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Applied Clinical Trials May 2021

COVID-19 has pushed patients across the healthcare spectrum–and especially those facing a diagnosis and treatment of cancer–to the brink, more than ever before. Today, cancer patients continue to push for their necessary screenings, advocate for surgeries and, for many of them, independently drive their own care while risking their health in an already overwhelmed medical system. Moreover, patients have lost their jobs and health insurance, compounding the immense stress and anxiety of everyday life.

Simultaneously, COVID has negatively impacted clinical trials, which can be more effective at treating cancer patients with advanced therapies compared to the standard of care. Many trials have experienced delays or even complete halts, with patients finding themselves unable to receive potentially groundbreaking treatments

Patients knew that cancer wouldn’t stop because of COVID, and they decided that enough was enough.

This created empowered, activated patients who began leveraging the tools available to them, including technologies like AI, to become fully engaged participants in their care alongside doctors. They’re taking back control of their health journey and learning how to make better informed treatment decisions.

So, why does this matter to the biopharmaceutical industry? Because the pandemic has exposed, and exacerbated, many long-standing issues that patients have dealt with for years that directly impact biopharma. Navigating very complex database networks to find the right treatment options and trials, for example, can be frustrating and confusing for patients given all of the medical jargon and eligibility criteria. Emerging from the year of COVID, these patients expect transparency and for their voice to be heard in an effort to change the industry for the better.

Biopharma companies can help revolutionize healthcare as we know it by first listening to the patient and taking their unique wants and needs into account. Do patients have the necessary resources that they need to manage their condition, using their doctors as partners? How can we leverage emerging technologies to assist in these efforts, provide patients with personalized treatment options and ultimately accelerate the biopharma industry’s forward progress?

Beyond COVID, technology will play a vital role in the evolution of cancer treatment and clinical trials. Thanks to AI, biopharma companies can now learn, for the first time ever, why cancer patients are deterred from participating in clinical trials. Is it the time and inconvenience required to travel to the site location? What are the patient barriers that biopharma can finally work to overcome to achieve more effective clinical trial recruitment, optimize clinical trial designs and avoid flawed data now that we are actually listening to the patient?

By bringing back the missing link–the patient–the industry will not only foster a stronger sense of trust between patients and biopharmaceutical companies, but it will also help to accelerate a drug’s time to hit the market for patients in need. It will create diversity in trials and make sure that everyone–regardless of socioeconomic status or location–has the opportunity to receive the best care possible. Instead of starting with sponsors, hospitals and investigators, let’s start with the patients themselves to truly make a difference.

This paradigm shift–from the biopharma industry leading the charge to making patients part of the process–is not merely a pandemic-era trend. The entire biopharma industry needs to partner with patients and leverage technology to drive real, meaningful change in how we treat cancer moving forward.

Medical Oncologist, former Deputy Chief Medical and Scientific Officer, American Cancer Society, current advisor for TrialJectory

Articles

Sparked by the pandemic, patients are now leveraging remote technology to take control of their healthcare.

Rise of the Activated Patient During COVID—Biopharma on Notice

The clinical research community is experiencing unprecedented challenges when it comes to treating COVID-19 and its associated symptoms, particularly tracking the impact of off-label use of existing medicines, repurposed drugs, new standard of care protocols, and new therapies under investigation.

These challenges have shown us, that as a community, in times of crisis, we must be ready to handle an increasing number of special situations, such as medication misuse, off-label use, medication and administration errors, and drug interactions. For example, we have also seen the importance real-world evidence plays in identifying risks associated with the COVID-19 vaccines that were granted emergency use authorization, as well as how critical real-time insights are to improving patient management and health outcomes.

Regulators have shared guidance to ensure global drug safety. In May 2020, FDA issued “Postmarketing Adverse Event Reporting for Medical Products and Dietary Supplements during a Pandemic.” Similarly, the MHRA has created a dedicated website to report side effects of medications and the use of medical devices. The EMA has also called on the medical community to report suspected side effects of therapies used to treat COVID-19 patients and to track drug interactions.

These initiatives call for the close, real-time monitoring of treatments that are used under emergency-use-approval and off-label use. We must understand their effectiveness and safety, especially while treatment protocols are frequently changing.

Undoubtedly, these challenges also impact clinical trials and the work performed by research teams, particularly medical monitors. As an example, off-label use of medications or use of drugs that are not part of the standard of care to manage COVID-19 symptoms increases the possibility of the occurrence of adverse events. These side effects will have to be evaluated not only in terms of their relatedness to the study drug, but also in terms of potential interactions. To protect patients’ safety throughout the course of a study in this environment, the role of medical monitoring should be redefined from an analog process perspective that heavily relies on reviewing spreadsheets, to utilizing modern review methodologies that focus on data science. To adapt to this need, medical monitoring needs to move from data handling in silos using old-school methods to new methods that enable the synchronous interaction of data monitors with stakeholders who handle data.

By continuing to use rudimentary tools and lacking expertise in data science, the productivity and quality of the medical monitoring team may be severely compromised. This poses a risk to roles that exist to identify and mitigate clinical risks in study design and conduct, providing strategic oversight that helps to ensure patient safety and data integrity. However, the medical monitor’s role doesn’t have to evolve into a more technical one, rather it must evolve to ensure the focus remains on what really matters–gaining valuable insights into the data.

The same way in which traditional clinical data management evolved to a more data science-focused approach, so too must medical monitoring. Medical monitors must be armed with improved data analysis tools. A modern electronic data capture platform, or any other platform or technology alone, will not enable this evolution in medical monitoring. That’s because using such systems often still involves unclean data and lengthy reviews, which do not allow for the identification of outliers and trends. Smart listings, visualization tools, and a deep understanding of the database beyond the study protocol, are a few items that will allow for a comprehensive review and that will enable monitors to grasp the bigger picture and make the most of the data. Understanding data science and the tools that support it is essential for medical monitors. With this knowledge, they will be better equipped to apply smart medical data review methodologies and provide valuable insights by making the most of clinical data assets.

