Moe Alsumidaie

Regeneron’s monoclonal antibody therapy was one of the first therapies to enter the market to treat COVID-19. The treatment was used early in the pandemic and received 

emergency use authorization by the FDA in November 2020

. Many in the industry have been curious about how Regeneron rapidly and successfully developed a therapy to treat COVID-19. In this interview, Bari Kowal, Senior Vice President, Head Development Operations & Portfolio Management at Regeneron, will discuss her experiences.

Moe Alsumidaie: Among the many obstacles faced when executing clinical trials under such urgent circumstances, what was the most challenging from a clinical development perspective, and how did Regeneron overcome it?

 The sense of urgency required to manage clinical trials amidst a pandemic is something we’re used to at Regeneron. Our response was to ensure we were resourcing appropriately to tackle what lay ahead of us. Early in the pandemic (Q1 2020), we began to think about three things: what kind of antibody cocktail we needed to develop, how we were going to plan in a matter of days—not weeks or months—and finally, how were we going to conduct the studies and execute them efficiently. It was groundbreaking to develop an antibody cocktail that quickly. There was a shared sense of determination across the company to complete the analysis to get it from a concept to an Emergency Use Authorization (EUA) approved therapy.

MA: Regeneron’s monoclonal antibody therapy was pushed through quickly. What was that experience like when it came to getting that therapy through trials and out to patients in such a short time frame?

 Our company commitment to doing the right thing, our decision-making process, and our experience creating innovative technologies enabled the process to happen quickly. Early in the pandemic, we did some work on our IL-6 receptor antibody, sarilumab, which we thought could be a potential COVID-19 treatment. Although we didn’t see efficacy there, we ran those trials swiftly, which gave us a strong foundation for the monoclonal antibody cocktail. We also presented our results from the monoclonal antibody trial to the FDA, other regulatory agencies, and physicians. All parties had the necessary confidence in the safety and efficacy of our therapy and that this would be a viable treatment for patients. It was fascinating to see how we could positively impact the globe with treatment options for COVID-19. 

MA:Tell me about how you upheld Regeneron’s scientific values when the globe was desperate for vaccines and therapies.

 Scientific rigor is at the heart of what we do. Our tagline is “Science to Medicine.” We adapt rapidly, even in a remote environment. Every time I’m asked how we did this so fast, I note we didn’t have to change how we went about doing things. We were already taking thoughtful action when we needed to, and we’ve always adapted rather nimbly to evolving situations and new data. So, while the speed and demand during the pandemic were like nothing we’d ever come across, we were able to pivot based on our demonstrated ability to remain flexible. Of course, one crucial element to our success is that Regeneron has built an unprecedented end-to-end suite of proprietary technologies for drug discovery, development, and manufacturing that has been used to develop transformational medicines over the last three decades for several different diseases, including COVID-19.

I don’t know many other companies that have instituted such a rigorous and robust program for COVID-19. Ultimately, we felt it was essential to have the necessary data to be confident in the therapy we developed.

MA: How did you keep your non COVID-19 pipelines moving forward during the ongoing pandemic?

: Managing our pipeline during the pandemic was undoubtedly not an easy task. Some colleagues and I were reminiscing about our work in January 2020. At that time, my team put together an impact assessment given our early knowledge of COVID-19 appearing in several countries outside the US. We could not have predicted what was coming, but we felt prudent to plan for the best- and worst-case scenarios proactively. We started by looking at our drug depot locations and whether they were affected before COVID-19 impacted the US. We acted on then-current data to plan for additional supplies for our existing trials. 

This ability to assess and direct the situation early was how we limited the effect on our portfolio at large. Some of our studies had to pause at specific sites with some countries on lockdown, but where we could keep going, we kept going. Ultimately, we began employing some of the decentralized tactics that aren’t necessarily new but weren’t utilized on an ongoing and consistent basis. For example, as we look at home health, you can do a fair amount to treat patients remotely with a home nurse—such as drawing blood and virological sampling. We also used telemedicine when patients could not visit our sites and asked patients to record their symptoms using their own electronic devices. I’m grateful to say the impact on our pipeline has been limited during this pandemic, and I indeed attribute that towards the planning that we did to prepare ourselves.

