COVID-19 and Clinical Trials: Past, Present, and Future

by Rachel Horovitz, Sheila Diamond, Phil Coran and Bill Broderick

Abstract
The COVID-19 pandemic, declared by the World Health Organization in March 2020, has had a significant impact on clinical trials. An analysis by Medidata1 based on cross-industry data from 5,222 studies and 198,120 study-sites shows a notable decline in new patients entering trials at study sites compared to pre-COVID baselines, and the recovery has differed based on geography (country-by-country) and therapeutic area (TA, by varying impact of the respective diseases). China experienced the initial outbreak of SARS-Cov-2, and new patient flow in clinical trials has since recovered almost back to levels prior to the pandemic. In contrast the pandemic in the United Kingdom and India impacted the flow of new patients entering clinical trial study-sites at the outset, and India has not gained much ground back. In Japan, new patient flow in June, July, and August was higher than pre-COVID-19 levels, likely due to pent-up demand. Among therapeutic areas, oncology saw the least impact in new patients entering study-sites and has shown the best recovery. Cardiovascular trials saw the largest drop at the outset of the pandemic but have since recovered tremendously.

A COVID-19 site survey conducted in April 2020 and again in August 2020 found that although sites are coping better with the pandemic now, almost half of respondents reported COVID-19 was impacting ongoing trials either a great deal or a moderate amount. In a similar vein, nearly half of respondents reported that the pandemic was impacting their ability to initiate new trials by either a great deal or a moderate amount. Despite these concerns, a majority of respondents are optimistic about the future of clinical trials. With the right tools and technologies, especially ones that enable trial decentralization/virtualization and agile responses to a continuously changing situation, patient data can continue to be obtained and trials can still be effectively conducted without compromising patient safety. This pandemic has highlighted the importance of adopting technologies that allow for remote data capture/monitoring, sending investigative products directly to patients, and data and analytics solutions to understand where and when to (re)focus efforts.

“Global regulatory bodies are trying to keep pace, issuing guidance designed to make running clinical trials easier and to collect robust data without sacrificing patient safety.”

Many of the observations and changes in clinical trials taking place amid the pandemic are likely to become permanent. Global regulatory bodies are trying to keep pace, issuing guidance designed to make running clinical trials easier and to collect robust data without sacrificing patient safety. Since each country has its own history of customs and practices, changes that regulators are willing to make are expected to vary around the world.

Introduction
Data generation, collection, and analysis is a key driver for the uptake of more precise medicine, including vaccines and related testing protocols. After COVID-19 was declared a pandemic in March 2020 by the World Health Organization, Medidata (a Dassault Systèmes company) has been monitoring the global impact of the biggest public health emergency in nearly a century on clinical trials and released its first data and insights COVID-19 impact report on March 23.¹

Eight subsequent releases followed every two weeks through mid-June, followed by monthly releases, with the latest published on September 21. Medidata’s insights are based on an analysis from the company’s cross-industry data that included 5,222 studies and 198,120 study-sites, as well as two site surveys conducted in April and August. The late April survey included more than 1,000 clinical sites, while the follow-up survey included 734 respondents. Just over half of respondents were from the United States and the vast majority were study coordinators or investigators. While the August survey indicated that sites were dealing with the pandemic better compared to April, it is likely that the negative effects of COVID-19 on new patients entering studies were likely undercounted given that many trials are still actively recruiting patients.

In response to COVID-19, it is important to note that global regulatory authorities have issued emergency guidance on trial conduct. Technology-related topics addressed include telemedicine/decentralization; consent and e-consent; expectations on electronic records/ signature rules; and remote monitoring, including remote source data verification (rSDV). Centralized monitoring activities are suggested, though not required, by most regulators. Flexibilities demonstrated by regulators may extend beyond the pandemic. In June, FDA Commissioner Stephen Hahn indicated a desire to make changes such as accelerated receptiveness to trial decentralization, master protocols, and real-world evidence part of the norm after the pandemic has receded.^2,3

Four key areas present challenges for clinical trial planning and conduct during the pandemic: 1) understanding the evolving situation; 2) reconsidering trial design to enable data capture; 3) maintaining quality of trials and supply of investigational therapies; and 4) accelerating and executing study start-up given that studies need to be up and running quickly with minimal safety risk to subjects and healthcare providers. COVID-19 is accelerating the adoption of technologies that address these four key areas and enable the virtualization/decentralization of processes, as well as data and analytics tools that provide the means to address these challenges effectively. Such tools provide: real-time insights into COVID-19 impact; models to understand disease recovery curves and leading indicators; virtualization of data capture through electronic consent; electronic clinical outcome assessment (eCOA); wearables and telehealth; computer simulated control arms (synthetic control arms) to reduce the number of patients needed; and centralized oversight and analytics to maintain quality.

