Discussion
In this study, we described a decrease in the initiation of phase III clinical trials in the UK that evaluate systemic anticancer treatments from 2019 to 2020, and a subsequent rebound in 2021 (figure 2). Importantly, the reduction in UK clinical trial initiation from 2019 to 2020 applies to both industry and non-industry-sponsored trials (figure 3). The 2021 rebound in clinical trial initiation in the UK was primarily driven by an increase in industry-funded trials.
Figure 3The per cent of industry-sponsored and non-industry-sponsored studies initiated in the UK each year. The stacked bars are colour-coded based on whether the study is primarily industry sponsored. Each bar is labelled with the corresponding count of initiated studies. The y-axis is normalised to show the percentage of industry-sponsored and non-industry-sponsored studies initiated each year.
Our study provides a granular investigation into trends in the UK’s oncology clinical trial initiation before, during and after both Brexit and the COVID-19 pandemic. This also provides an excellent barometer into the whole UK clinical trial landscape, as this therapy area accounts for one in four of all clinical trials.16
Our methodology is worth highlighting. When comparing trial initiation before and after Brexit (figure 1), we defined pre-Brexit and post-Brexit based on the post-Brexit transitionary period, which ended on 31 December 2020. We believe that the post-Brexit transitionary period is a better threshold for categorising trials into pre-Brexit and post-Brexit categories because the UK remained within the regulatory disciplines until 1 January 2021.21
In addition, we used the date that a study’s record was modified to include a recruiting site in each country to determine country-specific initiation dates. We chose this method over extracting the year from the study-wide start date because in 54% of cases there was a year gap between when a study recruits its first patient anywhere in the world and when that study opens a site in a specific country. A new record version is created whenever a study record is modified on ClinicalTrials.gov, which is closer to the ‘source of truth’ for the intent to recruit. However, this method for determining initiation year may lose accuracy for sites that were opened for recruiting near the beginning or end of a calendar year because responsible parties have a 30-day window to update the trial record following a change in a site’s recruiting status.22 Consequently, sites that were opened for recruitment after 2 December or before 30 January have ambiguous initiation years because two calendar years fall within the 30-day edit window.
Only RCTs present in ClinicalTrials.gov were included. In 2022, the UK began registering trials in the ISRCTN registry (https://www.isrctn.com).23 We also performed a search of the ISRCTN repository for trials absent in ClinicalTrials.gov and found only five trials that fit our study’s inclusion criteria. Lastly, certain industry sponsors mask their participating sites, introducing non-random bias into the analysis.
Previous reports identified a decrease in industry-sponsored RCT initiation in the UK. A report by the ABPI from 2017 to 2021 reported an approximately 40% decrease in the number of both studies and patients participating in industry-funded RCTs.15 The COVID-19 pandemic and Brexit are likely prominent drivers of this sharp decline.
Brexit uncertainty around departure from the EU regulatory framework and time-consuming regulatory hurdles are further de-incentivising industry sponsors from opening and enrolling trials in the UK. In contrast, an updated 2023 report by the ABPI indicated an increase in the number of industry-funded RCTs from 2021 to 2022.24
The immediate disruption of COVID-19 on worldwide clinical trial initiation was early reported in 2021, based on the Medidata Enterprise Data Store, estimating a 60% decrease in oncology trial launches during the pandemic period.25 Similarly in EU, an increase in clinical trials was demonstrated during COVID-19. The trends were mostly driven by the demand to face the pandemic, while non-pandemic-related studies were generally reduced at a maximum relative decrease of 32% across all diseases combined.26 Oncology trials displayed the highest proportion of disruption.26 27
A February 2023 report by the UK National Institute for Healthcare Research (NIHR) reported that RCT participation in England has rebounded significantly since the COVID-19 pandemic and now exceeds prepandemic levels. According to the NIHR, approximately 220 000 more people in England participated in RCTs in 2022 and 2023 compared with before the pandemic. The NIHR also reported an increase in industry-funded commercial studies in the UK compared with before the COVID-19 pandemic. Our results are largely concordant with the 2023 NIHR report, despite being limited to only phase III trials investigating systemic anticancer treatments. The average number of industry-sponsored anticancer trials initiated each year in the UK increased post-Brexit (figure 1). This suggests that new UK Government clinical development initiatives, such as the Innovative Licensing and Access Pathway, introduced after Brexit, are helping to increase the number of clinical trials being performed in the UK.28 Furthermore, the UK Government has also introduced a new consultation that may streamline clinical trials approvals, enhance clinical trials transparency, promote patient and public involvement and permit ‘low-risk’ trials to proceed with a minimal amount of red tape, potentially further boosting numbers.29
