Moe Alsumidaie

Many of us working in clinical operations often put the patient at the forefront of study design and execution. However,many of us have not participated in clinical trials as subjects and have no idea what it is like to go through the system to participate in clinical research. In this interview, Jane Myles, Director of Decentralized Trials at Covance by LabCorp, and former Head, Operational Intelligence and Innovation at Roche, discusses her journey as a clinical trial participant.

Moe Alsumidaie: Describe your experience participating in a COVID trial.

 Being in a COVID trial was essential to me for several reasons. I needed to feel like I was personally doing something to make a difference in finding a way through the pandemic. I wanted the experience of being in a trial, and it’s been hard to ever participate in a trial because I haven’t been ill, fortunately. So this was an opportunity where I could make a meaningful difference as a healthy volunteer. It was a way for me to think about how I would design a trial differently; as a clinical trial professional, I’ve always thought about operations from a theoretical perspective; being a patient in the trial helped me think about trial design differently. I believe all clinical trial professionals should experience what it is like to be a trial participant, and ‘learning by doing’ has provided insights I would never have gained otherwise.

MA: for a patient, navigating the steps required to participate in a clinical trial can be challenging. As someone who works in clinical trials, what was it like being a patient navigating the system to participate?

 Getting into the trial was more challenging and more demanding than I had imagined; even in a time of great need, with technology support to funnel the participants who were expressing interest, it took much persistence on my part. I had to follow through more than once to ensure that the research site and the sponsor knew that I was interested in participation. I was watching when the sponsor was going to open up the trial to participants by researching it in clinicaltrials.gov, triangulating where the sites would be, where I might be able to participate, and then contacting several sites directly, the recruitment vendor, and the sponsor. It took engaging three parties and multiple repeat follow-ups to participate. So, despite my clinical project management experience, I still faced challenges to participate; I can’t imagine what it must be like for prospective patients who have no idea how the system works. The lesson for me is that we have to make it easier for people who are willing to find out if they can be in the trial, and be mindful of providing them answers as quickly as possible to move them on to the next decision point. We need to make it easy for willing paticipants to get clear answers fast.

MA: What does it mean to have privilege when partaking in vaccine research as a participant?

 Privilege means having an advantage over others to partake in clinical trials. For example, simple things, such as internet access and having a smartphone to conduct ePROs. And there’s that level of knowledge that people with privilege have, such as understanding what a clinical trial is and knowing how to find where a study is being conducted. I work on clinical trials every day, so my team and my manager understood what it meant when I asked to take time away from work to participate, and they supported it with no questions asked. That’s privilege. Even educated and privileged people who do not work in science have misconceptions about clinical trials. For example, some people have asked me whether the vaccine will make me sick by exposing me to the virus. However, it was humbling to know that many people called me a hero by participating in research. That’s not why I entered or am sharing my story.

MA: What can be done to combat misinformation about vaccine research circulating on social media?

: I believe that patients have to be their champions to spread truthful information about clinical trials and vaccine research, especially in underserved communities. I decided to use social media to create more awareness around the trial process’s rigor; if you follow me on LinkedIn or even Instagram, you’re going to see that I’ve been posting every time I have a study visit, or there’s a study procedure, and it’s not about glorifying my participation, it’s much more about making transparent, what does trial participation look like? What does it mean to be unblinded? Was there rigor in the process? How did that happen? What was it like to learn you were a placebo patient? By spreading information about clinical trial participation, I hoped to raise awareness and trust in the system, and it worked; my followers got curious—lots of people reached out to me with questions.

MA: What was it like experiencing clinical trial decentralization as a patient?

