Moe Alsumidaie

Operating clinical trials of a COVID-19 drug comes with many challenges, not the least of the pandemic's limitations. NeuroRx CEO Jonathan Javitt, MD, MPH, and Head of Operations/CCO Robert Besthof discuss the logistics and clinical trial progress of their COVID-19 drug, aviptadil.

What challenges have you experienced in your studies during the COVID-19 pandemic?

 Probably the most significant challenge has been keeping our people at our study sites healthy. We had three study sites pause or slow down because staff members on the front lines got COVID-19, and some of them needed to be hospitalized. We had sites go down because hospitals were so overwhelmed that they needed to pull every competent person off research.

Keeping a study going in the middle of an epidemic is the opposite of what you would expect. People say, "Oh, there are a million cases. Enrollment ought to be easy." Yes, there are a million cases, but it is like trying to drink water from a fire hose.

When those sites faced challenges, what did you do? Did enrollment stop?

 Once a patient has been treated in our study, the endpoints—survival, recovery from respiratory failure, and whether the patient is on a ventilator or not—are collected automatically. However, enrolling people, getting the infusions done, and obtaining informed consent depends on highly trained people. If you lose them, you pause recruitment at that site until they recover.

 When we started the study, 70% of people who developed COVID-19 respiratory failure died of it, so survival was our primary endpoint. However, over the first three months of the pandemic, medical care got much more effective. Suddenly, everybody was getting anticoagulants and steroids. Ventilator use decreased, and survival rates doubled.

Our protocol was initially for COVID-19 associated acute respiratory distress syndrome, and then the Food and Drug Administration (FDA) released updated nomenclature that now everybody uses: COVID-19 with respiratory failure. That is critical because aviptadil targets the cells in the lung that make surfactant, which the lung needs to oxygenate the blood and the rest of the body. The new FDA nomenclature was ideal for our study. We were always targeting respiratory failure.

MA: What steps is NeuroRx taking to maximize operational efficiency in these clinical studies? What have you done to ensure enrollment and recruitment?

 The most crucial difference between the average pharma company and us is that we are doing the clinical operations ourselves. We used a Contract Research Organization (CRO) for the electronic data capture backbone, but we are running all the trial aspects. The study coordinators know they are not talking to some executive who is doing their study today and another study tomorrow; they are talking to us directly.

The thing probably driving enrollment more than anything is that the study staff see patients getting better. We have published X-rays with patients with this white COVID-19 lung clearing in 48 to 96 hours. The study staff has not seen that before with COVID. There is nothing health professionals want more than to see their patients get better.

 Our team is in close and continuous contact with the sites. When a site reaches out to us for something urgent, we respond, no matter if it is at night or on the weekends. COVID-19 does not pause, and neither do we. This is one element that distinguishes NeuroRx and has enabled us to progress this study so rapidly. If there are medical questions, we allow a rapid dialogue with a pulmonologist / critical care physician or a cardiologist / critical care physician, who support us in this study as consultants. 

This vital communication with the sites also helps us prepare for potential challenges, such as the recent surge of hospital admissions that required rapid provisioning of additional drug supplies or maintaining communication continuity when some employees went on furlough. 

We are very proud of having this level of trust and communication with our sites. Despite all the technology in this pandemic, the human element is critical.

MA: How did you determine site feasibility for the study?

 We had to have sites where the Intensive Care Unit (ICU) had critical care pulmonology facilities. We were looking for professionals who were double boarded in critical care and pulmonology. We wanted to be evaluating the functionality of our drug with the best possible care.

We also looked for people who have academic credibility with research experience and NIH grants. But first and foremost, we looked for outstanding clinicians with great clinical research teams, especially the coordinators; the kind of person you would want taking care of you if, God forbid, you were in an ICU with COVID.

What about choosing the location of the sites?

