Andy Studna

Brad Power, Founder of CancerHacker Lab, speaks about his innovative crowdsourcing approach to help cancer patients, his own battle with lymphoma, and the unique challenges brought to the table by clinical trials in oncology.

Podcasts

CancerHacker Lab

Dr. Hanne Bak, Senior Vice President of Preclinical Manufacturing and Process Development at Regeneron speaks about her role at the company as well as their work with monoclonal antibodies, the regulatory side of manufacturing, and more.

What Can ClinOps Learn from Pre-Clinical?

Dr. Peter Schueler, Senior VP Drug Development Services, Neurosciences at ICON, talks about topics discussed in a timely new book he edited titled 

Innovation in Clinical Trial Methodologies.

Dr. Peter Schueler, Senior VP Drug Development Services, Neurosciences at ICON, talks about topics discussed in a timely new book he edited titled Innovation in Clinical Trial Methodologies.

Innovation in Clinical Trial Methodologies

John Reites, CEO of THREAD Research, discusses how his organization is adapting to decentralized trials and efforts they're taking to increase patient recruitment. 

DCTs Top of Mind

Dr. Theodore Leng, MD, Medical Advisor to Verana Health and Director of Clinical and Translational Research at the Byers Eye Institute at Stanford, Stanford University Medical School, speaks about a recent study he led and presented in early May at the Association for Research in Vision and Ophthalmology Meeting.

Dr. Theodore Leng, MD, Medical Advisor to Verana Health and Director of Clinical and Translational Research at the Byers Eye Institute at Stanford, Stanford University Medical School, talks about a recent study he led and presented in early May at the Association for Research in Vision and Ophthalmology Meeting.

Recent Study Brings RWD Front and Center

 for 2020/2021. Featuring statistics from the organization’s 2020 CRO Industry Global Compensation & Turnover Survey, the report provides clinical research outsourcing companies around the world with data on compensation levels and employee turnover.

For this most recent edition of the report, the main headline continues to be a high rate of employee turnover within CROs, particularly for the CRA role. As shown in Figure 1 below, the average turnover in the US for clinical monitoring from 2015 to 2019 has been consistently high. Judy Canavan, Managing Director, Global Employer Services of BDO said, “The sense that [CRAs] can own their career is important, and organizations are really not enabling employees to do that.”

One influencer of CRA turnover in the US has been compensation levels. BDO found that companies’ approaches to compensation levels have remained mostly the same the last 10 years. The salary increase budgets of CROs in the US have only been around 3% or less. “The market rates of pay have been moving more slowly than one would expect given the demand for talent,” said Canavan. “This is a problem because there’s this huge demand for talent, but on average, the pay for a CRA-level one is only going up a little bit each year.”

Unsurprisingly, CRAs view switching companies as their best career choice. “Their (CRAs) value goes up faster than their salary value if they just stay within the firm,” said Canavan.

At the same time, CROs are finding ways to combat turnover. Canavan explained that companies are creating a wide variety of retention programs which can include compensation plans and merit-based rewards. She mentioned one organization in particular created competency-based career ladders. “This gave the employees a clear, defined path upward,” she said. “The employees actually felt like they owned their careers, and they (the organization) really did document a significant drop in turnover.”

In terms of how COVID-19 has affected CRA turnover, Canavan said it is a growing concern. She explained that things settled down mid-2020, but shortly after, companies were calling her with concerns about employees suddenly leaving for higher salaries. From a BDO-sponsored poll of 15 CROs year-to-date, US turnover was over 21% as of early November 2020.

The CRA role in of itself has also been changed by the pandemic. Kimberly Ray, consultant and working group leader, ACRP, said travel bans forced the role to become more virtual; field CRAs needed to learn how to use new technologies for analyzing data electronically as well as advising site staff to ensure trial operations continued.

While turnover remains high and decentralized trials (DCTs) continue to evolve, CRAs can be confident in their own job security during the pandemic. “Whether a DCT or not, more and more technology is being leveraged in clinical research. Therefore, the CRA role will continue to be needed but it will evolve,” said Ray.

The ACRP Working Group sees the field and in-house CRA roles merging to create a position that works with sites on different levels. “CRAs will be key in helping sites embrace change and navigating this new environment,” said Ray. “They will also likely be the first call when there are technology questions or issues.”

It’s not only at the site that Ray says CRAs’ roles will change in the age of DCTs. One new role needed for DCTs is a “virtual patient guide.” The CRA in this position will be responsible for guiding the patient through a trial via a virtual platform; they are the primary point of contact for the patient.

