Andy Studna

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.

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

Articles

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.

COVID-19 Puts Spotlight on Study Start-up

COVID-19 affects certain demographics differently than others. It has shed new light on the underrepresentation of diverse populations in clinical trials. This issue has always been prevalent in trials, but now with a worldwide pandemic pushing pharma companies to create a COVID-19 vaccine that works for everyone, it has become even more prevalent.

In this interview, Jody Casey, vice president, healthcare partnerships at Elligo Health Research, highlights how the pandemic has put the spotlight on diversity in trials, how Elligo is working with physicians to make studies more accessible, as well as what is in store for the future of appropriate representation in trials.

The underrepresentation of diverse populations in trials has been a problem for a long time. How has the COVID-19 pandemic shined even more light on that issue?

 It’s showing that trials cannot be done “business as usual,” and that sponsors cannot only go to their typical vaccine sites where they’ve always run vaccine trials. There needs to be a greater breadth of population and diversity in trials. Because a COVID vaccine is so critically important for all Americans, it’s been brought to light the fact that trials are generally lacking in diversity. In such urgent times, especially with COVID affecting certain demographics differently than others, it’s important that we have a vaccine that works for everyone.

How will Elligo be using its own research experience to identify these patients and their respective demographics that usually get left out of trials?

It’s all about the communities Elligo brings research to; we have a lot of reverence for that physician-patient relationship in a healthcare setting. We think that’s very sacred, so we go into local communities and enable physicians to run their own trials within their own patient populations. Elligo is in communities that are very diverse. The population of El Paso, Texas, for example, is over 80% Hispanic. We are running a very important, non-COVID-related trial there with two doctors who are bilingual.

Elligo is already in diverse locations and communities of color working with, as an example, an African American psychiatrist who is part of the National Medical Association (NMA), the largest and oldest national organization representing African American physicians and their patients in the United States. He’s also the CEO/president of Bay Pointe Behavioral Health Service, Inc., and South East Houston Research Group. It’s not just about our experience running trials, but where we’re running them. We are already there and have that footprint.

What kind of data is Elligo using to identify these patients?

A unique aspect of Elligo is that we securely access electronic health record (EHR) data from our physician partners. Sometimes within that EHR data, there is a designation for ethnicity that can help identify patients who otherwise wouldn’t have the opportunity to enroll in the trial because the patient wouldn’t know about it, or they wouldn’t have access. That is one way, but because Elligo has doctors in these communities already, it just naturally occurs.

How does the communication between physicians and their patients change when the patient transitions into being a candidate for a trial?

Often, the relationship with the physician is there and the physician is usually the one in the practice talking to the patient about the trial. The physician has the background information on their patient. This gives our physicians and their networks other care options for their patients.

What does the future hold for the representation of diverse populations in trials knowing the work that Elligo is doing right now?

 I feel very positively about the future. So many healthcare challenges in this country can be addressed if we just start talking about them directly and doing something about them. We need to go into communities, provide access to patients, and do the hard work of bringing them healthcare and research options. Elligo’s model is working so well that I believe it will be more broadly adopted. We will see much more of this community-based, physician-led research across the country.