 We learned early on. For instance, we announced that NYU Langone would be one of our lead sites. By the time we had the study set up, the epidemic had crested in New York, and new admissions had plummeted. So, we spent much time looking at the maps and understanding where the pandemic was headed next.

MA: Have there been any challenges with drug delivery?

 Drug delivery is subject to the challenges of our times. Fortunately, due to our team's close contact with the clinical sites, we can closely track the delivery of aviptadil to the sites.

The most unfortunate circumstances occur when final approval for the participation of a site and its first patient in our Expanded Access Program (EAP) is received on a Friday afternoon, and due to the remoteness of a site, shipping services are not able to deliver the drug until Monday. This affects rural areas more, but we aim to help no matter where you are.

MA: Could you tell me about your EAP? What kind of patients can access it?

 We have treated about 150 patients in the EAP. These are patients that have comorbidities that would exclude them from the randomized control trial. If these patients get to the point where they have developed respiratory failure from COVID-19, they have an 80% mortality rate. In our EAP, we have about 75% survival. We have people whose families worry that their loved one is terminal, and the patient goes home on room air. It is very striking.

Because of your hands-on approach, you must be interacting with patients directly.

 We have become part of families in some ways. We had two sons, both physicians, drive from Arizona to Los Angeles to get the study drug for their father. The families that have been able to get their relatives into the EAP have gone to great lengths to do it.

 Having lost family friends to COVID-19, we approach patients with great empathy. Most individuals call looking for any opportunity to treat a loved one who has been in a critical stage for several weeks. The hospital has told them that they had exhausted all options, typically because they are in remote locations and not participating in clinical studies.

We direct them to information on our website for a treating physician to apply to our EAP. We have to clarify that aviptadil is in clinical studies and that the physician must make the decision. Unfortunately, for some hospitals, the process can take several days and frequently more than one week, and the condition of the patient can continue to deteriorate.

 It is undoubtedly, the most challenging clinical trial I have ever been involved in, but by far the most rewarding.

, MBA, MSF, is a thought leader and expert in the application of business analytics toward clinical trials, and Editorial Advisory Board member for and regular contributor to Applied Clinical Trials.

Articles

NeuroRx CEO, Jonathan Javitt, and Head of Operations/CCO, Robert Besthof, discuss the logistics and trial progress of their COVID-19 drug.

The Challenges of a COVID-19 Clinical Trial

2020 felt like a decade. So much change has happened in our lives, both personal and career wise, and we have forced ourselves to push the boundaries to implement novel clinical operational methodologies and technologies at breakneck speed. In February 2020, when I was 

stranded in Madrid due to the COVID lockdown, I discussed available opportunities to decentralize trials and continue operations during the pandemic

. Was my discussion spot on or way off? What has changed in 2020? How will 2021 shape up? Let’s evaluate that.

When most of the world shut down in Q1 2020, 

many clinical trials came to a grinding halt

, study sites reprioritized their efforts towards essential tasks and shuttered their doors to on-site monitors, trial patients were missing study visits, and enrollment stopped. Clinical operations personnel were left to scramble in desperation to continue operating their trials and find patchwork solutions (offering transportation to subjects, demonstrating safety procedures around COVID, and continually engaging subjects) until FDA released 

a guidance document in March on operating studies during the COVID pandemic

 describing my thoughts on advancing decentralized clinical trial implementation and offering suggestions to the clinical research community, I hoped to garner comments and provoke discussions. Many colleagues in the clinical research community noticed and expressed what they were going through, to my surprise. Personnel who work in clinical innovation functions at big biopharmaceutical companies led the discussion and pushed towards implementing proven decentralization approaches. Other researchers indicated that there was much discussion amongst their colleagues to implement decentralized trial approaches.

It was clear: the decentralized clinical trial (DCT) approach was the most viable solution to continue operating clinical trials during the pandemic.