Looking forward, while CRA turnover continues to be affected by the pandemic, there is hope that the emergence of DCTs can curb some of the contributing factors.

is an Assistant Editor for Applied Clinical Trials. He can be reached at

Articles

New BDO CRO Insights Report reveals high rate of CRA turnover and what organizations are doing to combat it.

Turnover for Clinical Monitoring Remains High

The COVID-19 pandemic has severely impacted the conduct of clinical trials back years due to restrictions on in-person visits to investigator sites. Over the past 11 months, the industry has responded with an accelerated adaptation to decentralized trial methodologies.

In December 2020, Decentralized Trials & Research Alliance (DTRA) was launched to unite trial stakeholders with a mission of to make trial participation more accessible by advancing policies and best practices. In this interview, co-conveners of DTRA, Amir Kalali, MD and Craig Lipset discuss the new alliance as well as how COVID-19 has impacted the industry.

Andy Studna: How did the idea for starting DTRA first come about?

 Craig has been actively leading and advocating for decentralized research for more than a decade now, while I have been supporting convening and knowledge-sharing on decentralized trials for years through the CNS Summit. These conversations have been thoughtful and productive, but barriers to meaningful adoption have remained. We founded DTRA to go beyond the conversation by creating a neutral and sustaining space for collaboration to address the barriers to decentralized research. As a result, the organization and our approach draw on my experience in global clinical development, and creating non-profit and neutral collaborations, Craig’s experience in decentralized trials and leading consortia in clinical research, and both of our trusted networks of leaders that seek to go farther together.

AS: Would you have come up with the idea for DTRA if COVID-19 had never happened?

 Actually, like it has done in so many cases, COVID-19 complicated the effort. Planning for DTRA preceded the pandemic, COVID-19 delayed the DTRA in several ways as leaders in the field were heavily focused on executing study continuity strategies across the biopharmaceutical industry relying upon decentralized research tools. By mid-year, however, the urgent need for the benefits that could result from DTRA’s collaborative effort was clear, and leaders were ready to step forward.

AS: How do you anticipate achieving maximum collaboration between stakeholders involved in clinical trials?

 I think that our ‘big tent’ approach is an accelerator for collaboration. While some collaborations convene a single stakeholder group in order to address their specific challenges, DTRA is a multi-stakeholder initiative, which includes regulators, pharma sponsors, service providers, technology companies, site networks and patient organizations. Among our first needs as an organization was to establish our priority areas, a process which could have been challenged by our stakeholders potentially having highly divergent needs. But the priorities for decentralized research across stakeholders proved to have a remarkable degree of consistency, which provided DTRA with a shared vision and strong focus moving forward.

AS: What problems within clinical trials do you think COVID-19 has amplified and how can they be solved?

 Well, it’s clear that COVID-19 has underscored how fragile the clinical research enterprise can become–and it has contributed to that fragility. Despite the degree of shared resources and infrastructure across the sector, no single stakeholder owns or controls all of the components necessary for a successful drug development program. And, when pandemic-related lockdowns took hold across the globe, many study sites were unable to remain open and research participants were unable to leave their homes for study visits. But the research community was able to maintain continuity by drawing on other stakeholders that stepped forward, and embracing decentralized research solutions that had been available, but had struggled for adoption. We think this experience demonstrates how collaboration makes our shared ecosystem stronger, reduces risk, and drives progress.

AS: What are your goals for DTRA moving forward?

 DTRA goals include progressing shared solutions to common challenges while creating a community among the leaders in decentralized research, and to that end, the membership of DTRA has identified four priority areas. These include definitions, removing the ‘Tower of Babel’ created through sector—or organization-specific jargon by commonly endorsed archetypes of decentralized research, as well as key performance indicators. We must also use our collective experience to understand and share best practices that reduce risk and improve decentralized trial execution.

 They also include gathering data and information from across the community to promote knowledge sharing/education by providing educational resources for all stakeholders to improve awareness and appreciation for the impact of decentralized research; and identifying and removing remaining barriers to the global conduct of decentralized research, charting pathways to resolution. It’s truly exciting to see the dedicated support for these priorities and the collaborative effort needed to move forward from a group that now includes more than 100 committed stakeholders.

Co-conveners of the newly formed Decentralized Trials & Research Alliance, Amir Kalali, MD and Craig Lipset discuss the alliance as well as how COVID-19 has impacted the industry.

