Moe Alsumidaie

The entire world underwent the COVID pandemic, and the clinical trials industry learned a lot about how to adapt to that situation, such as utilizing technology and decentralized operational methods to maintain clinical trial execution during the pandemic, to name a few. Nonetheless, after Russia invades Ukraine, economists predict a world war, and the US is losing its ground as the dominant global power. Other economists predict a civil war in the US. Despite wars, patients will always need therapies, and the biopharmaceutical industry must protect and maintain its clinical trial infrastructures to deliver much-needed medicines. This article will discuss why the west is facing the potential for wars, what happens during wars, and some strategies for sustaining clinical operations during wars.

Let’s zoom out into a macroeconomic picture and explore what’s happening worldwide and in the US. I recently watched a shockingly disruptive but 

educational video posted by Hedge Fund billionaire Ray Dalio on world wars and the changing world order

. It got me to think more about where the US is in its influence and power in the world versus 

growing competitive powers, such as China

Through financial and economic indicators

, Dalio argues that the US is at a place where its power and greatness have peaked and is facing decline. For example, education investments have dropped significantly around the 1980s (and a reduction in innovation would inevitably actualize in 10-20 years from now), and the US has seen a consistent decrease in output, competitiveness and trade as seen in Figure 1 below.

Why is there so much internal turmoil in the US?

Internal turmoil and populism are arising from more considerable wealth disparities, as the few rich are becoming exceedingly wealthy compared to the majority of the poor. When there is only so much of the pie to split (i.e., country productivity and revenue), and the wealthy get a larger chunk of that compared to the poor, the poor view the system as unfair and attain populistic views. Additionally, the rich fund politicians to support their agendas, leading to more focused wealth and support (i.e., lower taxes and favorable changes in the political-legal structure to support the rich), further dividing wealth classes. Figure 2 below provides further insight into the timing of World War II in the late 30s when there was a wealth gap similar to the gap today and populism that arose during that time before the second world war.

Figure 2. Dalio’s US Wealth Gap Indicators

In addition, during populistic times, the chances of 

. Civil wars destabilize a nation’s productivity and provoke external rising powers to make military advances against declining powers. Essentially, the US is in this place because it spends (debt) more than it produces (income) and has made more frivolous than smart investments over the years.

Suppose we enter a civil or world war—how can you protect your clinical trial infrastructure?

While it is hard to believe, the United States is at an increased risk of facing both civil and external wars. Wars impose a horrific toll on countries and their economies; they are expensive and result in tremendous human suffering. While war may or may not occur soon, it is critical to prepare your clinical trial for one if the theory becomes a reality. Let’s discuss how wars can impact studies.

Target and build research infrastructure in stable global or local regions

During a world war, you are going to have countries that will forge allies (i.e., NATO with the West and China, Russia, North Korea in the East) and countries that sit on the sidelines and wait to see who’s winning the war, then ally with the winning side near the end of the war. Sideline countries tend to remain stable as they are not in the war path. Similarly, during civil wars, some local regions will be more stable than others. 

Countries and provincial regions that exhibit stability during a war are good places to invest and conduct research

 so wisely predict your countries and local regions and invest in building research infrastructure there

look for countries that have abstained from voting against Russian sanctions

. Those countries may be more likely to sit on the sidelines and remain stable during a war than those that have chosen a side.

Expect major disruptions—so, diversify by building global clinical trial infrastructure

The disruptions we’ve experienced during COVID may be similar to war, but war disruptions will have more enormous implications. For example, countries will impose economic sanctions, trade routes would be disrupted, and in countries under attack, power outages and danger to patients may outright halt your trial. Other areas to consider include investigational product manufacturing, raw materials and transportation, data collection disruptions, and regulatory authority backlogs. Furthermore, the potential for cyber threats and 

dormant cyberweapons targeted toward medical

 and clinical trial databases may exist and disrupt study sites’ electronic medical records, and biopharmaceutical clinical operations and data entry.

exploring countries and local regions and partner with GMP facilities that can manufacture investigational products and have protected trade routes with Eastern and Western countries or provincial regions

; having access to multiple trade routes and relationships with these facilities that you can later activate, would minimize shipping disruptions to sites in stable countries and local regions.

Select study sites and build clinical trial infrastructure in stable countries and regions

. For instance, I’ve done work in countries in Southeast Asia and South Asia and observed near-gold-standard clinical trial infrastructures; it may be worth reinforcing your clinical trial infrastructure in those countries and similar countries in different continents (i.e., Central Africa). This approach would diversify your clinical trial disruption risk.