 The trial I’m in uses ePROs to track my symptoms regularly, and I learned that my answers resulted in a definite trigger to the site to initiate a second level safety monitoring element in the trial. During my participation, I showed symptoms that were COVID-like, and I put it in my electronic diary via my smart device, and within a day, the site contacted me asking me for details about my symptoms. So, I registered my symptoms electronically, the site got flagged, they contacted me by phone and initiated a direct patient shipment to conduct a self-administered COVID test, which I had never experienced. It was an excellent opportunity for me to experience this first-hand as a patient, rather than being the person who designs the trial’s operational aspect. It all came full-circle when I started seeing the result of good clinical operational design as a patient; How does the signature work? Who gives me what materials? Who shipped the COVID test? How do I know where it came from and from which vendor? All those things became real, and I was pleased that it worked so seamlessly. As a clinical trial professional, experiencing what it is like to be a study patient helps me appreciate how important it is to contribute towards good quality by design that’s easy to use for seamless operations. 
If I could design the trial from scratch, there might be some more decentralized solutions I’d use, since that’s my passion. But, I understand that, from a sponsor’s point-of-view, speed and simiplicity are key to success, and we all benefited from those principles—We have vaccines available in record time!

, 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

Jane Myles, Director of Decentralized Trials at Covance by LabCorp, and former Head, Operational Intelligence and Innovation at Roche, discusses her journey as a clinical trial participant.

When Clinical Trial Professionals Participate as Subjects

There are similarities and differences in running a COVID-19 vaccine trial versus other vaccine trials. Specifically, the pandemic has offered opportunities to conduct trials in a new way, and the availability of patients is making recruitment very easy. However, the emergence of novel COVID variants may impact trial results for sponsors currently running COVID-19 studies. In this interview, Jessica Lee, SVP Clinical Operations and Global Integration at Inovio Pharmaceuticals will discuss her perspectives.

Moe Alsumidaie: What are the challenges of running a COVID trial?

 One of the common challenges in clinical trials—which became more 

pronounced at the onset of the global COVID-19 pandemic—is the need to safely and efficiently plan, design, recruit and ultimately run a clinical trial. However, INOVIO has been uniquely situated to support the fight against COVID-19 in large part due to the flexibility and scalability inherent in the development process for INOVIO’s DNA vaccines.

DNA vaccines are composed of highly characterizable plasmid DNA—small circular pieces of DNA engineered to produce antigens from target pathogens (e.g., viruses, bacteria, and cancer cells)—allowing for rapid, cost-effective scaling and manufacturing. As a result, at the beginning of the pandemic, our DNA vaccine candidate for COVID-19, INO-4800, went from design to human dosing in 83 days. We’ve also seen similar benefits across our 15 programs in development. For example, our DNA vaccine candidate for MERS, INO-4700, took 6.5 months to clinic and had a 95% response rate post-dose 2, as well as a 98% overall response rate.

MA: How could the introduction of new COVID variants impact trial results?

 The introduction of new COVID-19 variants is a challenge vaccine developers are currently facing. However, one of the hallmarks of DNA vaccines is the ability to rapidly respond to emerging infectious diseases. In fact, DNA vaccines have the ability to deliver cross-strain protection, covering more than one antibody and protecting against new disease mutations

INOVIO has been closely monitoring the evolution of COVID-19 variants, with a particular focus on the U.K., South African and Brazilian variants. With instances of these variants on the rise and the South African variant expected to be the dominant strain in the United States by March, this is an area of priority focus. INOVIO is currently evaluating the new variant impact on INO-4800, as well as working on a targeted vaccine response through the development of a new variant-match construct.

MA: What plans have you put in place to mitigate operational risks in your COVID trial?

 In order to prioritize the safety of our trial participants and staff alike, we have incorporated alternative means of data collection into the protocol that helps preserve study integrity, including telemedicine visits and home collection kits where trial participants can directly ship samples to the testing facility. INOVIO is also leveraging remote monitoring as standard practice and have embraced additional e-solutions, including e-consents and direct data capture to reduce transcription.

MA: How are you getting sites to prioritize your COVID trial?

 Multiple factors have contributed to interest in our clinical trial for our DNA vaccine candidate for COVID-19, INO-4800:

Across our platform, INOVIO has shown that DNA vaccines and medicines are able to treat and prevent a range of serious and life-threatening diseases related to HPV, cancer and infectious disease. Our DNA medicines are precisely designed DNA plasmids delivered by using INOVIO’s proprietary smart device into the body’s cells to produce a desired T cell and antibody-mediated immune response. DNA medicines are safe and tolerable; they can be quickly designed and manufactured – and unlike other types of vaccines – do not requiring freezing in storage or cold-chain transport.