New Alliance Seeks to Bring Increased Accessibility to Trials

As the new calendar year approaches, organizations are beginning to look forward to understanding the impact of ICH E6 (R3) in the fourth quarter of 2021. Despite E6 (R2) being released just four years ago, the industry is still facing difficulties in adhering to these current regulations.

 and sponsored by Oracle Health Sciences in late summer addressed what organizations can do to prepare for E6 (R3).

The webcast featured insights from three industry leaders; Crissy MacDonald, PhD, Executive Director, Client Delivery, The Avoca Group; Andy Lawton, Consultant, Risk Based Approach Ltd, and Elvin Thalund, Director, Industry Strategy, Oracle Health Sciences.

E6 was originally released in 1996, creating the first guidance for clinical trial context. In 2016, revisions were made to these regulations for the first time in 20 years, forcing an industry-wide shift as it attempted to adjust. With another update to E6 expected in 2021, there will be a gap of just five years between revisions.

“What we’re seeing is a shrinking timeline of these regulatory guidance revisions, and it’s likely related to the rapid changes in technology’s clinical trial design approaches,” said MacDonald. “We need to become more adept at adjusting our internal policies and procedures to comply with these newly changing regulations.”

Lawton highlighted the revisions to E6, as well as the latest revisions to ICH E8, that will encourage greater use of quality tolerance limits (QTLs). “Quality tolerance limits give us that one perfect gift of avoiding perfection, because we write our plans as if we’re going to achieve perfection,” he said. “We can move away from that definition of perfection to a defined quality basis.”

Currently, organizations use a trial-reporting system that includes a completely separate process for quality checks after the fact. “There’s [currently] a whole secondary process, in this case a TMF (trial master file) process, where now the true regulatory quality is being assessed. The solution could be a system which considers quality from the very beginning. It would include training operational staff members on ICH regulations and implementing quality checks early in the process,” Thalundsaid.

“When you then start receiving them (documents), you can now ensure your quality control based on the quality you had defined from the beginning,” Thalund said. “That’s where you now have quality by design built into your system and process.”

The E6 (R3) concept paper states that R3 will be a full rewrite and reorganization of the GCP (good clinical practice) guidance with a focus on the applications of GCP principle to the increasingly diverse trial types and retaining concepts already present in R2.

While MacDonald noted the industry’s tendency to have a reactive approach to new regulations, when it should be more proactive. “[The industry’s reactive approach] drives a decrease in adoption because there’s concerns without a clear understanding of what those regulatory expectations are,” she said.

To address this, MacDonald referred to the Pharmaceuticals and Medical Devices Agency (PMDA)’s idea of “horizon scanning.” This concept will consist of “scanning the horizon” to find emerging technologies in order to proactively prepare and make the necessary regulations a priority.

Although the ICH E6 (R3) revision is fast approaching, models such as horizon scanning and streamlined operational processes should be able to help organizations adjust to the newest set of regulations.

Recent webcast addresses what organizations can do to prepare for the next revision of ICH E6.

E6 (R3) on Horizon

The COVID-19 pandemic has brought new attention to clinical trials and is forcing the industry to rethink the best ways for patients to get involved. On Sept. 29, W2O announced the launch of Hū, a first-of-its kind Patient Activation Organization to accomplish just that.

In this interview, EVP and General Manager of Hū, April Lewis, discusses why the industry is seeing such a large drop in trial participation, how COVID is affecting trial operations, and what Hū is doing to better humanize trials.

You have 20 years of experience in the field of innovating trial operations. What do you think are the most valuable lessons you can take away from that time that are helping you in your current role?

 There are three things that I’ve learned that I carry with me. One, when we think about innovation, timing is everything; even the best innovations have to be met with a level of market readiness, adoption readiness, or maturity of a market in order to besuccessful.

The second thing is that data and evidence are only part of the story. As an industry, we’ve failed often because we look at data as the answer, when really it should be looked at as prescriptive guidance. I think data and evidence become most valuable when it’s balanced with experience and even sometimes instinct.

The third thing that I keep at the forefront of my mind is that patients aren’t waiting for us. If we stop and consider a trial, as we would consider a product, we have to think about whether or not that product is something that’s attractive. We take that approach with sites, so we often focus on whether or not a study is attractive, but we don’t take that same approach with patients. Thinking about what’s in it for patients is the thing that’s been missing.

The willingness to participate in trials has plummeted from 85% to just about 49% in the past year (CenterWatch). Why do you think we’ve seen such a such drastic drop like that?

 There’s copious amounts of misinformation around the pandemic, and that’s leading people into a state of paralysis and fear. I see it as a real opportunity for the collective R&D organizations to band together, change the narrative, and create a unified message.

