The Pharmacological Audit Trail (PhAT) comprises a set of critical questions that need to be asked during discovery and development of an anticancer drug. Key aspects include: (1) defining a patient population; (2) establishing pharmacokinetic characteristics; (3) providing evidence of target engagement, pathway modulation, and biological effect with proof of concept pharmacodynamic biomarkers; (4) determining intermediate biomarkers of response; (5) assessing tumor response; and (6) determining how to overcome resistance by combination or sequential therapy and new target/drug discovery. The questions asked in the PhAT should be viewed as a continuum and not used in isolation. Different drug development programmes derive different types of benefit from these questions. The PhAT is critical in making go-no-go decisions in the development of currently studied drugs and will continue to be relevant to discovery and development of future generations of anticancer agents.
Pharmacological audit trail; Biomarkers; Pharmacodynamics; Pharmacokinetics
Citation: Udai Banerji, Paul Workman Critical parameters in targeted drug development: the pharmacological audit trail doi:10.1053/j.seminoncol.2016.06.001
Available online 14 June 2016
Copyright: © 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND
Conflicts of interest
Dr Banerji has received research funding from Astra Zeneca, Novartis, Chugai, and Onyx. He has also received honoraria for attending advisory boards for Astex, Novartis, and Debiopharm. Dr Workman is a former employee of AstraZeneca and declares commercial interactions with Yamanouchi (now Astellas), Piramed Pharma (acquired by Roche), Genentech, Vernalis, Novartis, Chroma Therapeutics, Astex Pharmaceuticals, AstraZeneca, Cyclacel, Onyx Pharmaceuticals, Merck Serono, Sareum, Janssen, Wilex and Nextech Ventures. Dr Workman has received research funding from Vernalis for the discovery of HSP90 inhibitors, and intellectual property for this program was licensed to Vernalis Ltd., and Novartis. He has also been involved in a research collaboration with AstraZeneca in the area of stress and chaperone pathways, has been a consultant to Novartis, is a founder of Chroma Therapeutics, and is scientific advisory board member of Astex.
Drs Workman and Banerji are employees of The Institute of Cancer Research, which has a commercial interest in the discovery and development of anticancer drugs, including HSP90, PI3K, AKT, and HDAC inhibitors discussed in this paper.
The authors are grateful to patients and their families who have taken part in multiple phase I studies referenced in this article. The authors acknowledge funding from Cancer Research UK (grants C309/A8274/A309/A11566 and C51/A6883) to The Institute of Cancer Research. The authors further acknowledge funding under the Experimental Cancer Medicine Centres funded by Cancer Research UK and NIHR, CRUK to support our CRUK Centre and NIHR funding to our Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust.