You’ve overseen the progression of more than 30 drug candidates into first-in-human trials. What are the most common reasons promising oncology assets fail during early clinical development?
Lack of efficacy in terms of delivering tumour responses and/or survival benefit is the biggest reason for oncology drugs failing in clinical trials and being discontinued from development.
Success rates for drug approval from first entry into clinical trials sit in the 5-10% range. Perhaps not surprisingly first-in-class drugs targeting novel mechanisms suffer from the highest attrition – underscoring that this is, after all, a high-risk high-reward business. Key factors driving this failure include a lack of understanding of the biology of novel targets, a lack of biomarkers to identify those patients most likely to benefit from novel therapies and poorly predictive preclinical models.
Industry has shifted towards developing safer and more effective agents that build on established therapeutic concepts. This does however leave more space for organisations like CRUK to play in to identify novel biological axis.
In recognition of the risk associated with developing drugs targeting novel mechanisms industry has shifted a lot of focus towards developing safer and more effective agents that build on established therapeutic concepts. This includes antibody-drug and antibody-radionucleotide conjugates, T-cell engagers and tumour targeted bi- and tri-specific antibodies. This does however leave more space for organisations like CRUK to play in – harnessing our wealth of biological knowledge and expertise to identify and prosecute drugs targeting novel biological axis.
For researchers who've never navigated that preclinical-to-clinical transition, what are the most underestimated barriers?
Cost, complexity and regulatory requirements.
To progress a new drug into a clinical trial requires a drug to be manufactured at scale in a licensed facility in line with Good Manufacturing Practice guidelines. This is particularly expensive for biotherapeutics. A package of non-clinical safety studies will also have to be conducted in a Good Laboratory Practice compliant facility.
The data generated on a new drug candidate from this work must be presented to the regulatory authorities in specified document format for consideration of opening a clinical trial. CRUK’s Centre for Drug Development (CDD) have a long track record of success and extensive expertise in this area having progressed well over 100 novel agents into clinical investigation.
What kinds of collaborations do you think will define the next decade of oncology drug development, particularly for smaller companies trying to navigate translational and early clinical hurdles?
Small companies need to stay agile and nimble – they do not necessarily need to employ large teams with expertise across the drug development spectrum.
There are many consultants available that can provide advice across manufacturing, non-clinical safety, regulatory, quality etc. Designing and delivering a clinical trial that addresses key questions in the most appropriate patient population however requires the input of world-class clinicians and scientists with much of this expertise residing in academic centres. In supporting a wide array of scientific and clinical experts working in the cancer field, CRUK has huge convening power to access expertise in all aspects of cancer biology, translational science and clinical investigation.
Over-reliance on the use of poorly predictive animal models, particularly in the immunoncology field has compounded the attrition problem.
Looking across the current oncology pipeline, where do you see the biggest translational gap and what structural changes would make the biggest difference?
This comes back to the issue of attrition in clinical development and the failure of the vast majority of new drugs entering clinical investigation.
Our lack of understanding of the biology of many new targets and critically their relevance to the development of malignant disease is a key factor in this failure. Translating biological understanding into the identification of valid targets for drug discovery needs more attention. This requires a dedicated focus from drug hunters to probe target expression profiles, functional activity, redundancy, potential biomarkers of response and resistance mechanisms across multiple datasets and experimental systems.
Over-reliance on the use of poorly predictive animal models, particularly in the immunoncology field has compounded the attrition problem. The development of human tumoroid models that increasingly recapitulate elements of the tumour microenvironment holds much promise for providing more insights into the impact of modulation of drug targets on tumour biology.
About Rob Williams
Dr Robert Williams recently retired as the Chief Drug Development Scientist at Cancer Research UK's Centre for Drug Discovery and is now acting as a Development Advisor.
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