Applied Clinical Trials Editorial Staff

Fran Ross, consultant and TMF Reference Model Steering Committee member, spoke at Veeva’s TMF Innovation Forum in March, delivering insights from global health authorities around risk-based trial management and how that applies to TMF management. The following is a summary from the transcript from the event.

The International Committee of Medicines Regulatory Authority (ICMRA) released 

“Reflections on the regulatory experience of remote approaches to GCP and GMP regulatory oversight during the COVID-19 Pandemic”

 in November 2021. The position paper focused on adaptive processes, adaptive responses, and firm line on which inspections were most critical to human health, what inspections were most critical to quality, what inspections really had to be accomplished on site, and what inspections could accommodate a remote or hybrid modality.

Takeaways from the health authority perspective is remote or hybrid inspections will take more time to prepare and execute. Most problems revolved around the “start and stop” inspection workflow, ie., request records, records delivered in some electronic fashion, review records, get back with the inspectees, ask questions, get more records. Another was the lack of human interaction, ie., not everyone in the same room at the same time, or at a physical distance. Maintaining a flow of conversations or again, the flow of the discussions. And finally, was the fact that some health authorities have much less virtual or remote inspection experience than others.

Despite the fact that these were more challenging inspections, the results of the inspections haven't changed. There were no less FDA 483s, no less or more amounts of findings from the health authorities. So the takeaway is that there is a new landscape of face-to-face, hybrid and potentially virtual inspections--so prepare for all of them.

 came into effect April 14 of this year. This revision is “a siren call to industry to get on top of risk management of the entire clinical trial,” said Ross. It mandates that all clinical trials approach the protocol development with quality by design and assess all of the critical to quality factors across the study.

The impact on TMF management to ensure that actions of the trialists and the medical monitors are being recorded in the TMF. That there are risk management plans for all studies, risk assessment artifacts, and that quality by design and critical to quality assessments are conducted, those different records can be found and secured in the TMF.

Expectations that the draft of ICH E6 (R3) will be revealed in the third quarter. Rather than soften their demands on risk based trial management, it appears there will be more focused in making industry more responsive to risk based approaches and more focused on quality by design. From a TMF perspective, the expectation is that the artifacts proving that risk-based management and quality by design has been attended to.

EU CTR (536) went into effect January 2022, and very impactful for study startup. The regulation mandates that if you are conducting a trial in any European country, approval for all of those countries is delivered as a single CTA. Ross believes that artifacts called out in 536, can be slotted within sub-artifacts that are already identified in the TMF Reference Model. So there shouldn't be any major change from TMF operations.

TMF Reference Model is likely to join CDISC before the end of 2022. Ross reiterated that the steering committee members are very excited about this transformation “because the reference model has been a volunteer community effort since it's inception. And we really need to have more technology support to make the tool more robust, more available and move it closer to an industry standard that everyone can rely on.”

To that end, Ross maintained that CDISC understands the stance that the reference model itself has to remain freely available, as well as the artifacts, or related items including the exchange mechanism and the TMF plan also remain freely available.

While running mock inspections, make sure you include a thorough test of the remote access capabilities. And the health authorities are asking to make sure that you've got sufficient, fully available tech support and fail safe plans, if there's any technology or bandwidth hiccups.

Focus on TMF fundamentals regardless of the inspection modality. The TMF must be timely, accurate, and complete.

Ensure the completeness is supported by metadata from your eTMF systems, and by those who have completed the trial are giving you insights to the trial study stories.

Components of building a risk-based TMF management approach are straightforward, but include:

Where are the records and processes that are highest risk to being able to conquer inspection?

Plan the measurement of those high risk records and processes

Develop and activate a TMF risk management plan.

Include a change management plan to ensure the entire trial community is behind the new risk management plan.

Measure those impacts and once data is in hand, assess how it went.

Ross said, “At the end of the trial, all the time, all the money, all of the efforts of all of the trialists have been culminated down into what we maintain as TMF record. And t's time for us, as an industry, to make sure that the stakeholders understand how critical this record set is. And then we do it right, we do it right once, and we do it right the first time.”

Articles

Remote inspection and ICH guidelines among topics discussed at Veeva's most recent TMF Innovation Forum.

Trial Master File Insights

Rik de Greef, senior vice president of global quantitative science services at Certara, a biosimulation software and technology company, recently answered questions from 

 on the organization’s training initiatives in Africa, viewed by Certara as an untapped pool for talent in pharmacometrics.

Though a well-established part of drug development, demand for biosimulation—the use of computer-aided models to simulate complex biological systems—is growing, necessitating the need for more experts, the company says. 

: What inspired the Applied Pharmacometrics Training Fellowship in Africa and Certara’s investment in the program?

The fellowship program has been inspired by a number of factors that have nicely come together. Firstly, Pharmacometrics Africa has been providing training opportunities to many Africa-based scientists over the past years, which has brought them in touch with the methods and concepts of pharmacometrics. Still, a need was felt to train these scientists more in the applications of pharmacometrics to support decision-making in drug development. Certara shared this interest, as it wanted to broaden the global pharmacometrics talent base to be able to accommodate the demand of pharmaceutical clients for this bespoke skill set. Lastly, the academic and pharmaceutical partners are happy to contribute to the training of scientists from low- and middle-income countries but lack the infrastructure to do so. Our program brings these elements together and aims to concretely deliver a team of Africa-based pharmacometricians.

: The announcement said that the first cohort would start in January 2022. How is that inaugural class progressing?

Indeed, the inaugural class started with a virtual program in January. At this moment, the class is halfway through that part of the program. The class meets several days per week for classroom training and discussions. The students are very engaged, which makes for a great dynamic between them and the faculty of experienced pharmacometricians.

: When are you taking applications for the next cohort?

We are planning to run the program yearly. So, we probably will be taking applications for the 2023 cohort in the last quarter of this year.

: Are there specific challenges to teaching the doctorate-level scientists virtually in Africa?

There are no specific challenges to the teaching, it is the same as any type of virtual training environment. As faculty, you want to make sure that you maintain the engagement of the students during the training classes and in the course assignments.

: The press release stated: “Successful fellows of this program will be considered as candidates to form the first Certara consulting team located in Africa.” What is your timeline for that?

We are on track to have the first Africa-based consulting team for Certara start toward the end of this year, 2022.

Read more about Certara’s plans in Africa in ACT March’s Closing Thought 

Rik de Greef, senior vice president of global quantitative science services at Certara discusses the organization's training initiatives in Africa. 

Program Aims to Tap Africa's Potential in Pharmacometrics

: Since January 2020, the US Food and Drug Administration (FDA) has issued ten guidance documents for gene therapy program sponsors to align with the advances in research. How receptive have sponsors been to the various guidance and what are the key takeaways for companies in regard to maintaining regulatory compliance from these guidances?

 Sponsors have been receptive to these guidances and, in fact, appreciate the clarity they can offer. One of the challenges in developing products in the cell and gene therapy space is working in a regulatory landscape that is constantly evolving with the advancement of these novel technologies. Sponsors face the challenge of designing development plans and timelines to meet moving targets with respect to CMC requirements, clinical trial endpoints and criteria for approval. This is particularly relevant for cell and gene therapies in the rare disease space, where, due to potential accelerated approval programs, sponsors could be moving to commercial manufacturing scale up in a short period of time. In addition to working within these guidelines, sponsors should maintain an open dialogue with FDA with regard to development plan, clinical trial design and manufacturing plans and procedures. This can help eliminate surprises from the agency that could result in clinical holds, which can derail development timelines, and/or require costly additional development work, including additional clinical trials or comparability studies.

 As we move out of the pandemic, what issues specific to ATMP sponsors are coming to the surface?

 The biggest issues we’re seeing for ATMP sponsors as we move out of the pandemic are related to manufacturing and financing. Securing manufacturing capacity is a challenge. There are limited manufacturers with the expertise and facilities to manufacture cell and gene therapy products. In addition, this type of manufacturing requires skilled operators, and manufacturers are facing the same labor challenges seen in the rest of the economy. Beyond limited capacity, there can also be several issues that can arise in the transition from lab-based manufacturing in early development stages to scaled up production. For sponsors, manufacturing setbacks can be expensive, and, especially for smaller start-ups and academic spinouts, can significantly derail development timelines. Meeting projected time to market can be critical for these companies with respect to securing continued financing.

ATMP sponsors are also facing capitalization challenges in early 2022. In 2021, the bull market for life sciences companies began to stall. After seeing several high-valuation IPOs in the space, such as Sana Biotechnology, Lyell Immunoharma and Caribou Biosciences, there has been a significant slowdown. Several cell and gene therapy clients we were working with in the confidential registration statement process have paused their IPO plans. Given the climate in the capital markets, competition in the private financing markets has also increased, making crossover and venture financing more difficult to secure. Given these challenges, ATMP sponsors are now implementing cost-saving strategies to extend cash runways, which can, among other strategies, include limiting development focus to one or two programs at a time.In addition, ATMP sponsors are looking for more creative financing alternatives, such as strategic collaborations with large pharma partners, royalty financing, venture debt and support from inside investors, to get them through until the markets rebound.

 How is the local Cellicon Valley progressing? Milestones/achievements/messages?

