Coronavirus Disease 2019 Vaccine Trials (and Tribulations): How to Improve the Process of Clinical Trials in a Pandemic 

Abstract

Vaccine clinical trials have been essential to developing effective severe acute respiratory syndrome coronavirus 2 vaccines. The challenges of supply chain disruptions, infection control, study designs, and participant factors that affect trial procedures are reviewed, with specific solutions to streamline the clinical trial process.

With the onset of the coronavirus disease 2019 (COVID-19) pandemic, there was an urgency to develop and implement novel and effective severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) vaccines to reduce disease burden and mitigate the devastating social and economic effects of the pandemic. Randomized controlled trials (RCTs) are a vital component of the vaccine development process and use both treatment and placebo arms to evaluate the immunogenicity, safety, and efficacy of COVID-19 vaccine candidates in humans. RCTs have been the reference standard method to investigate new therapeutics or preventive agents and are necessary to achieve licensure from regulatory agencies, including the US Food and Drug Administration (FDA).

Historically, vaccine development from discovery to licensure has been a costly, lengthy and risky process, with an average of ≥10 years for a vaccine candidate to come to market and only a 6% success rate for any given product [1, 2]. In contrast, the time from discovery of the novel coronavirus in December 2019 [3] to publicly available effective SARS-CoV-2 vaccines via emergency use authorization (EUA) was less than a year. In the United States alone, there are now 3 SARS-CoV-2 vaccines available that have been rapidly implemented, with EUAs issued for Ad26.CoV.2 (Janssen Biotech) for adults aged ≥18 years, BNT162b2 (Pfizer-BioNTech) for children 11–15 years old, and full biologics licensure application approval for BNT162b2 for those ≥16 years and mRNA-1273 (Moderna) for those ≥18 years old [4–6]. While this is a remarkable achievement, with modeling showing that 1.1 million additional COVID-19 deaths were averted because of vaccination campaigns [7], conducting rigorous clinical trials has been challenging during the pandemic for both logistical and scientific reasons.

There has been critique that, despite the historical speed of the trials, the trials did not move quickly enough or fully answer questions needed to implement public health guidelines, at the cost of SARS-CoV-2 infecting and killing millions of people worldwide [8]. The COVID-19 pandemic has forced clinical trialists and scientists to rethink the usual infrastructure. It is essential that we reflect on the lessons learned from the COVID-19 pandemic to further improve vaccine clinical trials. In this review, we will dissect the anatomy of vaccine clinical trials and highlight the challenges that arose, as well as discuss solutions and approaches to improve the scientific process.

CHALLENGES OF CONDUCTING RCTs DURING A PANDEMIC

At their core, RCTs are laborious and slow, owing to the incredible effort required to enroll and monitor thousands of participants to the exacting requirements of a specific protocol over an extended duration of time. These usual tribulations are further compounded by unique challenges of conducting a trial during a pandemic.

Logistical and Site Issues

The need to rapidly accelerate enrollment and procedures was often at odds with the daily realities and logistical technicalities of the clinical trial sites. Clinical trials require direct and indirect support to function. Supplies and materials, especially personal protective equipment and swabs, were in global demand, especially at the beginning of the pandemic, with the unpredictable supply diverted to hospitals and healthcare workers on the front line [9]. These supplies were also needed for the clinical trials to be able to safely conduct participant visits and achieve end-point goals (eg, PCR with nasopharyngeal swab samples to assess for SARS-CoV-2 infections). Furthermore, there were shipping delays even in the usual equipment stocked in clinical trial spaces, such as adhesive bandages, toilet paper, and thermometers, had owing to the overall supply chain disruptions that occurred the pandemic unfolded.

The cost and availability of human resources were also greatly disrupted, as staff that usually drive the trials (including research assistants, nursing staff, regulatory affairs managers, pharmacists, and physicians) were diverted to either healthcare responsibilities or contract research organizations, chose early retirement, or left because of personal safety concerns or family responsibilities (eg childcare with the closure of schools). Recruiting new staff to meet the demands became difficult, with intermittent hiring freezes from academic institutions and pay cuts, which exacerbated already baseline shortages in clinical trialists and vaccinologists. Furthermore, even among the employed staff, chronic understaffing occurred owing to potential exposures and frequent quarantining.

