adherence app that can provide benefits in both the clinical trial and routine clinical setting. Denis Polyanskiy, founder of Trialcome, discussed how the industry can overcome issues with non-adherence.

 The term “patient compliance” refers to “an external source of patient’s motivation” or compulsion to take all the prescribed medications.

On the other hand, the term “medication adherence” refers to “a patient’s internal motivation” to take all the prescribed medications–without any external compulsion for example, from his/her physician. It is not about imperatives–but about the patient’s willingness to get healthy.

Therefore, “medication adherence” is the most suitable term to use in the context of a patient’s medication intake discipline level, because it is the patient’s willingness and conscious intention to follow to his/her prescribed medical recommendations which is one of the most important factors for treatment success.

Currently, medication adherence is an area in which there remain several unresolved issues and questions.

One of the key issues is the lack of any kind of industry-wide validated gold standard for measuring a patient’s medication adherence/non-adherence level. There are many questionnaire scales used in clinical trials as well as in general clinical practice, for example, the Morisky Medication Adherence Scale, as well as MARS and BARS Questionnaires, which can be completed by patients, by physicians or both–but there is an inherent and significant risk of estimation errors as a result of the human factor.

On the other hand, Directly Observed Therapy is the most reliable and objective approach for measuring a patient’s medication adherence rate. It is based only on objective metrics such as drug concentrations in biologic samples, etc. This approach completely excludes any possible measurement errors resulting from human factors, but it also has several limitations and is usually quite expensive.

There are plenty of digital health tools like mobile apps, wearables, smart pill boxes and bottles, which sit in the middle of these two extremes.

However, if we are truly willing to achieve the best results in improving a patient’s medication adherence rate–we should consider a more complex strategic approach–and not rely on just one or two tools. The development of a comprehensive patients’ medication adherence strategy, therefore, remains a critically important goal.

 There are two types of medication non-adherence: intentional, when the patient clearly understands what he/she is doing and the reason, and unintentional, for example, when the patient simply forgets to take his/her medication according to the prescribed schedule, or he/she becomes confused with the multitude of medications he/she should take daily.

There are three key reasons for unintentional medication non-adherence: patient’s forgetfulness; ignorance about the basics of his/her disease and the importance of being compliant with their medication intake schedule; and when many medications need to be
taken simultaneously.

The situation becomes significantly more complex when we look at the drivers for intentional medication non-adherence. For example, the patient may try to simulate an appropriate treatment-compliant behavior. Unique to the clinical trials environment, is an intentional non-adherent patient’s behavior: artifactual non-adherence is when a patient intentionally violates the clinical trial protocol as defined within their informed consent form.

All these issues can be identified with statistical data analysis describing the accuracy of how the patient is taking notes in his/her personal medications diary; with medications scheduling design software; and with several
specialized questionnaires.

Now it is possible to determine personal non-adherence drivers for each patient and to design personalized method(s) of medication adherence rate improvement according to an individual’s lifestyle and habits–both for unintentional and intentional non-adherence causes.

 Reminders and notifications are the most convenient way for the patient to stay on track, for example, with an array of smart tech and apps.

Patient education and training with a digest of relevant educational materials should improve his/her awareness in health and treatment areas.

It is now possible to improve trust and quality of patient-to-physician communications with the use of in-app text chat and voice/video calls where the patient can honestly and openly talk to the physician on any health-related subject.

A single secured vault as the one place for retaining all personal medication-related data would also help to reduce the number of personal non-intentional non-adherence cases.

Through the development of our medication non-adherence app, we focused our efforts on meaningful analysis as well as understanding the most important personal non-adherence risk factors for each individual patient, and therefore we will be able to identify the risk factors, correct them and eliminate them.

 First, there is an economic factor in the clinical trial setting. If we reduce the need to enroll additional numbers of patients into the study, we will also reduce both the related costs and shorten study timelines. For example, if the average medication adherence rate in the study declines by 20%, this means an additional 50% more patients will be required to maintain the equivalent statistical power. Today, many drug developers typically increase the size of study populations by 15% to reduce the impact non-adherence has on a drug’s statistical relevance, requiring longer and more expensive trials. For a typical Phase III study, this may cost an additional $5 million to $7 million.

Second, if we use the same tools in the clinical trials setting that will be used in general clinical practice setting, we will be able to smooth the gap between the real-world evidence setting and clinical study setting.

If we extrapolate beyond the clinical trial setting for a moment, then if the patient’s medication adherence rate increases, this means by default that the patient or healthcare provider will purchase more medication, which in turn will increase pharmaceutical company revenues. Better medication adherence both in the real world setting and clinical trial setting may lead to significant cost savings for healthcare and pharmaceutical industry players worldwide, with fewer medical complications arising from better adherence as well as better health outcomes for the patient.

