The impact of the Covid-19 pandemic on how clinical trials have progressed has been wide-reaching. Quarantines and social distancing requirements have limited patients’ abilities to access clinical trials under traditional enrollment models. This has been compounded by chronic shortages in healthcare staffing and resourcing with a major shift in efforts towards addressing Covid-19.
Drug developers already faced a high stakes risk-to-benefit evaluation before filing an IND and progressing to clinical trial, and these risks were only compounded by the pandemic. Despite the obvious challenges, almost 50% of clinical trials underway in the USA continued through 2020 and 77% of those planned for 2021 have progressed (Unger and Xiao 2021). So how was this achieved? Well new and radical approaches and novel tools were adopted to help streamline protocols and amend the processes around clinical trial recruitment, execution, and process. Now with this pandemic still with us, approaches to how clinical trials are conducted may have been changed forever.
Facing the Pandemic: Modified Approaches to Clinical Trials.
Participant-Centric Approaches: The pandemic has significantly altered the risk-benefit that drives the informed participation in clinical trials; essentially participants now must assess the increased risk of SARS-CoV-2 exposure within the healthcare environment, with the potential benefits of the treatment. This risk is only compounded by the adoption of descaled monitoring protocols throughout the trial as well as post-trial surveillance.
Back in the spring of 2020, many clinical trials were paused, leaving patients confused and feeling stranded. With the challenging time constraints, many clinical protocols for multisite trials were amended expeditiously by central committees rather than individual Institutional Review Boards. All of the changes created significant operational challenges in workflow, data tracking and compliance.
In some cases, both ad-hoc interim analysis and futility stopping rules have been implemented to help minimize the number of patients that need to be enrolled during the pandemic. Since these approaches also provide a checks and balance approach to the cost-effectiveness of clinical trials, it is likely that many of these approaches will develop into best practices for future trials.
The Epic Rise of Telemedicine
Our laptops have become a lifeline through many aspects of this pandemic, from online schooling to business continuity with zoom calls, we are now all more familiar with online media tools than ever before. This also includes the way we interact with our healthcare provider- with Telemedicine for many now representing the first route for medical intervention. For clinical trials, telemedicine has provided a safer way to monitor patients and help ensure safety remains a top priority, enabling the review of adverse events in near real time and ensuring that medications can be shipped directly to the patient (Lui et al 2020).
Patient monitoring and engagement through online communications is not without challenges. The adoption of wearables and remote patient monitoring tools has helped reduce the impact in this new approach but also catalyzed a requirement for novel data collection and tracking solutions under sometimes incomplete or murky regulatory guidelines.
So, does the answer lie in “Decentralizing Clinical Trials”?
At the center of any clinical trial is therapeutic delivery to the patients and subsequent clinical sample collection and analysis. Both activities have been highly impacted by the pandemic, and more local facilities have been enrolled to support IV-drug administration, laboratory investigations and imaging. Careful attention to appropriate accreditation and quality control programs have therefore been necessary at these smaller facilities. But this has been helped with new tools such as the use of E-signatures for enrollment and verification of consent that are a central component of clinical trial compliance.
Clinical trials involving Investigational Products (IP) have also required modification throughout the pandemic. Pharmacovigilance is of upmost priority to ensure the security, traceability, storage/transport conditions for the supply chain aspects, and accountability and compliance in the handling and use of IP materials. Oral therapies have the advantage of at home administration, whereas IV-administration relies on the scheduling of at home nursing visits or an appointment at these local clinics.
Along the same lines, home specimen collection is now being explored more widely, and with the development of self-use capillary blood draw devices from companies such as Tasso and Seventh Sense, at home specimen collection is becoming a real possibility for many trials. Currently, at home collections typically involves a visit with a nurse to provide venous blood draws, but as technologies advance, the volume of samples needed for analysis is becoming less and less, and these new blood collection devices will be able to fulfill many of the clinical sample collection requirements.
