Applied Clinical Trials Editorial Staff

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.

Articles

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.

Labcorp Drug Development Expands Remote Monitoring for Better Collaboration with Sites

Celularity Inc., a clinical-stage cellular medicine company developing off-the-shelf allogeneictherapies derived from the postpartum human placenta, announced the closing of a merger with GX Acquisition Corp., a special purpose acquisition company (SPAC). Proceeds from the transaction totaled approximately $138 million. The combined, publicly traded company will operate under the name Celularity, Inc., and its common stock will commence trading on the Nasdaq Capital Market on July 19, 2021, under the ticker symbol “CELU.”

Celularity’s Founder, Chairperson and CEO, Robert J. Hariri, MD, PhD, has decades of R&D experience. The company’s pipeline is centered on its biologic CYNK-001, a non-genetically modified cryopreserved human placental hematopoietic stem cell-derived natural killer (NK) cell therapy. CYNK-001 is currently in a Phase I trial for patients with acute myeloid leukemia (AML) and has been granted Orphan Drug Designation by the FDA for the treatment of patients with malignant gliomas. In addition, CYNK-001 received a positive recommendation from an independent Data Monitoring Committee to continue advancing the company’s Phase I/II COVID-19 trial.

Transaction with special purpose acquisition company totals $138 million.

Celularity Closes Merger with GX Acquisition 

With Africa emerging as the new breeding ground for innovative digital health solutions,

 and African Sustainable Development Advisors (Afrisda, Inc.), have signed a partnership agreement to support digital health implementation in Africa.

The COVID-19 pandemic has highlighted the need for global health solutions to benefit all nations. However, with Africa’s vast population bearing the world’s greatest disease incidence and significant healthcare shortages, the challenge and opportunity to increase the use of digital health solutions to benefit local populations, as well as increase real world evidence and data related to diverse populations for global therapy developments, makes this a key area on which to focus.

Digital technologies have already formed a vital part of the COVID-19 response worldwide, offering case identification, contact tracing and evaluation. These rapid responses leverage billions of mobile phones, online datasets, low-cost computing resources and advances in machine learning and natural language processing. However, more needs to be done, not only to address existing challenges but to maintain momentum beyond the pandemic.

Dr Djo Matangwa, co-founder and CEO of Afrisda Inc, explains: “We seek to raise awareness around the future of digital health in Africa to encourage donors and investors to support African governments and organizations, as well as private sectors working in Africa, as well as support African health authorities to design laws and policies that will strengthen Africa's health system as a key element in innovation and technology adoption.”

Vincent Keunen, founder and CEO of Andaman7, said, “COVID-19 has highlighted potential digital health roadblocks but this pressure on digitalization should be seen as an opportunity – not just for governments, but for innovators, donors and local organizations to provide essential health services that are affordable, reliable and tailored to local needs. There is already precedent for this. In telecommunications, many African countries skipped the classic landline step and went straight from no communications to mobile communications. The same was seen in the banking industry.”

Keunen also noted that his company’s technology, with solutions that work offline, can help in places where there is limited electricity and internet, as is common in Africa. “Someone could travel to a big city to charge their phone and connect to the internet and then use the app offline for a week. Looking beyond the patient, there is a huge opportunity to harness the power of decentralized trials, involving previously under-served demographics to improve research and treatments for all.”

 “Beyond COVID-19: The Future of Digital Health in Africa”

 on Tuesday, June 29, at 1pm ET. [7pm CET; 6pm BST (5pm GMT)]. ToThe webinar panel will feature:

Dr. Djo Matangwa, Co-founder and CEO Afrisda Inc. Toronto, Canada

Guest Speaker, Her Excellency Kilumba Nkulu, Vice-Minister of Public Health, DRC

Vincent Keunen, Founder and CEO Andaman7, Liege, Belgium

Daniel Messer, Vice President and Chief Information Officer for Digital Health & Technical Integration Population Services International, Washington DC, USA

Rosine G. Assamoi, Co-founder and Executive Vice President Afrisda Inc. Toronto, Canada

Eric Mutonj, Consultant ANICiis, Ministry of Health DRC

Dr. Amer Sattar, Director and Consultant in Public Health, Guinea Conakry

Dr. Mamello Muhanuuzi, Group Head of Medical Services & Quality Assurance, International Medical Group, Uganda

Jan Kennis, Digital for Development Lead Expert, Enabel, Antwerp, Belgium

https://us02web.zoom.us/webinar/register/WN_IdsLuXMYRoSBLwRkp2R3jQ

https://www.thelancet.com/journals/landig/article/PIIS2589-7500(20)30027-3/fulltext

Andaman7 and Afrisda, Inc. sign partnership agreement to support digital health implementation in Africa.

