Moe Alsumidaie

It is clear that the COVID-19 pandemic has changed the clinical trial paradigm. However, some companies have implemented a culture of innovation and have invested heavily in piloting novel technologies before the pandemic, which mitigated pandemic-related risks. In this interview, Disa Lee Choun, Head of Innovation at UCB, will discuss how the company has fostered a culture of innovation, and how the investment in piloting has benefitted clinical operational implementation during the pandemic.

Moe Alsumidaie: What challenges and impacts has COVID-19 had on clinical trials at UCB?

There were many challenges. One immediate challenge was the effect on clinical trial recruitment. This led to a temporary halt in our ongoing clinical studies and delayed the start of new studies. These actions were taken into consideration for patients and public health safety. Other challenges were that some sites were closed to patients, especially for ongoing studies. Also, sites were closed to site monitoring visits due to the local restrictions and lockdowns. For the participants, the concern was how they can continue to receive the treatments, how we can continue to collect the assessments, and how the investigating physicians continue to monitor their safety. Other considerations were around, for example, understanding and applying the new guidance from the regulatory agencies issued during this pandemic from FDA, EMA, and others. We were also investigating applying solutions we were piloting through our digital transformation initiatives to be deployed rapidly to minimize the impact on these ongoing clinical trials and to continue to ensure the patients’ safety and wellbeing.

MA: How did you overcome these challenges?

Within UCB, a team worked on contingency plans. It was a great collaboration from various experts to ensure that solutions and options were provided to ongoing and new studies. For example, one solution we implemented included direct-to-patient investigational drug shipments, which allowed patients to receive treatments at home. Usually, these activities would be done at the site. Also, a specific team was formed, led by me, focusing on supporting fundamental studies and identifying critical issues and prioritizing those and providing innovative solutions from, for example, telemedicine, remote assessments, wearables, devices, remote SDV/SDR (Source Data Verification/Source Data Review), with the intent to roll out to any studies that might need or require those solutions.

It was a great effort and coordination with various stakeholders and experts in the field. The positive side is that many of these solutions were already underway, and some were deployed in our clinical trials as part of our digital transformation. Any unforeseen issues were addressed by exploring with vendors, scouting the market, and finding specific solutions. We did our due diligence and qualified new providers in a short time, thanks to our established feasibility process during the piloting phase. Now, these solutions are available for the studies to use.

Another solution we looked at is the remote SDV/SDR. Although it is not part of my team’s scope, we started to look at how we can do this remotely. This activity is usually conducted at the site by the site monitor. Due to the pandemic, many of the regulatory agencies have now allowed this to be performed remotely. We started to investigate with our providers how we can deploy this as it is a critical activity, especially when we need to complete a database lock, and verify and clean the data.

Some of the challenges are applying the solution in mid-study. Although it sounds simple, we have many considerations, such as regulatory acceptance. A lot of our clinical trials are global studies, so we need to understand each country’s regulation and also to assess any changes to the protocol, updates on informed consent forms, changes to the risk management plan and the monitoring plan, changes on the way the data has been collected, stored, and even analyzed. This is all critical because we’re changing from the traditional way to a remote method; we need to ensure everything is documented correctly and assess the risks. With this contingency plan, we can minimize the impact on sites and participants during this pandemic. Also, it will support future situations like this, including natural disasters.

I want to highlight that studies that were not affected significantly by this lockdown are studies that already implemented full decentralized clinical trial (DCT) solutions. They have telemedicine solutions, including remote assessments.

MA: How did you leverage existing processes in piloting to implement DCTs?

As part of UCB’s digital business transformation, we have already been exploring and piloting different solutions to bring trials to patients’ homes. It includes DCT components like telemedicine. With this pandemic, the sites needed support to continue to monitor patients’ safety. This is where we looked at the current vendors and any enhancements they made on their solution. One example was a vendor who provided a way to capture the electronic patient-reported outcome (ePRO) at the site. We worked on the solution to provide this to be web-based so participants can complete it at home.

We also worked to allow assessments to be collected using the interviewer mode, where the investigator can connect with the participants to have them complete the assessments via a phone visit or televisit (videoconference), rather than them going into the site. We started to pilot these two solutions (ePRO and televisit) in two studies and then roll this out for the others. Having invested in piloting DCT models, we were able to efficiently implement them during the COVID crisis. 

