Introduction

The recruitment of subjects for clinical trials during public health emergencies, such as COVID-19 and Ebola, presents unique challenges. These challenges are influenced by factors such as case fatality rates, the totality of available data, platform safety data, regulatory approval status, and deployment status. This paper explores these challenges and proposes strategies to address them, drawing on examples from recent public health emergencies. 

It must be understood that support for high potential products and use of differentiated investment will be needed to reduce the potential for competition for subjects to be included in clinical trials. 

Principles

Case Fatality Rates and Data Availability 

High case fatality rates can create urgency but also fear, impacting recruitment. For instance, during the Ebola outbreak, the high mortality rate led to both a rush to develop vaccines and significant challenges in recruiting participants due to fear of the disease.[1] The availability of comprehensive data, including animal efficacy and immunogenicity data, is crucial in determining the feasibility of placebo-controlled trials.[2]

Regulatory Approval and Platform Safety Data 

Regulatory approval status significantly influences trial design and recruitment.[3] Initial approvals often necessitate decisions on whether to continue trials for additional safety data or to allow control groups to receive the active vaccine for protection[4]. Platform safety data, especially from previous trials, can support these decisions and enhance participant confidence[5]. 

Real-World Data (RWD) and Correlates or Surrogates of Protection (CoP/SoP) 

Real-world data play a critical role in assessing vaccine effectiveness post-deployment. When correlates or surrogates of protection are not established, joint efforts are needed to identify them[6]. RWD can provide insights into vaccine performance across different populations and settings[7]. For example, during the COVID-19 pandemic, RWD was essential in understanding vaccine effectiveness and safety in real-world conditions[8]. 

Applications 

Initial Enrollment 

Before regulatory approval, recruitment focuses on the availability of comprehensive data. As case fatality rates increase, the urgency for effective vaccines grows, necessitating robust animal and immunogenicity data to justify placebo-controlled trials [9]. Early-phase trials often face challenges in enrolling participants due to the lack of existing safety data and the experimental nature of the vaccines [10]. 

Post-Approval Recruitment 

Once a vaccine receives initial approval, the focus shifts to balancing the need for additional safety data with ethical considerations of providing the control group with the active vaccine. This phase often relies on platform safety data from earlier trials. For example, during the COVID-19 vaccine trials, once emergency use authorizations were granted, ongoing trials had to adapt to ensure ethical treatment of participants in control groups. 

Deployment and Real-World Evidence 

During deployment, recruitment strategies must adapt to the availability of real-world evidence (RWE). The quality of RWE varies by country, influencing decisions on further placebo-controlled trials versus observational studies. High-quality RWE can support ongoing vaccine benefit-risk assessments and guide public health policies. For instance, the use of RWE during the COVID-19 pandemic helped in understanding vaccine effectiveness in diverse populations and real-world settings. 

Special Populations 

Recruiting special populations, such as children, pregnant women, and immunocompromised individuals, requires tailored approaches. These trials often rely on immunogenicity data and may use adult populations as controls. Ensuring the safety and efficacy of vaccines in these groups is critical for comprehensive public health protection. For example, pediatric trials must consider ethical guidelines, informed consent, and the unique immune responses of children. 

Impact of Vaccine Availability

The data to be generated to support authorization may be dependent on the availability of vaccines in a public health emergency, as shown in Table 1. As vaccines become available for protection from a disease with high case fatality rates, the benefits of using correlates or surrogates of protection rather than controlled trials may outweigh the risks.

Table 1: Data generation based on availability of vaccines

Conclusions 

Recruitment for vaccine trials during public health emergencies is complex and multifaceted. It requires careful consideration of data availability, regulatory status, ethical implications and vaccine availability. Leveraging real-world data and establishing correlates of protection are essential for effective vaccine deployment. Tailored strategies for special populations ensure that vaccines are safe and effective for all segments of the population.