Blockchain Solutions- not just for Bitcoin anymore!
With the long-lasting lockdowns driving remote patient enrollment, there has been a significant shift to data collection using health apps, wearables, biometric monitoring tools, and Blockchain solutions to collect, verify and utilizes these different data sets have become the cornerstones of many clinical programs.
Over the last 4+ years, many clinical organizations have explored the utilization of Blockchain in clinical trials. Blockchain technology uses a distributed computer network, or ledger, to verify and store time-stamped transaction records and documents. Using verification certificates, the data is permanently intact and considered immutable. These can include smart contracts for patient enrollment, the control of test results and hospital analysis and data encryption. Collectively these features offer many advantages towards the rapid development, testing and Emergency Use Authorization (EUA) of Covid-19 vaccines and therapeutics, as well as support more traditional clinical trials through the FDA approval process.
For highly complex clinical trials involving personalized medicine approaches, Blockchain can support data encryption and enable the combining of diverse data sets (unstructured and structured) into so called longitudinal Data Lakes to track long-term efficacy and safety data to be harnessed more readily. The diverse and vast data sets generated in global clinical trials can be indexed using the Blockchain and mined using Artificial Intelligence (AI) and Machine Learning (ML) tools, and access controlled through structured permissions, all constructed using Blockchain.
Although still in its infancy, the integration of Blockchain technologies into clinical research is both momentous and timely with this pandemic, and by providing such overarching benefits, ultimately Blockchain solutions will help to ensure the development of safe, effective, and more economical medicines for all.
A New Paradigm of Sharing Data
The healthcare sector as a whole is far from one cohesive ecosystem, and in fact is composed of several industries working in isolation. From the research institutions, pharmaceutical companies, to the hospital networks, health-related information is often siloed and controlled with regulatory and privacy constraints. These challenges are compounded by the different formats of data based on their purpose and with no standardization even across different organizations within the same sector. The rapid spread of Covid-19 across the globe has highlighted the need for more cohesive data integration and sharing. Both short- and long-term studies are needed to understand the effect of comorbidities on patient outcome and identify effective treatment protocols that may have profound effects on public health surveillance (Dron et. al. 2021).
This pandemic also not only highlighted the importance of well structured, coordinated clinical trials, but also established a precedent for faster data sharing of anonymized data sharing. The National Institute of Health (NIH) supported this new effort with the establishment of The National COVID Cohort Collaborative (N3C) which is harmonizing Electronic Health Records (EHR) from thousands of Covid-19 patients to mine for predictive outcome biomarkers and effective therapeutic strategies through machine learning and use applied algorithms. Soon this will be applied to stratify newly infected Covid-19 patients as they enter the healthcare system (Cosgriff, C. V., et. al. 2020) and ultimately help to save lives.
The rapid spread of Covid-19 has become a historical turning point in global health research and been the origin of a tidal wave in corona virus-based studies. The hope is that this new paradigm shift in how data is handled, shared, and utilized by various stakeholders will continue beyond this pandemic and translate into best practices for how powerful data sets can be applied to study other diseases and accelerate both diagnostic and therapeutic tools across many areas of medicine.
Clinical Trial Participant Population Shifts through the Pandemic
One area that has been highlighted recently is the shift in clinical trial patient population profiles. Older participants, or those with co-morbidities who are at higher risk of poorer outcome from Covid-19 are less inclined to enroll, whereas individuals who have lost their jobs and health insurance, are now more open to participating in a clinical trial. This has resulted in a significant change in the profile of the clinical trial population. Additionally, the National Cancer Institute has indicated a reduction in access to secondary biospecimens through clinical trials has been impacted though the pandemic. In the past these biospecimens were used to support overall cancer research programs, and these efforts may now be delayed, possibly for years to come.