Decentralization implementation is the new norm

Many biopharmaceutical sponsors and study sites, large and small, 

 in light of FDA’s guidance. Sponsors reworked their clinical trial operations by creating new study site procedures (i.e., direction from IRBs, sending the investigational product to the patient’s homes, amending protocols, protocol deviation documentation practices, and safety reporting), trimmed their protocols to exclude unnecessary data, and brought on new technologies and services to support decentralized approaches, such as implementing 

. The rush towards decentralized technologies is valid, as some decentralized clinical trial companies reported a 

However, some industry segments were successful in implementing DCTs, whereas others were not. Big Pharma was at a significant advantage; the 

establishing internal technology transformation processes

 drove efficient and effective DCT approaches and techniques. Some other biopharmaceutical enterprises were not so fortunate, as they have 

attempted to incorporate antiquated methodologies and processes in DCT design, which has led to subsequent quality issues

As FDA warned in its guidance, clinical trial quality issues have likely arisen during the pandemic and have yet to be uncovered. Accordingly, clinical quality professionals have gone all hands-on deck to address clinical quality issues before they transpire into more significant problems. The biggest challenge during DCT implementation is that many sites have not had any experience with DCT approaches, and poorly designed DCT workflows have exposed study sites to compliance issues. Aside from the apparent remote site monitoring implementation, quality professionals focus on a solution that enables efficient virtual study quality assessments: 

. TMF audit processes include key document reviews (KDRs) conducted regularly to ensure document completeness and structured approaches towards conducting inspections, such as TMF access management plans, storyboard templates, and appropriate training. TMF audits 

, which inform more intensive audits. Sponsors are now formulating remote auditing procedures, including site preparation and training, audit communications, and technology setup. A focus on TMF quality and the conduct of remote audits seem to be what sites should expect soon to maintain quality oversight during the pandemic.

We will surely see a vaccine in 2021; nonetheless, experiencing a new “normal” will likely become a reality around 2024. Social distancing measures will still be in place for some time, governments will need to determine policies for vaccination validation, and COVID infection rates will need to be mostly eradicated before easing up COVID prevention measures. Additionally, people need time to get over the trauma of having dealt with a pandemic, and patients’ needs and expectations are changing drastically.

For clinical trials, 2021 will bring about a new norm for sponsors. Specifically, DCT approaches will likely be a part of every study’s design, and sponsors will have to deal with uncovering compliance issues and addressing them. 2020 has put us all through a journey; I’m optimistic 2021 will bring exciting opportunities for the clinical trials industry and the world as a whole.

What has changed in 2020? How will 2021 shape up? Let’s evaluate.

Clinical Trials in 2020: A Year in Review

Many industries have benefited from workflow technology, as they are readily available in many off-the-shelf forms. However, some sponsors and many study sites still use old-fashioned methodologies, such as excel spreadsheets, trackers, and paper forms to manage the clinical trial recruitment and screening process and provide feedback on prescreen failure reasons. In this interview, Ralph Passarella, CEO and Co-Founder, and Michael Lin, Executive Chairman and Co-Founder of Reify Health, will discuss how workflow optimization technology adapts to address clinical trial recruitment issues.

Moe Alsumidaie: Why is it essential to provide recruitment workflow support to study sites?

: While $4B a year is spent on technologies that support clinical trials, relatively little of that investment is spent on solutions specifically designed to help the frontline healthcare staff coordinate research and trial-related care for patients. Without the proper tools to perform the critical tasks of recruiting and enrolling patients, sites are left to manually do this work, leading to significant inefficiencies and delays. 90% of clinical trials experience a delay, and those delays can average a month or more. Knowing the impact clinical trials have on patients in need, Reify wanted to create a platform that both sites and sponsors can leverage to address the efficiency gaps in recruitment and enrollment. The industry needed a reliable, connected platform to manage patients and trial-wide enrollment. Our technology helps clinical sites quickly track, manage, and complete patient recruitment and enrollment and streamline communication with sponsors. The technology organizes the subject journey from prescreening through enrollment and facilitates data transfer (i.e., screen fail reasons) in secure format to sponsors. This not only improves enrollment outcomes but also supports the identification of bottlenecks in recruitment and protocol optimization.