Impact Of COVID-19 On New Patient Flow
The impact of COVID-19 on new patient flow has seen dramatic differences depending on the country and therapeutic area (TA) in question (see Figure 1). A variety of factors contribute to these differences, including differences in regional COVID-19 outbreaks and case rates, government policies, and actions taken in response to the pandemic. To allow for a consistent way of measuring and comparing impact over time, we are analyzing impact as compared to a pre-COVID-19 baseline.

China, faced with the initial outbreak, saw a significant impact on clinical trial patient flow in February at -80% of pre-COVID-19 levels, and by April had recovered to -12%. At a global scale, however, the world saw the largest impact on clinical trial patient flow in April, down -59% vs. pre-COVID-19 levels. This has steadily improved, with July at -10% globally, and facing a slight downturn in August, landing at -20% of pre- COVID-19 levels.

“Throughout these last few months, we have witnessed the impact of COVID-19 fluctuating, affecting TAs and geographies to varying extents over time. These fluctuations and variations underscore the need to continue to track real-time information at a granular level, thereby allowing researchers to make the best decisions on when and where to focus their efforts, run their trials, and get treatments to patients.”

India experienced the greatest impact in April with new patient flow plummeting -98%, though it has recovered and had a -71% decline as of August. In April, new patient flow in the United States was down -45% versus its pre-COVID-19 baseline. In August, that figure dropped to -22%. The United Kingdom saw new patient flow sink -87% in April, though in August it stood at a -40% decline. Elsewhere in Europe, Germany and Spain saw new patient flow drop -68% and -54%, respectively, in April, though in August, Germany recovered to pre-COVID-19 levels while Spain was still down -34%. One bright spot in clinical trial new patient flow is Japan. In April, Japan was at -60% compared to its pre‑COVID-19 baseline, but in August, the country was up by 25%.

New patients entering study-sites vary greatly depending on TA (see Figure 2). In April, trials involving new therapies for cardiovascular, respiratory and endocrine systems saw the largest impact with a drop of, respectively, -97%, -92%, and -82%, compared to pre‑COVID-19 baseline levels. Oncology trials were the least impacted; in April, they were down -41%, as compared to non-Oncology trials, which were down -65% vs pre-COVID-19 baselines. By July, patient flow for oncology trials was up 17% compared to pre-COVID-19 baselines, likely driven by patient backlog as more sites re‑opened.

Non-oncology studies continued to recover between April and July, and landed at -28% vs. pre-COVID-19 baselines in July. August represented a worsening across most TAs, in line with the drop seen across geographies, given the continuously changing impact of the disease, as well as policies and actions taken in response. Throughout these last few months, we have witnessed the impact of COVID-19 fluctuating, affecting TAs and geographies to varying extents over time. These fluctuations and variations underscore the need to continue to track real-time information at a granular level, thereby allowing researchers to make the best decisions on when and where to focus their efforts, run their trials, and get treatments to patients.

Regulatory Responses To COVID-19
In response to COVID-19, regulatory agencies around the world have issued guidance surrounding clinical trials in an effort to provide life sciences companies greater leeway to operate in a challenging environment. From a technology standpoint, the areas in the guidance deal with monitoring, consent, telemedicine/ decentralization, and direct investigational product shipment to patients. For example, in FDA’s guidance⁴ on conducting clinical trials of medical products during the COVID-19 public health emergency, updated in September, officials write that remote clinical outcome assessments (COAs) can be conducted during the public health emergency, including for performance outcome (PerfO), interviewbased clinician-reported outcome (ClinRO), patient-reported outcome (PRO) and observerreported outcome (OBsRO). The agency also advises that if on-site monitoring visits are not possible, sponsors should consider greater use of central and remote monitoring programs to continue oversight of clinical sites (see Figure 3).

In addition, conducting virtual clinical visits are also permitted. Health Canada has instituted many of the same permissions as the FDA in its COVID-19 related clinical guidance, such as delivery of investigational product directly to study participants and remote written informed consent. In its interim order,⁵ the agency stated that if participants are unable to travel to a site as specified in a study protocol, alternative monitoring is acceptable, though documentation is necessary to determine: the reason why it was done; the types of data that were collected; who provided the information; and how the source of information was verified. In such a situation, Health Canada allowed that a protocol amendment is not necessary.