Clinical trials are increasing in complexity with more data points, more data sources, more technologies, and more integrations, while the timelines get shorter and shorter. Increasing data transparency requirements and communication with regulators have already transformed operations. As such, medical monitors must embrace a data-savvy approach to continue proactively adding value.

Director, Global Medical Advisors, Bioforum

COVID-19 creates unique challenges for medical monitors.

Aligning Medical Monitoring and Data Science

Digital health technologies (DHTs) is an emerging term for technologies that use computing platforms, connectivity, software, and sensors for health care and related uses. In clinical drug development, there are some familiar uses, such as connected blood glucose meters in diabetes studies. However, there’s been limited uptake at scale outside certain therapeutic areas.

Taking a look back at the historical development of DHTs, Holter monitoring achieved the first radio-wave broadcast of an ECG signal in 1947. The measurement and transmission equipment was housed in a 38kg backpack–ironically perhaps enough to provoke a heart condition! Since then, the miniaturization of sensors and circuitry has enabled the development of wearable cardiac monitoring devices that can be unobtrusively worn for many hours, something we now see used in both clinical trials and routine care. Accelerometers that track physical activity (PA) and sleep have enabled passive monitoring with affordable and convenient devices since the early 2000’s,

 and in the last decade, the devices have become popular components of personal health tracking bands and watches.

Today, we see growing regulatory interest in the use of DHTs for the development of novel clinical endpoints in drug development, apparent in FDA’s development of patient-focused drug development guidances.

 Several novel, sensor-based endpoints have been accepted into the FDA’s Clinical Outcome Assessment Qualification program, including accelerometer-based measures for chronic heart failure (CHF), multiple sclerosis (MS), pain, and sarcopenia. In Europe, the EMA qualified the PROActive composite measure, which combines patient-reported outcomes data with activity monitor data for an endpoint in chronic obstructive pulmonary disorder (COPD) trials.

The interest in DHT usage is compelling. Not only does the technology enable more frequent measurement, but in some cases, measurements may be more accurate or convenient to obtain. Further, DHTs may enable measurement of constructs that have not been possible to measure before, and may enhance the oversight of patients between physical clinic visits. Despite this, our industry is slow to scale up the use of DHTs, perhaps due to the challenges and knowledge gaps below:

Does a DHT enable us to measure something meaningful?

Do we understand the evidence needed to support the selection of a specific
DHT device?

Do we have good implementation and data management standards?

Do we understand the relationship between endpoint properties and the specific
DHT device?

Gregory House MD, the fictional physician in the eponymous TV drama, had the mantra to never talk to the patient for insight into their condition. We’ve advanced from this approach FDA’s patient-focused drug development guidances establish the need to develop clinical outcome assessments that can be shown to effectively measure constructs that are meaningful to the patient.

 This applies to endpoints derived from DHT data.

DHTs may offer a suitable approach to measuring a meaningful aspect of health that is related to a study’s concepts of interest. However, careful consideration is needed to determine how to derive meaningful outcome measures from DHT data. For example, while we may rightly consider PA as an important concept to measure for many disease indications, is total steps per day or the time spent in moderate to vigorous PA (MVPA) always the most meaningful measure? A COPD or CHF patient, for example, may find the ability to conduct short bouts of purposeful walking at a steady, continuous pace the most meaningful. In this case, a measure of bouts of walking for a defined duration and pace may represent the most meaningful measure to derive from daily activity profiles.

In their work with the DIA Study Endpoints Community, Walton et al. described a useful framework for the development of meaningful endpoints.

 In essence, the process requires insights into the aspects that are most meaningful to patients–likely established through qualitative research in the patient group–to identify meaningful aspects of health from which to define concepts of interest for health measurements. By understanding these valued aspects, pertinent endpoints can be defined, and an appropriate measurement approach can be identified–which may include a DHT. See Figure 1 below as an example.

Evidence needed to support DHT device selection

Perhaps one of the main barriers to scaling up of use of DHTs in clinical trials is the underlying concern as to whether the data will be accepted by a regulator. However, several cross-industry consortia have made valuable contributions to define “fit-for-purpose” DHTs, and the evidence needed to support their use for clinical endpoints and regulatory decision making. Contributions were made by the Critical Path Institute’s ePRO Consortium,

 the Clinical Trials Transformation Initiative (CTTI),

 Using these, we now know enough about how to select a fit-for-purpose device and the associated supportive evidence for this concern to no longer be an issue.

Good data management and implementation standards

The literature doesn’t always provide a robust consensus on the implementation and data management standards for DHT use. In my review of clinical research studies that used an accelerometer to study PA in COPD, I found little consistency in implementation approaches, including placement location, duration of wear time, and endpoint studied.

For example, the 76 studies evaluated reported 80 different study endpoints derived from accelerometer data. Despite this, we can adopt an endpoint-driven approach to define implementation and data management approaches.

Using the example of PA measurement, the endpoint of interest drives implementation considerations. For example, placement location may be driven both by patient acceptability and optimization for measurement. The hip is close to the center of mass and is often the best location for energy expenditure measurements, at least in the lab setting. The wrist may be chosen for better wear compliance, but may overestimate PA or be insufficient at distinguishing light PA. The thigh is optimal for studying sedentary behavior due to the specificity in distinguishing sitting from standing, but only certain devices are suitable for this placement location (e.g., ActivPAL (PAL Technologies, Glasgow, UK)). Wear time may be similarly endpoint-determined. If studying total steps/counts per day or total MVPA time, wearing the device for the majority of the day will be important as well as measuring across a reasonable number of days to obtain a good overall PA estimate. However, if real-world walking speed or cadence is the endpoint of interest, these measures are typically quite consistent during purposeful episodes of walking across the day, so wear time will be important to capture a number of walking bouts and may not require all-day use.