 Philadelphia’s Cellicon Valley continues to grow. As home to the University of Pennsylvania, Children’s Hospital of Philadelphia, & Jefferson Health, Philadelphia has seen the advancement of key cell and gene therapy leaders, such as Dr. Carl June and Dr. Jim Wilson. Philadelphia continues to grow as an innovation hub, with promising startup and spin-out companies (including those guided by Dr. June and Dr. Wilson) finding a home in the Philadelphia area. At present there are over 30 cell and gene therapy companies and 60 labs in the region, as well as big pharma presence from GlaxoSmithKline, Bristol Myers Squibb, Merck, Sanofi, and Johnson & Johnson. Since 2018, several cell and gene therapy companies headquartered in the Philadelphia area, such as Cabaletta Bio, Castle Creek Bio, Century Therapeutics, and Passage Bio, have completed successful IPOs, with six IPOs in 2020 alone.

A recent major addition to Cellicon Valley is Discovery Labs and the Center for Breakthrough Medicine (CBM). CBM is the first and largest single-point cell and gene therapy Contract Development and Manufacturing complex in the world, offering plasmid, viral vector and cell therapy manufacturing as well as process development, analytical development and testing services all on one site. In early 2022, CBM and the University of Pennsylvania’s Gene Therapy Program signed a landmark collaboration agreement, to combine Penn’s knowledge and expertise in the development of gene therapies with CBM’s manufacturing capacity and singular focus on advanced therapies. As cell and gene therapy manufacturing demand is expected to continue to outpace capacity, the Discovery Labs and CBM will help support the growth of Philadelphia’s cell and gene therapy companies.

Porter discusses regulatory compliance, ATMP sponsors, and Philadelphia’s Cellicon Valley.

Q&A With Jennifer Porter, partner, Troutman Pepper

CVS is one of the most recognizable brands across the world. However, its work in clinical trials sometimes goes by the wayside. In this interview, Tony Clapsis, SVP, Clinical Trials Services, CVS, discusses recent advancements in the clinical trials space by CVS and how the pharmacy giant will attempt to reach more patients and healthcare providers (HCPs) than ever.

: CVS has been conducting clinical trials for about 15 years but announced last May a dedicated Clinical Trials Services business. What was the impetus for forming the business now?

The new business aims to harness CVS Health’s ability to reach more people and improve the health of communities across America through our local presence, digital channels, and approximately 300,000 dedicated colleagues—including more than 40,000 physicians, pharmacists, nurses, and nurse practitioners. Despite the important role clinical trials play in evaluating the safety and efficacy of investigational new drugs and devices, less than 4% of the US population participates in clinical studies. In addition, 80% of studies don’t meet participant enrollment deadlines, and an average of 30% of participants drop out before a study is completed.

We are helping to overcome the obstacles that result in these numbers by bringing to bear the considerable resources of CVS Health and our innovative approaches and experience to address the need to drive greater access to clinical trials across the communities we serve. About 80% of the US population and more than 40% of US vulnerable populations, as defined by an SVI (social vulnerability index) score of .5 or greater, lives within a five-mile radius of a CVS store.

ACT: Will every CVS location have clinical trials patient access?

 Our Trial Ready HealthHUB network is expanding and scaling rapidly. This expansion is done strategically based on several factors, including population, therapeutic area needs, demographics, and more. We currently have 10 sites in four states equipped to deliver clinical trials and are continuing to increase this number throughout this year and beyond.

ACT: CVS Clinical Trials Services recently announced a collaboration with Medable to use its clinical trial software platform. Is this your chosen technology for clinical trial data collection or will there be others?

Medable is the preferred technology solution for decentralized clinical trial (DCT) services. CVS Health works with many other companies to support clinical trials.

CVS Health and Medable are both committed to expanding engagement within clinical trials. Our collaboration, utilized in the appropriate settings, will help us work toward this goal. We see this as a great opportunity for two innovative companies with compatible solutions to drive innovation and results in this space effectively and at scale. Combining Medable’s software platform with CVS Health’s community reach and experienced MinuteClinic providers, we improve participant engagement, retention, and site data capture.

ACT: Clinical trials and patient healthcare are two separate areas in regard to regulations, data, and ethical intent; healthcare to treat patients and clinical trials to study the effects of a drug in patients. How will these two areas be managed successfully in the walls of a pharmacy or health clinic?

At CVS Health, standard of care and clinical trials are managed in accordance with applicable industry and regulatory requirements to ensure the safety and privacy of the patients and research subjects. The clinical trial teams handling studies are trained in accordance with applicable regulatory standards, including FDA regulations relating to good clinical practice (GCP) governing human subject protection and the conduct of clinical trials, and in accordance with the appropriate institutional review board (IRB) evaluation.

The clinical teams are trained to know when to apply standard of care operating procedures and processes vs. clinical study protocols and GCP protections to ensure that we are adhering to FDA regulations governing human subject protection.

Tony Clapsis, SVP, Clinical Trials Services, CVS, discusses recent advancements in the clinical trials space by CVS.

Utilizing Outreach and Communication 

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.

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.