Make it standard practice to use decentralized clinical trial (DCT) technologies

. Wars will make conducting research at study sites difficult, especially in unstable countries. Asking a patient to come to a study visit at a site when imminent physical harm is present is unethical. Moreover, patient migration is inevitable. While cell phone and internet services may become spotty, DCT technologies would allow you to collect more data. Additionally, consider using data collection technologies that do not require a constant internet/data connection to submit their data (i.e., data collection on a local device that would upload when a network connection is established).

 (especially ones that hold your clinical trial data) that either have or are established on robust technology platforms that have (a) 

regularly update their software to protect against cyber-threats

. For example, technology companies hosted on AWS or Google Cloud may be safer to use than those operating on a stand-alone database/environment. It would also be important to conduct cyber-security validations on study site health databases.

These perspectives are merely a few of many unanticipated issues during a time of war. The risks for internal (civil) and external (military) wars are rising, but, clinical trials must go on, and we must continue bringing therapies to patients despite the disruptions potential wars would present to clinical trials. Diversifying your clinical trial infrastructures and strategies can help your enterprise be more competitive and more likely to achieve its goals during warfare. Have a war plan.

Articles

Strategies for sustaining clinical operations during wartime.

Have You War-Proofed Your Clinical Trial Infrastructure?

Many sponsors have discussed the challenges of operating clinical trials during the pandemic, but there hasn’t been much discussion around the patient experience, and how patient feedback can help sponsors better design their studies to meet patients’ evolving needs. In this interview, Valerie Powell, Vice President of Research Services at HealthiVibe, discusses her experience with obtaining patient insights and helping her clients apply them to trial design and conduct in a pandemic.

Moe Alsumidaie: What challenges have you seen Sponsors and sites face as they continue to recruit and retain patients in global clinical trials during this pandemic?

 The challenges fall into at least three categories. First of all, many study subjects are fearful and unwilling to attend in-person trial visits, so they either aren’t enrolling or are dropping out. Secondly, patients and caregivers are focused on daily living issues during the pandemic, not on medical care, including trial participation. Lastly, site staff burden has increased sharply. Hospital-based sites are dealing with COVID surges, with some PIs being called into service to help and study staff adapting to changes in their work environments, working from home or juggling study requirements with cumbersome on-site pandemic precautions. The studies themselves are taxing staff, as they deal with delays, cancellations, and protocol changes to accommodate the shift to virtual visits, and the significant burden related to remote monitoring visits.

MA: How has patient willingness to enroll in clinical trials changed? What are you hearing from patients now?

 Clinical trial participation can be scary—and now, we have the added fears of contracting the virus at site visits and receiving an experimental treatment during a pandemic. While this fear can decrease willingness to participate, changes to trial designs—telemedicine and home health visits—can make participation more attractive if done in ways that resonate with patients and caregivers. A shift that I expect could have an even more significant impact is the increased familiarity with clinical trials (due to the COVID-19 vaccine trials being in the news). This familiarity can breed acceptance.

First, patients are hearing and learning more about trials. Now laypeople who have never considered a trial know more about the trial process, which builds comfort and helps break down misconceptions. Second, because of the worldwide focus on the need for a vaccine, the public sees the value of clinical trials in a new and real way. Finally, the emphasis on involving diverse populations in the vaccine trials could help break down some barriers in enrolling diverse populations in our trials. I’m hopeful that we will see prolonged support of clinical trials and reduced stigma around participation – it could be a small silver lining to this pandemic experience.

MA: What are patients requesting to help make them feel safe participating in clinical trials during these challenging times?

 To feel safe and be willing to participate, what patients want is not always what the sponsors expect. It varies by therapeutic area, the severity of the disease, demographics, and other factors. For some conditions, patients are very enthusiastic about home visits and telemedicine; in other conditions, such as severe chronic illnesses and cancers, we see patients asking for reassurance that they’ll still see the study doctor regularly – that’s what will make them feel safe, despite the pandemic. Some patient populations are also very enthusiastic about using devices – vital sign monitors, sleep monitors, and adherence apps, to name a few – while others are resistant due to discomfort with the technology or privacy concerns. Ultimately, each trial and each patient population are different. Designing a trial and testing technologies with the targeted patients remains the best way to ensure you’ll have robust enrollment and retain trial subjects.

MA: How have sponsors and sites pivoted to meet the needs of patients during the COVID pandemic?

 As mentioned, many sponsors have shifted to home health nurse visits and the use of study-support technologies. The pandemic has also caused us to finally take a close look at the burden of study participation—frequent and extended study visits, multiple procedures—and find ways to scale back study requirements to focus on need-to-know data, not nice-to-know data. Many sites have taken a hands-on approach to explain study requirements, reassuring patients, and genuinely coaching study subjects throughout the process. The most successful sponsors have engaged both sites and patients to learn what will work for them before implementing any changes.