Data collected that does not meet minimum wear time considerations are typically discarded, although work is underway through the DIA’s Study Endpoint Community to explore other approaches in handling missing data amongst the rich, time-series data collected by some DHTs.

Endpoint properties and different devices

An important question to endpoint developers using DHTs as a measurement instrument is whether endpoints are device-dependent or device-agnostic. This information will allow us to answer important questions such as:

Can I interchange DHT devices within a study or across a development program?

Can I compare the results from different development programs measuring the same endpoint with different DHTs?

Can I adopt a bring-your-own-device (BYOD) approach to DHTs?

This is a common question in the field of patient-reported outcomes, and we understand the importance of ensuring the measurement properties of validated patient-reported outcome measures are conserved when implemented in different formats (e.g., paper, smartphone, tablet).

At this time, we do not believe DHTs provide enough equivalence evidence to support device-agnostic endpoints for some key measures. For example, Bender et al.

 studied concordance of PA measures provided by Fitbit, Garmin, and Apple devices in healthy volunteers within free-living conditions for 14 days. Their evaluation concluded that step count, distance traveled, and calories burned could vary significantly between devices used concurrently–the total step count differing by up to 30%. Measurement differences occur even with research-grade devices. For example, in the development of the PROActive measure, a monitor-specific data conversion was needed to derive the endpoint consistently using either of the two selected activity meter models.

 However, such differences in processed daily summary and epoch data may be mitigated by applying a common algorithm to raw accelerations data collected by different devices when access to this raw signal data is available. Differences between devices have also been observed in other areas such as optical heart rate sensors.10

Endpoint developers should consider the degree of tolerance between acceptable devices to maintain a reliable endpoint when different measurement devices are used. If this cannot be achieved, a sensible approach would be to standardize use of a particular DHT device within a development program, or select a device manufacturer with backward compatibility in the measurements provided.

DHTs offer great potential to measure constructs more frequently, more accurately or conveniently, or to measure things we have been unable to measure before. These technologies enable greater oversight and monitoring of patients between site visits and within decentralized trial models. We should apply DHTs when they offer an appropriate approach to measure a clinical endpoint related to a study concept of interest. As we have explored, endpoints derived from the DHT-collected data should measure aspects of health that are meaningful to the patient.

We know enough about the evidence needed to support device selection and endpoint validation requirements to scale up the use of DHTs in clinical trials. While consistency between makes and models still needs to be considered, researchers should retain a single device if demonstrating measurement equivalence across devices is a concern.

The drive towards greater use of remote assessments will see more work emerging in defining and validating clinical endpoints derived from DHT data. We can expect to see continued interest and an increase in the use of DHTs in drug development programs to support regulatory decision making.

Troiano RP, McClain JJ, Brychta RJ, Chen KY (2014) Evolution of accelerometer methods for physical activity research. 

https://doi.org/10.1136/bjsports-2014-093546.Evolution

FDA (2017) FDA Patient-Focused Drug Development Guidance Series for Enhancing the Incorporation of the Patient’s Voice in Medical Product Development and Regulatory Decision Making. 

https://www.fda.gov/drugs/development-approval-process-drugs/fda-patient-focused-drug-development-guidance-series-enhancing-incorporation-patients-voice-medical

Gimeno-Santos E, Raste Y, Demeyer H, et al (2015) The PROactive instruments to measure physical activity in patients with chronic obstructive pulmonary disease. 

https://doi.org/10.1183/09031936.00183014

Walton MK, Cappelleri JC, Byrom B, et al (2020) Considerations for development of an evidence dossier to support the use of mobile sensor technology for clinical outcome assessments in clinical trials. 

https://doi.org/10.1016/j.cct.2020.105962

Byrom B, Watson C, Doll H, et al (2018) Selection of and Evidentiary Considerations for Wearable Devices and Their Measurements for Use in Regulatory Decision Making: Recommendations from the ePRO Consortium. 

https://doi.org/10.1016/j.jval.2017.09.012

Clinical Trials Transformation Initiative (CTTI) (2017) Recommendations on developing technology derived novel endpoints. 

https://www.ctti-clinicaltrials.org/projects/digital-health-technologies

Society DM (2020) The Playbook: Digital Clinical Measures. 

Byrom B, Rowe DA (2016) Measuring free-living physical activity in COPD patients: Deriving methodology standards for clinical trials through a review of research studies. 

https://doi.org/10.1016/j.cct.2016.01.006

Bender CG, Hoffstot JC, Combs BT, et al (2017) Measuring of fitness trackers. 2017 IEEE Sensors Appl Symp 1–6. 

Bent B, Goldstein BA, Kibbe WA, Dunn JP (2020) Investigating sources of inaccuracy in wearable optical heart rate sensors. 

https://doi.org/10.1038/s41746-020-0226-6

 VP, Product Intelligence and Positioning, Signant Health

Increased use of remote assets will showcase new endpoints derived from digital health technologies.

Utilizing DHTs for Clinical Trial Endpoints

Over the last year, sponsors and CROs have embraced centralized monitoring and risk-based quality management (RBQM) in a bid to keep trials on track under extenuating pandemic circumstances. The shift may have been out of necessity initially, but the benefits–from accelerated development timelines to a higher likelihood of study success–have been obvious. Now, there is no putting the genie back in the bottle: RBQM and centralized monitoring are here to stay.

