How biomarkers are used in medicines development?

At each stage of development of a new medicine, many compounds under investigation will fail and will not be taken further (also known as ‘attrition’). Biomarkers have the potential to increase the efficiency of medicines development, by:

• Speeding up clinical trials: they can be used to detect an effect (or lack of effect), earlier and more frequently than if only a clinical endpoint is used. For example:
• A panel of biomarkers has been used in the early phases of a clinical trial for a psoriasis treatment. The biomarkers included ‘epidermal thickness’ (i.e. thickness of the outer layer of skin) and the activity (expression) levels of several genes. These were both measured in skin biopsies.^[1]
• Haemoglobin levels have been used in phase III trials to support development of therapies for ‘type 1 Gaucher disease’. This is a rare disease that affects multiple organ systems and shortens life expectancy, but can take years to progress.^[2]

• Streamlining clinical trials: they can help with prediction (forecast), early detection and monitoring of adverse reactions.
• One of the most common serious side effects of medicines is damage to the liver. Biomarkers that give an early indication of liver health have long been used during medicines development, and new ones are still being discovered. ^[3]
• The importance of safety biomarkers was highlighted in 2011, when new guidelines were proposed for their validation.^[4]

• Improving clinical trials through better patient selection: this reduces ‘heterogeneity’ (diversity) and is the most common aim in using genomic biomarkers in medicines development.^[5] Genomic biomarker(s) can be used to:
• Identify patients with a particular disease sub-type or severity – for example, most but not all patients with ‘chronic myeloid leukaemia’ have the ‘Philadelphia’ chromosome, a particular genetic abnormality.
• Exclude patients at increased risk of serious adverse reactions – for example, melanoma patients are at risk of their condition getting worse if treated with kinase inhibitors and their tumours do not have a certain mutation in the ‘BRAF’ gene.
• Identify patients with a high chance of benefitting from a particular medicine - for example, kinase inhibitors and patients with BRAF-mutated melanomas. In the same way, genomic biomarkers can be used to avoid exposing patients to a new medicine if they are unlikely to benefit.

• Improving our understanding of the way new medicines work, and leading to novel approaches to medicines development in both non-clinical and clinical phases.
• Showing an added ethical benefit notably in avoiding harm to patients by avoiding exposure to potentially ineffective or unsafe medication and conversely helping to select patients with a high probability of benefitting from a specific medication.
• A trial can be stopped sooner if no benefit is to be gained by the patients in the trial.
• A medicine that is having a positive effect might be authorised sooner and hence be prescribed earlier for patients who will benefit.

References