Africa Emerges as Digital Health Proving Ground

Clinical research sites are modernizing trial operations with site-centric applications to provide a digital patient experience. Crofoot Research Center, a Houston-based practice that has run over 200 clinical studies in rare disease, is one site realizing the benefits of using patient-centric, site-first solutions.

With an eRegulatory system and eConsent from Veeva Systems, Crofoot is shifting from manual and paper-based processes to more streamlined, digital execution. Charles Sydnor, CCRA, ACRP-CP, project manager at Crofoot, discussed how offering a digital patient experience in trials enables the site to provide better patient care.

: What challenges did Crofoot experience with traditional, paper-based informed consent?

 Patient reach and accessibility have always been our biggest barriers in studies. COVID-19 made reaching new patients even harder, as most could not physically come into our practice. Using paper-based consenting wasn’t a feasible option because of the travel, distance, and safety concerns, impacting our reach and preventing many patients from considering research as a treatment option.

Over the years, we have seen how paper complicates execution, reduces efficiency, and provides limited accountability. Using paper, paying for storage, and hiring additional staff to manually check all the consent forms for completion, errors, and appropriate signatures dramatically increased our economic burden.

Lastly, we want to ensure that the potential participant understands the study, especially the risks and benefits. The traditional paper-based model of consenting does not lend to better participant comprehension but rather the exact opposite. Handing a 20-plus page consent document is an intimidating and overwhelming event, and many participants complain that the font can be too small for review.

ACT: How has paper-based consent impacted the patient experience?

 Ideally, we’d want to give patients as much time as possible to consider participation, ask questions, and talk to their support system at home before choosing a trial. But once a patient travels into our practice, they usually feel pressure to make a quick decision to avoid another visit. That pressure takes a toll on patients who want to consult family members before deciding to participate in a study, leading to early opt-outs.

Patients also have to come in for a screening, often not scheduled on the same day as consenting. An appointment to provide consent could be in several days or several weeks, but it almost always ends up in another visit for the patient. Thus, paper consent increases the patient burden of participating in trials, requiring more time and travel.

ACT: How has Crofoot’s shift to digital improved the patient experience?

Since we already had an eRegulatory system in place, it made sense to bring in an eConsent solution that enables seamless exchange of information. Implementing eConsent has given patients the flexibility to review documents on their own time and wherever they feel most comfortable.

As clinical research protocols become more complex, the patient’s complete understanding of a study is paramount. Using eConsent allows us to format study information in a more digestible form. This ensures that each participant fully understands what they are signing up for. It is important to remember that each person has different needs, and removing paper will optimize the patients’ experience.

We’ve noticed a significant improvement in patient understanding of studies with eConsent. Numerous patients have expressed gratitude for the ease at which they can access documents, allowing review with those closest to them.

ACT: What improvements has your research center achieved by using eConsent?

 Our mission is to reflect the diversity of Houston. But patient reach has been the most significant barrier for us to overcome. This makes our efforts to digitize consent even more critical. eConsent has helped us gain access to individuals in rural areas and underserved communities that may not have access to healthcare.

eConsent allows us to provide patients with more flexibility and minimizes travel. Patients appreciate this, as we’ve seen an increase in recruitment numbers and participant diversity.

Using a digital consenting solution that can exchange information with our investigator site file (ISF) has removed many of the hurdles we experienced for years with paper filing and maintaining ICF logs. As a result, our team is now better prepared to review documents, ensure accuracy, and seamlessly file a patient’s information.

In addition, audits are now handled more efficiently. Our digital solutions allow sponsors and CROs to quickly validate information and ensure all our activity is compliant. Having the ability to share documents across our systems and with our partners has allowed us to work more systematically and cost effectively.

For research sites thinking that the cost of technology is a barrier to adoption, this isn’t always the case. For us, as a small private practice without a large budget, eConsent presented a very achievable point of entry. We have significantly reduced our administrative workload and expenses on storage, printing, and tangible goods. Using a digital consenting solution has improved productivity, enhanced the patient experience, and increased our site’s ability to handle larger workloads.

ACT: You’ve now implemented an eRegulatory system and eConsent, two solutions transforming how research sites work. What advice would you give a site considering new technology?