MA: How has the pandemic changed the culture of innovation at UCB?

Our Development Solutions team has been undergoing a technology transformation implementation for the past several years. The silver lining of the pandemic is that it has accelerated implementing innovation in general and in DCT. Either the full version, the entire virtual, or the hybrid model, we call it the virtual sites or virtual visits. I have seen a mindset shift towards implementing innovative solutions and DCTs. Teams realize the importance of adopting remote solutions and being open to finding new solutions that might resolve the problem. Again, it’s just adapting to new ways of working. Overall for us, DCT adoption has increased by 400% in our trials, and we’ve been supporting new studies that are coming along. To elaborate, we evaluate how we can conduct the trial remotely by creating value for patients, reducing the burden, and providing flexibility - where we bring the clinical trials to the patient’s home rather than patients having to travel to the site. Providing options and catering to the needs of the participants and having a mindset of patient centricity are key in today’s environment, where patients expect services to be centered around their lives.

MA: Has COVID made a difference in clinical operational execution at UCB?

Yes, I think so. The clinical operations teams have always been open, but sometimes there might be hesitation if you’re the first one implementing something new because there are new challenges to overcome and a lot of planning and preparation, including how to ensure regulatory acceptance. So for me, the new model is working with regulatory agencies when we’re trying to implement some of these innovative solutions in an agile manner, also receiving feedback from our participants and sites to create the value for patients and ensure that we can bring the right solutions to a study by reducing the site and patient burden. With the current guidance that the regulatory agencies have provided to the industry, we’ve seen some flexibility where in the past, we were not able to do some activities remotely to now being able to do so. I hope that we continue to operate in this manner. This is something that I am passionate about, especially thinking about innovation, bridging with science to speed up the drug development process.

, 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

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Disa Lee Choun, Head of Innovation at UCB, discusses how they have fostered a culture of innovation, and how the investment in piloting has benefitted clinical operational implementation during the COVID-19 pandemic. 

Big Pharma Was Prepared for COVID-19

While the COVID-19 pandemic has impacted numerous clinical trials, some biopharmaceutical enterprises have adapted their medical products and have applied them towards COVID. What is particularly interesting about this interview with Sudarshan Hebbar, CMO of CalciMedica, is that it reveals how the FDA, ethics committees and safety consortia have responded to helping to advance the application of novel therapeutics towards COVID.

Moe Alsumidaie: How has COVID impacted your clinical programs that are currently underway, and what has happened as a result of COVID?

Initially, our program was geared at treating patients with predicted severe acute pancreatitis based on the presence of systemic inflammatory response syndrome (SIRS) and hypoxemia. We were planning to start a Phase IIb trial after working with the FDA and finalizing the protocol when the pandemic hit the United States. Several patients with acute pancreatitis also present with respiratory failure and acute respiratory distress syndrome (ARDS), areas where we had observed signals of efficacy—lowering IL-6 levels, protection of respiratory function in these patients—and our investigators thought it would be a great idea to test our drug in COVID-19. The first thing that we did was make a rapid pivot in our development program, requiring us to work with different divisions of the FDA. The acute pancreatitis program was being overseen by the division of pulmonary and rheumatology products. We had to file the IND with the division of antivirals and what I always tell people is that the FDA has been great to work with—within ten days of us filing the IND, we enrolled a patient in the clinical trial.

During this time, we worked closely with the FDA to get the protocol up and running very quickly. As we started the clinical protocol and the study, what happened was interesting. Since Auxora has a novel mechanism, a lot of the IRBs that we worked with wanted us to do an open-label trial in case there were any drug-related serious adverse events (SAEs). This way, the doctors would know immediately if an SAE was related to our drug. We were also told by IRBs to be careful because we gave an immunomodulator to patients who potentially had severe immune dysfunction. We ended up setting up an independent safety review committee to look at the data very closely. After only the first day, we had patients enrolled in the trial, and 12 had been treated with our drug, and six had been assigned to standard care when they conducted their initial safety review.