These supply issues for both physical equipment and human resources posed great challenges for how to safely conduct on-site study visits. At a time when little was known about the transmissibility of SARS-CoV-2 or infection control measures, clinical sites were required to adapt their trial spaces to abide by the ever-changing public health guidance for the safety of both participants and staff. Some sites were able to creatively find solutions—acquire office space that was no longer in use during the pandemic or create outdoor spaces with tents for participants’ visits—although some sites without this luxury had to either decrease the number of participants in a day or expand the work hours with early and late hours, as well as weekend openings, to reduce crowding and maintain infection control policies.

Study Design: Phases, Outcomes and End Points, and Participants

Although RCTs are designed to be the simplest path to demonstrate efficacy of a new drug product, the development from the preclinical stage to licensure is lengthy, with each phase (from phase 1 to phase 4) conventionally progressing in a stepwise fashion and requiring months to years to complete each phase. Clearly this laborious and protracted process is misaligned with the pandemic induced urgency to rapidly develop a preventive agent. At the beginning of the COVID-19 pandemic, even the preclinical data were intrinsically limited since there were no validated SARS-CoV-2 animal models. To address this issue, preclinical and toxicology data from related vaccines (SARS coronavirus and Middle East respiratory syndrome coronavirus candidates) were used to expedite much of the preclinical vaccine development work [10].

The clinical trials were further designed to have overlapping phases. Indeed, manufacturers began large-scale production of vaccines before the accumulation of data and results from the phase 3 trials, which was financially risky since the vaccine product may have failed for either safety or efficacy reasons. Design considerations for the primary end points of the phase 1–3 studies were especially challenging. At a time when little was known about SARS-CoV-2 pathogenesis and disease, even less was known about appropriate laboratory assays, with no validated tools to measure clinical outcomes. Furthermore, study end points had to be defined based on limited data, with reliance on home questionnaires (via smartphone applications), home oxygen monitoring, and sampling kits that could be sent by mail. Identifying a reliable and practical molecular target for primary end-point analysis was problematic, with several types of assays in development and insufficient data initially to know the validity of a given test. In addition, the testing materials and reagents had to be both scalable and available for all the clinical trial sites to maintain consistency across study procedures. How should a clinical trial be designed with meaningful end points when knowledge is simultaneously building and shifting the targets? As researchers grappled with this task, heterogeneous targets and different assays were selected across different vaccine candidate trials, which later limited the ability to compare outcome measures across vaccine products.

Recruitment and enrollment of participants, especially for phase 3 vaccine trials that require 30 000–40 000 participants, is often difficult even under the best circumstances. Unlike volunteers who have disease and seek trials for therapeutic benefits, volunteers for vaccine trials are healthy individuals who may not have a direct health benefit from the study product (or may receive placebo) and are exposed to potential harm from the product [11]. Identifying high-risk and willing participants was problematic owing to many of the issues described above, including staffing issues (resulting in decreased recruitment efforts) and ability to maintain COVID-19 infection control practices, as well as the need to ensure safe transportation and study flow for the participants. In addition, with misinformation equally as viral as SARS-CoV-2 transmission and an overflow of data and publications (followed by an unprecedented number of retractions and redactions) highlighted in the media [12], overall trust in science among the public was low. This directly affected the trials and outreach efforts. Many of the communities most affected by COVID-19 had concerns about COVID-19 vaccines and the trial process, which limited participation [13, 14].

Another criticism of the trials involved the exclusion of special populations, such as pregnant women, immunocompromised individuals, and children. Paradoxically, these vulnerable populations are historically protected from phase 3 vaccine trials, although if the vaccines are efficacious, these individuals eventually receive the vaccine without significant data to support their use in these populations. Clinical trials for the pediatric population were initiated in March 2021 after the initial efficacy and safety signal in adults, with special considerations for dosing and side effects [15]. However, for other special populations such as pregnant women and immunocompromised individuals, the vaccines were mostly studied using observational cohort studies or real-world evaluations, which often have many confounding variables.

