By Dr Catarina Carrao
The threat of the coronavirus disease 2019 (COVID-19) pandemic has highlighted the importance of global health. This pandemic has put an incredible pressure on researchers, regulators, and policy makers that tried their best to move swiftly but safely in a time of uncertainty1.
Even though the pandemic is still not over, it’s about time to evaluate and analyse what we can do better in terms of clinical science.
It is well known that the development of effective vaccines to combat infectious diseases is a complex multi-year and multi-stakeholder process2. In order to accelerate the development of COVID-19 vaccines, governments and regulatory agencies mounted an operation that bridged the public and the private sector infrastructure and expertise, to deliver not one but multiple efficient vaccine products that are now being administered around the globe1.
Key evaluation criteria included robust preclinical data, experience with the vaccine platform, evaluation of the vaccine design and prediction of efficacy, dosing regimen, manufacturability, and anticipated safety profile2. The selections included vaccine platforms such as mRNA with the potential for rapid advancement to the clinic; viral vector platforms with substantial clinical history; and, traditional adjuvanted protein-based vaccines2. Choosing both new and traditional vaccine platforms was a key winning strategy of achieving more than one successful product.
Also, the paradigm of industry-sponsored independent but harmonized phase 3 vaccine trials allowed for placebo-controlled trials with closely aligned primary endpoints (e.g., prevention of symptomatic COVID-19); and, powered to be able to establish a point estimate of vaccine efficacy (VE) of >50% with the lower bound of the 95% confidence interval (CI) above 30%, as demanded by regulators2-4. Plus, study size was adjusted to obtain final analysis within 6 months; and, in addition, common independent data safety and monitoring boards were established with impartial expert clinicians and statisticians to oversee the trials2.
On top of that, to ensure enrolment of racially and ethnically diverse populations - which were disproportionally affected by COVID-19, clinical research specialists worked side by side with clinical trial- and participant-recruitment sponsors to report real-time indicators and projected COVID-19 incidence, in order to inform decision making for site selection and prioritization, as recently reported by Bok et al2.
The vaccination campaigns highlighted the need for novel approaches to support diverse participant enrolment. For example, senior scientific leadership has participated in community forums to raise awareness for study participation, and used public/social media to engage communities5. Also, the COVID-19 Prevention Network (CoVPN), launched a web-based participant-screening registry whereby individuals could self-report relevant household, social, and health status indicators in order to facilitate participant screening by trial site recruiters6.
Researchers guided by social marketing theory, have created and tested various recruitment message designs using patient-centric approaches that trial participants could test and support in social media platforms7. By using a streamlined process for patients to self-identify and discover clinical research studies for which they may be eligible to enrol, this researcher team managed to use market segmentation concepts based on pre-existing individual characteristics to tailor direct-to-patient recruitment in the background of rare diseases7. We can see how this can be an efficacious approach in the case of long COVID-19 patients that have such disparate symptoms, but can be positively identified using such direct tactic.
Also, with increasing amounts of medical data available to researchers from electronic health records and wearable devices, Artificial Intelligence (AI) algorithms have the potential to speed up recruitment for different types of clinical trials and expand access to treatments8. Not only that but, clinical trials can now be conducted entirely virtually, with patient-facing technologies that eliminate the need for in-person interactions9,10. One such example was the ADAPTABLE study (Aspirin Dosing: A Patient-centric Trial Assessing Benefits and Long-term Effectiveness), the largest decentralized clinical trial to date that remotely managed the informed consent, enrolment, and randomization of participants while allowing them to report their health outcomes from the comfort of their homes11.
Modern technology is an ally of continued clinical monitoring, which has massively got of-the-ground with the enforced lockdowns of the COVID-19 pandemic. Researchers from the University College of Cork12, Ireland, recently published a report highlighting the first-hand experience gained in a clinical research facility that managed both academic and commercial clinical trials in the times of the pandemic. In this institution, ethics committee and ethics applications for trials were modified to allow for telephone clinical visits where the trial would be introduced by the clinician during a standard of care visit; and, the research team would then follow up with participants. The Patient Information Leaflet and consent were also posted to participants with return by mail; and, trial participants were then followed up by phone with the research nurse and Principal Investigator12.
