Scientist looking into microscope

Understanding the factors that prevent innovative research discoveries from making it to clinical trials is a multifaceted problem. One question which our new article addresses is whether current research practice and the factors that influence the conduct of pre-clinical research permit or hamper the timely progression of laboratory-based observations to clinical trials.

The article debates to what extent a deep mechanistic understanding of a potential new therapy is required before commencing early clinical trials, and whether patients are better served when mechanistic and clinical studies progress side by side.

It is plain for the public eye to see that academic curiosity and discovery inevitably creates yet more questions and more unknowns.

Chris Bunce - Professor of Translational Cancer Biology, University of Birmingham

It is plain for the public eye to see that academic curiosity and discovery inevitably creates yet more questions and more unknowns. The authors draw an analogy between the old proverb about “big fleas having little fleas upon their back to bite them, and little fleas having littler fleas and so ad infinitum”, and the desire of researchers for deeper understanding of biochemical and molecular processes in health and disease, fuelling the hunt for yet smaller ‘fleas’. The authors hope that their article will foster discussion about what ‘size of flea’, that’s to say depth of understanding, is appropriate to argue for clinical experimentation.

To illustrate our arguments, the authors remind us of four historical examples of the development of hugely impactful and paradigm changing innovations in the treatment of blood cancers. Importantly, three of the examples document the undertaking of clinical trials before having a detailed understanding of how the drugs worked. Instead, clinical and laboratory research progressed alongside one another leading rapidly to considerable patient benefit.

One of these success stories will come as a major surprise to many, which was the introduction of Thalidomide as successful therapy for a blood cancer called myeloma. Thalidomide was originally marketed to reduce nausea and to aid sleeping in pregnant women with devastating consequences. However, outside of pregnancy, it has proven a very safe drug and in early trials demonstrated considerable life extending properties in myeloma. These trials were undertaken with little or no understanding of the anti-myeloma activity of Thalidomide. However, the trials were made possible because the drug was known to be safe. This is at odds with current research paradigms that may take long periods of highly expensive research providing deeply understood mechanisms of action of drugs that ultimately are ineffectual or unsafe when introduced in patients.

We worry that the modern-day hard and soft governance of medical research make future innovations such as the introduction of thalidomide in myeloma, less and less likely. Amongst the obstacles highlighted by the article is the unintended consequences of the career structure for research scientists, where more detailed experimentation to achieve publications in major journals are seen as the necessary currency of job security, funding success and career progression. The authors also acknowledge that academic journals equally operate in a competitive market and their success is linked to the ‘strength’ of the science they publish. Together these influences create an environment of competition for funding and publishing that, when coupled with the inherent inquisitiveness of researchers, fuels a peer review process that recommends or even demands very detailed work linked to deeper and deeper mechanistic understanding of drug actions.

The article identifies that all four success stories were driven by passionate, talented, and motivated clinical researchers determined to improve the outcomes for their patients. The authors argue that the stories identify that the ‘size of flea’ that is acceptable in the clinic to both patients and their doctors is contextual to their experience not those of laboratory researchers, pharma, or legislators. Reciprocally therefore, there is a danger that science and academia, in their pursuit of excellence, may delay or indeed prevent potential medical discoveries from ever reaching the clinic.

Chris Bunce - Professor of Translational Cancer Biology, University of Birmingham