When the pandemic hit in early 2020, unnecessary face to face contacts, including clinic visits, were halted and regulatory bodies recommended fresh risk assessments for all ongoing studies. This shift framed the traditionally conservative sector in a new light. Suddenly, concepts such as remote and centralized monitoring along with the broader RBQM paradigm, which have long been lingering at the side lines of clinical trial management, were brought into sharp focus. As companies navigated the minefield of regulation and inherent risk, tailored assessment and decentralized data collection became essential. Meanwhile, their benefits, pandemic or no pandemic, became obvious.

RBQM, with its ability to quickly prove therapies are safe and effective, can dramatically accelerate the drug development pathway. It drives up data quality and allows early risk detection, both of which are crucial to supporting the pace of programs and making high efficacy treatments widely available in the shortest time possible.

As such, we are now seeing an industry-wide move towards this new way of working. In a recent poll taken from our webinars, out of 650 industry representatives, 56% said there were either already implementing RBQM or were about to start. A further 25% said it was already an integral part of how they run their trials. Overall, 81% are either implementing or have already fully adopted RBQM.

 and addressing the huge additional risks the pandemic introduced to clinical trials was a daunting task. Yet, organizations were unfazed and worked quickly to develop the tools and processes they needed to ensure their studies could continue safely and effectively. 

One CRO, a global leader in early phase clinical research services, for example, applied CluePoints’ complimentary COVID-19 package, which incorporated a SARS-CoV-2-specific Risk Assessment template, to more than 100 studies. They used the tool, which features relevant risk categories, associated considerations, and detailed Key Risk Indicators (KRIs), to define COVID risk and establish mitigation procedures. For them, and many other organizations like them, going through this process has demonstrated the value of proactive risk mitigation in protecting data integrity and maximizing the chances of trial success.

RBQM solutions provide a way of identifying, visualizing, managing, and documenting the risks that could impact the outcome of a clinical trial. The method has proved its worth during the pandemic, especially in the race to find a vaccine, where at least one sponsor organization utilized the approach to support the rapid development of their product.

Centralized risk monitoring software allowed the sponsor to interrogate data from more than 100 global sites in near-real time. Using a combination of KRIs, quality tolerance limits, and statistical data monitoring techniques, a central monitoring team was able to conduct twice-weekly risk review meetings with the study team. This allowed potential issues to be identified, investigated, and rectified before they even had a chance to affect data quality.

By focusing on speed, accuracy, and reliability, the sponsor was able to mitigate risk to both patient safety and data integrity. In doing so, they were able to lessen any potential delays to final approval submission at a crucial point in the global health crisis.

Across the sector, every effort is being made to achieve unprecedented progress with vaccine trials and COVID-19 treatments. Several leading CROs have selected RBQM solutions to ensure that no data quality stone is left unturned in this mission. Such platforms allow clinical trials to detect risks as early as possible, meaning corrective action can be taken in record time–and this is a benefit that far transcends the pandemic.

Developers and sponsors around the world are united in their aim to get life-changing new medicines to the people who need them as quickly as possible. And, as demonstrated above, RBQM helps organizations to do just that. In addition, robust RBQM solutions allow teams to access information centrally, collaborate on investigations, and document any mitigations or remedial actions. Not only does this result in a clean dataset, but it also creates a reliable audit trial for regulatory scrutiny.

Traditional site monitoring methods, such as source data verification (SDV), are quite simply unable to provide the same level assurance within such rigorous processes and rapid timelines.

Centralized monitoring is another pertinent area in the field of clinical trial management. Cloud-based centralized monitoring solutions allow sponsors to interrogate clinical and operational data in real-time, increasing efficiency, improving patient safety and reducing costs.

Since early 2020, on-site monitoring has not, in the main part, been possible, and central statistical monitoring has presented a proven alternative. Statistical algorithms that interrogate study data accurately and in an unsupervised manner help to identify risks early. This allows stakeholders to focus their attention on atypical sites, patients, regions
or countries.

It has proved extremely useful during the pandemic, but this approach, which regulators have long advocated, seems set to stay in a world where remote working has gone from a “nice-to-have” to imperative for business continuity. Fortunately, it is possible to eliminate or reduce on-site monitoring without significantly impacting trial oversight. Sponsors and CROs utilize a centralized monitoring platform that triggers site follow-up by web-based applications, phone, or email if risks are detected.

Last year was an opportunity to reflect on what matters most–and it is vital not to lose sight of what we can achieve when we work collaboratively. By seizing the moment, we can continue to aspire to even greater achievements.

It has been an extremely challenging time for clinical trial management, but it has also demonstrated the benefits of early risk identification. As such, COVID-19 accelerating the implementation of RBQM solutions. The approach allows study leaders to use the risk assessment process to first identify and then focus on the most critical data–the safety and endpoint data that matters most to each individual trial. It has proven invaluable in effectively managing studies to database lock with all the necessary assurances.

Clearly, the inability to physically visit sites has tremendously impacted onsite monitoring, and sponsors have increased their reliance on techniques such as centralized monitoring. In this respect, COVID-19 has accelerated a movement that has been simmering since the 2016 release of ICH E6 (R2) and has helped to drive change away from inefficient, legacy practices.

Organizations are now committing to adopting these data-driven approaches as their permanent operating practices in the future. Astellas, for example, has said it has no plans to revert to SDV transcription checking, which the company has said does not provide the same value as risk-based management.

The pandemic has demonstrated the value of modern clinical trial management, meaning it will undoubtedly ensure that the long-promised shift to risk-based methodologies will finally become reality.

Sponsors know that if they are to have any chance of seeing an increase in drug development pipeline activity, they must do more with less. Virtual trials, remote monitoring, wearables, and RBQM are all attractive ways of doing just that, but, up until now, adoption has been slow.