Denis Polyanskiy, founder of Trialcome, discusses how the industry can overcome issues with non-adherence.

Addressing Medication Adherence Challenges

Clinical trial collaboration between sponsors, CROs, and sites has been difficult because of heavy reliance on manual processes. In particular, the use of email and paper to share information with research sites slows down studies. When COVID-19 hit, it made working together even harder, accelerating the adoption of new strategies and technologies to keep trials afloat. Through these efforts, positive change is happening as the industry shifts to more connected, digital trials.

CROs are at the forefront of clinical research and recognize that effective collaboration is vital to keep up with stricter evidence requirements and growing complexity in studies. In fact, according to a recent study,

 simplifying information sharing is a top priority for CROs to reduce manual processes (78%), speed execution (61%), and improve collaboration (57%).

Labcorp Drug Development is one of the CROs leveraging digital solutions to advance trial operations and collaboration during the pandemic and beyond. A Q&A with Jeff Wiley, head of oncology, global clinical project delivery at Labcorp Drug Development, sheds light on how Labcorp Drug Development, a global leader in nonclinical safety assessment, clinical trial testing, and clinical trials management services, is using remote monitoring to advance the industry toward new levels of connectivity.

How did your journey towards remote monitoring start, and how has it helped during COVID-19?

: At the start of the pandemic, Labcorp Drug Development had a clinical research associate (CRA) conducting monitoring onsite with an April target for database lock. The sponsor planned to complete the associated clinical study report and make their investigative new drug (IND) submission by December. But while the monitor was on site, we found out that a COVID-19 patient was at the clinic. Our CRA quickly went home, and we faced risks for delay in our timeline.

We had to act quickly and implement an alternative monitoring strategy to ensure study timelines were upheld. Thankfully, we were already working on adding Veeva SiteVault, an eRegulatory system with remote monitoring capabilities, at the research site. Less than two weeks after the incident, we had a system in place and remote source data verification (SDV) was initiated. Four weeks later, all SDV was completed, and the database locked shortly after. By acting swiftly, we experienced no timeline delays and could execute without compromising data integrity or patient safety.

Q: How has the use of remote monitoring evolved at Labcorp Drug Development?

: When we evaluated all of our monitoring worldwide across various therapeutic areas, we learned that only 10% of our sites were conducting CRA visits remotely before the pandemic. At the height of the pandemic, that number rose to more than 70%. So we see remote monitoring as a key element to improve efficiency in trials, and its use will likely continue to grow.

Q: Why do you think remote monitoring was used so sparingly pre-pandemic?

: As with most industry changes, the adoption of remote monitoring has been slow because of concerns around patient privacy and access. But COVID-19 accelerated change across the industry, and when we think of the increase in remote monitoring as a small indicator for evolving trends, significant advances are happening that have been a long time coming for life sciences.

Q: What are the challenges of enabling remote monitoring?

: Incorporating remote monitoring capabilities can be done quickly, but first and foremost, it is essential to gain the sponsor’s agreement. Each organization has different approaches for remote monitoring and SDV, and it can take some time to get buy-in for newer technologies. This is especially true because sponsors need to understand how the solution handles patient privacy and security. 

Country regulations relating to remote monitoring and data privacy can also be a barrier to adoption. Labcorp Drug Development decided to create country-specific requirements and evaluated the impact of pandemic-specific guidance issued by regulatory agencies to enable teams to make quick decisions at the project level.

Lastly, sites need to be informed about the systems being used as soon as possible. An eRegulatory system like SiteVault is built specifically for sites, and a CRA only gains access when the site provisions it for a specific study. Alignment with sites is a must for remote monitoring to work. 

Q: What advice can you share with companies looking to transition to remote monitoring?

: With remote monitoring comes an inherent requirement to upload or download records that need to be imported into the eRegulatory system. To avoid misappropriation of time and effort, monitoring strategies should incorporate limited remote source data verification. The strategy should focus on critical data that supports trial endpoints and patient safety.

Often the most time-consuming process we face is working with the sponsor to understand system privacy and security structures, including the appropriate handling of personal health information. Your software provider should have an extensive library of information on their website to assist in this process, and all organizations should take the time to understand these controls.

Veeva Systems, Veeva Unified Clinical Operations Survey: Annual CRO Report, 2020

Jeff Wiley, head of oncology, global clinical project delivery at Labcorp Drug Development, sheds light on how Labcorp Drug Development is using remote monitoring to advance the industry toward new levels of connectivity.