MA: What still needs to be done to ensure successful, patient-centric clinical trials during COVID times and beyond?

 Engaging with patients to co-design clinical trials is still seen as an optional activity by most sponsors. Even sponsors who engage patients regularly often do so when it’s too late and a protocol cannot be changed. I’m hopeful the challenges of operating studies during the pandemic have begun to cause a shift—that sponsors see the benefit of engaging patients early and often. Some of our clients give patients and caregivers a seat at the table from very early in the development process, before portfolio entry, to identify meaningful endpoints and effectively shape clinical development programs. For those of us who’ve dedicated our careers to this work, that’s a very good sign. It is true patient engagement.

, 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.

Valerie Powell, Vice President of Research Services at HealthiVibe, discusses her experience with obtaining patient insights and helping her clients apply them to trial design and conduct in a pandemic. 

Let’s Not Forget the Patient Perspective in Clinical Trials

As the clinical trials industry moves towards decentralized approaches to clinical operations, the world of electronic data is changing drastically to offer sponsors more efficient data collection and higher quality data through novel technology integration and implementation. In this interview, John Reites, CEO of THREAD Research, will discuss these changes.

Moe Alsumidaie: What is driving the significant rise in demand for electronic Clinical Outcome Assessments (eCOAs)?

 There’s an increased need for clinical trials to capture patient-reported outcomes and patient-reported outcomes through clinicians in Phase Ib, II, and III studies. Specifically, electronic patient-reported outcomes (ePROs) and clinician-reported outcomes (ClinROs) – which represent the most utilized eCOAs in study designs—are becoming a standard in pre-approval studies across most therapeutic areas.

eCOAs are no longer only being used at a structured visit level. They are being completed in between clinic visits, during telehealth virtual visits, at-home health visits, and within some unscheduled visits. Studies have a growing need for more routine quality-of-life scales and other validated scales to be conducted outside of clinic visits. We’ve seen a significant increase not just in ePRO and ClinRO use but in performance outcome assessments (PerfOs) and observer-reported outcome measures (ObsROs). These assessments are being requested more often as validated scales, with varying implementation complexity levels, and via sensor data integrations within the platform. There is also an increase in the number of new ObsROs for previously uncaptured data points in new and rare disease areas.

While eCOA use overall was already on the rise, its use has increased with the desire and ability to capture data not just during study visits but also more frequently between visits and higher recall requirements.

MA: Why has there been a need to increase data collection frequency, and what benefit is that providing to researchers?

 Advocacy groups, researchers, regulatory bodies, and payers have been requesting more routine inclusion of patient-focused endpoints for years with regulation support. Factors like patient quality of life (QoL) have moved from exploratory to primary and secondary endpoints at an increasing rate.

The increased data capture and frequency are about better-quality data because they are collected more consistently and timely at the source. Instead of patients keeping diaries, lists, and answering questions that require substantial recall, they can complete an eCOA on their phone immediately when alerted or during a brief telehealth Virtual Visit with the site. The ability to provide consistency and better data quality through these eCOAs with decentralized clinical trial (DCT) approaches is a crucial reason we see an increase in their use. The ability to capture trial data in this manner has made it possible for studies to use eCOAs at scale for remote capture in the Americas, EMEA, and Asia Pacific.

MA: Would it be helpful for patients to be able to see their data while they are submitting it?

 It can, but I think there’s a bit of an art and science balance to this answer. Scientifically, and as required by some validated ePRO, a participant’s ability to see their answers before final submission and/or see past data responses is needed. Giving this access is essential and helpful for participants as a feature. In our participant app, we offer patients the ability to view past responses, summaries, and upcoming activities, including some dashboard visualizations. This helps our customers achieve a variety of complex eCOA implementation requirements.

The art side of this discussion is that we have to be cautious not to overwhelm study participants from a user experience perspective (and the study teams that will also see this data). We may be excited to offer 50 data points in an amazing series of charts, but it could have a negative effect. In most participant insights we have gathered, providing only the critical data of interest back to participants is the desired goal. Focus on these key insights with a specific focus on the user experience is what we see achieves a mutual benefit for participants, sites, and sponsors utilizing complex eCOA. 

MA: What considerations are sponsors using when selecting an eCOA that can be conducted via telehealth virtual visits?

 A large majority of eCOA can be conducted on-site and/or via telehealth virtual visits while maintaining its validation requirements. We have been capturing eCOA during telehealth virtual visits for years in various Phase II-IV studies where the context of use and ability to capture the eCOA as required during the telehealth session mimics the on-site visit experience. The overall experience of capturing the eCOA is very similar to the on-site experience, but we provide various more flexible device options that are routinely available in the market today.