The pandemic has provided the catalyst the industry needed to take the risk-based bull by the horns. And in moving from theory to practice, it has proved the approach can accelerate development while protecting data integrity.

https://www.outsourcing-pharma.com/Article/2020/12/07/How-has-COVID-19-impacted-clinical-trial-data-collection

https://www.ema.europa.eu/en/human-regulatory/overview/public-health-threats/coronavirus-disease-covid-19/guidance-medicine-developers-other-stakeholders-covid-19

https://globalforum.diaglobal.org/issue/september-2020/looking-to-the-future-with-rbqm/

https://www.centerwatch.com/articles/24898-remote-monitoring-wont-require-post-pandemic-re-monitoring-fda-says

 Chief Commercial Officer and Co-Founder, CluePoints

How it has taken a global pandemic to reinforce the intrinsic benefits.

Why Centralized Monitoring and RBQM are Here to Stay

Clinical Research Associates (CRAs) are in the unique position of working directly with sites to support and actively observe the progress of sites and their patients when participating in a clinical trial. During the height of the COVID-19 pandemic, this core aspect of a CRA’s role was altered greatly, with many sites unable to continue research and/or unable to accommodate visitors, therefore forcing a change in the method of monitoring source documentation and challenging their relationship with site staff. Being prepared for remote monitoring, it was important that I carefully navigate this new change with my sites and ensure they felt fully supported and comfortable throughout.

As healthcare workers have had to adapt to the ongoing public health crisis, the CRA role has also had to accept and support site adaptation to new trial elements. As a CRA in the UK, I worked with sites on implementing these new methods of data collection and patient oversight, including direct-to-patient study drug shipments, use of home health services, and far more reliance on patient symptom reporting than pre-pandemic. A CRA’s role in reviewing and verifying study data has adjusted to being conducted entirely remotely for many studies, which has certainly not been without its challenges.

The work of a good CRA is invaluable to a successful clinical trial and is bolstered by a strong relationship with the clinical staff at the site. CRAs have had to adapt to regulatory changes, client guidance, and the changing site needs, assisting sites with new methods of performing subject visits and capturing data, and working closely with investigators to support their management of trial subjects. Our role as an advocate for our sites and their patients and our skill of understanding the trial and its challenges from both the sponsor and site’s sides is more important than ever. Though sponsors, CROs, and sites all share the same core purpose in research for improving the lives of our patients, the practicalities of running a trial are often what sets us apart. Protocol mandated procedures and methods of data collection, though seemingly straight forward, have met challenges at sites when faced with hospital visitor restrictions, government travel restrictions, the risk of COVID-19 associated with visiting hospital, vulnerable patients, redeployed staff, limited time…the list goes on! This in turn has only cemented my knowledge that collaborative working and a good relationship between a CRA and their sites is crucial to the integrity of the trials and their patients.

Additionally, sponsors had to be flexible and adapt their trials to sites, recognizing the pressure sites are under and following their lead in prioritization of their clinical needs in times of huge clinical demand. Many research staff were redeployed to assist in other clinical areas, recruitment onto many research studies was put on hold, opening of new studies was halted at times, and subject visits were frequently cancelled or delayed to reduce the risk to vulnerable patients. The decision to halt and restart clinical trial visits and recruitment through the peaks and troughs of the pandemic lay with the institutions themselves, who were best able to assess their capacity and capability for individual trials and study teams.

Alongside the CRA’s role in supporting sites, their typical role in conducting source data verification (SDV) and monitoring of study sites has had to adapt to remote monitoring. Remote monitoring was introduced to enable CRAs to access source data and conduct monitoring visits without travel to the site. Though the industry is moving towards a decentralized model including more remote practices, this was mostly a new method of monitoring for sites and presented many challenges. Remote monitoring visits are being conducted with and without SDV. The decision about whether SDV can be done is based on a number of questions:

Does the site use Electronic Medical Records (EMR)? If so, is EMR used for all medical records, or part paper, part EMR?

Does a CRA get direct access to source EMR for consented patients? If so, is their EMR set up to be accessed off-site? Can CRAs get access remotely if so?

Is remote monitoring approved by local and central authorities?

From my experience in the UK, the majority of remote monitoring performed during the COVID-19 pandemic has been performed without SDV due to challenges in meeting the necessary criteria. When it has not been possible to access a site’s source, remote monitoring has allowed site monitors to continue to review the electronic data capture and vendor reports and hold regular discussions with their sites to review study and subject progress. Remote monitoring without SDV, though challenging, has still been found to be valuable in highlighting and resolving issues, maintaining good working relationships with the sites, ensuring data is entered, training site staff, and ensuring the ongoing success of the study.

At times when a CRA is able to access full source documentation remotely via EMR, CRAs have been able to continue on their core role monitoring data, ensuring the integrity, accuracy, and validity of data, and the safety of patients. In cases when CRAs are given remote EMR access, often not all source is electronic and there is no access to paper notes, therefore the complete SDV cannot be done. In these cases, when CRAs can return to sites, they will need to review subject visit source documentation which has been completed remotely with access to all subject records including paper notes, to ensure nothing is missed.

Full SDV is considered “gold standard” for remote monitoring, and my discussions with my colleagues indicate that this approach is more developed in many countries in mainland Europe due to them having an appropriate EMR system which is accessible remotely. The situation in the UK has resulted in a substantial backlog of data to be monitored, which will take several months to clear, and that backlog, for many studies, appears to be noticeably less in many mainland European countries. From my discussions with staff at the sites, it seems that the installation of an EMR system may not be sufficiently high on the priority list to be awarded funding by individual sites or trusts. The UK government has pledged increased financial support for research within the NHS, and from a remote monitoring perspective, it would be ideal if some of this funding went into a single pan-UK EMR system or, if that proves impossible, multiple EMR systems which can seamlessly “talk” to each other. Examples of both arrangements already exist in many countries in mainland Europe, and satisfy GDPR requirements sufficiently to allow trial monitors to access relevant records remotely to perform SDV.