Our COVID-19 vaccine candidate, INO-4800, has in its early phases of development, has proven to be safe and tolerable. Peer-reviewed Phase 1 data –published in late 2020 in The Lancet’s 

 – found INO-4800 to be immunogenic in 100% of subjects, including neutralizing antibody and/or T cell responses, with no series adverse events reported.

Beyond our COVID-19 candidate, INOVIO recently shared OS18 data from our novel combination trial of INO-5401 and INO-9012, which found that at 18 months, that 70% (14/20) of MGMT promoter methylated GBM patients were alive, and 50% (16/32) of MGMT promoter unmethylated patients, which is the more difficult to treat group, were alive after 18 months.

MA: How is a COVID trial different from other trials?

 Clinical trials for infectious diseases present similar challenges to the COVID-19 trial, including the inherent challenge of finding a newly infected population with high enough numbers to demonstrate efficacy. Unfortunately, this challenge did not arise for COVID-19, as many people were infected daily in various areas around the world. As a result, many vaccine programs – which traditionally have to wait for seasonality or need to travel to other regions where infection rates are high—were able to demonstrate efficacy in a shorter period of time.

But future COVID-19 vaccine developers will have a more challenging time with recruitment because more people will have access to approved vaccines and more people will be protected as additional vaccine products become available. The hope is that the incidence of infection and severe hospitalizations will decline, and so, as a vaccine developer, I expect to see slower recruitment rates in regions like the US, which contributed significantly to the early COVID-19 vaccine trials. In such cases, vaccinated developers will need to conduct trials in regions with high incidence rates due to low access to approved vaccines.

MA: There are lots of social media groups spreading misinformation about COVID vaccines. What can be done to combat misinformation?

 As a scientist and someone who has dedicated her life to pharmaceutical innovation, I can tell you about the important role of vaccines. As a member of the community, I also understand and appreciate that there are a lot of questions, concerns and fear about vaccines. I think there’s great value in a broader dialogue about vaccines to drive both greater awareness, understanding and clarity. [For example, our study plans to partner with community leaders to help us stop the spread of misinformation about COVID-19 vaccines.]

Jessica Lee, SVP Clinical Operations and Global Integration at Inovio Pharmaceuticals discusses her perspective on the emergence of novel COVID variants and how they could impact results for sponsors currently running COVID-19 studies

Running a COVID Vaccine Trial

Since the beginning of civilization, social injustice has plagued humanity and will continue to infiltrate many situations and institutions. The biopharmaceutical industry and many others have been combating social injustice by employing initiatives to include diversity in the workplace. However, driven by recent events, there has been an increasing focus on publicizing diversity in clinical trials—not only because of social injustice but also because of medical necessity. In this interview, Amy Davis, Sr. Director of Clinical Development Oncology at Eli Lilly, will discuss her perspectives on the topic.

Moe Alsumidaie: Can you discuss how COVID-19 has impacted minority inclusion in clinical trials?

 The pandemic has further exposed the persistent health disparities in clinical trials that disproportionately impact black Americans and other racial and minority groups. At Lilly, we are continuing to heighten our focus on this issue to ensure we’re doing everything we can to continue identifying and reducing barriers while increasing enrollment of racially and ethnically diverse patients.

A key pillar in our diversity enhancement plan is to create clinical trial strategies that reach diverse patient populations across many therapeutic areas to ensure that patient participants match the composition of the U.S. population. Next, we’re working to intentionally select a diverse range of trial sites and investigators to ensure that we have more women and racial and ethnic minority populations in our investigator groups. We’re also looking to increase our diverse representation through partnership and collaboration with patient groups, regulatory agencies, healthcare providers, etc. And finally, Lilly is looking at trial designs both within inclusion-exclusion criteria and allowing for more virtual and decentralized trial visits. While these decentralized capabilities were initially launched as a solution to continuing trials amid the pandemic, these flexibilities may also allow us to reach minority patients more effectively.

MA: Can you speak to how Lilly is applying this plan to oncology in particular?

 When Lilly did a retrospective analysis of our US trials, over the last 12,000 patients, 39% of those patients were minority patients, roughly about the same number as the US population. But when you dig into those numbers, you’re going to see higher percentages in areas like diabetes, which isn’t necessarily surprising because diabetes is more common amongst minorities. But we haven’t done as well in areas such as oncology.