The Safety Review Committee gave us the go-ahead to keep going, and the FDA also asked to see some of the data because they, too, were concerned about the potential issues of using immunomodulators in a viral infection. We shared the data with them, and by the time we heard back from them, we had increased enrollment from 18 to 30 patients. They wanted us to stop enrollment in the open-label trial and transition to a blinded trial. We took that to mean that they were impressed with the data and wanted to see more.

We then worked with the FDA on rewriting the protocol to make sure that we met their needs. We also got their permission to publish the data and went through a peer-review process that resulted in a publication in 

, and notably, this study is one of the few that is randomized and has been peer-reviewed. The other thing that has been helpful for us in this transition is that the RECOVERY trial came through, and we knew that our drug would be beneficial in combination with other drugs or an immunomodulator.

We have a particular mechanism of action, and when dexamethasone and Remdesivir came to be used and shown to be effective in patients, we started to recommend it to all our sites. We believe that antivirals plus the steroids are great to use in combination with our drug. The FDA has allowed us to be flexible in changing the focus of our development program, they’ve worked well with us on that, and I think that this is the real key to protocol development and clinical trials here, the ability to be rapid and flexible in how things are done.

MA: Do you predict a difference in enrollment rates in part two of the trial?

Yes, so previously, the pandemic was starting. Nobody knew what was going on, so we enrolled very rapidly. We enrolled 30 patients at three sites in less than a month. We believe that things may change now in that the patients may be a little different. They may be much younger patients who may not have the same degree of respiratory failure. So, I think clinical trial enrollment will be more challenging in this stage of the COVID-19 pandemic.

MA: Many clinical trials are now going into decentralized modes where all study operations are being done remotely. How are you approaching that in your COVID protocol?

We’ve incorporated decentralization since the beginning of the study and have followed up with patients by telephone. Clinical research associates (CRAs) follow up with the sites remotely through their electronic medical records (EMRs). We haven’t physically been to any of our sites. Everything has been done remotely through telecommunications, and this includes communications with patients. By law, patients can now provide consent with electronic signatures. At one of our sites, patients sign a consent form on an iPad, and the IRBs have approved that as a means by which patients can provide consent. The study coordinator doesn’t go in the room, and they can handle the entire consent process electronically.

We’re working with a contract research organization (CRO), and we have a small number of sites activated, and we plan to activate 40 sites throughout the course of this part of the study. What we’ve worked with the sites on is the ability to access their EMR remotely, and if they don’t provide remote access to their EMR, we ask them to provide remote access to the data so that CRAs can then verify the data and do the quality checks of the data. Electronic communication with the sites is the norm for us now, and electronic oversight of the data, that’s of the source documents, is also the norm now. We haven’t had a CRA or any of us enter a site. All study operations are now being done remotely.

MA: What study endpoints are you focusing on right now, and how have you incorporated the study design to help achieve those endpoints?

We’re taking the sicker patients, the ones who have respiratory failure. The endpoints are hospital-focused. Time to recovery is the endpoint that the FDA asked us to look at using their ordinal scale, the same scale that Remdesivir already used, and that’s going to be the primary endpoint.

The secondary endpoint, which we think is a significant endpoint, is the composite endpoint of death or mechanical ventilation. So, can we keep people off the vent, and can we prevent them from dying? And that’s what we saw in part one of the trial, that the drug is doing remarkably well. If we see the same results in part two of the trial, we think that this will be a significant advance in the treatment of patients with respiratory failure, and so the endpoints will be mainly hospital driven.

MA:What’s next, and what about global expansion? Do you plan on running studies in Asia?

We hope to get an emergency use authorization, and we plan to incorporate this study into a general ARDS program. So, we would go back to the pulmonary division, do a second study, as mentioned with all causes of ARDS.

In terms of global, yes, we’ve thought about that. Being a small biotech company, we started in the United States. We knew everybody here, and we didn’t have the resources to go globally, but if part two of this trial goes well, I think it will be easier at that point to raise the required resources to take this global then.

Sudarshan Hebbar, CMO of CalciMedica, reveals how the FDA, ethics committees, and safety consortia have responded to helping to advance the application of novel therapeutics towards COVID.

