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European Biopharmaceutical Review

An Image of the Future

Josep Prous at Thomson Reuters looks at the impact that imaging biomarkers are having on drug development

Biochemical and molecular markers have had a significant impact on medicine and drug development in recent years, giving clinicians and researchers the opportunity to infer biological states in patients and in response to drug interventions. Biomarkers include a broad spectrum of variables that can range from a series of gene sequences and mutations, through to mRNA expression profiles, tissue proteins, blood-based tests, anthropometrics data and physiological parameters.

Now imaging biomarkers are coming into their own, offering earlier detection of some diseases than molecular markers and enabling practitioners to see into the body without the need for invasive procedures, which is of great benefit to clinicians and patients. They are also allowing researchers to see for the first time how their candidate drugs are behaving in great detail, from determining the percentage of receptors occupied by a drug on target cells to looking at a drug’s ability to cross the blood/brain barrier. This, in turn, can save time and money at the drug development lab bench.

Hundreds of imaging biomarkers are already being used in drug discovery and development, as well as in the clinic. At Pfizer, for example, imaging-based endpoints are widely used in translational oncology research (1). Within the last two years, GlaxoSmithKline (GSK) has established a clinical imaging centre in London which uses imaging biomarkers to help determine dosing for central nervous system (CNS) drugs. Merck also has a preclinical imaging centre.

The promise of imaging-based biomarkers to streamline drug discovery and development and healthcare is enormous, yet we are still at the beginning of imaging biomarkers’ rise to prominence. Recent advances in imaging technology and the ability of imaging-based biomarkers to provide often-unobtainable guiding information has prompted a dizzying surge in imaging biomarker research and development (R&D). A recent Web of Knowledge search on ‘imaging’ returned more than half a million items and a search for ‘imaging biomarkers’ returned more than 3,000 citations from 2005 to 2009 (2).

TYPES OF IMAGING BIOMARKER

Biomarkers are measures of a normal biological process in the body, a pathological process, or the response of the body to a therapy. Imaging-based biomarkers employ a variety of technologies to capture images of anatomical and physiological changes in the body.

X-Ray

In clinical settings, x-rays are emitted towards the body, passing through it and creating an image recorded onto film, or more recently, digitally. X-ray technology has been in use for over 100 years and has served to identify structural markers in biomedicine for almost as long.

Computed Tomography (CT)

Sometimes also called computed axial tomography (CAT scan). In this technique, x-rays are used to take a series of 2D images which are then digitally converted into a 3D image. CT was introduced during the 1970s and its use has expanded widely.

Positron Emission Tomography (PET)

A short-lived radioactive tracer isotope, fluorine (18F) for example, is injected into the body, usually attached to a probe molecule that accumulates in the tissue of interest. The isotope emits a positron (an anti-electron) which travels a short distance before colliding with an electron. The collision annihilates the two particles and emits two gamma rays travelling in opposite directions which are detected by a scanner. Computerised tomography assembles a 3D image of the area of interest. The first PET machines for use in humans were introduced in the early 1970s.

Single Photon Emission Computed Tomography (SPECT)

A gamma ray-emitting tracer isotope is introduced into the body and a gamma camera is used to collect multiple 2D images, which are later assembled into a 3D image. SPECT is significantly less expensive than PET, in part because the tracer isotopes are longer-lived and less costly. However SPECT’s resolution is also lower than PET.

Magnetic Resonance Imaging (MRI)

No ionising radiation is used, instead, the subject is placed in a powerful magnetic field which aligns the nuclear magnetic field of atoms, usually hydrogen atoms, in the body’s water. Radio frequency signals are used to alter the atoms’ magnetic alignment and the resulting signal is detected by scanners. MRI is better at distinguishing soft tissues than tomography. The first MR image was published in 1973, the first cross-sectional image of a living mouse in 1974, and the first studies performed on humans were published in 1977.

In addition, optical imaging is frequently used in drug discovery and preclinical animal research, and is increasingly used in the clinic for humans, for example with optical CT scanning. Ultrasound is also often used in the clinic and has recently been explored as a drug delivery method.