MA: What challenges have you seen in the clinical trials space over the years, and how can it improve?

 Trial timelines need to get shorter and become more predictable. As I mentioned before, 90 percent of trials face some delay. Eighty percent of all clinical trials either fail to enroll enough patients or fail to enroll patients on time. Despite all of the advances made in drug development—from precision medicine to real-world evidence—significant pieces of the pipeline remain painfully slow, especially recruitment and enrollment. 

At Reify, we believe we haven’t seen a meaningful improvement in recruitment and enrollment because we, as an industry, haven’t focused enough on solving challenges for research sites—the true engines of clinical research. The healthcare staff at these sites—research coordinators, nurses, investigators, etc.—are responsible for an immense amount of work identifying, reaching out to, educating, managing, and caring for the patients engaging in clinical research. Yet, historically, this group has been forced to rely on antiquated and manual processes and tools to do that work.

By focusing on the workflows of research site staff, we built a platform that substantially reduces their workload 

 provides sponsors with the information they could not previously access. This approach—starting from the site staff workflow and connecting it to sponsors—is how we’re driving faster (6 weeks faster than plan, on average) and more efficient (16% more patients per month per site) enrollment for half of the top-20 global biopharmaceutical companies. 

MA: How has the current environment impacted the clinical trials space and your approach?

 The COVID pandemic is (1) drawing more attention and scrutiny from the public with regards to the efficiency and speed of trials; (2) pushing the industry to adopt new ways of working to accelerate COVID vaccine and therapeutic development; and (3) forcing the industry to develop new processes to run non-COVID trials safely during a pandemic.

On the first point, Reify is built on the idea that there are parts of the clinical trial process that can run substantially faster—namely, recruitment and enrollment—while not sacrificing safety and efficacy. If we invest heavily in those pressure points, as we are, we can get safe and effective therapies to patients faster.

On the latter points, we’ve also seen some incredible work being done by sites and sponsors to build entirely new approaches to running clinical trials for COVID, such as fully mobile clinical trials wherein a site can be deployed and set up anywhere in the country within 48 hours. This work’s immense complexity makes the traditional paper-based approaches to connecting and engaging with patients a non-starter. Instead, StudyTeam is being used in such trials to digitize, simplify, and accelerate the process.

MA: How could a solution like this work for sites? How about sponsors?

 For sites, we’ve replaced paper or Excel-based tools with a cloud-based solution that’s built around their workflows. Additionally—and this is critical—StudyTeam for Sites is not another place for sites to log in and input recruitment and enrollment information for a sponsor; it 

 those systems with one platform for managing recruitment workflows that can also communicate with all of their sponsors securely and in real-time. 

For sponsors, they can view the real-time insights and gain valuable recruitment and enrollment insights they have always struggled to access. This allows them to see enrollment trends across the entire trial and make rapid decisions that drive more efficient enrollment. For example, they’re able to see which inclusion and exclusion criteria cause the most prescreen and screen failures to inform consideration for protocol amendment. We are connecting sponsors and CROs to the workflow of their research site partners around the world.

Finally, and perhaps most importantly, sites can automatically share recruitment progress with sponsors through StudyTeam, virtually eliminating the need for sponsors to ask every site for recruitment updates every week. Sites using StudyTeam spend significantly less time documenting and sharing information with their sponsor and CRO partners and more time recruiting and enrolling patients.

MA: Where do you see the clinical trials space evolving a few years down the line?

 With the increased attention the clinical trials space has received in the last year, there’s a genuine possibility we see significant progress in the next few years. One area we’re particularly bullish about is the idea that research can operate more like a functioning ecosystem where each stakeholder group is equally aware of and invested in participation. 