MA: Professionals in clinical operations tend to be very conservative about running their trials and want things to be done the traditional way. And you keep mentioning that Regeneron has an innovative culture, but I’m sure there are always naysayers out there. How has this challenge essentially changed the perspectives around implementing novel decentralized approaches in clinical trials?

: I think this is a turning point for our industry and clinical trials. I have seen the industry as a whole recognize how we have progressed our trials at a speed that we hadn’t in the past. Regeneron intends to take advantage of the lessons learned from this past year. With that being said, I don’t expect us to constantly be moving at the speed of the pandemic in the future. I think that’s unreasonable for a standard trial, but I know we can take away key learnings on how to plan and conduct tests faster and be nimbler as an industry, not just at Regeneron.

There are limitations to our innovation from a regulatory standpoint. There are regulations and guidelines that we must follow. As a leader of our clinical trial execution at Regeneron, I have spent much time this year thinking about how we can make development more innovative. For example, we’ve developed novel digital endpoints using wearables to get information for our trials, which we hadn’t in the past. We’re using insoles to predict gait and falls in some of our skeletal muscle trials. We’re also conducting pulse wave analysis to predict heart failure. These are technologies that we hadn’t been looking at as much in the past that we’re starting to look at now to get more real-time data.Through the pandemic, it’s become apparent there are easier, less costly, and more patient-centric ways to execute a trial.

MA:What will drug development look like in the post-pandemic world?

 We’ve internalized more of our trials and assessed whether our operating model could adapt in ways that will enable speed and cost-efficiency. For example, we developed a role to focus specifically on innovation, which we didn’t have before. While we’ve had pockets of innovation roles in our patient and digital endpoint groups, this role will coordinate across all of global development and look at how we utilize the various aspects of innovation—whether that’s happened in our systems group or even within the Regeneron Genetics Center, to benefit the system as a whole. We’ve also hired those who specialize in operational analytics within clinical development. These data scientists are reviewing operational data, not just our clinical data, to extensively benefit our modernization of clinical trial work.

It’s through that lens that I’ve been thinking about our work. What are the roles, and who are the right people to carry the future of Regeneron? We thought a lot about what the clinical research associate of the future looks like. I believe remote monitoring is taking place, and analyzing data in ways that we haven’t been able to before is within our immediate future. This new, transparent digital data flow hasn’t been perfected yet, but we’re certainly on our way.

, 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

Bari Kowal, Senior Vice President, Head Development Operations & Portfolio Management at Regeneron, discusses her experiences about how Regeneron rapidly and successfully developed a therapy to treat COVID-19. 

Inside Regeneron’s Monocolonal Antibody Development

The pandemic has dramatically impacted many aspects of clinical trials, ranging from operations to recruitment/retention to clinical trial public perception and technology. In this interview, Lan Fong, Founder and Principal Consultant at Avery Biopharma Consulting and Venture Partner at Congress Avenue Ventures, discusses her perspective on how the pandemic is shifting the clinical trials industry.

MA: How has the pandemic impacted COVID versus non-COVID trials?

 The impact on non-COVID trials was prominent because they have been deprioritized within the clinical trials industry, and the priority has shifted towards COVID-related trials. For non-COVID-related trials at sites, it has been challenging to execute protocols with traditional methodologies in an environment experiencing many disruptions. For example, sites had to have COVID testing measures and protocols in place, limiting patient visit capacity and volume at sites. Sites have had to re-adjust their staff schedules and face the need to ensure enough social distancing procedures if a patient comes in for less than 30 minutes for a quick blood draw or a short assessment. There also have been impacts on patient retention; for instance, if a trial is being executed in a large city, such as Boston or New York, most patients who commonly use public transit did not want to continue using that mode of transportation, henceforth, missing study visits or dropping out of the study altogether. As a result, there have been many COVID-related protocol deviations. Regulators have also issued new guidance around COVID-related disruptions to clinical trials, and as a result, CROs have defined a new category of COVID-related protocol deviations to capture them as a separate category in the clinical study report.

