The TRISTAN Approach
Imaging biomarkers play a massive role in drug development and healthcare. When developed and validated, IBs can be invaluable in preclinical safety assessment, in early phase drug development, in regulatory drug development, in labelling and in managing adverse effects of drugs in clinical practice. Well-known examples of important IBs include ultrasound-derived left ventricular ejection fraction in cancer therapeutics-related cardiotoxicity, and DEXA-derived bone mineral density in drug-induced osteopenia. Both of these IBs are used to manage safety issues all the way from preclinical to marketing, and they are frequently employed by regulators in drug labelling.
Careful review of these and other successful IB developments, together with other, less successful IB developments, shows that a different roadmap is required for IB validation than for validation of conventional “biospecimen” biomarkers, and in particular the need for parallel rather than sequential approaches to technical (or assay) validation, standardisation, biological validation, and clinical validation. It is also critically important to establish the benefit of any new IB over existing non-imaging assays, otherwise it is unlikely to be adopted.
A further example of a massively important IB is objective response using RECIST: the development of this imaging biomarker was led by one of our participants (EORTC, current chair EGE de Vries) using their data warehouse, with the involvement of Pharma companies and Regulatory authorities. RECIST is now routinely used in drug development and approvals. It is this expertise in EORTC, together with their access internationally to cancer patients (a group for whom the call topics are particularly relevant). The focus for this consortium is much wider than oncology, as we include important rheumatology and other patient studies in imaging based approaches for detection and characterisation of drug induced liver injury (DILI) and drug induced interstitial lung disease (DIILD), metabolic therapies are included in our approach to better address bio-distribution of biologics, and we recognise that drug safety is crucial in all disease areas.
This project includes a mixture of well-established (although not yet standardised) approaches, such as CT in DIILD and gadoxetate-enhanced MR in the liver, together with highly innovative approaches involving PET, fluorescence, 129Xe MRI and 1H MRI. It is inevitable that some of the highly innovative approaches will prove more promising than others, and so we included several go/no-go decision points at which only the most promising IBs will be continued.
Get more background information on the need and potential value of imaging biomarkers.
Concept and approach for assessment of DILI
Although DILI is caused by hundreds of drugs in humans and may result in severe symptomatic liver injury and/or life threatening acute liver failure, the frequency of human DILI caused by individual drugs is low and very few of the drugs cause liver injury when tested in animal safety studies. Consequently, DILI usually is not recognised prior to Phase 3 clinical trials, or post-marketing. Furthermore, the currently used biomarkers of liver injury (plasma ALT and bilirubin concentration) are unable to discriminate prospectively between patients who sustain only mild and reversible liver dysfunction if drug administration is continued and those who progress to sustain marked liver injury.
For further details on the TRISTAN work programme for assessing liver transporter function please refer to the Liver Transporter Assessment Subsite.
Concept and approach for assessment of DIILD
Drug induced interstitial lung disease (DIILD) can be caused by over four hundred different drugs in humans, however the frequency of human DIILD caused by individual drugs is often low and not recognised prior to Phase 3 clinical trials, or post-marketing. Although DIILD management usually involves CT, there is no standardised IB recognised by drug developers or regulatory authorities. There is an urgent need for specific and sensitive IBs of DIILD both for use preclinically and early phase drug development to avoid progressing drugs with DIILD liability, and for use in regulatory drug development and post-marketing to manage patients and assess reversibility.
For further details on the TRISTAN work programme for assessing DIILD please refer to Assessment of DIILD Subsite.
Concept and approach for improved detection of the bio-distribution of biologics by PET imaging
The biodistribution of biologics can be monitored noninvasively using imaging techniques (including positron emission tomography (PET), fluorescence imaging and mass spectometry imaging) in order to understand the distribution and the fate of bio-therapeutics (biologics) in vivo after sc and iv administration. With these imaging techniques, the spatial distribution of biologics in the various biological compartments can be studied quantitatively. Imaging will provide information on the localisation of the biologic and mass spectrometry analyses will provide information on the molecular integrity of the protein/peptide. However, the technique to visualise and quantify the biologic in the different subsequent organs such as liver, kidney, brain is still in its infancy and not standardised yet for application in the pharmaceutical drug development process.
For further details on the TRISTAN work programme for improving the quantification of biologics in tissue please refer to the Bio-Distribution Subsite.
standards, protocols and guidance documents for download
The overall aim of TRISTAN is to ensure that each selected IB, following standardisation, is technically validated (i.e. drug developers and physicians can employ it anywhere it is needed); biologically validated (i.e. faithfully and accurately reflects the underlying pharmacology/pathology); and is clinically validated (i.e. forecasts clinical outcome when combined with the best available clinical characterisation and other biomarkers more accurately than clinical characterisation and other biomarkers alone).
We will ensure that data relevant for methodological validation of IBs are made available in this web sites download area in agreed formats. Appropriate downloads are facilitated and encouraged, and standards, protocols, guidance and tools will be maintained current, version-controlled and appropriately disseminated.