DEVELOPMENTS IN IMAGING BIOMARKERS

Imaging technologies and biomarkers, x-rays for instance, have been used in the clinic for years but the push into drug R&D is more recent. It used to be just exploratory activity but now it is increasingly tied to development and partially used to make development decisions (3). The type of imaging biomarker used depends on the drug development phase. Optical methods such as microscopy and high content screening, where fluorescent tags or antibodies are used to visualise proteins, dominate early discovery work and are used in assessing target expression and function, as well as compound screening and lead discovery. Preclinical animal studies – focused more on efficacy, toxicity, pharmacokinetics and pharmacodynamics – rely more on PET, SPECT and MRI, along with optical methods.

Translational research is one area receiving a huge boost from imaging. Both MRI and PET combined with CT provide very good imaging biomarkers to assess response to treatment. This has had an important impact on development as, in the past, it was necessary to sacrifice animals to establish proof of response. Now, imaging biomarkers can be used over time without having to sacrifice the animal.

This growing ability to use imaging biomarkers to conduct longitudinal studies in the same animal is reducing cost, saving time, providing better progression data, and bolstering confidence in results. Subtler therapeutic effects and negative toxicity signals are often detected earlier and more easily, and laborious biochemical assays can be avoided. Recognising the power of imaging biomarkers to provide critical molecular and anatomical data has led to major pharmaceutical companies using imaging more aggressively.

The use of other forms of imaging in drug development is more experimental. For example, functional MRI, a specialised form of MRI that is used to determine neural activity by visualising blood flow, is often used in academic research but has so far proved less useful in drug development. And few imaging biomarkers are used in late-stage clinical trials because it is harder to verify the links between the biomarkers and clinical response. Establishing a validated imaging-based surrogate endpoint is even more difficult.

Most examples of use in late-stage trials are in oncology and neurology. For example, the size of a tumour can serve as an imaging biomarker using MRI, CT or even ultrasound. PET and SPECT can be used to assess tumour metabolism and proliferation. Tumour angiogenesis, detected with MRI or sometimes ultrasound, is also a kind of imaging biomarker, and there are MRI protocols to assess lesion sites in multiple sclerosis (4).

One concrete example of an imaging biomarker in the clinic is the use of the fluorine isotope combined with the glucose analogue fludeoxyglucose ((18F)FDG) in PET/CT to diagnose tumour recurrence in colon cancer. Serving as a surrogate of glucose metabolism, PET/CT imaging is crucial in detecting colon cancer recurrence compared to biochemical markers because we need localisation of the recurrence to offer surgery, the only curative treatment in these types of patients.

THE CHALLENGES FOR IMAGING BIOMARKERS

Despite their potential, imaging biomarkers face many hurdles before they can be widely adopted, from standardisation and a regulatory policy in its infancy, to finding ways to store and analyse the resulting plethora of information. Fortunately, both users and providers are well aware of the issues and many groups are tackling them. A good though extreme example of the staggering data volume challenge is Eugene Myers’ work on imaging mice brains. Myers, a Howard Hughes Medical Institute investigator, is a coinventor of the BLAST algorithm used in DNA sequencing. But standardisation is perhaps the biggest challenge in this budding field. Differences in vendor equipment and user practices, as well as varying ideas about what to measure – and how to measure it – are all important standardisation issues (5).

These questions are less an impediment to early discovery work, but become critical as you move to the clinic. Several organisations are working to solve them. The Radiological Society of North America has a working group on the topic and the Biomarkers Consortium, a project overseen by the Foundation of the National Institutes of Health in the US, has specific projects underway (6). One project is attempting to standardise dynamic contrast MRI, which is used in cancer to measure blood flow. Using prostate cancer as the model, the plan is to gather data across 10 or more clinical sites and create sets of benchmark data points that can be used to create and then validate a standardised model (7).

A similar project is standardising carotid MRI, which measures atherosclerotic plaque size to distinguish vulnerable from stable plaque. Involving 10 to 15 imaging centres, the consortium is going to pay for 80 patients to be measured using different scanning techniques across the sites and document the variability between the sites and scanners.