COVID-trials have been just as challenging to execute during the pandemic. COVID studies are pressed against aggressive timelines and face delays in site activation, manufacturing delays, and supply chain issues. There are also investigational product stability and logistical issues, such as monitoring expirations and ensuring stability at specific time points while operating in a tumultuous and rapidly changing environment, as there were shutdowns and delays in transportation. Even though clinical research centers prioritized COVID-related protocols, there were also site activation and IRB approval delays as much of the work had to shift to being conducted virtually when previously the sites, IRBs, and vendors were not necessarily set up to do so.

MA: How have the disruptions impacted minority group participation in clinical research?

 Recruiting minorities has always been incredibly challenging, even before COVID; reaching out to diverse groups has inherently been difficult because, despite FDA mandates for minority inclusion in clinical trials, there has always been less willingness for minorities to participate. Throwing in pandemic challenges has not only hurt overall study recruitment but, recruitment especially for minorities. For example, in larger cities, patients could quickly attend clinical trial visits via public transit. However, since few patients want to take public transit, they don’t have the means to afford different and less risky transportation options (i.e., Uber, Lyft). There has been a massive increase in recruitment and retention budgets from sponsors to support patient transportation and recruitment. It’s a tough decision for a sponsor because, sometimes, if sponsors have poor recruitment/retention strategies or are trying to learn how to recruit a particular patient population in their trial, they will not yield a good return on their recruitment/retention budget investment (ROI). Then you throw the challenges of being in a pandemic, and that decreases the ROI. So, sponsors have had to take a hard look at their enrollment projections and their statistical analysis plans to see if they can reduce the number of subjects needed to evaluate the study’s endpoints. Sponsors have also conducted early data cuts and interim analyses to see if they can uncover early signals.

MA: How has the pandemic impacted public perception of clinical trials?

 With the pandemic and the development of the COVID vaccines, I believe people have come to appreciate the need for clinical trials, and it has put this clinical research front and center. Before the pandemic, clinical trials were not something many people thought about, so I’m glad that it has raised awareness and emphasized the importance of clinical research and the need for clinical trials. Additionally, people now understand the importance of drug development and how badly we need to increase the speed at which new treatments are developed. Vaccine development has been accelerated, timelines have been shortened to address the critical need, and some traditional drug development barriers have been broken due to emergency protocols used to accelerate COVID vaccine development. It has also been a delicate balance between government and industry to establish trust and rigor in science; to successfully accelerate drug development without compromising subjects’ safety is challenging. Despite that, I believe people now understand what’s so essential about clinical trials and hopefully support those efforts.

MA: How many ways exist to execute decentralized clinical trials?

 The adoption of decentralized strategies has been discussed a lot, and I’ve seen two different ways of approaching it. First, many clinical trials center around major medical institutions that have been doing clinical research for a long time. I’ve seen integrated research organizations (IROs) making naive research sites into clinical trial sites by supplementing them with clinical research staffing, such as traveling CRAs and CRCs. The IROs implement their own SOPs at the sites and provide data entry, quality management, recruitment, and staff support to sites to operate studies and conduct visits at patients’ homes. Second, some companies are working on digital solutions, such as electronic consent, electronic clinical outcomes assessments (eCOAs), and electronic patient-reported outcomes (ePROs). Other solutions are moving away from paper and onto electronic modes of data collection, or eSource. Additionally, there is a sudden shift in patient support solutions for recruitment and retention. For example, some companies are providing transportation services or conducting mobile nursing/ phlebotomy. While these platforms have existed for some time, never has there been more need for more digital solutions that can integrate seamlessly with existing systems and databases. 

Another interesting trend I’ve seen includes integration strategies and capabilities into CROs, which have provided exposure and growth opportunities for companies specializing in decentralization. Some of these companies have acquired smaller companies that were building these capabilities and are in the process of integrating with their existing platforms. The goal is to make it a seamless and more familiar platform for sponsors to bring those capabilities onto their trials since the CROs have already vetted and conducted due diligence on these companies. However, the execution and actual integration can be challenging.