How Covid-19-Related Clinical Trials Have Impacted Our Assessment of the Importance of Participant Populations
The pandemic has also highlighted the significant health disparities faced by many people from minority racial or ethnic groups. Reports from across the world indicate that the frequencies of SARS-CoV-2 infection, hospitalization and mortality are disproportionately high in these minority ethnic groups who are also more frequently affected by poverty, and with limited access to nutrient dense foods and wellness programs. Against FDA recommendations, these populations were highly under-represented in all of the US-based clinical trials for Covid-19 vaccines [typical trial demographic: 70% whites, 11% black/African American, 0.4% Native Americans/Alaska Natives and 12% Hispanics/Latinos] (Flores, L. E. et. al. 2020). The underlying reasons for this are difficult to determine, but most likely a symptom of socio-political, socio-economic, cultural and language barriers.
Why is this important? Well improving racial and ethnic diversity in clinical trials can profoundly impact subsequent vaccination rates with minority groups, as well help identify safety profiles for different racial and ethnic populations. The representation of all demographics within clinical studies can help provide education around vaccine effectiveness and address vaccine hesitancy through community engagement.
Similarly, US-based clinical trials for the Covid-19 vaccines reported only 12% of participants were over the age of 65. Since advanced age is associated with poorer outcome from Covid-19, this seemed like a major oversight in the clinical study protocols. The root of this most likely lies in the fact that our immune responses to vaccination tend to decrease as we age; it was therefore less desirable for trial sponsors to include this population in early clinical trials that were racing for EUA approval. As these Covid-19 vaccines now move from EUA to full FDA approval status, phase IV clinical trials encompassing a more comprehensive spectrum of the population will be needed.
Sadly, this is not an issue unique to Covid-19, in fact the NIH has been working for decades to address this disparity through guidelines including the NIH Revitalization Act of 2000, and NIH Policy and Guidelines on The Inclusion of Women and Minorities as Subjects in Clinical Research 2001, as well as through collaborative research studies (Loree, J. M. 2019; Knepper and McLeod, 2018). The issue spans across clinical trials to study all aspects of medicine from oncology to autoimmune diseases and infectious diseases. Hopefully, this current situation will highlight further the need to address this lapse in the clinical trial process and ensure that population differences in drug responses are based on scientific observation, rather than anecdotal evidence.
There is no doubt that the Covid-19 pandemic has required the life science and healthcare industries to completely reinvent their approaches and clinical protocols. Decentralizing clinical trials has enabled the majority of clinical trials to advance through 2020 and 2021 while helping to maintain the safety of trial participants. Technological solutions for patient monitoring and testing have also played a major role. Innovative at home sample collection devices partner well with high complexity platforms such as flow cytometry that supports rich clinical data sets using lower sample volumes.
Electronic informed consent and data handling, security, governance, and sharing have played an unprecedented role in addressing the pandemic, and evolving Blockchain solutions have come into their own to enable researchers to complete clinical protocols and then mine data and model predictive markers. FlowMetric is ahead of the curve when it comes to handling large data sets securely and for several years has been in partnership with BurstIQ to develop and utilize Blockchain solutions to clinical data handling and utilization.
Across the globe, clinical trial teams have adapted protocols and processes to accelerate trials without compromising safety. There are many examples of innovative practices borne out of the pandemic that many in the industry hope will become embedded in mainstream clinical best practices moving forward.
- Unger, J. M. and Xiao, H. The Covid-19 pandemic and new clinical trial activations. Trials vol. 22. Article number: 260 (2021); https://doi.org/10.1186/s13063-021-05219-3
- Liu N, et al. Telehealth for noncritical patients with Chronic diseases during the COVID-19 pandemic. J Med Internet Res 2020 Aug 07;22(8):e19493
- Dron L., et. al. Clinical Trial Data Sharing for COVID-19–Related Research. J Med Internet Res 2021;23(3):e26718. doi: 10.2196/26718; PMID: 33684053; PMCID: 7958972
- Cosgriff CV, Ebner DK, Celi LA. Data sharing in the era of COVID-19. The Lancet Digital Health 2020 May;2(5):e224