The cost of new technology is often an issue and imaging biomarkers are no exception. Much of the Big Pharma community has invested in dedicated imaging groups while many smaller companies are doing so ‘virtually’, by using the equipment of other companies. Persuading payers in the healthcare system, such as insurance companies and government agencies, is another hurdle. Regulatory agencies are less of a stumbling block. Many are enthusiastically embracing and promoting the development of imaging biomarkers, as exemplified by the US FDA’s strong support in its 2004 Critical Path Initiative (8). However, regulatory agencies are understandably cautious and may move more slowly than researchers would like.

The surge in biomarker development broadly and imaging biomarkers in particular has complicated researchers’ efforts to track progress in the field. Managing information for molecular biomarkers is less problematic as there is a framework in place, but this is not the case for imaging biomarkers. There is a need for a hierarchical ontology management system to make sense of the explosion in publication of information – standard indexing guidelines and vocabularies also need to be developed.

Looking ahead, it will be interesting to examine the information trends for imaging biomarkers. For molecular biomarkers, current data shows that around 50 per cent of the biomarker information being published is related to oncology – will the distribution of use for imaging biomarkers be any different? Being able to show where major research is focused will be invaluable for research organisations when it comes to allocating resources.

CONCLUSION

Imaging biomarkers are the new kids on the block in drug development, but their advantages, from saving time, detecting subtler drug effects and bolstering confidence in early results, mean they look set to stay. In the clinic, imaging biomarkers are providing earlier diagnosis and localisation of disease, as well as helping clinicians navigate treatment by determining whether drugs are working – a strategy that will save money in the long term.

Challenges remain though: some imaging biomarkers need more evidence behind them before they can be relied upon as a true surrogate of clinical features; scientists are ankle-deep in data and processes must be standardised before imaging biomarkers can reach their full potential. But all these challenges will be surmountable in the coming years as the research and medical communities work together with regulatory agencies to make sure that imaging biomarkers have their full impact.

References

  1. Next Generation Pharmaceutical, Translational Research and Biomarkers, Dominic Spinella, Pfizer, Issue 11, 2007
  2. Web of Knowledge search on the term ‘Imaging’, 1st January 2005 to 31st December 2009 (624,575 items); Web of Knowledge search on the phrase ‘Imaging Biomarkers’ for period 1st January 2005 to 31st December 2010 (3,135 items)
  3. Interview with Oliver Steinbach, the Head of the Bio-Molecular Engineering Department at Philips Research Laboratories, August 2009
  4. Howes OD et al, Mechanisms underlying psychosis and antipsychotic treatment response in schizophrenia: insights from PET and SPECT imaging, Rabiner interview, Curr Pharm Des 15 (22): pp2,550-2,559, 2009
  5. Imaging as a Biomarker: Standards for Change Measurements in Therapy Workshop Summary, www.mel.nist.gov/msidlibrary/doc/NISTIR_7434.pdf, National Institute of Standards and Technology, 14th to 16th September, 2006
  6. RSNA Quantitative Imaging and Imaging Biomarkers, www.rsna.org/Research/qiba.cfm
  7. Interview with David Wholley, Director, Biomarkers Consortium, Foundation for the National Institutes of Health, http://www.biomarkersconsortium.org/, January 2009
  8. FDA Critical Path Initiative, March 2004

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Josep Prous Jr is Vice President and Chief Scientific Officer at Thomson Reuters. For the last 15 years, Josep has been responsible for the development of scientific and technological applications, including the design of new information systems, the development of electronic publications and the creation of online continuing education services for the medical community. Before joining Thomson Reuters, he acted as Executive Vice President of Prous Science. Josep holds a Bachelors degree in Chemistry, a PhD from the University of Barcelona and a MBA from ESADE. He is a member of the American Chemical Society, the American Academy for the Advancement of Science, the Special Libraries Association, the European Federation of Medicinal Chemistry and BioCat.
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