 The thought of implementing new technology was scary for me at first. But digging in and investing the time has paid off. My advice to sites exploring new solutions would be to commit and follow-through, from evaluation to deployment. Bringing in technology takes a lot of work upfront and is a cross-team effort, but in the end, the benefits for your research site can be transformational. That level of change and improvement to site operations allows you to spend more time where it makes an impact: with patients.

Charles Sydnor, CCRA, ACRP-CP, project manager at Crofoot, discusses how offering a digital patient experience in trials enables the site to provide better patient care.

Shifting from Paper to Digital Patient Consent

Pfizer, Moderna and Johnson & Johnson have started to expand COVID-19 vaccine clinical trials to include pregnant women and children under 12 years old, and soon Pfizer will begin trials on children two to five years of age. With scientists reporting the pandemic may never be fully controlled until children are vaccinated, the questions of ethics, safety and speed turns to that patient cohort. To get more insights, 

 spoke with Michele Russell-Einhorn, Chief Compliance Officer at Advarra, a provider of integrated regulatory review solutions, as well as research quality and compliance consulting services and clinical site technologies.

Applied Clinical Trials: Advarra’s IRB and IBC supported 100% of Operation Warp Speed (OWS) vaccine trials. Can you explain Advarra’s role?

 Advarra has been honored to have played its role in overseeing research to find ways to prevent, treat and diagnose COVID-19. We have as our largest service, the IRB review service, but also has the institutional biosafety service (IBC), which precedes the IRB review. For the research studies that are part of Operation Warp Speed, we’ve either done the IBC review for that research, or the IRB review for the research or both. In the case of Moderna, we did the institutional biosafety review, and we did the IRB review.

ACT: Was there anything different about reviewing protocols for the OWS initiative than any another trial?

 It really wasn’t what was different about this from another trial, as much as what’s been different about research in the pandemic, as a whole. We have been overseeing 700-plus main protocols in COVID-19. And with every one of them, there’s a sense of urgency. And notwithstanding the urgency, there’s also a need to maintain quality and expertise.

The companies have been working very hard to get these agents out to the public. It’s a miracle that in March last year, the country was starting to shut down and here we are, a year later, and we have four vaccinations. Operation Warp Speed was really the catalyst to place all of the pandemic research into this more urgent category.

The other issue is that we are used to drug and device development taking a long time, and this took 11 months. But it doesn’t mean there’s anything wrong with it, and notwithstanding the issues with AstraZeneca and J&J, every once in a while, there’s a commercially available drug that gets recalled by FDA. And the fact is that an FDA approved drug may have gone through eight years of drug development and a 300,000-person Phase III trial, but everything has some risk, and we need to balance the risks.

This is an opportunity to look at how did we do this in 11 months. And what can we learn from this and take going forward for all
other research.

ACT: How was the company able to process the amount of documentation required to protect patients in those trials?

 Advarra has many years of experience in the area of multi-site research and has been overseeing research with upwards of 300 sites. In order to do that, we have always needed to have a system in place that incorporates all the people—the board members, IRB members, operations staff, and others—who can receive and review the documentation and ensure that it’s communicated and acted upon.

We’ve always been able to take a main protocol, manage hundreds of sites, the unique informed consent forms from these sites, the many amendments that come in that then have to be acted on and communicated back to this individual sites, the unanticipated problems.

When the pandemic hit, Advarra was already 60% remote, so it didn’t affect our workforce. We knew what needed to make the rest of the company remote-based. Our system itself was already set up to receive urgent submissions and unique informed consents and to immediately manage a main COVID-19 protocol that involve, for example, 200 sites. We have always been efficient in our reviews, with comparisons between academic institutions and an independent IRBs, so we had to become even more efficient at the same time that we maintained quality.

ACT: Pediatric participation in clinical trials is necessary, but also concerning for parents and guardians. How has industry helped them feel more assured

 One issue that came up at the beginning of the pandemic was can the IRB regulations manage COVID-19? But it’s really no different than when gene therapy or CAR-T came along. The answer is that for IRB’s, the 111 criteria is really quite good 

. It can be applied to CAR-T cell research, gene therapy, and indeed COVID-19 research…you have to make sure that risks are reasonable, and that subject selection is equitable. That there’s appropriate data and safety monitoring. But for anything that’s HHS-supported or conducted, and also for FDA regulated research, we have the specific requirements for pediatric determinations. And so again, we see the foresight in putting forward those specific regulations to protect that population of minors works in with respect to COVID-19.