As sites adapted to remote monitoring and continued to accommodate monitoring visits when possible during the COVID-19 pandemic, another challenge arose around EMR access. In some instances, EMR access is given directly through a web-based system the CRA can log into independently; at other times a member of the site study team screen shared the EMR remotely. Screen sharing has its own challenges, as it relies on the study coordinator’s time, which is especially limited during the pandemic. Additionally, it was necessary to have an open and honest relationship with the study coordinator, as the study coordinator had to follow requests from the CRA to navigate the source documentation for a reliable and full review.

Though this period has been challenging for monitoring clinical trials, it’s clear those who were able to adapt and learn from this pandemic will only go on to further trial success in the future, strengthening their relationships and building their skills in advanced trials innovations as the industry moves to a more decentralized model.

Clinical Research Associate III, Pediatric Site Network—UK Site Relationships Manager, PRA Health Sciences

COVID-19 reshaping the roles of CRAs overseas as industry shifts to remote monitoring.

Navigating New Changes During the Pandemic

A simple question: Will remote site monitoring (and remote patient monitoring), adopted out of need over the last year, become permanent assets in clinical trial protocols?

The simple answer is yes. The success achieved in the creation of the coronavirus vaccines, from speedy development to speedier authorization, leaves little doubt that remote monitoring has value. COVID-19, said Samuel Volchenboum, MD, PhD, MS, University of Chicago Medicine, forced the issue of enrolling patients and running trials remotely.

But define value: how and to what extent? Is the value sought in a piecemeal fashion, as in wanting cost savings from fewer site visits? Or by focusing on patients, making enrollment and adherence more attainable by allowing use of apps or wearable devices so they can participate from wherever they live? Or just looking for those anomalies, findable in real time, which therefore allow protocol tweaks if need be?

No, said those interviewed for this story, the sole way to get total value out of remote monitoring is to design the entire trial with checks and balances, recording data in real time so there is control and transparency, ensuring all sources are traceable, trackable and analyzable. In other words, trying remote monitoring without imbuing the protocol with risk-based quality monitoring from stem to stern will save neither money or time.

Which brings us to discussion of the complex answer. Before COVID-19, these checks and balances were available, but few sponsors wanted any part of them. Using source data verification and electronic data capture was familiar and comfortable. And most companies invested in their own configured systems developed in the 2000s. Those systems didn’t include the necessary and facile software as a service that can pinpoint the across-data-type anomalies that we have today, said Lisa Moneymaker, vice president, Clinical Operations Technologies, Medidata. “Tech [inside industry] couldn’t
support this.”

Further, Penelope Manasco, MD, MDMS, founder, MANA RBM, added that having new tech doesn’t change mindset. “I think traditional methods are deeply ingrained. Whenever we talk to a [client] they say, ‘but this is how I learned to do clinical trial oversight.’ It is a mind switch.”

In addition, Moneymaker points to an oft-discussed industry characteristic: “Industry is slow to pivot; it’s one thing to say be risk-based, but in many ways, we are extremely risk averse,” said Moneymaker. However, she noted that if industry doesn’t start making changes such as incorporating transparency trial-wide and monitoring data in real-time to ensure data sources are verifiable, industry will find it difficult to reach its desired ROIs.

Which leaves advancing remote-based quality monitoring where?

It’s not as if any stakeholder has to go far to see what remote-based monitoring can do. A relatively ordinary event, set into motion 21 years ago, precipitated the following: a diagnosis of pediatric acute lymphoblastic leukemia (ALL) today is no longer an absolute death sentence as it was 50 years ago.

In 2000, two pediatric oncology groups merged to become the Children’s Oncology Group. Soon after, the human genome was mapped, allowing researchers to delve into the genetic reasons why a child can develop ALL,

 giving pediatric oncologists better ways to diagnose and treat. In 1975, the death rate was 1.1 out of 100,000 children. By 2013, the rate was 0.2.

 Today, most children diagnosed with ALL make the five-year survival threshold.

But these aren’t the only reasons, said Volchenboum, also director of the university’s Pediatric Cancer Data Commons. The trials’ uniform design, standardized data language, use of central monitoring, and the heterogeneous patient population have all contributed to that survival rate.

By running these trials consistently across sites, with all data trackable, traceable, and compared to baseline, with protocol constantly followed, COG achieved “[five-year] cure rates for acute leukemia to go from 0 in the 1950s, to over 90% for acute leukemia,” he said.

Elsewhere in the world, Beijing specifically, researchers looked at how they could implement strategies that would reduce the impact of COVID-19 on staff and patients involved in 572 oncology trials. The authors established a remote management model, making changes to trial processing, enrollee management and quality control. Measures used to achieve compliance rate included differences in rate of protocol compliance, patients lost in follow-up or trial withdrawal and deaths. The study published last month, said the researchers obtained a compliance rate of 85.24% for 3,718 patients, during both COVID-19 outbreaks. No one was diagnosed with COVID-19, the authors said.

More than 1,000 studies were suspended between March 1 and April 26 last year, 905 indicated in clinicaltrials.gov that COVID-19 caused the suspension.

 Cynthia Matossian, MD, an ophthalmologist in Bucks County, Pa., who regularly conducts clinical trials, had no trials running during the pandemic shutdown. Many of her peers weren’t as lucky. “They had to stop in the middle of it.”

Oracle surveyed 252 industry professionals in November, asking how the pandemic had affected ongoing clinical trials. Survey respondents said COVID-19 has caused longer enrollment times (49%), amended protocols (45%), and paused protocols (41%).

The Oracle survey also showed that while two-thirds of respondents were using remote data collection in their trials—patient apps, ePRO and wearables—nearly half of these professionals said a primary concern with using new sources and methods of data collection was just that; shifting gears would mean adopting a new approach to manage, review, and interpret the data.