In some trials, electronic consent methods were used in order to continue trial recruitment whilst minimising face-to-face contact with potential participants, with systems set-up quickly with support from specialist programmers15. In some circumstances, they have been used as an alternative to paper consent, though still used in the context of a face-to-face setting. According to a commentary published by E.J. Mitchell and her team from the University of Nottingham Clinical Trials Unit, whilst this has reduced the amount of paper handling and arguably provided a more streamlined efficient approach to consent in trials, electronic consent could be most useful when truly “online” and not reliant upon site staff providing participants with a smart device to complete the electronic consent form15.
Distant interactions with clinical trial participants implemented in response to the pandemic included mailings or drop-off of devices, such as physical activity monitors or pulse oximeters, or even in vitro diagnostic devices called Smart IVDs for remote diagnostics of outcome measurements3,14. A success example was by Dr David Lipscomb, from the Sussex Community Foundation NHS Trust, UK, that during lockdowns has continued monitoring some of his patients' albumin-to-creatinine ratio using a urinalysis dipstick developed by Healthy.io that was posted to patients and then analysed by a mobile phone application14. As we can see, remote approaches for clinical trials offer sponsors and investigators numerous advantages: efficiency, cost effectiveness, improved patient compliance and acquisition of datasets that capture broader populations13.
Remote patient monitoring is now a reality that goes beyond laboratories and in-person meetings to get more accurate data, and keep patients enrolled in a patient-centric way18. Devices and technologies are there not only to get results, but also to create a human-centric experience that can be adapted to help patients and improve clinical research. Bluetooth and iCloud enabled devices can collect health-related data in real-time, which creates more efficient systems of monitoring the patient and serve its needs. Orthogonal, a leading developer of mobile and cloud applications for medical devices and diagnostic companies, has several FDA cleared software systems for continuous clinical monitoring in different fields (e.g., cardiology, diabetes, neurology)19. What we are seeing now is that the patient and the physician will be at the centre of the clinical trial stage, fully democratizing the clinical investigation even though remotely20.
Of course, none of this comes without effort or resistance. We all know how the clinical trials industry is understandably resistant to change for operating studies until they are well proven and scalable. But the pandemic drove the need for innovation and flexibility with the restructure of clinical trial operating models to support decentralization; such as conducting telemedicine visits, delivering investigational medications to patients’ homes, and collecting data through electronic means, such as electronic patient-reported outcomes (ePROs) – essential steps for clinical trials to move on in times of lockdown.
For example, according to Dr. Flaherty and team from Massachusetts General Hospital Cancer Center, Boston, USA, streamlining of clinical trial procedures to preserve potential patient benefit while minimizing risk associated with investigational therapies were also made during these strenuous times22. Standard Operating Procedures (SOPs) have changed to support remote monitoring, specifying the need for remote access to Electronic Medical Records (EMR) systems and other source of data23.
Other areas where SOPs have changed involved shipping investigational medication directly to the patients’ homes, and allowing for study visits to be conducted remotely. Penn Medicine Abramson Cancer Centre in Philadelphia, USA, was one of those that implemented these measurements to keep clinical trials up and running24.
Astonishingly, regulators quickly addressed the need for changes as shown by several guidelines published by EMA and FDA during the last year25-27. According to Dr. Wecker, Director of Clinical Process Improvement & Innovation at Zogenix, sponsor institutions were also quick to adapt, allocating resources and creating processes that enabled enlarged access to EMRs and other source data systems, while maintaining high patient privacy protection levels23. What came out of all this was a real positive change in the industry, where the collaboration between parties in order to overcome key hurdles was a major break-through, with the realization that a lot more can be done as an industry by working together for the good of the patients. The recently launched Good Clinical Trials Collaborative, led by Professor Martin Landray at the University of Oxford, is a welcome initiative that aims to review the principles of randomised clinical trials based on the experience provided by the pandemic and provide new guidelines for the future15,21.
But despite there being a common goal that should unify resources and efforts, clinical research efforts around the world might easily be described as chaotic at times, and exclusive of many low-income and middle-income countries (LMICs). According to J.J. Park and research team at University of British Colombia in Vancouver, Canada, the global collective clinical trial response to COVID-19 has occurred with inadequate collaboration between researchers, with many clinical questions partially addressed through multiple small randomized trials, designed to measure only biomarkers or putative surrogate end points1.