Study procedures had to constantly adapt to the vicissitudes of the pandemic itself. The protocols underwent multiple revisions to address new data, align with product and end-point kit availability, and react to shifting realities of the pathogen with new circulating variants. Amid these adaptations, participants’ perceptions and expectations had to be considered as well. For example, as seen in the mRNA-1273 and BNT162b2 trials, an early efficacy signal was seen <6 months into the trial. At the core, trial participants must be protected and allowed access to the product if it is shown to be efficacious; this is essential to maintain trust and transparency with the study participants and the community. However, how should new information and knowledge be incorporated into the study design, rationally and ethically, while maintaining scientific rigor?

For most of the phase 3 efficacy trials, an unblinding phase was introduced midtrial when this efficacy signal was confirmed and the vaccine was granted EUA by the FDA. This allowed for participants to remain in the study and have additional data collected, although at the cost of losing the placebo-controlled value of the study [16]. The EUA approval of the mRNA-1273 and BNT162b2 vaccines in December 2020 further influenced the other vaccine candidate trials, for vaccines manufactured by Janssen and Novavax. Many participants left these studies in favor of obtaining an EUA-approved vaccine, thus compromising the results from those trials.

SOLUTIONS AND NEW APPROACHES

The challenges affecting the COVID-19 vaccine clinical trials offers a unique opportunity to reflect on the clinical trial process. Many solutions were developed in “real time” and reactionary to immediate demands. However, a thoughtful exploration of these challenges can yield novel ideas and approaches for future conduct of trials that will expedite regulatory and administrative affairs, engage a more diverse range of participants, streamline the study visits, encourage data sharing and transparency, and allow for flexible trial designs (Table 1).

Partnerships and Shared Platforms

Public-private partnerships should be established immediately (eg, the COVID-19 Prevention Network [CoVPN]), with clear organizational structures, roles, and responsibilities with the goal of fast-tracking vaccine RCTs by offsetting financial and operational risks typically associated with vaccine development. Under this organizational umbrella, efficacy trials would benefit from a common data and safety monitoring board, common laboratory assays (even across different industry-sponsored products), public sharing of protocols and informed consent documents, and to the extent possible, common protocol templates and data systems [17]. Funders should rely on well-established clinical trial sites and networks, such as Division of AIDS–funded clinical trial units and Division of Microbiology and Infectious Diseases–funded vaccine and treatment evaluation units, to implement trials quickly and leverage surge capacity areas when feasible, using, for example, National Institutes of Health–funded Clinical and Translational Science Awards. At the local level, it is essential to secure early institutional buy-in and establish rapid response teams (biosafety, Office of Clinical Research, contracts, and institutional review boards) to ensure prompt institutional approval on RCTs. Establishing this infrastructure not only would allow for rapid initiation of trials but also would enable consistency across vaccine candidate protocols and management.

Rethinking Trial Designs: Adaptive and Flexible Models

Flexible and adaptive trial designs are critical to success, especially in the context of a new pathogen. As described, overlapping the preclinical stage and phases 1, 2, and 3 was necessary to expedite discovery and clinical testing, with some studies even incorporating all 3 phases into a single protocol (eg, NCT04368728). However, future study designs should carefully determine appropriate transition points, for example, by determining the level and quality of data required to advance from phase 1 to phases 2 and 3. Historically, phase 2 has served to further refine and optimize the dosing and schedule. With a more fluid and adaptive model, this important step could be better integrated into phase 1 investigations. Designing each phase with earlier interim analyses and ongoing safety evaluations throughout may help acquire relevant data in an expedited fashion.

Furthermore, while RCTs are the current reference standard, alternatives to placebo-controlled trials should be considered. Human challenge studies [18], noninferiority studies, and immunogenicity studies (once correlates of protection have been established) are more efficient and less costly. Indeed, early analysis and identification of a correlate of protection is essential to allow for rapid iteration and allow bridging of immunogenicity data, which would be useful to evaluate efficacy in populations that were not strictly studied in the trials, determine efficacy quickly (and at less cost compared with RCTs) of novel vaccine candidates, and investigate the efficacy of vaccines against new variants as they emerge [19].