The ability to conduct these assessments with the participant, site, home health nurse, and/or rater can be completed using the telehealth virtual visit approach that is device agnostic, does not require a provisioned device, and allows the users to be anywhere while conducting the assessment. This more flexible process fully achieves all eCOA license holder requirements such as user interface specifications, form factor restrictions, and process steps.

It is important to note that my above comments reflect a majority of eCOA but not all. As an industry, we have some eCOA that have not yet been digitally validated for use and/or require face-to-face interactions. We see several eCOA with these restrictions being developed/researched to convert them to support virtual use potentially, but this will take some time for the shift to be complete. In these cases, many processes enable these eCOAs to be captured in coordination with the other eCOAs conducted in-between visits and/or during telehealth virtual visits.

MA: How do devices such as wearables and sensors work with eCOAs in telehealth?

 Sensors, including wearables and medical devices, are captured via the same platform as another type of eCOA data. This data is typically captured continuously in-between visits and during structured visits via in-clinic, telehealth, and home health visits. Let’s use an example to answer the question.

In the case of a medical device (i.e., spirometer, blood pressure monitor, glucose monitor), the study participant has their kit that includes their provisioned medical device. When their visit is ready to start, they will have their device and study app. During the visit and when the medical device assessment is ready to be completed, the site team member will ask the participant to start the activity. The activity will then guide the participant in completing the medical device assessment with coaching as needed. As soon as the activity is complete, the medical device data is available for the site team member to review and move to the next part of the visit. This process works the same way, whether on-site or telehealth virtual visits.

In supporting our customers’ studies, we have learned that when you do a virtual visit, the clinician can see the patient using a device, and they can coach them and direct them just as they would during an in-clinic visit. Then, within a few seconds, the data is available for the clinician to see. While they’re not in the same physical location as the participant, they can mimic and conduct the entire assessment using sensor-based eCOA during the virtual visit.

At THREAD, we’ve been supporting eCOA completion at the site and via telehealth virtual visits for years. Although it may sound simple, there are several complexities in eCOA implementation, and telehealth learned from experience. The ability to conduct eCOA via hybrid approaches, including in-clinic visits, telehealth virtual visits, and home health visits, is an approach that most studies can utilize globally when all validation, multilingual and regulatory requirements are met. I am excited to see and be a part of our industry’s shift to more flexible, hybrid, decentralized approaches that include eCOA as key study endpoints.

John Reites, CEO of THREAD Research, discusses how data collection is changing as the industry moves towards decentralized approaches.

How Decentralized Trials Are Virtualizing and Revolutionizing eCOA

There has been much discussion on the move towards decentralized clinical trials (DCTs) amidst the wake of COVID-19, and a new movement (

) is emerging to push clinical operations personnel and biopharmaceutical enterprises to continue with DCT approaches in clinical trials. COVID has forced biopharmaceutical enterprises to move at breakneck speed to implement DCT approaches. However, many biopharmaceutical sponsors with little or no clinical innovation experience and limited resources have implemented poorly designed DCTs in a rush to sustain clinical operations during COVID. This poor implementation manifested in poor clinical quality, non-compliance, and good clinical practice (GCP) related deviations at study sites. In this article, I’ll discuss some of the significant forces currently impacting global operations, FDA foresight on operating clinical studies during COVID, and the subsequent compliance issues manifesting from poorly executed DCT operations.

recently emerged to continue the innovation spurred during the COVID pandemic. This movement’s approach suggests that the clinical trials industry has gotten a glimpse of the future of clinical trials, where clinical operations can run seamlessly, efficiently, and reliably by using future technologies and methodologies that support DCT execution. For example, many sponsors have implemented eClinical and decentralized technologies to keep the patient at home. Examples include eConsent, eSource, telehealth visits, home-nursing visits, and remote monitoring, to name a few.

One of the risks that this movement emphasizes is that the industry will go back to its old ways after the pandemic is over; The reality is that the pandemic is not going away anytime soon, and the world has radically transformed to a point where it is unfathomable to go back to the old ways of clinical trial execution. However, this risk is valid, as the clinical trials industry is very comfortable with implementing tried and true traditional methodologies of clinical trial execution, no matter the cost or impact on clinical trial efficiency.

FDA guidance during COVID-19 public health emergency

on operating clinical trials during the COVID pandemic has pushed sponsors to move towards DCTs. FDA specified in its guidance that “ensuring the safety of trial participants is paramount,” and that sponsors should do whatever it takes to ensure that patients are protected. Recommended strategies branch out to alternative methods of safety assessments (i.e., virtual and decentralized visits) whenever possible, home-nursing visits, shipping investigational medical products to the patients’ homes, modifying protocols to include any changes to visit procedures, and virtual monitoring visits.