We know that the mortality rate for African-American women diagnosed with breast cancer is 40% higher than that of white women. As we’re starting to think about our next wave of breast cancer studies, there are several things that Lilly is putting in place. One is conducting an African-American Oncology patient journey to better understand barriers to entering trials. The second thing we’ve done is a partner with advocacy groups that support women of color with breast cancer. We’ve also reviewed our protocol design to ensure that we aren’t inadvertently excluding women of color. Through technology, Lilly is also enhancing our knowledge of patients’ diversity being screened at trial sites. This will enable us to understand better which patients sites are screening and why they’re screening out of our trials. So those are some very intentional things that we’re implementing now with our upcoming breast cancer studies.

MA: There seems to be much misinformation going around on social media that patients essentially start to believe about clinical research. What is Lilly doing to combat misinformation?

: First and foremost, you have to understand the issues at the root of this mistrust. Look at the Tuskegee experiments as one example. We are working with patient and advocacy groups to understand better the driving forces leading patients to form these opinions and ensure we are doing everything we can to address that and build trust. 

One of the things we enacted in our COVID trials was a more intentional use of imagery in our recruiting campaigns. Not only were racially and ethnically diverse individuals seeing patients like themselves in our clinical trial education materials, but we were also engaging with community clinics and urgent care locations to help provide educational materials where underrepresented patient populations seek treatment and information. Presenting educational and factual information in the appropriate settings helps build the trust required to combat misinformation about clinical trials.


MA: Why is diversity important in clinical trials?

 We know that people respond differently to medicines based on sex, race, ethnicity, and other factors, so including diverse representation in our trials ensures we’re making medicines that will be as effective as possible for all patients that need them. And that’s been our goal, not just recently, but for more than a decade with the work we’ve done to increase diversity within our trials.

MA: There’s been a lot of recent change and polarization in the country, spurring many new social justice initiatives. Is Lilly in any way involved? Or what are your thoughts on Lilly’s involvement with these new social justice initiatives?

 Racial and ethnic inequalities in the US and many other countries are enduring issues that impact us all. Lilly certainly has a responsibility as a significant employer to take action on issues that affect our employees, business, and communities. In 2020, Lilly launched a racial justice initiative that focused on existing and new diversity work within Lilly and our communities. This is a multi-pronged approach. It includes expanding diversity in Lilly’s clinical trial programs, which I’m helping to lead company-wide, joining forces with other major companies to hire, train and advance African-Americans into 1 million family-sustaining jobs through our partnership with the OneTen coalition, doubling our spend with diverse suppliers and building and strengthening our existing community and national partnerships to help drive social change.

MA: You’ve been with Lily for over 20 years; how has your journey and perspective of the clinical trials industry changed regarding diversity?

: I’ve worked in many roles, some that have been closer to clinical trials and some in other areas of project/portfolio management and integrated drug development. For over a decade, Lilly has focused on improving clinical trials’ diversity, but there’s more work to be done. I think the COVID pandemic, along with just looking at our data, has shown us that we weren’t where we needed to be despite our best efforts.

In the work I do now, I lead individuals that manage the development and execution of our Oncology clinical trials, so I get to personally see the direct impact that collaborating with some of these external patient and advocacy groups has on our Oncology work. It’s exciting that there’s even more momentum within the advocacy space, the regulatory space, and across pharma. COVID made us all a little bit more creative in how we implemented our clinical trials, like the push for more decentralization which could help enhance trial diversity. I’m looking forward to the progress we will make over the next few years, and I think you’re going to notice significant improvement across the industry.

Amy Davis, Sr. Director of Clinical Development Oncology at Eli Lilly, discusses her perspectives on diversity in clinical trials and the workplace.

Expanding Clinical Trial Diversity Amid Social Injustice

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.

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

Moe Alsumidaie

Articles

When Clinical Trial Professionals Participate as Subjects

Running a COVID Vaccine Trial

Expanding Clinical Trial Diversity Amid Social Injustice

The Challenges of a COVID-19 Clinical Trial