Starting last year, said Rajneesh Patil, IQVIA’s vice president, Digital Strategy and Innovation, 60% to 70% of its customers looked at incorporating these standardized, transparent, remote monitoring methods into their protocol design. The on-site operating model is shifting to remote source verification and data quality is more significant because of site access, he said. From the patient’s vantage point, having a protocol design that is easy to follow, allows for wider participant involvement, including people living in remote areas.

Patil said if the trial design allows review of patient data remotely and holistically, sponsors will learn what analytics can do to safeguard endpoint information, such as finding if there are unreported endpoints and pinpointing incorrectly enrolled patients. Pharma also learned that patients stay in trials if they can report remotely. “They don’t have to drive to the site,” he said.

Agreed, said Oracle’s Jim Streeter, global vice president, Life Sciences Product Strategy. “They stay in the trial if it is remote. That is one thing [the industry] learned.”

Designing a remote-based quality monitoring trial is work, said Patil. Upfront, it requires more rigor around planning and design to ensure it is quality-focused. With a more seamless upfront design, and more patient adherence to on-going site compliance, data can be locked for analysis faster. “We can close 30% to 40% quicker than in a traditionally run trial,” he said.

While some specialties may work better with remote site monitoring, like ophthalmology, many specialties work well with both remote site and remote patient monitoring. Studies on the latter often focus on oncology. One oncology study that examined remote patient monitoring noted that decentralization could improve the trial’s adaptability, as these trials have sick patients who aren’t close to a test site, and other complexities.

Matossian conducts trials primarily on dry eye disease. The five trials her group recently started or will start soon all have remote site monitoring. Before COVID, Matossian would conduct patient observations and fill out various paperwork. Monitors would come on-site to review the papers, ensure consents were properly filled out, etc. Now all data are sent via portal via scan and upload. For her, remote site monitoring means cost savings for sponsors because the information is collected via portal, therefore, not requiring costs related to travel. COVID-19, she said, has “created a new way of looking at things. Moving forward, we have to be nimble and adapt.”

Regulators in the US and Europe were prescient: both FDA (in 2013) and EMA (in 2010) told sponsors that they embraced remote monitoring. Said FDA: The agency “specifically encourages greater use of centralized monitoring methods where appropriate…”

And both agencies asked sponsors to rethink its definition of what constitutes an important error. Capturing a wrong age or comorbidity shouldn’t affect outcomes as long as those errors are distributed throughout the trial sites.

But, FDA wrote, missing an adverse event could alter an endpoint. The EMA noted that resources should be used to address “the most important issues and priorities, namely patient safety and the quality of trial data.”

Manasco applauded the regulators. “They came out as visionaries.”

What is super important, said Patil, is to know what the critical data points are and to make sure they have integrity and quality. “Every single database has errors; they are never 100% error free.” All endpoint data—the lab work, safety checkpoints, patient eligibility—must be congruent. They must be analysis ready.

Manasco wants everyone to meet the Pancake Man. On the worksheet, a trial participant was three feet tall and weighed 200 pounds. He is a real person, she said, so most likely taller than a hobbit. Investigating the worksheet, she heard from a trial assistant that those figures were on the worksheet, so it is correct.

“We hear this all the time, they say data is right and we say it is not compatible with life,”
said Manasco.

Medidata has uncovered possible data fabrication. In one situation, hypertension was included in the intake medical history, but no hypertensive readings were recorded throughout the study, said Moneymaker. In another case, a look at adverse events across the sites showed at least three events on average, but a site with data anomalies did not have any.

At Oracle, data management has lined up data against data for years. “Data management can create a set of queries so the outliers don’t happen,” said Streeter. An oncology study can have 800 to 900 edit checks that can be unimportant or not even necessary to check, he said. One of the more interesting anomalies that Oracle has found are male participants with pregnancy tests. There are the checks and balances, he said, whether caught by the data manager, the CRA review, or the statistical review.

Some inaccuracies are inherent in trials because people will be people, especially if they are children. Volchenboum said the problem with diaries and surveys is that people do not fill them in as instructed. “I used to see children in the waiting room with their diaries. They were supposed to take notes every night, instead of scribbling vigorously in my office.” But with a wearable, “we can see if they are wearing it. If not, nurses can call. Data will be much more accurate.”

Manasco agreed: “If you don’t police your patients, you won’t know how good the quality of your trials are.” And that may become more of a factor since studies show that participants like remote; they like wearables; and they will even use their own phone.

COVID-19 might have led industry down the path to the remote-monitoring waters, but will it drink?

Pharma is more sipping than slurping. Sponsors have had a difficult time getting their heads around that it is more important to focus on executing the protocol correctly and ensuring that the right metrics are delivered than results, said Manasco.

One Oracle client has two out of its 18 trials using remote technology. Why? “They are still trying to figure out how to work it. This company saw the advantages of it and are trying it out,” Streeter said. There are a lot of questions from sponsors on how to add the technologies in.

But Volchenboum has some answers; five years ago he co-founded a company called Litmus Health, which is a platform for data collection for wearables in clinical trials. Litmus develops metrics for wearables. The algorithms need to be transparent, he said, otherwise, the sponsor couldn’t report the data because it wouldn’t know how the findings were calculated. The wearable has to be used in the trial for what it was designed for, per FDA.

Right now, said Moneymaker, industry is at a unique tipping point, because pharma trials that survived the COVID-19 clinical trial freeze-out are in hybrid transitional-remote monitoring mode. “Those that could pivot, already had pieces in place.”

Pharma’s trepidation is easing, said Volchenboum, because “It is too attractive a way to collect data.” FDA thinks so; The rules and regulations for using what it calls drug development tools were published in the federal register in November.