Do you think that more literacy around trials will help people warm up to them and if so, why?

 Knowledge is power. Right now, people’s knowledge is wrapped up in a lot of noise. I truly believe we could fix that if we did a better job of providing resources to the general public around the value of trial participation. For example, what it means for our ability to future-proof care options by participating and some of the practicalities of participation, we’d really move the needle. However, this is a conversation that isn’t a one-size-fits-all, and requires us to not only combine forces as an industry, but to be consistent in our messaging, and keeping in mind that we need to personalize the conversation with patients in order to stay engaged.

How will Hū be utilizing social and behavioral evidence to increase patient participation in trials?

 We’ve built a model that predicts which patients have the highest intent to participate and it has shown high correlations. In addition, when we look at other industries, behavioral economics techniques have increased desired action by 41%. I’m not suggesting that we’ve been able to achieve that metric yet, but in other industries behavioral economics has been able to influence action and increase it to the desired state by 41%. So, we’re building out our tools and our techniques to leverage behavioral economics to provoke action in the same ways. For example, we are building out an innovative platform for gamified, scaled, digital patient insights. It’s a technique that’s going to highlight patient preferences and motivations that can be used by study teams in study design and delivery. This is a massive shift from the professional patient advisory board that gets used today. The third thing we’re using social and behavioral data for is working on a model to predict patient participation. This will allow us to predict what patients have highest interest or intent to participate, but the next step is translating that into enrollment rates. If we’re able to achieve that projection and prediction methodology, that will be a huge game changer.

What do you think are the most important elements for any company to consider when it comes to humanizing these trials?

 The most important elements start with listening and learning. We need to do a better job in understanding the patient lexicon; giving consideration to ethnic insights and the patient motivations. If we can combine listening with evidence and data, we can start to develop and analyze, get to a strategic goal, and have a strategic conversation that personalizes the way we engage with patients more effectively. The tactics are the last thing; by doing the upfront work and understanding the patient, adding in the evidence, and getting to that conversation blueprint, that allows us to build tactics that are going to have more meaningful effects on the ability to not only motivate a patient to participate, but to maintain that motivation throughout the trial.

How do you think that the pandemic has shed more light on the issue of the decreasing participation in trials?

 I think COVID has brought light to participation in clinical trials in general and has brought conversations about them to the table. I think that participation is a systemic issue and it requires a systemic response. We know, for example, if we think about diversity and inclusion in trials, there’s been under-representation of underserved populations for many years, but COVID has really brought this to light in particular. COVID has also brought to light the complexities and the reasons that are multifaceted; things like skepticism, lack of trusted relationships, and questionable data. Our approach at Hū is one that considers partnership as a balanced approach to not only civic and community engagement and partnership, but balancing that with medical and pharma partnership, as a means to take that systemic response.

EVP and General Manager of Hū, April Lewis, discusses why the industry has seen a decline in trial participation and what Hū is doing to combat it.

Industry Forced to Rethink Patient Participation in Trials

At the outset of clinical trials—prior to enrolling the first patient—a considerable amount of work is done in planning and setting up a study for success. Collectively referred to as study start-up, these decisions can have a great impact on timelines and budgets. While the COVID-19 pandemic has slowed down the implementation of new trials, study start-up has the advanced technology necessary to overcome sucha large hurdle.

In this interview, Sujay Jadhav, global vice president, study start-up, Oracle Health Sciences, touches on how COVID has affected study start-up and what new perspectives it has forced the industry to have on its own challenges.

How did the pandemic affect study start-up in the beginning vs. study start-up about six months later?

 In March, not long after the pandemic was spreading globally, Oracle created a study start-up response team, which developed and released several COVID-19 specific application enhancements to help our customers:

Activate workflows were modified to allow certain tasks to take place simultaneously. This was a critical enabler for COVID-19-specific therapeutics and vaccine studies where operational time savings were critical.

We released a new organization-specific Analyze report to allow clinical trial teams to assess the impact of COVID-19-related delays at the study, country, and investigator level. This allowed pharmaceutical companies and CROs to better plan the revised schedules for studies and assess the resource and financial impact of the pandemic.

Oracle support teams immediately prioritized all support requests related to COVID-19 clinical trials to ensure expedited response.

In the present, six months after the outbreak of the pandemic in the U.S., we are seeing a resurgence in studies, which are either new, or previously placed on hold.

Do you think the pandemic has shined new light on challenges that may have existed in study start-up beforehand?