The FDA also forewarned sponsors of the potential issues that may come from rapid decentralization, such as missing endpoint data (due to patient discontinuation, changes in study visit schedules, and missed visits), delayed data collection due to healthcare disruptions, and additional safety monitoring for patients who cannot access investigational medical product.

One of the most prominent sections and emphasis in this guidance document includes conducting informed consent remotely; it is clear FDA expected that there would be a significant influx of consent amendments, as they expected many sponsors to amend the protocols to incorporate changes related to operating their clinical studies during the COVID pandemic. The FDA outlines a complicated and convoluted process in its guidance if an eConsent is not available to the patient. For example, study sites are required to send the ICF to the patient electronically, conduct a telephone/video conference call with the patient, and provide sufficient documentation (i.e., identification of personnel on the call, review of the ICF and any questions patients may have, and obtaining verbal confirmation from patients of trial participation). Subsequently, the patient is required to sign a blank piece of paper with a written statement about their voluntary agreement to partake in a specified study and send a photo of that document to the site or mails it. Once received at the site, the study staff are to attach this document to the consent form and generate a note to file explaining the consenting circumstances with this method.

The FDA also expected that major deviations and GCP non-compliance issues would arise due to COVID control measures and monitoring changes. In its document, FDA specified that sponsors should implement alternative and decentralized approaches to monitoring to maintain trial participants’ safety and data integrity, such as enhanced centralized monitoring, phone calls with study sites to review updated study procedures, evaluate trial participants’ status, study progress, and conduct remote monitoring. However, FDA also recognizes that decentralized monitoring could result in missed findings, which would later be identified in on-site monitoring visits. Any missed findings and deviations are to be documented, and the cause for missing the deviations/non-compliance issues should expressly point to the modified monitoring procedures during COVID.

Some large biopharmaceutical sponsors were prepared and had the budgets to implement DCT measures, such as rolling out eConsent using established technology systems, adjusting their centralized monitoring practices, and implementing remote monitoring using specific technologies. These methods protected sites from non-compliance because these methods have been tested in clinical innovation pilots, have less room for human error, and could rapidly be verified by monitors. However, many other sponsors with minimal or no DCT or clinical innovation experience were left to scramble to put poorly designed methodologies together, which exposed study sites to GCP non-compliance and major protocol deviations.

For example, some sponsors have followed FDA guidance on conducting consent remotely and have not relied on eConsent technology. The implementation of such methodologies has resulted in poorly designed consenting case report forms (CRFs), a lack of proper consenting documentation, missed consent form signatures, and sometimes consenting couldn’t be verified due to staff turnover. Furthermore, monitors could not identify these deviations for several months, as sponsors did not equip their monitors with the appropriate technologies to properly perform remote monitoring visits. Now that new COVID safety procedures are implemented, and monitors can physically access sites, they discover a slew of major protocol deviations and GCP non-compliance issues.

How to make clinical innovation and DCTs work

Some large biopharmaceutical sponsors have enjoyed stepping into the future by implementing novel technologies that support DCT execution and seeing them work. Nevertheless, many sponsors who could not afford DCT technologies (do not know the return on hiring DCT vendors) and lack clinical innovation experience are left behind with major non-compliance issues and protocol deviations amidst the pandemic. Implementing DCTs must be done with the latest technologies and clinical operational design expertise to minimize human error. The examples I see first-hand prove that implementing DCTs using traditional methodologies will result in significant issues. Biopharmaceutical sponsors who have had a good experience with DCTs will likely support moving forward and #NOGOINGBACK, whereas sponsors who did not risk going back to traditional methodologies.

Moe Alsumidaie, 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.

A discussion of the forces currently impacting global operations, FDA foresight on operating clinical studies during COVID, and the subsequent compliance issues manifesting from poorly executed decentralized clinical trial operations.

New Compliance Issues Emerge Amidst COVID Clinical Operations

COVID has caused many study disruptions, and the clinical innovation investments that big pharma companies put in before the pandemic are now coming into play. The concept of clinical innovation has changed, as have cultures on adopting clinical innovation. In this interview, Hassan Kadhim, Director, Global Head of Clinical Trial Business Capabilities, Clinical Innovation & Industry Collaborations at Bristol Myers Squibb, will discuss his perspectives on how the pandemic has shifted clinical innovation.

Moe Alsumidaie: How has COVID impacted the clinical trial environment?