MA: What other areas from sponsors have arisen as a result of decentralization?

: Remote monitoring and risk-based monitoring have been hot topics for a long time. In the past few years, there’s been much debate around whether you need to do 100% source data verification or if the monitoring plan can be centered around critical variables. Sponsors and CROs also have to decide between on-site monitoring, remote monitoring, or partial remote monitoring, depending on the ease in which the CROs, vendors, and sites can use a fully secure, Part 11 compliant source data platform. Despite this topic being discussed for many years, many sponsors are hesitant to move away from 100% source data verification, and many vendors are not equipped to perform remote monitoring. While every piece of clinical trial data is essential, the necessity of source data verification on every data entry also depends on whether the case report forms were created thoughtfully and intentionally, without unnecessary data fields. While the industry has been slow to move away from traditional methods, it is now more critical than ever to adopt innovative solutions to execute clinical trials in modern times, especially amid a pandemic.

Lan Fong, Founder and Principal Consultant at Avery Biopharma Consulting and Venture Partner at Congress Avenue Ventures, discusses her perspective on how the pandemic is shifting the clinical trials industry.

Pandemic Impact on Trials, Public Perception, and Decentralization

Clinical operations personnel are known to exercise rigidity in their operating models and are resistant to change. However, the COVID pandemic has forced many to expand their perspectives to operate in this new environment. In this interview, Dr. Peter St. Wecker, Director of Clinical Process Improvement & Innovation at Zogenix, will offer a unique perspective on clinical studies operations challenges and changes that sponsors and sites underwent during the pandemic.

Moe Alsumidaie: I hear that there is a decline in new trials started in 2020. What factors are contributing to that?

 The decline in new trial starts last year came from a multitude of places. COVID has had a significant impact on companies’ decisions about whether it was the right time to start new trials. Sites, for example, experienced limited or decreased staff availability. For us, the challenge of getting in touch with sites and were able or ready, with the demands of COVID, to start a new trial. Additionally, with the changing landscape in regulations, sponsors have been figuring out how to navigate new regulations, which may also be contributing to their readiness to start new trials.

Naturally, we had to deal with the initial shock of being in a pandemic, and adjust to the way we work nowadays, being fully remote. The initial challenge was how to keep studies operational while being completely remote; for example, when we’re not able to visit sites and patients cannot go in for their study visits. The clinical trials industry is understandably resistant to change and embracing new technologies and innovative methods for operating studies until they are well proven and scalable. For instance, even though niche vendors exist and offer remarkable technologies to advance decentralization and remote access to sites, it was not easy to scale across study teams.

When companies boast about their success stories of implementing decentralized clinical trials, I think that’s been the exception to the rule. The reality is that we’ve used our existing systems to deal with patient access, site access, and team access; we had to uproot all of that and change our processes from the ground up. Not to mention the challenges of convincing and training clinical operations personnel to execute studies using those new processes in a brief timeframe. After we restructured our clinical trial operating models to support decentralization, such as conducting telemedicine visits, delivering investigational medications to patients’ homes, and collecting data through electronic means, such as electronic patient-reported outcomes (ePROs), that’s when we started to see progress in trials continuing successfully.

MA: What would you say was the most exciting innovation that you’ve seen emerge from this pandemic?

 The most exciting innovation I’ve seen is how rapidly regulators addressed needed changes in clinical operations during the pandemic and sponsors’ quick response to change how they operate trials during the pandemic. As an industry, these recommendations were valuable, as we could leverage the regulators’ recommendations to allow for studies to go on. That partnership with sponsors and how they’ve made those adjustments quickly, given how slow we’ve seen some changes occur in the past, has been great. I also found that the ability of clinical operations personnel to rise to the challenge and exercise their impressive creativity and brainpower to find novel solutions and operating practices was mind-blowing.

MA: What was it like to transition the organization into a remote working model?