From the perspective of the IRB, the requirements for data safety monitoring as appropriate for as sent by minors, for permission from parents, is already there to apply to COVID-19 research. But one thing about the pandemic was situations of children on ventilators, which is very sad, very difficult. You might have a research protocol, where you decided that assent was required from minors. But the IRB hadn’t considered waiving that assent in regard to ventilators. As the pandemic evolved, and we saw how serious it could be, we realized that we had to ask extra questions. An IRB can always go back and review something as necessary. And sponsors can come always come in and modify protocols. But how this impacted some minors could be heartbreaking at times.

ACT: What would be cause for concern by an IRB if included in an Informed Consent Form for children?

 This actually raises issues that apply to both a pediatric population and an adult population. But in regard to COVID-19 and research involving children, there are certain medical conditions like asthma and obesity, that make individuals more vulnerable, more susceptible to severe illness. If you had a research protocol seeking to enroll minors, and it required them to give up standard of care therapy in order to participate and they had asthma, that would be cause for concern by the IRB. An IRB might say that the risk of giving up the standard of care option is not reasonable in terms of the benefit the individual might get from participating in the research.

The other issue is mandatory biopsies, in either the pediatric or adult population. Research often includes a requirement for a mandatory biopsy, which is different from what I would call an extra blood draw, or an extra bone marrow, where the procedure is already happening but requiring more of it at the same time. But a mandatory biopsy is a different activity. It’s separate from a procedure the participant is already being asked to go through. That mandatory biopsy could be minimal risk if it’s, for example, a skin biopsy. But it could be very serious if it’s a liver or lung biopsy. And when you’re dealing with investigational agents under FDA oversight, there are frequently protocols that include mandatory biopsies because they want to see how the drug is working, how it’s manifesting itself in tissue. So it’s not an unreasonable request, but it has to be carefully evaluated.

There has been a lot of discussion around the issue of mandatory biopsies. The Secretary’s Advisory Committee on Human Research Protections (SACHRP), discussed it in their annual meeting and ASCO had an article about it. It’s become a bit of a
hot topic.

ACT: What other trends are on the table for ethical pediatric research?

 We’ve drawn lines to review this research for adults vs. pediatrics for numerous years. And we need to ask whether we should be drawing those lines as sharply as we have been. Since we do make a distinction between a minor and an adult, and a 17-year-old is considered a minor. But most 17-year-olds wouldn’t consider themselves minors and 17-year-olds who are in college wouldn’t consider themselves not capable of giving consent. Maybe it’s time for us to rethink the definitions of a minor and whether they actually remain useful, given the state of research
right now.

Michele Russell-Einhorn, Chief Compliance Officer at Advarra discusses safety, speed, and ethics in COVID-19 vaccine trials.

Protecting Patients in COVID-19 Vaccine Clinical Trials

Big pharmas join clinical research marketplace

Inato, a global industry marketplace that matches research sites to the right clinical trial protocols, announced over 500 sites across more than 30 countries are participating in its Marketplace. Sanofi and Merck KGaA, Darmstadt, Germany have also joined the Marketplace, which Inato says will further its mission to accelerate the pace of medical innovation to improve people’s lives.

Using a data-driven approach—coupled with a high-touch qualification and support process—the Inato Marketplace provides research sites the opportunity to search and match for trials based on their qualifications, interests, and patient needs. By matching sites and trials on a global scale, the Marketplace enables trial sponsors to work with a broader range of qualified sites and rapidly expand the pool of patients engaged in their trials.

Senators Edward J. Markey (D-Mass.), Thom Tillis (R-N.C.), Gary Peters (D-Mich.), and Susan Collins (R-Maine) have introduced the Research Investment to Spark the Economy (RISE) Act to authorize nearly $25 billion in support to US researchers who have been impacted by the COVID-19 pandemic.

Although coronavirus-related research is a current federal government priority, most other research has been delayed due to closures of campuses and laboratories. The people who comprise the research workforce—graduate students, postdocs, principal investigators, and technical support staff—face financial and other hardships from the disruption of their research activities. The RISE Act would provide necessary relief to preserve the current scientific workforce and ensure that the US is prepared to continue its global scientific leadership once this crisis ends.

GCSA Intrinsic is supporting the UK clinical research industry by providing an internationally-recognized quality benchmark for sites focused on attracting commercial clinical trials.

