As imaging technologies and techniques evolve and accelerate, the process is becoming a feature in phase-III trials, in particular, the use of surrogate markers, endpoints and imaging biomarkers to measure the effectiveness of investigational drugs in trials.

Biomarkers are defined as laboratory measurements "that reflect the activity of a disease process", according to the Journal of The American Society for Experimental NeuroTherapeutics. They provide a meaningful, quantitative endpoint that can be extracted from an imaging method, such as, say, tissue perfusion.

They are also commonly used in the context of diseases of the nervous system, for example in MRI imaging around multiple sclerosis and Alzheimer’s and in PET scanning for conditions such as Parkinson’s.

A surrogate marker, by comparison, according to the US Food and Drug Administration (FDA), can be defined as "a laboratory measure or a physical sign that is intended to be used as a substitute for a clinically meaningful endpoint". The term is used when there is an established link between something measurable and a clinically meaningful outcome.

But, with any advance come new challenges. One key issue for the industry and regulators alike has been the need to create more robust guidance on the control, standardisation, validation and use of these innovative markers. In 2011, for example, the FDA developed draft guidance for clinical trial imaging endpoint standards.

Yet, as Phil Murphy, head of GlaxoSmithKline’s global imaging unit, points out, the potential for such cutting-edge imaging techniques in the development of new therapies is seen in the industry as vastly exciting.

"Broadly, imaging is used for two purposes, either to inform early phase decision-making, for example, PET studies of drug bio-distribution, or for contributing to registration endpoints, such as CT scans to define disease progression in cancer trials," he explains.

"For early decision-making, the industry focus is to use technologies such as imaging to better characterise the drug, for example drug dose and mechanism and to get early indications of efficacy.

"Imaging for registration endpoints tends to rely on more simplistic imaging that is sufficiently robust to be deployed across many study centres. There, the focus is on efficiency and quality of coordinating multicentre imaging.

In terms of the clinical research setting, imaging is now being used very broadly.

"Translating methods emerging from leading academic centres into drug development tools will remain a focus for the industry."

"Generally, we see tremendous progress in using imaging to build on previous successes in areas such as neuroscience and oncology. At the same time we see great progress in other areas, such as respiratory, cardiovascular and other applications," says Murphy.

"This is all building on a broad platform of imaging science research that is seeing great developments across methods including magnetic resonance imaging, computed tomography, ultrasound, positron emission tomography and optical imaging."

Shining lights

It is against this backdrop that imaging biomarkers and surrogate endpoints are increasingly coming into the frame and proving their value.

"Across the industry, there are many examples where such methods have been integrated into early drug development and such imaging biomarkers are used as endpoints," Murphy explains.

"An example is the use of dynamic contrast-enhanced MRI as a pharmacodynamic endpoint to study anti-angiogenic drugs. Such methods have been used broadly across industry. While complex to implement, they can provide early insights into drug mechanism and efficacy."

One certainty is the potential of these new techniques to continue to provide new insights into disease and its response to therapeutic intervention.

"Translating these methods emerging from leading academic centres into drug development tools will remain a focus for the industry," Murphy explains. "Increased complexity brings challenges in terms of accessing methods at centres that have the technology and ability to recruit subjects. Furthermore, standardising methods across centres, which will be needed for some studies, will require support from academic centres and specialised CROs."

"As imaging science grows we are likely to continue to see methods, such as MRI offering increased sensitivity to detect disease and treatment response, and molecular imaging probes, whether using PET or optical imaging, being used clinically to study drug mechanism in small subject cohorts.

"Across all methods there will likely be a greater understanding of how we interpret imaging findings – with a need for more linkage between imaging and the biology of the disease.

"Imaging science research is a broad endeavour with multiple subspecialities around techniques and applications, for example molecular imaging of cancer and functional brain imaging.

"Accessing the required expertise to use these methods will require the industry to engage externally with many centres and experts, to catalyse development of new techniques and translate methods to application in drug development."