Following Brexit, UK clinical trials regulations have started to diverge from the EU. New harmonised EU clinical trial regulations, long demanded by the pharmaceutical industry, have sought to align clinical trial conduct across the EU.30 31 This will allow for single applications for trials run in different European countries and reduce administrative burdens for researchers and pharmaceutical companies.32 The new European Medicines Agency (EMA) Clinical Trials Information System (CTIS) was introduced on 31 January 2022, and is a vital step in facilitating the conduct of large pan-European clinical trials. However, the CTIS is focused on industry-sponsored trials, and will place new demands (eg, financial) on academic and other non-industry studies. Furthermore, a recent EMA report on the EU monitoring status on clinical trials showed that non-commercial multinational countries are still poorly represented, suggesting that greater work is required towards cross-national harmonisation.33 The UK will retain alignment with the EU on some aspects of clinical trial conduct (eg, manufacturing, assembly, data management and regulatory evaluations), which should facilitate the conduct of pan-European trials.32 34 But overall, the significant divergence in clinical trial regulations between the UK and EU will likely impede wider collaboration in oncology, and beyond, most notably for academic-led studies with limited financial resources. It is hoped that UK re-engagement in pan-European projects, such as Project Horizon, may help to mitigate these effects.
Our study has shown a resurgence in the UK’s clinical trial initiation from 2020 to 2021 that was primarily driven by an increase in industry-funded trials. This is potentially due to new UK Government post-Brexit pathways (eg, innovation and licensing access pathway) for clinical trials and regulatory review coming online providing a well-needed boost to reverse this decline.10 Notably these findings, despite being limited to only phase III oncology clinical trials are concordant with the UK Government O’Shaughnessy report.35 The UK experienced a decrease in non-industry-funded trials from 2020 to 2021 (figure 3). This pattern was reciprocated in other high-income regions (eg, the USA and Canada) and may suggest a re-equilibration of clinical trials at the close of the global pandemic. However, this pattern shows that despite the boost to commercial trials, non-industry (eg, academic) trials remain in significant decline and need further UK Government support. Furthermore, it is likely the initial uncertainties around UK participation in the Horizon Europe has had a detrimental effect on this sector beyond oncology studies.36
Global trends in overall clinical trials also appeared to have slowed in 2023, with a 15% decline compared with 2022 and 22% compared with 2021.37 However, for oncology, the general trend is an increase in clinical trials (with neurology and immunology), overall sharing more than a half of all new clinical trial launches, rising from around 40% prepandemic.37 Notably, our data show a small increase in the number of RCT initiation in the EU, compared with the UK, following Brexit, this increase is likely linked to several new EU Cancer initiatives (eg, EU Cancer Mission) to boost research and innovation in the EU following the COVID-19 pandemic. Following the departure from the EU, the UK will no longer be able to benefit directly; however, engagement in wider projects (eg, Horizon Europe) may allow for some degree of participation, potentially boosting UK-EU clinical trial engagement. Furthermore, several UK charitable organisations (eg, Cancer Research UK, Nuffield Trust, The Health Foundation) have produced recommendations to help guide, and increase, UK clinical trials participation in oncology and beyond.38–41 However, it remains to be seen how the UK will perform as the global clinical trials landscape continues to evolve, and the cumulative effects of Brexit continue to mature.
Our study demonstrated a drop in the initiation of phase III clinical trials that evaluate systemic anticancer treatments in the UK in 2020. This study should serve as a benchmark to monitor clinical trial initiation, and the potential success of UK Government interventions (eg, innovation and licensing access pathway) to prioritise this, as the UK moves forward independently from the EU. However, our methodology is descriptive and cannot tease apart the relative impacts of Brexit and the COVID-19 pandemic on clinical trial initiation in the UK. It is also recognised that Brexit is both an event and an ongoing process which will have long-lasting implications for many years to come. Furthermore, our study period does not include the agreement of the Windsor Framework (February 2023), and rejoining Horizon Europe, which has important implications for the UK-EU oncology clinical trials engagement moving forward.42 43 Future studies should further evaluate the direct impacts of these significant events on the UK’s clinical trial apparatus in 2023 and into the next decade.
