Abstract by Débora Dalmas Gräf

Innovation in vaccine development have enabled extraordinary public health achievements, improving life expectancy and quality of life across the globe. However, developing new pharmaceuticals has historically been a resource and time intensive process, usually relying on randomized controlled trials (RCT) for evidence of clinical benefit. In recent years, additional data sources for regulatory decision-making have gathered attention. Real-world evidence (RWE), which arises from data collected outside of research settings, has sparked optimism, both for its potential of improving the generalisability of findings, and for providing insights about the effect of medicines under routine clinical care.

This PhD thesis aimed to investigate if RWE has contributed to the regulation of vaccines and where it can potentially be leveraged to improve vaccine assessments. I reviewed the clinical evidence generated in connection with the development and regulatory assessment of vaccines that underwent the centralised approval procedure in the European Union between 2012 and 2022. I also investigated evidence gaps, particularly for special populations such as paediatric patients, elderly, pregnant, breastfeeding and immunocompromised individuals, who are often underrepresented in RCTs. Finally, I explored if populations vaccinated in the real-world are similar to populations eligible for inclusion in studies supporting vaccine regulatory decision-making, using a recently introduced herpes zoster vaccine as a case study.

I would like to highlight four points as the main findings of this project. First and foremost, vaccines have been thoroughly and systematically tested and assessed before marketing authorisation. Second, RWE did not make a significant contribution to the benefit–risk assessment of vaccines so far, with the exception of COVID-19 vaccines, where RWE contributed to evaluations of effectiveness, safety, and adequacy of vaccine schedules. Third, special populations such as pregnant, breastfeeding, and immunocompromised individuals were rarely included in the studies that contributed to regulatory decision-making, and this has also reflected in poor information availability on product labels. And fourth, there is a substantial gap between the populations included in studies supporting vaccine approvals and populations vaccinated in the real-world.

Supported by the studies in this thesis, I suggest that RWE can be a complementing source of evidence for regulators, especially to better inform decision-making regarding populations not previously addressed in randomized studies. However, there is an urgent need to generate high–quality evidence for underrepresented groups, and RWE might not be fit-for-purpose in many situations. Policies to foster inclusion in vaccine research are needed, and coordinated efforts across academia, vaccine developers, and regulators are key.