When COVID began emerging, it impacted the workforce because we could not meet in person and collaborate with our stakeholders and designing studies and in planning for study timelines. From logistical and organizational perspectives, it has already affected the pharma industry and many different industries. As a result, there was an adaptation going from in-person schedules to fully remote collaboration for a long, sustained time. But on top of that, where it impacted clinical research the most is the patients. First of all, healthcare institutions, especially at the peak in March and April, were getting overwhelmed with COVID cases. Suddenly, what we observed was that the hospital networks had to rightly prioritize the acute crisis by treating COVID patients and patients suffering from life-threatening diseases rather than from other indications and conditions.

For clinical research, patients started thinking twice before going to the sites, which created the situation for us in pharma to find solutions and quickly address recruitment, enrollment, and retention. Despite that, many pharma companies put a halt or a pause to their clinical research portfolio, which has delayed many study starts, study enrollment, and forced everyone to rethink what we can change to adapt to this new environment.

What was that experience like internally?

 They say necessity is the mother of invention—and by the same token, innovation. COVID has created the necessity for innovation. It has forced everyone to think differently because the entire environment around us has changed, and we all realized that clinical innovation was a necessary tool to enable new approaches for designing and implementing clinical trials. Organizations that had a head start (i.e., they had vital clinical innovation programs, had experimented in many different approaches and technologies, whether it’s decentralized trials or remote monitoring, or really anything that in the past (pre-COVID) was considered maybe a nice-to-have at the time) experience an easier transition to the recovery efforts compared to organizations that did not invest in clinical innovation. 

Nonetheless, for everyone, this experience reinforced and emphasized the need for innovative trial approaches as it really came down to portfolio continuity. If you want to continue doing clinical trials, you likely cannot continue doing them in the old paradigm and ignore the impact of COVID-19. Maybe you can do it for some sites, for some regions, but on an enterprise level, on a global level, knowing that the pandemic was a global occurrence, we noticed a varying degree of impact in different countries and different regions.

MA: What is it like for managing in-person visits, say from patients to monitoring visits?

When there are surges in COVID cases, you will find that patients will have the valid question come back to their minds: “Should I go to my clinical trial visit? Is it that important? Should I risk myself of being infected?” So, anything that enables patients to participate remotely will be critical. Anything that allows the transfer of data directly from the electronic source (i.e. eSource) will be a difference-maker. Remote monitoring has also become increasingly important; CRAs, for example, may be asking: “should I go to the site and expose myself?” or, “can I do monitoring activities differently or remotely?” If we enable remote monitoring, that could also be a difference-maker from an efficiency perspective for running trials. When we are forced to think about how we adapt those components to enable clinical research, we will likely see that the long-term impact of the COVID crisis may be further adoption of innovative trial approaches and hopefully sustaining that kind of flexibility in clinical trials to drive real change.

MA: What kinds of technologies are now in demand to be used in clinical trials?

Anything that enables patients to participate remotely, providing flexibility for patients to be in the trial. We noticed that with COVID, many sites, especially big institutions, have now adopted eConsent as a platform for trials that they conduct. This was also in some cases a mitigation measure in a pandemic to keep trials running. To emphasize, this is the site adopting eConsent, not the sponsor pushing eConsent to the site. We realized many sites are not only interested but are going full-blown implementation with eConsent in their practice. As a sponsor, it’s time for us to consider eConsent as a commodity and not an innovation, and address working with sites that have eConsent versus those that don’t and how do we create this ecosystem, where multiple eConsenting modalities are all considered valid is something sponsors will need to adapt to.

The same is true for telemedicine. We know that several healthcare institutions were already using telemedicine in their familiar healthcare setting, but now the necessity created with the pandemic brought an immediate need to use telemedicine in their clinical trials as a mitigation measure. Some sites already had telemedicine solutions; others didn’t. Sponsors are thus left with the optionality of using the site’s own telemedicine technology, or push telemedicine as a solution to the sites. I think a flexible ecosystem is probably the happy medium we as an industry need to strive to, where the site will use their own telemedicine platform when available and get the sponsor’s telemedicine provided solution where the site doesn’t have one available. And all of that in the same study! This “trial-with-options” mantra is where we need to adapt to as an industry.

And then, of course, it raises again to the forefront the approach of decentralizing clinical trials, so allowing a fully remote approach in some cases or a hybrid in other cases, or just a flexible model where for the majority of visits in a study, the patient has the choice to do the visits in person at the clinic, or remotely using technology.

MA: How has COVID changed the culture of adopting innovation in big pharma?

