Last week, researchers, funders and clinicians celebrated International Clinical Trials Day. It’s been 269 years since James Lind performed his now famous first ever clinical trial looking at treatments for scurvy. But fast forward almost 270 years and clinical trials are more complex than ever before.
We are at the beginning of the stratified or precision medicine era, which essentially seeks to treat the right patient with the right medicine at the right time. A simple concept to understand, but a difficult challenge to deliver. The promise of stratified medicine is immense and we have seen great strides in recent years, especially in the field of new cancer treatments. We've also seen rapid developments in underpinning technologies, such as next generation sequencing, that have the potential to speed up early-phase research and development and identify new targets for disease modifying therapies at an unprecedented rate.
But the development of a medicine isn't just performed in a test tube. Any new medicine still has to go through a rigorous clinical development program before it can be submitted to the regulatory authorities for a licence. While an increased molecular understanding of disease has facilitated drug discovery, it has also led to smaller patient populations as we stratify within diseases. These precision medicines are only effective for a sub population of patients with the disease, who are identified by specific biomarkers. For example, whereas there may be a very large number of breast cancer patients, there may be a much smaller number with a particular genetic mutation in their cancer, such as BRCA1 mutations. This can make it difficult to identify and recruit sufficient patients into clinical trials to demonstrate the potential medicine is safe and effective.
These challenges have led to the development of innovative trial designs to test new therapies which include 'umbrella' and 'basket' trials. An 'umbrella' trial is a single trial that tests multiple targeted medicines based on the molecular mechanism of disease. For example, patients with a specific disease, such as small cell lung cancer, will be molecularly tested and then based on their individual mutations (e.g. EGFR , KRAS/BRAF, VEGF/VEGFR-2 ) they will be put into different 'arms' of the trial and given a different medicine targeted to their mutation, as opposed to other new medicines targeted against different mutations. Meanwhile a 'basket' trial involves recruitment of patients with different types of cancer but a common mutation, for example, BRAF, in which a companion diagnostic is used to screen likely responders from among the broad patient population for treatment with a precision medicine. Overall, these new trial designs seek to improve the efficiency of clinical research; by testing several products in parallel for a single disease or several diseases with a single product, we are effectively running several trials as one.
However, these innovative trial designs are very complex and bring with them new challenges, for industry, academia, clinicians and regulatory authorities and patients. In recognition of the challenges and opportunities these trials bring, the ABPI and MHRA held a joint meeting last autumn under the banner of the Ministerial Industry Strategy Group (MISG) New Technologies Forum on Umbrella/Basket Protocols. This meeting offered an exciting and unique opportunity to bring together regulators (the MHRA and EMA), industry, academics, clinicians and patient groups to move forward dialogue on the use of these trials. The meeting examined current and prospective industry and academic use of these protocols, alongside perspectives from key regulatory agencies, to explore 1) how they can be used to develop an appropriate clinical evidence base, and 2) how this evidence can be used to support regulatory approval. A full meeting report is available here.
The meeting identified a number of emerging challenges facing all stakeholders including:
The meeting also identified some potential areas for future work, which could address some of these challenges. Ultimately this Forum, and future meetings and discussions, should support and enhance the use of these trial methodologies, which will accelerate the development of stratified medicines for the benefit of all stakeholders, but most importantly for patients.
Clinical trial designs have progressed significantly since the days of James Lind, and these changes continue to bring challenges as well as benefits. However, forward looking discussions about these new innovations, such as the Forum meeting above, demonstrate the importance of ongoing open dialogue between industry, regulatory agencies and wider stakeholders, with the aim of making medicines development more efficient and ultimately bringing better treatments to patients faster.