At Zogenix, we were well prepared, as we invested in a robust internal IT infrastructure, which supported an easier transition to remote access for all of our employees. It is essential to trust employees to achieve the study’s deliverables and milestones by the defined timelines, despite the challenges that come with working from home. From what I’ve seen, we’ve been successful in our transition, and we have embraced remote work as a part of our lives and culture.

MA: Have there been any changes in SOPs to support these new changes?

 Before the pandemic, my experience was that many sponsors would never allow CROs to conduct remote monitoring of study sites and would have SOPs specifically prohibiting such practices. Now the SOPs have changed to support remote monitoring, specifying the need for remote access to EMR systems and other source data. Other areas where SOPs have changed involve shipping investigational medication directly to the patients’ homes and allowing for study visits to be conducted remotely.

MA: How have study sites responded to these novel remote procedures?

 Like everyone else, I think sites have been challenged with staff working remotely and figuring out how to address resource challenges. Sites were overwhelmed and put under much pressure by all sponsor companies, suddenly coming up with new processes and changing their procedures for running studies during the pandemic. Not only that, but each sponsor company was also operating their trials differently, so sites have expressed concerns that they were receiving calls from multiple people and companies wanting to do things differently.

Then there were institutional changes that site staff had to deal with, such as resource allocation and creating processes to enable remote access to their EMR and other source data systems while maintaining high patient protection and privacy levels. Despite these challenges, sites have been innovative and have been working fast to give sponsors access to their electronic systems to support remote monitoring while maintaining the protections and the well-being of patients, monitors, and site staff. This was a remarkable feat that sites have achieved to adapt to this new environment.

MA: What has this pandemic done to the clinical trials industry?

 What comes out of all this is a real positive change in the industry, the collaboration between parties, and sharing pre-competitive information to overcome hurdles. There have been many great discussions, webinars, and virtual conferences where sponsors, sites, CROs, and others have shared their ideas for how to best overcome these challenges. And we’ve all, in many ways, come together to help each other. We can still be competitive but can accomplish a lot more as an industry by working together for the good of the patients. We can always be good corporate citizens for our shareholders, our patients, and healthcare while still sharing best practices that we can all use to run studies and get new medicines developed in these challenging times.

Dr. Peter St. Wecker, Director of Clinical Process Improvement & Innovation at Zogenix, offers his unique perspective on challenges and changes that sponsors and sites underwent during the COVID-19 pandemic.

Biopharmaceutical Clinical Studies Operations Changes During Pandemic

It is no surprise that the COVID pandemic severely disrupted operations in many industries, including clinical trials. Some personnel had thought clinical trials were booming during the pandemic era. However, data from 

 shows a 38% drop in new clinical trials started in 2020, as illustrated in 

Figure 1: New Clinical Trials Started by Year

This trend infiltrates all disease indications, including immunology. While there are apparent reasons why new clinical trials dropped in 2020, I wanted to know if I was missing anything. This sent me on a hunt for information, and I’ve discovered interesting trends, which I will share with you in this article—both apparent and not-so-apparent.

The most common trend discussed amongst executives was study site impact and lack of resource availability for clinical trials. Specifically, study sites, especially medical research institutions, focused most efforts on managing COVID patients and implementing new processes to comply with local COVID regulations to maintain patient care and safety. Additionally, the focus of many research initiatives at sites turned to therapies focusing on COVID, causing delays in study site selection, startup, and approval. “Most institutions have been impacted not just operationally to bring in subjects to execute studies, but also in staffing and moving through their internal challenges to operate trials unless the study is directly related to COVID treatment or vaccines. In my own experience—working on trials, not COVID related—it is possible to keep things moving—but with a lot more hurdles,” said Jeff Harris, MD, PhD, Senior Medical Director at Denali Therapeutics.