A Journey: Biotech, FDA, and Safety Committee Responses to COVID 

Disruption of everyday life as a result of the COVID-19 pandemic, civil unrest, and negative influence of social media have caused a number of anxiety-provoking stressors to skyrocket this year. Consequently, prescriptions of potentially addictive anti-anxiety drugs called benzodiazepines have increased amongst Americans. Shawn Singh, Chief Executive Officer of VistaGen Therapeutics, discusses the company's ongoing efforts to treat and help manage the anxiety symptoms related to these triggers and the anxiety-related disorders they provoke, initially in subjects suffering from Social Anxiety Disorder (SAD), and the FDA’s consensus on the design of their pivotal Phase III study of PH94B, a neuroactive nasal spray, for acute treatment of anxiety in adults with SAD.

MA: As a result of COVID-19, clinical trials across the board have experienced delays in both operations and patient recruitment. How will VistaGen tackle these challenges?=

The highly statistically significant (p = 0.002) published Phase II study of PH94B in SAD, with Dr. Michael Liebowitz, creator of the Liebowitz Social Anxiety Scale, or LSAS, as principal investigator, involved anxiety-provoking public speaking challenges (preparing for and delivering a short speech) conducted in a clinical setting before impartial audiences.

Our consensus with the FDA supports using the same design in our pivotal Phase III study of PH94B for the acute treatmet of anxiety in adults with SAD. We are developing PH94B as an acute, as-needed (PRN) nasal spray that a person can take when the anxiety-provoking stressor is predictable and, within just 10 to 15 minutes, get relief from those symptoms.

As we move into Phase III, while there is no timeline for where we will be in the context of this pandemic, there are specific guidelines from the FDA and certain considerations for sponsors regarding ongoing and planned studies that will need to be followed. Fortunately for us, due to our consensus with FDA on our study design for Phase III, we do not need subjects to go out into the real world and experience a diverse range of anxiety-provoking stressors and then report back to us on their experiences. Alternatively, our study will be driven by a standard anxiety-provoking trigger (preparing for and delivering a short speech to a small audience) and conducted in a clinical setting over a brief time period (3 to 4 visits over about 4 weeks), potentially involving a telemedicine component. Clinical trial sites across the country are making things as safe as possible for staffs and study subjects. There are far fewer subjects in waiting rooms these days, which allows for social distancing.

While some may be hesitant to visit a clinical site, particularly right now, we believe many subjects will be eager to obtain some mental health services under these conditions—especially for SAD, an anxiety disorder affecting about 20 million Americans, even before the pandemic.

Now more than ever, patients around the world need new medications that go beyond the standard of care for anxiety, depression, and suicidal ideation. For patients who have a debilitating mental health condition, our goal with PH94B for SAD, as well as for several other anxiety disorders, is to develop and offer an innovative, life-changing treatment that goes beyond the current standard of care and allows patients to manage their anxiety to the point where they are able to live their lives as the ideal version of themselves—a crucial driver for everything we do.

MA: The last time that we spoke with VistaGen, the Company had 

just completed its Pilot Phase III study 

for PH94B. Recently, VistaGen announced a positive meeting with the U.S. FDA on critical aspects of the Company's upcoming pivotal Phase 3 clinical study of PH94B. Can you elaborate on this consensus?

We reached consensus with the FDA on all key aspects of our pivotal Phase III study of PH94B for acute treatment of anxiety in adults with SAD. VistaGen and the FDA are now aligned on the pivotal study design. When we are on the other side of what we hope will be successful efficacy and safety outcomes in our Phase III studies, we are confident the studies will support our NDA submission. Our initial goal for PH94B is for it to be the first FDA-approved, rapid-onset, PRN acute treatment of anxiety for adults with social anxiety disorder.

The efficiencies associated with having the same challenge for all subjects in the study—that being only a single public speaking challenge—after randomization are significant. The duration of each subject’s involvement in the study will be very manageable and the relatively modest cost of the Phase III study, along with the study size due to lower potential statistical variances due to the standard laboratory-simulated challenges and assessment, are notable. Based on our statistical plan submitted to the FDA, we do not need the study to be as large as previously envisioned; our enrollment target is 182 completed subjects. This is an efficient number, even with potential COVID-19-related impacts on clinical trial recruitment and execution. We anticipate that the study will be conducted at 12 to 15 sites in North America. We estimate that enrollment of 182 completed subjects should be doable by screening about 400 potential subjects. Those who do not qualify for the pivotal study may advance into our safety study, which we plan to conduct in parallel.