The United Kingdom’s guidance (updated on November 11 2020) speaks to similar topics including: options for direct investigational product shipment to patients, risk assessment guidance, maintaining data integrity, trial decentralization, and remote monitoring.⁶

The European Medicines Agency (EMA) is also allowing remote monitoring through centralized monitoring of data acquired by electronic data capture systems, such as electronic case report forms (eCRFs), central laboratory or electrocardiogram (ECG)/imaging data, and electronic patient-reported outcome (ePRO) “that can supplement and temporarily replace on-site monitoring through a remote evaluation of ongoing and/or cumulative data collected from trial sites, in a timely manner.” In its guidance,⁷ the agency is also allowing direct shipment of investigational products to trial participants’ homes under certain conditions. In addition, EMA is allowing limited remote source data verification, though for very few trials in cases for trials involving a COVID-19 treatment, or in the final data cleaning steps before database lock in pivotal trials investigating serious or life- threatening conditions with no satisfactory treatment option. The verification should focus on the quality control of important data such as primary efficacy and safety.

In its guidance,⁸ the Australia Department of Health mentions alternative models for conducting clinical trials. This includes decentralized trials in which participants can take part remotely and data captured through devices that can then be sent to study investigators. The department also notes that remote data verification is “in the public interest” as it protects the safety of both participants and researchers. The guidance also calls on human research ethics committees to consider actively encouraging alternative models for trials, where appropriate.

“Most biopharmaceutical and medtech companies are contending with the impact of COVID-19 across countries, sites and TAs”

COVID-19 Site Survey
(For the following items in this section, see Figures 4-8 for details)
Compared to the first survey conducted in April, results from August indicate that sites are now coping better with the pandemic (as of October 2020). In August, 12.3% of respondents said that COVID-19 was impacting them a great deal, 21.5% said by a moderate amount, and 24.9% by an average amount. Nearly half of respondents—48%—said that COVID-19 was affecting their ability to initiate new trials by either a great deal or a moderate amount, and 18.5% said by an average amount. In April, when respondents were asked if their ability to conduct ongoing trials was impacted, 69% answered yes. In the latest survey, the biggest impact of COVID-19 by activity reported was the ability to enroll and recruit patients. Other significant impacts reported were the increased cost of personal protective equipment (PPE), financial implications of canceled trials, and financial implications of delayed milestones.

The two most frequent responses to COVID-19 cases that sites have implemented are amending protocol (42.8% of participants) and switching patient visits to virtual (40%). Other common responses reported by sites include halting patient recruitment for ongoing trials (39.2%), extending patient visit window (32.6%), delaying a study (31.3%), and shipping investigational drugs directly to patients (27.4%).

Despite the difficult environment sites are operating under, most respondents said they are optimistic about the future of clinical trials. Nearly 60% of respondents said they were either highly optimistic or slightly optimistic. Just 16.5% of sites reported being either slightly or highly pessimistic.

Technologies Mitigating Impact Of COVID-19
On Trials As noted in the Introduction, Medidata’s analyses uncovered four main challenges in the current situation: understanding the evolving situation; reconsidering trial design to enable data capture; maintaining quality and supply; and accelerating study start-up. To meet these challenges, many technologies are being utilized that are allowing sponsors to continue running trials while minimizing trial disruptions during the pandemic.

Most biopharmaceutical and medtech companies are contending with the impact of COVID-19 across countries, sites and TAs, necessitating the need to develop risk mitigation and trial recovery plans. One way to address this challenge is by utilizing data and analytics to benchmark the impact of COVID-19 on trial performance; understand leading indicators of recovery to identify countries that are likely to recover next; build disease level recovery curves; and monitor ongoing performance to decide when and where to focus efforts. To supplement the insights on COVID-19 impact on trials and enable companies to respond, Medidata built an offering as part of its Acorn AI company to provide COVID-19 benchmarking and impact and recovery forecasting based on its data repository from ~6,000 ongoing trials across 90+ countries.

Data capture has become more difficult this year given that many patients find it difficult to make it to trial sites. An eCOA solution, however, allows for the conversion of a site-based data capture form to a remote one. Further, patients can download an app to their own mobile device that provides for data capture in a form that records and notifies researchers of any missed visits. Another challenge for sponsors is understanding the safety of treatments under review for a different indication than what was initially approved, such as chloroquine.

A synthetic control database (SCD)⁹ can support research through aggregated data and enhance what is known about a drug’s safety profile beyond what is available through published research. Additionally, it allows the comparison of historical trial data against real‑world data from claims or electronic medical records.

This can provide validation in trial design, drive better understanding of inclusivity of patient populations to better reflect real-world clinical practice, and potentially decrease sample-size requirements for event-driven trials.

Although some on-site monitoring activities have resumed, it is likely that we will see a more limited access to sites in the near-term, given the continuing waves of the pandemic. For most sponsors, this will necessitate a remote monitoring strategy and a risk-based quality management (RBQM) program. In addition, sponsors must quickly determine the risks to subject safety and data integrity with as little impact to the site as possible. Remote source review technology¹⁰ can collect, de-identify, manage, review and verify critical study documents via secure browser-based uploads. Sending investigative products directly to patients’ homes has become increasingly popular during the pandemic as more patients are either unable or choose not to go to trial sites. A randomization and trial supply management (RTSM) system can be configured to allow this.