Small trials may be quicker to plan and complete, but inadequate statistical power can lead to false claims of failure or implausibly large effects when significant28. Multiple protocols enrolling at the same institution can complete for participants with the same diagnosis. Heterogeneity in treatment effects is also difficult to identify from small studies, particularly of homogeneous populations28. The outcome of a series of recent publications in the journal Lancet Global Health highlights that inconclusive research findings from many clinical trials reemphasize the importance of high-quality clinical trial research1.
Woodcock & LaVange29 from the FDA Centre for Drug Evaluation and Research have already shown that the use of master or core protocols are more efficient to test multiple therapeutics across many sites and diseases. Also, Kimmel and his team28 at the University of Pennsylvania Perelman School of Medicine, based on their pandemic experience have recently highlighted the need to use existing networks of institutions to streamline large-scale trials; and, use stakeholder input (including patients) into the trial design to ensure relevancy of study outcomes, reduce barriers to recruitments (e.g., remote informed consent), and provide more cost-effective follow-up (e.g., use of EMRs). Dr. Katherine Tuttle, a nephrologist and executive director for research at Providence Health Care in Washington, USA, points out that her centre can now get clinical trials running in a matter of days, rather than having to wait six weeks or more, as was typical before the pandemic30.
Master protocols - whether umbrella, basket, or platform trials - can tremendously improve efficiency of clinical trial resources by including one or more interventions in multiple diseases or a single disease, as defined by current disease classifications; with multiple interventions, each targeting a particular biomarker-defined population or disease subtype29. Master protocol trials share key design components and operational aspects achieving better coordination than what can be attained in single trials designed and conducted independently. Some take advantage of existing infrastructure to capitalize on similarities among trials, whereas others involve setting up a new trial network specific to the master protocol29. If designed correctly, master protocols can last decades, with innovations from the laboratory quickly translating to clinical evaluation. As the targets for new drugs become more and more precise, there is no alternative but to move forward with a master protocol.
The coronavirus pandemic also called for real-time safety surveillance of vaccinating masses of individuals in a relatively short period of time. As such, post-licensure monitoring systems were created as post-authorization safety surveillance tools by the regulatory agencies4,31,32. Certain rare adverse events associated with immunizations (or any medication, in fact) can only be detected once millions of individuals have received the intervention; as such, during the past year, it was reassuring to observe regulatory safety systems in action, detecting potential adverse event signals in real time (e.g., anaphylaxis and thrombosis-thrombocytopenia associated with mRNA and vector vaccines, respectively; and a possible association between mRNA vaccines with myocarditis in younger individuals)2.
The truth is that pharmacoeconomic and post-marketing surveillance studies based on direct use of clinical trial efficacy metrics are flawed and outdated33. What we are seeing now is that Real-World Effectiveness (RWE) can be assessed using case control and observational studies that inform how well the vaccines/medications perform in broader populations after authorization, including in those with a wider range of underlying health conditions, greater age distribution, and in less-controlled clinical settings2. There is a clear need to develop and validate functional and relevant approaches for the translation of clinical trial efficacy to the real-world setting33. We may say that EU MDR Post-Market Surveillance (PMS) just got a “pat-in-the-back” from the pandemic.
The way clinical trials are conducted in the European Union (EU) will undergo a major change when the Clinical Trials Regulation (Regulation (EU) No 536/2014) comes into application on 31 January 202226. The Regulation will harmonise the assessment and supervision processes for clinical trials throughout the EU via a Clinical Trials Information System (CTIS), which will contain the centralised EU portal and database for clinical trials foreseen by the regulation. This together with the disruptive COVID-19 pandemic that we are still living, has enforced change into a system with substantial aversion to innovation in normal times. Let’s seize the moment and embrace the change.
Dr Catarina Carrao gained a PhD in Biochemistry from Northeastern Ohio Medical and Pharmacy University and an M.Phil in Biochemistry at the University of Beira Interior. She has worked as a researcher at Max F. Perutz Laboratories, Yale Cardiovascular Center at Yale University School of Medicine, and the Center Cardiovascular Research (CCR) at Charité Medical University.
