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Why long-term follow-up should start early in vaccine trials

In 1974, the World Health Organisation (WHO), at the request of its members, launched the Expanded Program on Immunisation (EPI). The aim was to make life-saving vaccines available to all globally. A study published in Lancet to mark the 50th anniversary of the EPI showed the impact of the initiative on public health. The study’s authors found that the program averted 154 million deaths.1 The EPI program is estimated to have been directly responsible for a 40% reduction in infant mortality during the same period. According to the study, as many as 146 million deaths were averted in children under five years old, including an estimated 101 million in infants under one year old. 

Recent outbreaks of familiar vaccine-preventable illnesses such as measles (in the US and abroad3) and pertussis (in the EU4 and especially the Czech Republic5) have reignited debates about vaccines. Vaccination programs can be cost-effective and life-saving public health tools. A crucial factor in any vaccine program is the ability to demonstrate the vaccine’s efficacy and safety. Demonstrating safety and efficacy ensures that the vaccine is effective for its intended use, and that the benefits outweigh the potential risks, safeguarding patient well-being. Vaccine programs only succeed when the public feel confident in the safety of the vaccines in question. Similarly, vaccine trials only succeed when participants are willing to join them. Trial participants put their health in the hands of vaccine developers for the greater good of humanity. In doing so, they need to be confident that potential trial-related risks are mitigated and managed by the vaccine trial team. While long-term follow up (LTFU) was always a critical element of vaccine trials, there has been a recent push from regulators to follow up for longer periods. This means sponsors need to be prepared to gather data that demonstrates vaccine safety and efficacy over a more extended term. This data can be used to increase trust with physicians and patients and to demonstrate vaccines’ effectiveness and safety. 

How COVID-19 changed vaccine trials

Before the COVID-19 pandemic, vaccine trials were a relatively niche area of clinical research. Typically, trials took between 5 and 10 years to conduct efficacy and safety studies. The urgency of the COVID-19 pandemic led to an unprecedented acceleration of vaccine development timelines. At the same time, regulators fast-tracked the regulatory review and approval process for vaccines. ICON provided clinical trial services to support one of the largest and most expeditious randomised clinical trials ever conducted. Our team helped accelerate the sponsor’s mission to develop the world’s first safe and effective investigational vaccine for COVID-19 vaccine to be approved. This partnership redefined industry expectations in terms of trial management and speed, while never compromising safety, quality and integrity. However, the speed with which vaccines became available may have unintentionally contributed to public fears about vaccine safety. Addressing these fears requires both effective communication and long-term data. While communication is largely in the hands of physicians and public health officials, sponsors have a significant role to play in gathering the necessary long-term data. 

Demonstrating long-term safety starts in the early phases

When it comes to demonstrating long-term safety, vaccine developers should start with the end in mind. Planning for long-term follow up (LTFU) when designing study protocols will ensure the right data is captured both during and after a vaccine trial. Today sponsors can draw from a wide array of real world data (RWD) to understand the long-term impact of their vaccine or treatment. Clinical trial tokenisation (CTT) enables sponsors to follow patients for years after the trial ends by substituting Personal Identifiable Information (PII) with a unique token or deidentifier. This token is then used as a reference point so that real world healthcare data can be analysed to understand trends in disease, indication and post-exposure safety/effectiveness patterns without compromising patient privacy. Patient data can be captured discreetly allowing sponsors to track large volumes of real world patient data for cohorts of study participants. This provides real world evidence (RWE) of vaccine efficacy and interactions with other illnesses or drugs. However, to leverage CTT, sponsors must ensure that participants consent to being followed for a specified period of time once the trial is over. 

When designing a study sponsors should consider what the minimum follow up period will be. While this may be dictated by the regulatory requirements, it can be worth considering a longer follow up period as well as the possibility of extension studies. Sponsors must also decide whether to deploy passive or active surveillance of participants and what data points to capture. Special attention may be necessary to account for population-specific groups such as older people, pregnant women or immunocompromised individuals as well as those with comorbidities. Sponsors will need to demonstrate to regulators that they have received informed consent and that the data is secured to protect patient privacy. 

The future of vaccine trials

Having begun this article with a look back at the half-century of vaccination through the WHO EPI, it seems apt to close with a look to the future. As sponsors and supporters of vaccine trials we have a responsibility to conduct long-term follow up that demonstrate the continued safety of vaccines for years to come. By incorporating long-term follow up, RWD, and RWE strategies in clinical trials from as early as possible, sponsors will help ensure the success of their vaccine programs. In doing so they can support individuals to confidently make informed decisions about vaccination. This National Immunisation Awareness Month we thank both past and future vaccine trial participants for contributing to the development of safe and effective vaccines which save lives. 

 

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References

  1. Shattock AJ, Johnson HC, Sim SY, et al. Contribution of vaccination to improved survival and health: modelling 50 years of the Expanded Programme on Immunization. The Lancet. 2024;403(10441):2307-2316.
  2. COVID-19 vaccinations have saved more than 1.4 million lives in the WHO European Region, a new study finds [press release]. Copenhagen: World Health Organization, 16 January 2024.
  3. Harris E. Measles Outbreaks in US and Abroad Prompt CDC Vaccination Alert. (1538-3598 (Electronic)).
  4. ECDC. Increase of pertussis cases in the EU/EEA. 2024.
  5. Holt E. Pertussis outbreak in Czech Republic. The Lancet Infectious Diseases. 2024;24(6):e359.
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