Scientists at the Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London and in our joint Drug Development Unit with our partner hospital, The Royal Marsden NHS Foundation Trust, developed the Pharmacological Audit Trail for a new era of modern precision therapies which target the molecular changes and abnormalities that drive the initiation, progression, evolution and resistance cancer cells.

Many of these therapies have since been shown to be more effective and cause fewer harmful side-effects than traditional cancer drugs which tend to affect all dividing cells in more of a blanket approach.

Previously, drug development was geared to this previous era of one-size-fits-all mechanism of cancer treatment, with therapies all going through a similar set of standard pre-clinical tests before entering trials on diverse populations of patients.

Very little mechanistic evidence was collected during clinical trials – which made rational decision-making very difficult. This approach was increasingly out of touch with advances in our understanding of cancer biology and in methods for investigating how drugs work in the body.

The Pharmacological Audit Trail (PhAT) was originally conceived as a framework for evidence-based drug discovery and development by Professor Paul Workman – who was CEO and President of the ICR from 2014 to 2021.

Working with clinical colleagues Dr Udai Banerji, and Professors Johann de Bono, Stan Kaye and Ian Judson, who are all based at the ICR and our partner hospital The Royal Marsden, he demonstrated the value of PhAT in clinical trials of many different drug classes, including inhibitors of HSP90, PI3 kinase, AKT, HDAC and many others.

The PhAT approach makes intelligent use of biological discoveries and technologies to thoroughly measure key performance indicators for drugs throughout their development, from the laboratory to the clinic.

This helps scientists to focus scarce resources on the most promising therapies, spares patients the side-effects of treatments that will ultimately not help them, and gives a truer picture of the effectiveness of a therapy in those patients it is designed to help.

And by monitoring biomarkers of drug response – for example, molecular changes in tumour biopsies or in the blood, or the appearance of tumours on scans – scientists can make informed decisions about drug development without having to wait years to see the final results of large clinical trials.

We have seen many examples of the major benefits of using the PhAT during drug discovery. In particular, its use facilitates rigorous and robust decision-making throughout all of our drug discovery projects and in each of our early clinical trials – by ensuring a secure linkage all the way from the drug interaction with its target through to therapeutic activity in the patient.

The PhAT has also been adopted by academic research organizations and biotech and pharma companies around the world.

By helping scientists to focus their efforts on the most promising new therapies, ensuring that drugs candidates have the right pharmacological properties, and making certain that clinical trials are appropriately designed for personalised medicine, we are saving patients from needless harm.

Additionally, we are saving money by terminating development of poor-performing therapies early and preventing the shelving of effective targeted drugs because of negative results in groups of patients they were not appropriate to treat.

More recently, the PhAT has been updated to incorporate determination of mechanisms of cancer adaption, evolution and drug resistance, Which means that therapy can be adapted to stay ahead of malignant progression.

Importantly, the PhAT approach now incorporates the use of liquid biopsies, including sequencing circulating tumour DNA in the blood and molecular analysis of circulating tumour cells. This has the advantages of avoiding the need for tumour biopsies to obtain biomarker and mechanistic data; allowing multiple serial measurements to be made over time; and enabling resistance mechanisms to be detected very early, allowing switching of therapy much sooner than was possible previously.