MA: How does VistaGen plan to further evaluate efficacy, safety, and quality for its Phase III trial compared to the currently available treatments? What data are you generating from your trial that would make it stand out compared to other therapies on the market for the treatment of SAD?

There is absolutely nothing on the market today that is FDA-approved for the acute treatment of anxiety in adults with SAD. The only FDA-approved drugs for the treatment of SAD are antidepressants, which take weeks to deliver a therapeutics benefit, if at all, a long onset period that we believe many SAD patients find inadequate. In addition, the side effects of antidepressants often are experienced almost right out of the gate.

With PH94B, we are not focused on developing an alternative to the antidepressants approved by the FDA for SAD. Rather, we are focused on creating a better treatment alternative to benzodiazepines, or “benzos,” which are frequently prescribed off-label and used—especially in the midst of the COVID-19 pandemic—for SAD and other anxiety-related indications.

PH94B's key features distinguish it, and are majorly different, from the benzos currently being used. In studies to date, PH94B is a drug that works rapidly like a benzo, but does not require systemic uptake and distribution to achieve its anti-anxiety benefits and does not cause the many challenging side effects and safety concerns of benzos-sedation, cognition and memory impairment, and risk of misuse or abuse. In our opinion, that makes PH94B a total game-changer for acute treatment of SAD and potentially many other anxiety disorders. We have received the FDA’s first ever Fast Track designation for development of PH94B for SAD.

MA: How is VistaGen set to potentially achieve both time- and cost-efficiency in the clinic for this study based on the FDA's feedback?

Our consensus with the FDA reduced the required number of primary efficacy endpoints in the study to a single efficacy endpoint using the Subjective Units of Distress Scale (SUDS), reduced the required number of clinical patient visits significantly during the study, thereby, considerably reducing the overall size of the study, while still maintaining appropriate statistical power, and eliminating potential data variability related to diverse anxiety-provoking experiences by having the single laboratory-simulated public speaking challenge used in the key Phase II study remain the same and be used for our pivotal Phase III studies. 

Shawn Singh, Chief Executive Officer of VistaGen Therapeutics, discusses the company's ongoing efforts to treat and help manage the anxiety symptoms related to the triggers and anxiety-related disorders COVID-19 provokes, and the FDA’s consensus on the design of their pivotal Phase III study of PH94B.

Pushing Late-Stage Treatments Forward in the Clinic  

The COVID-19 pandemic has shifted the clinical trial industry toward decentralization. Many organizations and investigators are realizing the benefits of implementing decentralized clinical trial approaches, as they can collect high-quality data more efficiently, and the approach is widening the ability for researchers to collect different types of data that could be more competitive than traditional data-collection methodologies.

In the following interview, Rasmus Hogreffe, former Head of Virtual Trials at LEO Innovation Lab

and current VP of Decentralized Trial Innovation at Medable, and Morten Kirkegaard, head of clinical operations and co-founder at REDO-neurosystems, discuss their experiences with decentralized clinical trials.

Moe Alsumidaie: Why is it important to transition into decentralized trials now?

 The decentralized trial approach is hugely advantageous, as it enables us to increase data quality in our electrophysiologic clinical trials. This approach is in line with real-world settings, as we are capturing patient data where they are in their environment, without the interruption to their lives or the added stress of coming to the clinic, which introduces factors of variability and induces a bias in our clinical observations.

In a traditional clinical trial, there is an average of 20 visits where the participants need to be transported to the site to collect a blood sample, take an ECG, and measure various vital signs. Imagine if we could do, all or some of this, from the participants’ homes, using clinically validated devices.

Everything has been put on pause with COVID-19, and we are carefully assessing how to manage chronically ill patients to ensure patient safety, due to their increased risk of infection from COVID. We must consider the risk of a pandemic going forward because when conducting a traditional clinical trial, this current situation is critical to both patients and the produced data.

MA: Will clinical trials become entirely decentralized in the future?

