Are investigator-initiated clinical trials becoming an ‘endangered species’?

Investigator-initiated clinical trials (IITs) are at the core of innovative thinking in health research generating data in real-world settings that influence global policy. Although diminished funding and a reduced workforce pose significant challenges, IITs should be championed as the best model to deliver unbiased, independent health research.

A recent report by the Association of the British Pharmacological Industry shows a small increase of 3.7% in the number of industry clinical trials initiated between 2022 and 2023,¹ suggesting a slow recovery of UK competitiveness in clinical trials research. As opposed to commercial trials, IITs are non-for-profit studies where the research idea, study design and conduct are led by a non-commercial institution acting as sponsor. In Europe, sponsors are usually publicly funded bodies such as national health services or higher education organisations, whereas commercial trials often involve large, international projects designed to investigate the effects of new interventional medicinal products (CTIMPs), IITs address more specific research questions and have a broader scope of investigative methods—including innovative surgical interventions, novel diagnostic or screening procedures, or observational designs, often with direct impact on clinical practice and improved patient outcomes. Crucially, although commercial studies, mainly phase III, account for 46% of interventional trials in the UK, most of the patient recruitment takes place in IITs,² underscoring the need for ongoing support to maintain the pipeline of innovative non-commercial research.

Significant challenges, however, exist. Where commercial trials benefit from larger, more secure funding and dedicated research expertise towards management and study conduct, IITs are vulnerable to limited funding streams, often hugely competitive; smaller teams and changes in the regulatory landscapes generating larger administrative burdens and complex regulations. Furthermore, pharma funding has decreased significantly since the COVID-19 pandemic, with companies less likely to support independent studies not fully aligned with their commercial agendas. Further threats come from a dwindling work force and the reported decrease on the number of clinical academics and research-active clinicians and other health professionals.³

Yet, the true challenge lies in the unexpected, as illustrated by the investigator led phase IIIb treatment strategy trial:GOLMePsA (GOLimumab and Methotrexate versus methotrexate in early Psoriatic arthritis) .⁴ Although the study had a ‘negative’ result, that is, it did not confirm the original hypothesis, it answered a clinically relevant question, with the potential to inform future guideline development. Supported by a pharma grant award and underpinning a PhD programme with an expected delivery time of 3–4 years, GOLMePsA benefited from a team of established researchers backed by an NHS Trust experienced in sponsoring commercial and non-commercial research. Nonetheless, GOLMePsA faced a seemingly impossible array of setbacks, among others, the roll out of new regulatory research guidance, drug supply shortages triggered by Brexit, a Medicine and Healthcare products Regulatory agency (MHRA) inspection and a global pandemic (figure 1). Beset with two recruitment pauses and eight changes in study personnel, the study took an extra 6 years to complete recruitment, running into significant costs. Eventual success saw a PhD award, and two manuscripts to date,^{4 5} noteworthy, since a substantial proportion of studies remains unpublished, with non-publication associated with ‘negative’ results.⁶ This publication bias limits the body of scientific evidence available to healthcare professionals and policymakers with the potential for ineffective or harmful interventions and waste of healthcare resources.⁷

Figure 1. Schematic diagram illustrating the timeline from idea conceptualisation to manuscript publication of the investigator-initiated Phase IIIb GOLMePsA clinical trial spanning 13 years.

Abbreviations: GOLMePsA (GOLimumab and Methotrexate versus methotrexate in early Psoriatic arthritis); eCRF: electronic Case Report Form; ICH: International Council for Harmonization of technical requirements for pharmaceuticals for human use; IMP: Investigational Medicinal Product; QA: Quality Assurance; LPLV: Last Patient Last Visit; EULAR: European Alliance of Associations for Rheumatology; LTHT: Leeds Teaching Hospitals NHS Trust; MHRA: Medicines and Healthcare products Regulatory Agency.

In conclusion, current global challenges contribute uncertainty to the future of IITs, which are otherwise essential to generate real-world data of safe and effective interventions in healthcare research. An improved dialogue between funding awarding bodies and the pharmaceutical industry together with investigators and regulatory organisations is needed to align priorities and improve efficiency in the delivery of IITs, while safeguarding the independence of researchers and procuring the best evidence to improve clinical care provision.