The regulatory processes as they relate to early data from clinical trials are also an important component. The FDA’s role is to evaluate the full body of evidence and determine safety and efficacy for a novel product; full approval and licensure should not be expedited, and thorough evaluation is necessary to maintain this important safeguard. However, with the expeditious nature of the vaccine clinical trials, the FDA used the EUA mechanism to rapidly enable availability of COVID-19 vaccines to the public. By definition, the EUA allows for authorizations based on limited evidence, with consideration of direct risks and benefits in the context of a public health emergency [20]. While the EUA was overall beneficial and allowed for rapid distribution of COVID-19 vaccines earlier in the pandemic, further refinements and criteria for EUAs should be addressed, with improved transparency [21].

In addition, independent reviews by experts (eg, the Vaccines and Related Biological Products Advisory Committee) are essential to address decisions regarding the EUA and provide a platform for open communication with scientists and the public, allowing increased trust and confidence in the process by the public. Perhaps further expansion or increased frequency of these independent review committees would help enable the FDA to iteratively reflect on emerging data and reassess interventions as pandemic conditions change (eg, in response to variants of concern or waning of immunity and considerations to deploy booster immunizations). Educating the public and clinicians on the differences between EUA and full licensure is also warranted, since confusion about terminology can lead to further misunderstandings and mistrust of vaccines and the regulatory processes that govern approval [22].

Clinical Trial Management and Visits: Streamlining the Process

Visits should be streamlined favoring online consenting, telemedicine visits, use of smartphone apps for safety monitoring and provision of home thermometers, oximeters, and testing kits for participant’s self-monitoring. Using these technologies will not only reduce in-person visits and directly address many of the logistical barriers described above but will also use more cost-effective and efficient tools, with the benefit of more fully engaging the participants [23]. However, with technological adaptations, researchers should also evaluate strategies that are inclusive for elderly populations and people with low health literacy who may not be as facile in using e-Health tools. Other approaches are warranted as well, both to reduce the burden of on-site visits and to expand access to trial participation. For example, hiring personnel for home visits and partnering with home health agencies to conduct research visits at alternative locations to the research site are important strategies to pursue.

Building Trust and Engaging the Community

Recruitment should reflect the population we serve. While central registries can be very beneficial, involving local leaders as well as neighboring healthcare systems is a crucial strategy for success. By local outreach efforts to communities about vaccines in particular and research in general, a more successful partnership can be developed and nourished. Strategies to improve communication with the public are also essential to combat widespread misinformation. While sharing of information has been conducted mainly through press release, timely manuscript write-up, transparent review process, and prompt publishing of papers (eg, using preprint servers, online posting after peer review, or reporting results on clinicaltrials.gov) should be prioritized. Tackling misinformation is of utmost importance, and clear and continuous communication with the community, the scientists, and the participants regarding evolving information is essential to allow for iterative feedback of scientific developments and perceptions. A coordinated Learning Immunization System [24] is one model by which to involve key stakeholders, including the communities most affected, to begin to open effective communication and build trust. Such targeted methods can help address mistrust and misperceptions regarding vaccines and clinical trials.

CONCLUSIONS

The speed and successes of the COVID-19 vaccine trials have been remarkable and have altered the course of the pandemic. Clinical trialists and scientists have proved that the typically slow machinery of RCTs is not necessarily warranted and that a safe and rigorous process can be achieved more efficiently. However, further refinement and novel strategies are necessary. New pathogens will continue to emerge, and pandemics will continue to plague our global ecosystem. Investing in preparedness is essential. Continuous investment in global research and training the next generation of vaccinologists (eg, through nationally funded vaccinology T32 training grants) are priorities. Furthermore, with the COVID-19 pandemic particularly affecting underrepresented minorities, we must also focus on increasing the diversity of our research staff and faculty and promote continuous training in cultural competency. Through these actions, we will ensure safe, collaborative, and inclusive clinical trial processes that will continue to advance our scientific knowledge.

Notes

Financial support. This work was supported by Sanofi, Quidel, Merck, Pfizer, and Lilly (funding to N. R.’s institution: Emory University).

Supplement sponsorship. This supplement is sponsored by the Precision Vaccines Program of Boston Children’s Hospital.

References

Author notes