The COVID-19 pandemic threw all of our lives into unchartered waters, but with the pandemic officially declared ‘over’ by the World Health Organization in May, thoughts switched to a return to ‘normal’. Yet, the global economy, social and healthcare systems will never be the same, with years of major disruption inevitably leaving their mark. The clinical development industry is no exception. While the sector rose to the immediate challenge of COVID-19, demonstrating that with the right resources and data, new therapies can be quickly developed under pressure, the lasting impacts from the pandemic are beginning to make themselves known.

At the mid-point of 2023, Phesi conducted a new analysis of 13,490 phase 2 and 3 clinical trials to explore how clinical development has fared in the first six months of the year. The data reveals a concerning increase in trial cancellations and avoidable protocol amendments driving up cycle times and costs. The findings also point to new disease areas receiving an influx of investment as the focus on COVID-19 drops. With these changes will come new challenges and shifting priorities – the question for sponsors now is how to prepare for the trials of the future.

Since 2020, COVID-19 has naturally been a priority for the clinical development industry, falling in the top five most studied disease areas for three years running. But now the tide is turning. A separate Phesi end of 2022 analysis saw a decline in the number of recruiting trials for COVID-19 therapies. This trend has continued as successful vaccines, new therapies and efficacious repurposed drugs were identified – helping to bring the pandemic under control. Most importantly, there are very few available patients for clinical research due to reduced spread.

Phesi’s new analysis of over 13,490 clinical trials recruiting patients in the first six months of 2023 identified solid tumour, breast cancer, stroke, depression and prostate cancer as the five most studied indications (Figure 1). This was the first time since the beginning of the pandemic that COVID-19 has not been in the top five. The data shows the clinical development sector is now clearly re-allocating resources to other disease areas. Oncology has long been – and continues to be – an area of high investment, but depression has also entered the top five.

With an estimated 5% of adults affected by depression globally, it is reassuring to see research directed towards such a prevalent disease. Increased interest from the pharmaceutical companies is likely driven by greater public awareness and campaigning by patient groups.

‘Oncology has long been – and continues to be – an area of high investment [for clinical trials], but depression has also entered the top five’

At the same time, there is now deeper understanding of the underlying causes of disease as research has advanced, with the link between serotonin levels and depression thrown into question last year. What’s more, the last major class of antidepressants – SSRIs – was discovered more than forty years ago, and interest in new treatment avenues, such as psychedelics, has propelled this disease up the clinical development agenda.

There will be particular challenges for sponsors conducting clinical trials in the area of depression. With ethical issues surrounding placebos, and the high variation in patient characteristics – such as age, disease severity, disease presentation and comorbidities – seen in people with depression, it is difficult to identify target patient groups. Trial design and protocols must therefore consider a huge number of complicating factors. There is also the challenge of understanding the current standard of care and having a more granular overview of patients to select the right candidates for a trial. Companies will need to design protocols carefully to ensure that each cohort is considered and the selected endpoints are relevant.

With contextualised data from 1,945,206 depression patients and a digital twin platform, we can optimise the clinical development pathway and maximise the value of development assets, design improved protocols with fewer amendments and eventually reduce or eliminate the need of patients on the control arm.

Aside from the shift in investment priorities, Phesi’s mid-year 2023 analysis also revealed underlying issues that continue to impact clinical development. Worryingly, trial cancellations are at their highest level in seven years. Some 31% of clinical trials were cancelled at phase 2 in the first six months of 2023. This is likely due to the reduced interest in COVID-19 trials, but also the continued fallout from the many trials that were delayed or affected by additional amendments due to reallocation of resources and recruiting challenges during the pandemic. Patient data quality may have also been impacted by the pandemic.

Pre-COVID-19 levels of phase 2 attrition were around 20%, but with the pandemic and associated lockdowns causing delays, recruiting challenges and data collection issues, the clinical development industry is clearly still struggling with the effects three years on. Moreover, we predict that it will take around two more years to iron out the kinks created by these issues, and so can assume that phase 2 attrition will remain at this level for some time.

The high level of trial cancellations is also a stark warning that the costs of clinical development are set to rise. Of added concern is the knock-on effect from delays and cancellations on the rate that new therapies reach patients in need. The strain of trial cancellations on the global drug development pipeline will be severe, and it is vital to tackle unnecessary trial amendments and cancellations to improve productivity. How can we alter protocol design to achieve this?

Figure 1 The top five most studied disease indications in the first six months of 2023

As trial cancellations put industry productivity in jeopardy, sponsors will be looking to recoup losses in other areas. Trial amendments – an avoidable symptom of poor trial protocol design – can drive up costs by as much as $7m per phase 3 trial. Yet with a deeper understanding of the typical patient profile and characteristics, these additional costs and delays can be reduced.

Patient age is an instructive example. Of the 13,490 phase 2 and 3 trials recruiting for patients in the first half of this year, more than 6% (872) had one or more patient age-related amendments. Some indications are more vulnerable to amendments caused by issues with age representation in participant groups. Crohn’s disease, sickle cell disease and amyotrophic lateral sclerosis (ALS) are most prone to age-related amendments, with more than 15% of trials for these indications requiring at least one amendment due to patient age. Neuroblastoma, pulmonary arterial hypertension and multiple sclerosis (MS) are also more vulnerable to age-related amendments, with more than 10% of trials for these diseases amended.

By taking a more complete view of the patient population targeted by the therapies under study – and understanding which disease areas are more prone to amendments – sponsors can design more effective protocols. Analysing historical trial data, as well as patient and physician records, produces a statistical knowledge of target patient characteristics to avoid amendments. This kind of data-led approach affords the industry an opportunity to proactively optimise trial design and improve clinical development productivity.

With access to more data than ever before – including data from patient records, laboratory research and experiments, clinical studies and decentralised trials, and scientific publications – now is the time for the industry to modernise, become data-led and boost patient experience. To deliver the trials of the future, sponsors must use data to improve the design of clinical trial protocols. This will give trials a higher chance of success and ensure new therapies get to market faster. Modern approaches such as predictive analytics in protocol design, AI and digital patient profiles will empower the industry to overcome enrolment difficulties, accelerate clinical trials and avoid amendments – improving overall productivity.

This shift to more modern approaches will revolutionise clinical development, whether via the use of data in eliminating placebo arms, conducting trials with smaller patient groups or by simulating trials in silico. By using data to highlight and address potential issues ahead of time, trial design can be streamlined to ensure patients get the treatments they need more quickly. As sponsors move towards smarter trials, the chances of a successful outcome will improve and the development of therapeutics accelerated. By improving management, analysis and application of data, and adopting external control arms, we can take an important step towards a more data-driven and patient-centric clinical development industry.

Gen Li is President and Founder of Phesi