Most patients today are either unaware of clinical research as a treatment option, don’t know how to get involved, or are hesitant to participate. On the flip side, many physicians and providers want to join the clinical research community but are turned off by its perceived complexity, startup costs, etc. By connecting and empowering these stakeholders with information, tools, and other resources, we see clinical research becoming a more commonplace treatment option in the broader healthcare system.

Ralph Passarella, CEO and Co-Founder, and Michael Lin, Executive Chairman and Co-Founder of Reify Health, discusses how workflow optimization technology adapts to address clinical trial recruitment issues.

Workflow Optimization Moves to Clinical Trials

Many biopharmaceutical enterprises who have invested in clinical innovation pilots before the COVID-19 pandemic have now benefited—not from the innovative technologies themselves, but rather from the processes they have established to evaluate and implement novel solutions rapidly during the pandemic. This is especially the case in larger biopharmaceutical enterprises, such as Novartis, that have established a culture of innovation. In this interview, Craig Serra, who works in Clinical Technology and Innovation at Novartis, will discuss his perspectives on clinical innovation implementation during COVID.

Moe Alsumidaie: We’ve seen many challenges with COVID throughout the industry. Was Novartis prepared to address these challenges? If so, how?

 Unequivocally yes, and I think there were two main places that we were prepared. First, organizationally and culturally. As this once-in-a-half-century event came avalanching at us, I saw all levels of leadership enabling us to focus on being safe and to take care of ourselves, family, and each other. This has been a continual message to make sure we stay focused on that. Since that culture already existed, it appears effortless, which is just truly remarkable. Second, from that position of strength and safety, we were able to stay sharp on running clinical trials. One of the earliest actions was an extremely robust and comprehensive risk assessment of the entire portfolio, with support and leadership from a central cross-functional team made up of tremendously smart and dedicated colleagues. Based on that assessment, strategies and tactics were reviewed and changed where needed, and those could be related to areas like process, technology, and resourcing. We have enacted mitigation plans where needed to protect the integrity of our trials and ensure continuity of treatment and trial integrity.

From a trial monitoring perspective, this has included collaborating differently with the clinicians who conduct our trials, as well as with regulatory bodies. This has enabled our CRAs to undertake a number of activities remotely that traditionally would only be conducted at clinics and hospitals, such as remote monitoring and remote consent. We are successfully minimizing impact by enabling direct-to-patient medication delivery supported by home nursing services and virtual safety assessments. We remain confident in the advancement of our pipeline and at this time, the impact on our ongoing clinical trials is manageable. Essentially, having the right culture was 

 driver of solving problems rapidly across one of the industry’s broadest portfolios, and it was accomplished with grace and elegance in the face of such a tremendous challenge.

MA: As an innovation leader, how do the investments in innovation impact clinical operations’ adaptability and speed? For example, did you use any technologies you’ve vetted before during pilots and implemented during COVID? And if so, what were those technologies?

 This is another area of strength stemming from our culture. There is a tremendous organizational investment of time, money, resources, and effort into innovation. We often think of innovation from a technology point of view, but there is much more to it. You can innovate and disrupt in areas like process, methodology, partnering, standards, and mindset. It is about investing in the destination. Of course, we pilot and test out new capabilities and technologies related to all sorts of buzzwordy things, but it was our decision-making process that was the real innovation. We had very thoughtful but rapid decisions being made with equally fast execution. To quote Apollo 13 astronaut Jim Lovell when talking about the Apollo 11 moon landing: “It’s not a miracle - we just decided to go.” Our significant investment in technology and digital solutions has helped us to support our drug development activities during this unprecedented time. For example, we are utilizing the SENSE digital technology implemented in 2018 that allows us to track, in real time, all of our clinical trials (500+) in more than 70 countries at the level of individual patients and shift to contingency plans rapidly as the situation evolves. We’ve also developed and deployed predictive surveillance tools that give teams the ability to proactively and dynamically manage current and future waves to minimize impact of COVID-19-related disruptions. 

