Accessibility and safety profiles of immune checkpoint inhibitors: from regulatory approval to real-world pharmacovigilance study

Abstract

This research aims to investigate the situation for immune checkpoint inhibitors (ICIs) in oncology practice worldwide. By examining disparities in ICI accessibility across different regions, rare adverse reactions and safety profiles of off-label use, we hope to identify barriers to equitable and safe ICI use and suggest actionable recommendations for improvement of the worldwide utilisation of ICIs.

While ICIs have revolutionized cancer treatment, there are still challenges in its global application. Previous research highlighted that there were disparities in ICI availability and regulatory approval timelines between high-income countries and low- and middle-income countries. However, the specific reasons for these disparities are unclear. Furthermore, disparities in disease burden, medical capacity and regulatory jurisdictions in the different regions have not yet been well studied for their effect on the accessibility and outcome of ICI. Additionally, the safety profiles of ICIs, particularly for rare adverse reactions and in off-label use settings, remained unexplored. Previous studies often lacked robust data on the incidence and management of immune-related adverse events (irAEs), especially for different populations.

To address these gaps, I designed three complementary studies. The first study examined global disparities in ICI approval and availability, focusing on the delayed regulatory approval and clinical evidence gaps. The second study investigated the risk of myocarditis associated with ICI use in advanced non-small cell lung cancer (NSCLC) patients by leveraging a nationwide cohort in China to assess real-world safety concerns. The third study analyzed irAEs from both off-label and on-label ICI use through the FDA Adverse Event Reporting System (FAERS) database, aiming to reveal new adverse reaction signals and clinical priorities. Together, these studies provided a comprehensive view of ICI use, from regulatory barriers and global access inequities to specific safety concerns and off-label risks.

The first study revealed that the US generally approved ICIs faster than the EU and China, with significant differences in review durations and evidence requirements contributing to these disparities. Notably, off-label ICI use is prevalent in regions with approval lags, raising safety concerns, especially for vulnerable populations. These findings illustrated an important need for international regulatory cooperation and studies to optimize clinical trial designs to generate local evidence. This study provided a foundation on understanding the global inequality of access to ICIs and made a platform for future exploration of safety and regulatory issues in the other two studies.

The second study found that ICI therapy was significantly associated with an increased risk myocarditis in advanced NSCLC patients. Even after the first three months of treatment, this risk remained high, indicating the need for longer-term monitoring. By classifying myocarditis as a serious safety issue, this study underscored the importance of close monitoring and appropriate management for patients who receive immunotherapy with ICIs. It also demonstrated the value of real-world evidence (RWE) in addition to clinical trial data, especially in the evaluation of rare and severe adverse events. These results are important to establish a safety evaluation monitoring scheme and enhance the prognosis of patients receiving ICI therapy.

The third study demonstrated that off-label and on-label ICI use have similar distributions of irAE toxicities, with no significant difference in cumulative incidence over time. However, off-label use of programmed death-ligand 1 (PD-L1) inhibitors was associated with an increased risk of irAE-related death. This study demonstrated the importance of closely monitoring for severe immune-related adverse events in non-indicated situations and identified possible dangers in using PD-L1 inhibitors outside of approved indications. By analysing in detail the safety characteristics of non-indicated use versus use within approved indications, this study contributes to filling the gap in knowledge about the safety of ICIs in clinical practice and facilitates clinical decisions.

In conclusion, this thesis provided important guidance on the global application of ICIs. It showed some difficulties faced in regulatory coordination, safety monitoring, and equitable accessibility. The research findings require the establishment of international joint review mechanism to simplify the regulation process and improve accessibility of immune checkpoint inhibitors. It also highlights the need to develop treatment guidelines for different races and to introduce advanced technologies, including artificial intelligence, to improve the diagnosis and prediction of AEs. Moreover, promoting adaptive approval pathways and real-world studies (RWS) will help to make strong evidence for extraordinary uses of ICIs and to improve benefit-risk balance of ICIs. By addressing these challenges, the research promotes building a fairer, safer and more effective global landscape of ICIs, in turn improving cancer treatment and outcomes for patients globally.

Date of Award	18 Jul 2026
Original language	English
Awarding Institution	University of Nottingham
Supervisor	Mainul Haque (Supervisor), Weihua Meng (Supervisor) & Jinling Tang (Supervisor)