| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||
Full Paper |
Translational Medicine and Technology, GlaxoSmithKline, Greenford, UK
Correspondence: Dr A Dzik-Jurasz, GlaxoSmithKline, 891-995 Greenford Road, Greenford, Middlesex UB6 0HE, UK. e-mail: andrzej.s.dzik-jurasz@gsk.com
 |
Abstract |
|---|
 Top Abstract References |
|---|
Developing and bringing drugs to market is a costly business. It is estimated that for every new chemical entity (industry jargon for a new drug) brought to market, firms can expect to have average cash outlays for research and development of US$403 million [1]. Taking other factors into consideration increases these costs to US$802 million. The pharmaceutical industry's spending on research and development was estimated to be almost US$13 billion in the year 2000. The trend is only likely to rise.
Strategically it is therefore prudent to focus on common disease pathways that if successfully modulated will target the greatest number of pathologies and patients. One such complex of pathways manifests phenotypically as angiogenesis. The modulation of angiogenesis currently attracts considerable scientific and business interest, especially with the recent approval of Avastin (Genentech, South San Francisco, CA) for the treatment of colorectal metastases. News of Genentech's success added billions of dollars to its market price. Most clinical trials targeting angiogenesis are focused on inhibiting the process but applications are also emerging where angiogenesis is therapeutically promoted as in ischaemic cardiac disease.
Early drug discovery has changed beyond recognition in the last 10 years, because of technological advances in miniaturization and automation. High throughput screening and microarray analysis are two key enabling technologies that catalysed the development of proteomics and genomics. The sequencing of the human and many other genomes in addition to a plethora of transgenic animal models have resulted in an explosion of potentially exploitable therapeutic targets. In high throughput screening, for example, large libraries of compounds are screened for inhibition or binding to recombinant proteins from cloned genes. Tens of thousands of compounds are screened daily in this fashion and angiogenic targets are no exception.
Despite the wide use of these new technologies the delivery of new chemical entities to market has fallen below initial predictions [2]. It is now apparent that in silico (gene or protein chips) or in vitro success does not immediately translate to the complex in vivo environment. The bottleneck to the drug development process is therefore shifting towards live organisms including man. Human studies expend considerable human and financial resource such that a multicentre trial frequently approaches tens of millions of dollars in cost. Any strategy therefore that might substantially and safely reduce the costs of a trial is worth investigating. Such a technology needs a strong scientific evidence base and to be validated against the biological mechanism or be shown to reflect clinical outcome. Ideally, external regulatory authorities will accept the imaging technology as a valid end-point. All the clinical imaging modalities (PET, CT, MRI and ultrasound) have demonstrated promise in influencing decision-making in the field of angiogenesis.
Data on the pharmacokinetic, pharmacodynamic, toxicity and the disease modulation profile of a compound are essential in the assessment of a drug in clinical trial. Biomarkers [3], in particular, are integral in this decision-making process. Any biomarker, of which imaging is an example, is expected to be validated, robust, easily reproducible, cheap and allow for high patient throughput. As noted earlier, acceptance of the technology as a suitable read-out by regulatory authorities would confer a significant incentive for investment in and use of that technology. Clinical imaging, even for diagnostic purposes is not cheap and the requisite expertise for conducting angiogenesis studies in man remains scarce. It is encouraging that MR read-outs of angiogenesis and its modulation are being validated against the underlying biology. Unfortunately, the role of and difficulty in studying angiogenesis in man by imaging remains mostly unappreciated other than by experts in the field. In addition, the fact the technology is not widely available as an "off the shelf" tool limits its application in multicentre trials. A particularly welcome result would be evidence of imaging leading to compound attrition or "compound kill". This strategy aims to identify compounds that are likely to fail without having to resort to costly and time consuming late phase clinical trials.
Functional (physiological) read-outs of tumour vascularity have demonstrated their prognostic and early assessment of response capability at an earlier stage than currently possible via conventional radiology. These strengths should be exploited in future research and effectively communicated to a wider audience of decision makers. All too often the excitement of scientific curiosity can lead to a lack of practical focus. Developing imaging technologies to support early/late clinical trial imaging can only successfully be accomplished through close collaboration between physical, biological and clinician scientists. It is the needs of the clinical trial that are paramount and any imaging solutions should be easily implemented and methodologically sound. The need to accommodate speculative research is acknowledged but it should not dictate research policy.
The escalating need of industry to deliver new compounds to market and the financial pressures on academia present novel collaborative opportunities to both parties. One such approach is illustrated by the announcement of a collaborative centre to be sited at the Hammersmith Hospital site of Imperial College, London. The project is a collaboration between GlaxoSmithKline, Imperial College, London and the Medical Research Council of the UK and will include a GlaxoSmithKline clinical imaging centre. Broader questions for industry–academia to consider include who pays for future investment of novel imaging research? Should industry continue outsourcing imaging research and supporting traditional academic posts as is current practice? By what metrics does either party judge success? Should academia take the initiative, and engage industry once it has products to supply?
Those investing more broadly in clinical imaging support to drug development should also be aware of the competition from non-imaging biomarkers. Decision making tools are being developed (i.e. gene chips) that retail at a fraction of the cost of imaging. Investment in an imaging procedure is unlikely if a pharmacological issue can simply be resolved by a biochip sampling 0.5 ml of blood. Clearly imaging will provide additional clinical data but awareness of competing technologies is prudent when developing novel imaging strategies.
Angiogenesis imaging and its therapeutic modulation in man is a powerful tool that merits additional research and investment. Decisions in drug development are ultimately governed by scientific and commercial considerations and therefore industry's imaging needs are focused differently from those of academia. The scope for interaction then, particularly in the field of angiogenesis imaging in man is considerable.
|
References |
|---|
|
TopAbstractReferences |
|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| BJR | DMFR | IMAGING | ALL BIR JOURNALS |