The GCSA gold standard has been ratified by a global advisory board of industry experts from a broad range of global and UK organizations. According to Board members, GCSA will either enhance existing standards that some UK research centers have, or it will help improve and raise the standards of those centers that are trying to build their research capacity, thus allowing these centers to promote themselves as global competitors

Jazz Pharmaceuticals plc and GW Pharmaceuticals plc have entered into a definitive agreement for Jazz to acquire GW for $220 per American Depositary Share (ADS), in the form of $200 in cash and $20 in Jazz ordinary shares, for a total consideration of $7.2 billion, or $6.7 billion net of GW cash. The transaction is expected to close in the second quarter.

The combined company will be among the leaders in neuroscience. GW has a scientific platform and a deep pipeline of cannabinoid product candidates, as well as highly specialized manufacturing expertise. GW’s lead product, Epidiolex oral solution, is approved in patients one-year and older for the treatment of seizures.

A compilation of recent notable news developments that pertain to the clinical trials industry.

News Notes (January & February)

Syneos Health acquires emerging-biopharma-focused CRO Synteract

Syneos Health, a fully integrated biopharmaceutical solutions company combining a contract research organization (CRO) and contract commercial organization (CCO), has agreed to acquire Synteract, a full-service CRO focused on the rapidly growing emerging biopharma segment. Synteract has built a solid reputation in this space, providing deep therapeutic expertise in oncology, rare and orphan diseases, neuroscience, dermatology, and pediatrics. The company’s client base comprises primarily pre-revenue companies, a segment in which Syneos Health has growth opportunities. Synteract’s 700 employees across North America, Europe, Asia Pacific, and Africa have supported more than 4,000 Phase I-IV clinical trials across 26,000 sites in more than 60 countries.

The acquisition will enhance Syneos’ position in the marketplace, particularly for serving customers across the small to mid-sized (SMID) category. According to industry estimates, funding to the biotech sector has shown no signs of slowing down, remaining near all-time record highs.

Health-management information company SomaLogic, Inc. has struck an agreement with FDA’s Division of Applied Regulatory Science to evaluate the use of large-scale analysis of proteins (proteomics) for the identification of biomarkers that may be useful in demonstrating biosimilarity of a proposed biosimilar to a reference biologic.

The collaborative project will use data generated on the SomaLogic SomaScan Platform, which makes 5,000 protein measurements simultaneously in small samples of blood, to compare changes in circulating proteins following treatment with FDA-approved biologics. The protein measurements from an FDA-approved reference biologic could then be compared to those generated by a candidate biosimilar drug.

Advarra, a provider of institutional review board (IRB), institutional biosafety committee (IBC), quality and compliance consulting services, and research technology solutions has acquired IntegReview IRB, an AAHRPP-accredited central IRB. As a market player in early phase clinical research, the addition of IntegReview enables Advarra to continue its expansion of comprehensive review solutions capabilities in North America.

The Austin, Tex. headquarters for IntegReview will become the first Advarra office in the southern US.

According to a report by Bizwit Research & Consulting, the worldwide DNA sequencing market garnered a valuation of $4.7 billion in 2019 and is projected to record a year-over-year growth rate of 11.3% during 2020-2027. Increasing demand for DNA sequencing in biological research applications and across various medical fields such as virology, biotechnology, medical diagnosis, forensic biology, and biological systematics is expected to augment the industry growth in the upcoming years.

The rising prevalence of cancer, the report notes, serves as a major growth impetus for the global DNA sequencing industry. Nearly 18.1 million new cancer cases were recorded in 2018 and the number is expected to climb to 27.5 million by 2040, the report says, citing data from the International Agency for Research on Cancer.

eGenesis, a biotech using gene editing technologies for the development of safe and effective human-compatible organs, tissues, and cells to address the global organ shortage, has initiated a research collaboration with Duke University School of Medicine. The arrangement will encompass evaluation of gene-edited pancreatic islet cells in non-human primate recipients as a prerequisite to advancing to human clinical trials. This collaboration is in addition to an existing eGenesis partnership with Massachusetts General Hospital, established in 2017.

The first independently accredited Trial Master File University (TMF University) is getting ready to launch its inaugural training series on Jan. 11, 2021. TMF University engages students with a combination of high-quality virtual instruction along with standardized educational competency requirements to prepare internationally qualified TMF experts. It is being facilitated by LMK Clinical Research Consulting and has received accreditation from the International Accrediting Organization for Clinical Research (IAOCR).