A lot of conversations need to take place among players in the clinical trial space to achieve standardization across the board, Moneymaker said. Industry, vendors, purchasing, and companies like Oracle, Medidata, IQVIA need to mind-meld because the tsunami changes that a digital transformation requires demands nothing less.

Doing a side-by-side comparison of different oversight methods with remote quality assurance is a project MANA RBM’s plans for the near future. “We need to test how we do clinical trials better. We haven’t done that as an industry. We need to be data driven in oversight.”

Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)–Health Professional Version. Updated Feb. 4, 2021.

US Mortality Files, National Center for Health Statistics, Centers for Disease Control, Table 28.4; 1975-2013.

American Childhood Cancer Organization. What Is The Expected Lifespan Of A Child With Leukemia? September 10, 2018.

Zhiying Fu, Min Jiang, Kun Wang, Jian Li. Minimizing the Impact of the COVID-19-19 Epidemic on Oncology Clinical Trials: Retrospective Study of Beijing Cancer Hospital. 2021. 

Malke Asaad, Nilofer Khan Habibullah, Charles E. Butler. The Impact of COVID-19-19 on Clinical Trials. 2020; Ann Surg. Sep; 272(3): e222–e223.

Oracle Press Release. Survey: COVID-19-19 the Tipping Point for Decentralized Clinical Trials. Nov. 18, 2020.

Aaron C. Tan, David M. Ashley, Mustafa Khasraw. Adapting to a Pandemic — Conducting Oncology Trials during the SARS-CoV-2 Pandemic. 2020. 

Clinical Cancer Research | Perspectives. 

U.S. Department of Health and Human Services, Food and Drug Administration. Guidance for Industry. Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring. August 2013.

EMA. Reflection paper on risk based quality management in clinical trials. 

Cureus Pugliese L, Woodriff M, Crowley O, et al. (March 16, 2016) Feasibility of the “Bring Your Own Device” Model in Clinical Research: Results from a Randomized Controlled Pilot Study of a Mobile Patient Engagement Tool. 

Federal Register. Qualification Process for Drug Development Tools; Guidance for Industry; Availability. A Notice by the Food and Drug Administration on 11/25/2020.

Pandemic-forced move to remote monitoring calls for industry-wide collaboration.

Maximizing the Value of Remote Monitoring

Pfizer, Moderna and Johnson & Johnson have started to expand COVID-19 vaccine clinical trials to include pregnant women and children under 12 years old, and soon Pfizer will begin trials on children two to five years of age. With scientists reporting the pandemic may never be fully controlled until children are vaccinated, the questions of ethics, safety and speed turns to that patient cohort. To get more insights, 

 spoke with Michele Russell-Einhorn, Chief Compliance Officer at Advarra, a provider of integrated regulatory review solutions, as well as research quality and compliance consulting services and clinical site technologies.

Applied Clinical Trials: Advarra’s IRB and IBC supported 100% of Operation Warp Speed (OWS) vaccine trials. Can you explain Advarra’s role?

 Advarra has been honored to have played its role in overseeing research to find ways to prevent, treat and diagnose COVID-19. We have as our largest service, the IRB review service, but also has the institutional biosafety service (IBC), which precedes the IRB review. For the research studies that are part of Operation Warp Speed, we’ve either done the IBC review for that research, or the IRB review for the research or both. In the case of Moderna, we did the institutional biosafety review, and we did the IRB review.

ACT: Was there anything different about reviewing protocols for the OWS initiative than any another trial?

 It really wasn’t what was different about this from another trial, as much as what’s been different about research in the pandemic, as a whole. We have been overseeing 700-plus main protocols in COVID-19. And with every one of them, there’s a sense of urgency. And notwithstanding the urgency, there’s also a need to maintain quality and expertise.

The companies have been working very hard to get these agents out to the public. It’s a miracle that in March last year, the country was starting to shut down and here we are, a year later, and we have four vaccinations. Operation Warp Speed was really the catalyst to place all of the pandemic research into this more urgent category.

The other issue is that we are used to drug and device development taking a long time, and this took 11 months. But it doesn’t mean there’s anything wrong with it, and notwithstanding the issues with AstraZeneca and J&J, every once in a while, there’s a commercially available drug that gets recalled by FDA. And the fact is that an FDA approved drug may have gone through eight years of drug development and a 300,000-person Phase III trial, but everything has some risk, and we need to balance the risks.

This is an opportunity to look at how did we do this in 11 months. And what can we learn from this and take going forward for all
other research.

ACT: How was the company able to process the amount of documentation required to protect patients in those trials?

 Advarra has many years of experience in the area of multi-site research and has been overseeing research with upwards of 300 sites. In order to do that, we have always needed to have a system in place that incorporates all the people—the board members, IRB members, operations staff, and others—who can receive and review the documentation and ensure that it’s communicated and acted upon.

We’ve always been able to take a main protocol, manage hundreds of sites, the unique informed consent forms from these sites, the many amendments that come in that then have to be acted on and communicated back to this individual sites, the unanticipated problems.

When the pandemic hit, Advarra was already 60% remote, so it didn’t affect our workforce. We knew what needed to make the rest of the company remote-based. Our system itself was already set up to receive urgent submissions and unique informed consents and to immediately manage a main COVID-19 protocol that involve, for example, 200 sites. We have always been efficient in our reviews, with comparisons between academic institutions and an independent IRBs, so we had to become even more efficient at the same time that we maintained quality.

ACT: Pediatric participation in clinical trials is necessary, but also concerning for parents and guardians. How has industry helped them feel more assured

Michele Russell-Einhorn, Chief Compliance Officer at Advarra discusses safety, speed, and ethics in COVID-19 vaccine trials.

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Applied Clinical Trials May 2021