Yes. Study start-up is a continual focus because it has such an impact on clinical trials. Problems with start-up, more than any other phase of a clinical trial, have the greatest potential to increase timelines and budgets. Fortunately, technology for study start-up has advanced to the point that current solutions can do what Excel never will—automatically trigger workflows as a clinical trial unfolds.

It has also become possible to set and track milestones, improve communications among partners, act as a central repository for study documents, and integrate the flow of information from various data sources in a compliant manner—functions that are critical to successful site-activation processes as more clinical trials become global and complex.

Furthermore, companies with purpose-built solutions may have an advantage to monitor impact closely and accelerate the responses needed, where possible.

How can predictive analytics and effective study planning help CROs and sponsors run effective and accurate studies during these challenging times?

Machine learning is a quantum leap in the field of predictive analytics, helping ensure accurate and successful forecasting, more accurately and significantly earlier than humans do. It is these predictions that can help to drive planning and informed decisions.

It is this proactive planning that can mitigate mistakes that can impact overall product development costs.

For example, in the case of under-enrollment in studies, an entrenched industry problem, machine learning using leading indicators contained in the clinical development plan (e.g., indication, phase(s), key inclusion/exclusion criteria, etc.) can be used to help ensure that the required sites can be found, so enrollment success can be predicted, prior to the protocol being written and approved.

In addition to the machine learning capabilities embedded in Oracle’s Activate solution, the study planning tool allows sponsors and CROs to fully plan all of its study start-up milestones from protocol approval to activation.

Leveraging multi-plan comparison and visualization tools, users can scenario-plan to determine the best countries and sites to activate, based on the characteristics of the study, to hit enrollment goals in the fastest possible time.

What special programs or efforts around COVID-19 has Oracle made available for sponsors/CROs?

Many pharmas and CROs have pivoted quickly to develop and test potential COVID-19 treatments and vaccines—we at Oracle are working very closely with customers to support those efforts. As of today, the Oracle Cloud is running 93-plus clinical trials to test the safety and effectiveness of COVID-19 drugs and vaccines, across 53 different customers. These trials span many countries and hundreds of investigator sites.

Additionally, Oracle is supporting the National Institutes of Health’s Coronavirus Prevention Network (CoVPN)—formed to respond to the global pandemic with a goal of registering one million volunteers for large-scale testing of vaccines. As part of this initiative, Oracle developed and provided a Cloud System called the CoVPN Volunteer Screening Registry to identify and screen volunteers who want to participate in COVID-19 vaccine clinical trials.

How are new approaches (such as decentralized trials) changing the landscape of study start-up all together?

 Currently, studies which have pivoted to utilizing remote devices and/or virtual visits because of the pandemic, are following a traditional study start-up process. These studies have had their protocol amendments approved by the IRB/EC due to the immediate need to have these studies continue.

The industry expectation is that the use of decentralized clinical trials will continue at scale post-pandemic. This will require assessment and direction from regulatory agencies.

The adoption of decentralized clinical trials will have significant impact on study start-up, as the sequence of processes can change. For example:

Subjects can be found and enroll in trials before or separate from sites and primary investigators.

Devices and virtual tools must be validated prior to being deployed. It is still not clear if this is under the responsibility of the site/principal investigator (source data), or the sponsor/CRO (case data).

These impacts will first be realized when there is an option to run a trial using traditional visits and any regulatory risk has to be assessed.

In addition, digital transformation will also put extra emphasis on the site selection process. As a result, assessing site ability to leverage telehealth will be a factor in site selection.

Beyond what you already discussed, what else do you think the future holds for study start-up?

 In the near future, study startup will be significantly impacted by:

Regulatory changes: The forthcoming ICH E6 (R3) “Good Clinical Practice (GCP)” (draft scheduled for end of this year) will introduce quality by design (QbD) and associated metrics (e.g., QTLs). Quality, which must be ensured upfront in operational systems such as study start-up, instead of after the fact, in systems such as eTMF (electronic trial master file) and QMS (quality management system).

Decentralized clinical trials: As discussed, the pandemic has forced the use of decentralized clinical trials and this use is likely to continue post-pandemic.There may also be more emphasis on a site’s ability to leverage telehealth, as a key factor in the site selection process. We may also see an acceleration in the use of patient hot-spotting technology, which allows the ability to mine electronic health record (EHR) and electronic medical record (EMR) data in a de-identified way to identify a higher quality of patients.

Sujay Jadhav, global vice president, study start-up, Oracle Health Sciences, spoke with ACT on how study start-up has been impacted by the pandemic and what its future holds beyond COVID.