I'm sure you probably know about the innovation adoption life cycle, where whenever there's some innovation that's introduced in any industry or any market, there's usually the innovators that introduce it, then there's the early adopters, the early majority, the late majority and then the laggards. If an innovation is really good and provides real benefit, with time everybody adopts it and that time could take months to years, but it's generally a question of time. I think what COVID did, is change the culture of innovation, where for some of these innovations, we were probably in the pharma industry at a stage of, having a good portion of early adopters, but the early majority hadn't really joined. What COVID did is it pressured the system so much that it accelerated the transition from early adopters to early majority. By the same token within clinical innovation, there has been a culture shift towards accelerating many of the innovations that were in the pipeline to help us prepare for the future. I think this is the cultural shift that everybody recognized is needed to mitigate the very real (and now realized) risk of disruption of clinical research due to a pandemic. The rest remains on us as an industry from a tactical perspective and change management on implementing and enabling the adoption those innovations to work for our studies, sites, and patients. There’s still much work to do, but what changed is the perception of the culture and its sentiments.

MA: What will clinical innovation look like in the future?

Innovation means different things to different people, and what’s an innovation today, may no longer be called innovation in 10 or 15 years (or less). For example, EDC, which 20 years ago, was the innovation of the hour is now a standard technology that is essential for every trial. I think what COVID has done is that it propelled all the things that we call innovation today in 2020; it has accelerated their trajectory to no longer stay in the “innovation” category for too long. In the future, I think that decentralized trials may become the norm in the industry. Post-COVID, I think there will still be innovations that perhaps we haven’t thought of today.

I think when the dust settles and we as a society come out of this pandemic, we will look back at this period as a period that really pressured everything to accelerate the innovation of its time (for many different industries).

, 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

Hassan Kadhim, Director, Global Head of Clinical Trial Business Capabilities, Clinical Innovation & Industry Collaborations at Bristol Myers Squibb, discusses his perspectives on how the pandemic has shifted clinical innovation.


COVID Shifts Clinical Innovation in Big Pharma

	The biopharmaceutical industry is now making strides in gene therapies by focusing on patients with specific genetic traits. However, that approach comes with challenges, as these patients have to express the specific genes required to qualify for studies. Some methodologies are emerging to address this challenge by creating genomic libraries, and subsequently, identifying patients that would be good candidates for gene therapies. In this interview, Karmen Trzupek, Director of Clinical Trial Services at InformedDNA, will discuss how to address these challenges.

Moe Alsumidaie: What are some of the main things biopharma companies and CROs need to know about genetics-based clinical trial programs?

: The first thing biopharma companies should know, which often comes as a surprise the first time they incorporate genetics into a clinical trial, is that genetic test results are complex. Laboratory advances in genetic testing have led to a massive shift in the way patients are tested. Early in my career, we used to test patients for one gene at a time. It was a very hypothesis-driven approach based on our clinical suspicion. But today, the standard of care in genetic testing for many diseases is to perform extensive panel-based tests, where literally hundreds of genes can be tested at once. Of course, in many ways, this is a good thing: It's led to a considerable increase in the detection rates for many diseases, for instance. However, our ability to do that kind of genetic testing has far outpaced our understanding of the meaning of variation in the human genome. So, we get back genetic test reports with lots of variants of uncertain significance, which can be very confusing to both patients and providers.

	On another related note, coming up with a plan for the return of results of genetic testing is critical in a program. Since these results can be much more complicated than many standard medical tests, there really needs to be a plan for the delivery and use of that information. Many physicians today who are ordering genetic testing for a clinical trial, never have before ordered genetic testing, or have done so in a very limited way. Physicians often tell us that they're not confident interpreting these large-scale genetic test results, or if they are comfortable with these reports, they just don't have the time in their practice to sit down and have lengthy conversations about genetics with patients and their families. Biopharma companies need a plan for someone to take the time to disclose and explain the results of testing.

MA: Can you discuss the challenges clinical trials are facing as they work to bring more than 2,500 gene therapies in their pipeline to the market? 

: One major challenge in the design of the actual program is that gene-based clinical trials typically target a very, very small subset of the total patient population. It makes finding patients even more difficult than usual. We see many organizations starting to think in different ways about how to face that challenge. One of the ways that we've seen a number of pharmaceutical companies address this is by developing natural history studies or patient registries. By screening patients in advance of their intended interventional trial, trial sponsors or CROs can start to build rapport in the patient community and establish a group of engaged patients prior to starting  enrollment.

	Companies are also overcoming this challenge through telemedicine-based outreach and screening. When I read the article based on your interview with 

, I was really struck when she said that, today, ensuring that trials are accessible to patients locally is so critical to engaging them in healthcare product development. At InformedDNA, we bring specialty genetic services to patients where they are, providing them a genetic specialist with expertise in their rare disease without that patient incurring the time or the cost associated with travel.  