 My vision is to bring the choice back to the participant. Some participants see great value with face-to-face contact with healthcare professionals, whereas many participants don’t have the time to take part in clinical trials. I envision that 90-95% of all clinical trials will be in a hybrid design in the future, including a combination of virtual or decentralized visits, home visits, and site visits. This will enable us to collect better data while reducing subject burden.

MA: What impact will decentralization have on the clinical trials industry?

 I predict that decentralized trials will create an explosion of new studies, as decentralized clinical trial technologies will expand access to many smaller biopharmaceutical companies and investigators who today are unable to afford to conduct research using the traditional method. Data shows that we could expect to see a threefold increase in the number of clinical trials over the next 10 years. In parallel with this growth, we will also experience a deficit in healthcare professionals involved in clinical research.

 In my case, I am the lead principal investigator at my institution, and we do not have the funding necessary to outsource clinical trials. We are now evaluating moving forward with wearable devices in a practical approach instead of the traditional method, and that will allow me to improve research conduct efficiency, as I don’t have to be with the patient during study visits physically. Since our decentralized trial design is entirely automated, all we need to do is consent the subject, ship the device to subjects with an app containing instructions on study procedures, and we can monitor all the data from a central position.

One major challenge we face is a lack of clarity from regulatory agencies; in Denmark, for instance, the regulatory agency does not act in an advisory role. The agency supplies guidelines that investigators have to adhere to but does not advise on one’s mistakes. It would be helpful to have a standardized template from regulatory agencies to streamline processes and procedures that are accepted by these agencies.

Patients are now getting used to having their entire lives virtualized, and it is time for regulatory agencies to modernize the standardization of decentralized clinical trial conduct.

 Exactly. Remember, we are all focusing on the same mission—we want to develop better treatments faster for patients suffering from a disease. The pandemic has encouraged the biopharmaceutical industry and regulatory agencies to rapidly and radically rethink the traditional drug development process. As the saying goes, hard times bring on the most significant innovations, including the way we think, design, and conduct clinical trials

MA: What will happen to companies who don’t innovate and don’t move into decentralized trials?

The same thing that happened to Blockbuster; they didn’t innovate and went bankrupt from surging online demand gobbled up by Netflix. That is a clear example of a company that did not follow the market and missed out on digital transformation. We have also seen the destruction of many companies through the introduction of digitalization; Airbnb is disrupting the hotel industry, and Uber is shaking the taxi industry. The biopharmaceutical industry isn’t going to be any different and should use digital and technology where it makes sense.

Specifically, the biopharmaceutical industry needs to think about being more cost and time-efficient in R&D. There is a definite advantage to adopting the decentralized approach. Companies who stick to the traditional way of conducting clinical studies will not have the same access to the type of data collected by digital solutions. That data will be the competitive advantage that will get a medical product approved by regulatory agencies, as well as gain payer coverage adoption.

 For us, the pandemic and its impact on patient fear, as well as government shutdowns, was not something that any of us were expecting. As a startup biopharmaceutical enterprise, we are still in the developmental phase of our medical products, and our timelines are critical. Right as we were planning to launch our study, COVID hit, and that caused significant delays. The pandemic forced us to think about decentralization strategies when designing new clinical trials, and the opportunities decentralization opens for us. While the pandemic harmed us, our new strategy moving toward decentralization is a win, as we thought about collecting data that we believe will make us more competitive, all while protecting subjects and site staff from pandemic related infections.

 From the COVID-19 pandemic, we have learned that we are agile. We can use digital tools to run decentralized clinical trials. Post-COVID, I do believe that we will see a significant shift in adopting the decentralized approach. The pandemic has moved the authorities, sponsors, and healthcare professionals to think in a decentralized manner, and skepticism about the approach has been erased. That is a big plus for innovation in the industry. While it, unfortunately, took a virus to start this dialogue, it is known that every crisis creates opportunities for growth and adaptation.

, 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

Rasmus Hogreffe, former Head of Virtual Trials at LEO Innovation Lab, and current VP of Decentralized Trial Innovation at Medable, and Morten Kirkegaard, Head of Clinical Operations and Co-founder at REDO-neurosystems, discuss their experiences with decentralized trials.

Author | Moe Alsumidaie

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