Testing risk tolerance levels in biopharma

Another interesting trend appears to be changing risk tolerance levels from biopharmaceutical executives in launching new studies. To elaborate, biopharmaceutical companies have had to evaluate their portfolios and focus resources on saving existing studies rather than launching new studies, which could have caused a reduction in new studies started. “During this time of unknowns, companies shifted their near-term strategies and mindsets into salvage mode—focusing resources on saving active and top priority studies, and as a consequence, delaying starting new trials,” said Steve Shevel, Vice President Operations, Clinical Development, and Quality at Hawthorne Effect, Inc. Other risks include sponsors exhibiting fear of patient safety and liability issues regarding COVID infections. “One of the major challenges I saw was around ensuring patient safety and evaluating liability during the pandemic. Of course, we don’t want to put patients in danger by requiring them to attend study visits at sites that were not prepared to employ local recommendations for social distancing and PPE to protect patients from contracting COVID,” said Glenn Morrison, Vice President, Neurology Clinical Development at Alector. “We had to conduct study site reviews to ensure they have the necessary SOPs and COVID prevention processes to protect patients,” added Morrison.

One of the challenges is supply chain-related disruptions. For example, supplies used to manufacture investigational product and lab kit availability were disrupted, halting new trials and causing delays in ongoing trials. “We saw supply chain issues, especially from the labs, focusing much of their efforts on COVID testing and providing supplies for COVID. This resulted in supply chain issues from materials to lab kits,” said Glenn Morison of Alector. “We have seen impacts on biologic manufacturing, where resources and supplies were focused on COVID needs, which resulted in delays of new trial material availability,” indicated Adriana Manzi, Managing Director at Atheln Inc.

Since COVID became an issue, regulators focused on guiding the industry to operate their active trials during COVID and advance COVID therapies. The shift in priorities caused delays and slower response times, which could have also contributed to reducing new trials. Steve Shevel of Hawthorne Effect indicated, “the FDA refocused its resources towards emergency use authorization (EUA) diagnostics and treatments for COVID. Any new trials that did not have a focus on COVID would not get looked at by the FDA, so companies started backing off from launching new trials.”

Suppose anything good came out of the pandemic. In that case, it is the fact that investments are pouring into biopharmaceuticals, and investors are taking more risk, which will not only likely result in a surge in new clinical trials started over the next several years but also advance science and new medicines to new and unprecedented levels. “I observed more investments in the preclinical space. We went through this cycle where there would normally be an investment in companies that had already de-risked the issues that might emerge in the development process, so they were focusing on companies with late-stage assets. We are seeing a renewed interest in investing into bacterial and viral research, and a carry-over effect is a renewed interest by investors into companies that work on drugs to treat infectious diseases,” said Pamela D. Garzone, Chief Medical Officer at Calibr, a division of Scripps Research, Inc.

Another good outcome of the pandemic is that it has fast-forwarded the use of decentralized clinical trial technologies; the use of such technologies was slowly gaining ground; however, they are now front and center in clinical trial adoption and investor interest. For example, THREAD research recently secured $50M in funding

 “The unforeseen benefits of the pandemic include driving clinical trial execution into the 21stcentury. Using digital tools and employing virtual study design are allowing patients to participate in their own homes. These approaches will benefit clinical trials in the future, as they make our studies more resilient,” added Glenn Morrison of Alector.

The pandemic has disrupted the world, and clinical trials were not excluded, as indicated by the drop in new trials started, and issues including study sites, lowered risk tolerance levels by biopharmaceutical companies, supply chain disruptions, and shifts in regulatory priorities. However, disruptions tend to be associated with new opportunities, and current opportunities include increasing risk acceptability by investors into earlier-stage biopharmaceutical companies and migration into digital and virtual solutions to clinical trial conduct.

https://www.wsj.com/articles/water-street-and-jll-partners-add-50-million-to-thread-commitments-11597273200?tpl=privateequity

https://techcrunch.com/2020/11/19/medable-raises-91-million-for-its-clinical-trial-management-software/

Though the industry was expected to boom with new studies—data shows a significant drop in the amount of new trials started in 2020

Moe Alsumidaie

Articles

Inside Regeneron’s Monocolonal Antibody Development

Pandemic Impact on Trials, Public Perception, and Decentralization

Biopharmaceutical Clinical Studies Operations Changes During Pandemic

2020 Experienced 38% Drop in New Trials