MA: The culture in ClinOps tends to be conservative; they tend to not want to take any added risks in their studies, and the existing process already works. How has that changed during deployment and after COVID?

 There’s this surrealness to the world right now, and the evidence that I see is that a lot of excess risk aversion has been shelved. There continues to be unwavering executive leadership support and an ability to go for it, whatever the “it” happens to be for any given person. I think that will continue to be baked into the fabric of an already progressive organization. I am talking about achievements like clinical database builds in two days and protocols being finalized in a week. We know that isn’t sustainable, but we see what is achievable, and that is key. I like to use a physics analogy. Momentum is mass times velocity. Mass is the sheer amount of matter, and velocity is the rate at which a position of something changes. We have this enormous mass of an industry, and even if the rate of us moving forward slows down, the net effect is still forward momentum for an entire industry.

MA: Could you tell me a bit about how the innovation paradigm has changed? People used to call eConsenting pilots innovation, decentralization innovation. What becomes that new definition of innovation after COVID?

 I often refer to an imaginary bar that we need to get over for something to be innovative or a continuum related to incremental vs. disruptive innovation. However, the more I have thought of it, the less interested I’ve become in a label. The perception of what is “innovative” ranges from what most would consider process improvement to quantum computing level innovation with a Grand Canyon-sized bucket of stuff in between. We inherently want to solve problems and deliver value, which has to be at the cellular level of an organization. Of course, I tend to go to a big pharma thinking way regarding having infrastructure and resources available. Small companies and those trying to solely deliver their core products or services experience much more difficulty in implementing innovation if it isn’t already in their corporate DNA, as there are only so many hours in the day. The solution to that is inter and intra industry collaboration, and the shift is seeing that in big bold letters on the marquee. I am witness to the sharing of knowledge and de-siloing happening exponentially. And while there is obvious “foot-in-the-door” and advertising value for service and technology providers offering solutions for free, they need to be thanked for doing so and inherently helping in a paradigm shift.

MA: How will the business process for running pilots change after COVID?

 I sure hope it doesn’t remain the same! Of course, this is now part of our program, where I lose some friends. The depth and breadth of our industry’s development world is truly astounding, but anyone that’s been to a doctor in the last few years sees that we are still held hostage by the magical fax machine. Most of the time, it seems like Guttenberg himself made a Faustian bargain with the healthcare industry. With that and the myriad of stakeholders to consider as table stakes, I think the way we approach “innovation realization” will change relative to a couple of core aspects. First, everyone talks about “failing fast,” but that ends up being worthless (literally, worth less) if we take two years to decide to try. Let’s borrow from our pandemic learnings and make rapid, thoughtful decisions on what we want to do, including funding those ideas.

From there, we can at least get substantial experience with whatever it is we are interested in, specifically for novel and ultra-transformative ideas—sort of like an “innovation idea internship,” which I just made up now. The second change is closely related to that, with this almost inherent need for pilots and proof of concepts (which I am as guilty of as anyone), often for ideas that aren’t that groundbreaking. If we wanted to implement MS Office, we wouldn’t pilot it, would we? So why pilot something like eConsent? We know enough about its value, what regulators think of it, what patients think of it, and so on. I would urge just going for it or not going for it, but why pretend it’s a Falcon 9 launch? Of course, going for it still includes a comprehensive project deploying the solution at scale, with all the bells and whistles of PMBOK-worthy project management. We owe it to patients to go for it. We can’t wait for the last dance to have our first dance, and anyone that’s been in middle school understands what I mean.

Read more about Craig Serra’s role in pharma, 

Craig Serra, who works in Clinical Technology and Innovation at Novartis, discusses  his perspectives on clinical innovation implementation during COVID.

Moe Alsumidaie

Articles

The Challenges of a COVID-19 Clinical Trial

Clinical Trials in 2020: A Year in Review

Workflow Optimization Moves to Clinical Trials

How Novartis Overcame COVID Through Clinical Innovation