	Another challenge that clinical trials are facing around gene therapies is heavy competition in the pharmaceutical and clinical trials space, which is well known and established. I think this competition is in direct opposition to the collaboration that we need in the rare disease world. With a rare disease, we must find ways to get industry, patient groups, patient advocacy organizations, clinical providers and even multiple industry groups to all come together for the same cause. Ultimately, we all want to accelerate the pace of clinical trial research and find meaningful treatments for these rare diseases. And I think that the competition we've historically seen in the pharmaceutical space does not serve the rare disease population well.

MA: How is the incorporation of genetic testing implicating cost and time goals? What types of best practices can biopharmaceutical companies put forth to overcome these hurdles?

: For most genetic diseases, genetic testing is not the standard of care. There are some exceptions like with cystic fibrosis, the most common recessively inherited genetic disease in the U.S. population. Most patients in this country with cystic fibrosis have previously undergone genetic testing, so they already know the genetic cause of their disease; but this is not the case for most rare diseases. When a pharmaceutical company or a CRO is starting to target a rare disease, they have to think about how to incorporate genetic testing into their own clinical development program. They can't just rely on reviewing medical records and finding the genetic test results to determine whether or not that patient might qualify. They have to ask questions such as, "How do I find patients who might have this particular genetic disease?” And then, “How do we implement a genetic testing program to support those patients in obtaining and understanding genetic testing?"

	Obviously, finding the right patients for the trial impacts cost and time because both are going to be increased when you think about implementing that second testing step. While that may be an added expense and it does take some time, if the clinical development program can find ways to incorporate screening remotely, it will actually decrease total costs by identifying patients remotely who are more likely to be engaged, and then more likely to travel to the clinical trial centers for evaluation.

MA: What implications do genetic testing and genomics have on clinical trial and protocol design? 

: I’ve spoken with a number of different sponsors regarding how they think about incorporating genetic testing into their protocols or into their clinical development program. To me, any genetic testing program should do two things: One, it should benefit the patient population broadly, and not just the patients who are going to qualify for that study eventually. Two, it should ideally benefit the sponsor in ways that go beyond that first trial. Earlier, I talked about how we see these large-scale panel-based tests, and there is a benefit to that in many cases. While we don't always want the most extensive test, panel-based testing can sometimes address both of these needs. 

	If you have a patient population where there are many different underlying genes that can cause disease, a pharmaceutical sponsor could say, "Well, we're only going to test for this one gene that we're currently targeting for our clinical trial." However, let’s say only 5% of your patient population has that particular gene as the cause of their disease. If you only target that one gene, you are excluding 95% of those patients, which over time, can lead to fatigue and lack of engagement in that patient population. Instead, if the sponsor utilizes a more substantial test that has a much broader appeal to the patient population, many more patients will find answers to questions about their disease. The program will still identify the genetic cause of disease in that initial 5% but will support other patients simultaneously. This can then benefit the sponsor as well, because they're engaging the broader patient population and, for the next therapy they develop in that disease group, they have already identified a set of potential clinical trial candidates. 

MA: A big challenge in the new era of genomic therapies is identifying patients who have a particular mutation in their genes. As this field starts to evolve, would you expect genetic testing to play a role in recruitment? 

: I'll give you an example of something that we're currently doing that I think really shows a model we should be working toward in genetics. We're currently supporting a program in collaboration with the Foundation Fighting Blindness, a patient advocacy organization that supports patients with inherited retinal disease. In that patient community, there are more than 200 different causative genes. All of these patients have degenerative forms of retinal disease, but the underlying genetic cause varies. When the first FDA-approved gene therapy came along for the treatment of a genetic disease, which was LUXTURNA by Spark Therapeutics, it only targeted one of those 200+ genes, for which a very tiny portion of the patient population qualified. Now, we’re seeing many other clinical trials pop up, sponsored by different biopharma companies, and targeting different genes.   

	To meet this challenge, the Foundation Fighting Blindness is hosting and sponsoring a genetic testing and genetic counseling initiative, with well over 300 providers participating all over the country. This is a big contrast to five to ten years ago, when there were fewer than 30 physicians routinely ordering genetic testing in this patient population, and they were primarily located in academic research centers. Now, utilizing the Foundation Fighting Blindness program, we see genetic testing being initiated at the community level with local retina physicians, and not solely at large academic medical centers, which patients may have to travel hundreds of miles to reach. Patients get tested, and the test results come directly to us since we’re providing telemedicine-based genetic counseling. We interpret the test results and provide medical management information to the patient, as well as provide the needed guidance for family members who might also be at risk and may consider testing. Finally, all of that data goes into the registry through the Foundation Fighting Blindness, which acts as a central resource for clinical trial information for patients in this community. 

With the biopharma industry making strides in gene therapies by focusing on patients with specific genetic traits, Karmen Trzupek, Director of Clinical Trial Services at InformedDNA, discusses how to address the presented challenges of this approach.