Timing has become an increasing constraint during the pandemic, and it is imperative for the industry that studies are up and running quickly. It is now possible for an RTSM with basic Electronic Data Capture form to be set up in two weeks for a randomization-only study, and three weeks for randomization and basic trial supply management. Negotiation and budgeting platforms¹¹ can accelerate a site’s study start-up by eliminating contracting and budget negotiation delays. This program allows sponsors to develop accurate and detailed site budgets; ensure fair, data-driven investigator payments around the world; engage investigators directly to share study budget details; and then review and edit proposed budgets and contracts. In addition, transaction records are readily available for analysis and compliance risks are mitigated in IIS grants through an audit trail of negotiation activity.

Conclusion
COVID-19 has significantly impacted all aspects of clinical trials, from patients to biopharmaceutical and medtech companies, as well as sites and investigators running trials. For everyone’s benefit, clinical trials need to continue to run, without compromising patient safety. The industry needs to ensure that treatments are getting to the patients that need them, and that research and scientific progress can continue, especially in the face of a pandemic. Data and technologies exist that can enable the continuation of trials during COVID-19 while maintaining patient safety, and enable an agile response, ongoing data collection, and centralized oversight. The changes we have observed are likely here to stay. This is a positive as it will lead to higher efficiencies in execution while reducing burden on patients and sites, and will accelerate the delivery of new therapies to patients in need.

Acknowledgements
Ron Katriel, Jingshu Liu, Laura Katz, Robbie Buderi, Bentz Raphael, Joshua Hartman, Trey Moore, Matthew A. Stetz, Aniketh Talwai, Fareed Melhem, Jenni Li, Jonathan Block, Daniel Poppy, Paul Oestreicher

 

Rachel Horovitz leads Product Strategy for Acorn AI’s Intelligent Trials product portfolio, and is the Product Lead for Trial Impact Analytics, a new off ering launched in response to COVID-19. Prior to her current role, she was the Head of Strategic Initiatives at Medidata and led the creation and launch of the Medidata Institute. Before joining Medidata, Rachel spent several years at Bain & Co. and Rothschild, advising healthcare and technology companies on a broad range of strategic issues and decisions. She holds a Master in Biomedical Engineering from the University of Bern in Switzerland, as well as an MBA from the MIT Sloan School of Management and a BS in Economics from Th e Wharton School, University of Pennsylvania.

 

Phil Coran is a Principal in Global Compliance & Strategy at Medidata Solutions. Phil has had numerous interactions with regulatory authorities including the US FDA and the EMA. Prior to joining Medidata, Phil was at Pfizer for 12 years in Medical Quality Assurance where he conducted dozens of GCP site audits (worldwide) and technology compliance audits. Phil is a Certified Information Systems Auditor (CISA) & Privacy Professional (CIPP/US), a Fordham School of Law JD and University of Washington MBA. Phil is a member of the New York and California Bar and a frequent speaker on clinical trial related topics including GCP and emerging technologies and is a Team Lead for the Clinical Trials Transformation Initiative (CTTI) Mobile Clinical Trials project.

 

Bill Broderick has over 30 years of healthcare experience focused on the use of evidence to drive the development and marketing of healthcare technology, to prove the value of pharmaceuticals, and to measure quality and outcomes across the care continuum. Bill is currently the VP of Product Marketing at Medidata. He has worked at several leading Contract Research Organizations (Quintiles (now IQVIA), Median Technologies and Syneos Health), medical device and telehealth providers (Bosch Healthcare), healthcare payers and consultancies (UnitedHealth Group and Davies Consulting), Home Care Providers (Coram) and Hospital Systems (Lovelace). Trained as a biological scientist, Bill uses this background along with his formal business training and experience in marketing and management to drive a better global healthcare system focused on innovation. Bill is a graduate of the University of Notre Dame, St Louis University and the University of New Mexico.

 

Sheila Diamond, MS, CGC leads the Medidata Institute and scientific business development as part of Acorn AI, by Medidata, a Dassault Systèmes company. She drives thought leadership and builds relationships with life science partners to judiciously integrate advances in data and technology into precision medicine and patient care. Sheila is a board-certified genetic counselor with specialties in rare diseases, neurodegenerative disorders, and elective whole genome sequencing. Prior to joining Medidata, she worked at the Genomes2People research program at Brigham and Women’s Hospital and Harvard Medical School, conducting empirical research on the medical, behavioral and economic impact of using genomic information in medicine and in society. Sheila is a diplomate of the American Board of Genetic Counseling (ABGC) and a member of the National Society of Genetic Counselors (NSGC). She received her Masters of Science in Genetic Counseling from the Boston University School of Medicine.

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