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introduction W

e enter a new year with the news that there were 21 new drug approvals by the FDA in 2010. This compares with 25 in 2009, 24 in 2008 and 17 in 2007 – all low numbers and with no sign of a consistent upward trend. It is not surprising, therefore, that most of the articles in this edition of DDW are, not for the first time, devoted to technological, methodological or organisational suggestions for improving this situation which would, in so doing, increase the return on investment in R&D in pharma and biotech companies.

It is interesting to note that in my introduction to the very first number of

DDW more than 10 years ago, I wrote “Big pharma will rely increasingly on smaller companies, many of them in the so-called biotechnology sector, to develop and exploit new technologies and methodologies to provide new leads”. This has, of course, happened to some extent but not perhaps to the degree that some expected. However, external partnerships of one sort or another are still, probably increasingly, being advocated especially as big companies are drastically reducing their internal R&D budgets. One of our authors in analysing the current situation questions the ‘once stable model of ‘closed’ development’ and states that 15% of pre-clinical drug research operations are now outsourced and quotes the result of a survey suggesting that this percentage will increase over the next few years. Experience has shown that these outsourced operations do not manage themselves.The ability to manage them, often from a considerable distance, becomes critical and a new set of skills will need to be developed within large companies to ensure that this is done well.

Because of the disparate nature of these partnerships no single measure gives a satisfactory assessment of their added value. The discovery of a viable new drug candidate is, presumably, the ultimate successful deliverable. However, as is pointed out by the authors of another of our articles, less tangible but still valuable, deliverables like, for example, the development of a new technology are more difficult to evaluate. These authors describe a new assessment tool which they claim will enable meaningful comparison of partnerships, will highlight important factors and will recognise that the value of partnerships often changes over time. The use of the assessment tool is described using three partnerships as examples. On the technological front High Throughput Screening (HTS) has been the ‘workhorse’ in drug discovery laboratories for many years. We carry two articles which report on surveys of users exploring the current situation with regard to the reliability of automated HTS assay systems and to the use of label-free technology in HTS. Regarding reliability, our author states that “it is a well known fact that an impromptu visit to a Pharma robotic screening facility is unlikely to result in the visitor seeing an integrated HTS assay system in full operation”. There are many plausible explanations for this of which poor reliability is but one. However, the results of the survey, reported in detail in these pages, appeared to corroborate the view that HTS systems have had a high degree of downtime and that a significant proportion of this can be attributed to reliability issues. This fact does not seem to have become apparent to some users, nor has much attention been given to assessing the economic impact of this downtime. It does appear, however, that system integrators are now focusing on delivering reliability and have identified and implemented many improvements which are listed in our article.

The second survey referred to above has revealed that label-free technology, although relatively new to HTS, is being used increasingly. Costs associated with it have reduced and both throughput and detection sensitivity have improved. Advantages include the ability to use more types of cells including human primary cells and stem cells. These, and other, cells can be explored in a situation more closely reflecting their natural environment. Challenges do remain; they are discussed in our article as are developments aimed at overcoming them.

Stem cell technology is also advancing and there is current interest in induced Drug Discovery World Winter 2010/11

pluripotent stem (iPS) cells which are one of the two types of pluripotent stem cells, the other being embryonic stem (ES) cells. Generation of human iPS cells was independently reported by two groups in 2007. They are derived using a reprogramming process in which terminally differentiated somatic cells are induced to a pluripotent state, ie a state in which they can give rise to any of the 200+ cell types in the body. We include an article which discusses the potential for iPS cells in drug discovery. In principle they could provide physiologically relevant cells for screening for toxicity and potential efficacy. Their potential in this regard is discussed as are the challenges which need to be overcome before they can be used routinely in drug discovery laboratories.

Another area of much current interest is in the use of biomarkers in the drug discovery and development process. Already biomarkers are much used in the clinical arena where, as is pointed out in one of our articles, all diagnostics are really biomarkers. The concept of ‘personalised medicine’ is gaining ground often based on the presence or absence of given biomarkers in sub-groups of patients. In drug development there is increasing interest in the use of biomarkers as predictive tools in clinical trials. In all these uses of biomarkers it is essential that they give reliable information, ie that they are validated, and this has proven in some cases to be quite problematic. Our authors suggest that this situation may be improved by the use of protein biomarkers rather than the nucleic acid-based biomarkers on which most attention has been focused up to now. They discuss this, pointing out that there are challenges in this approach, not least the cost and complexity of assaying protein biomarkers.

The use of monoclonal antibodies (mAbs) as diagnostic, as well as therapeutic, agents is discussed in another article. Since the introduction in 1986 of muromonomag as an immunosuppressant for reduction of rejection in transplant patients, a number of other mAbs have entered the market and several of them are now in the list of top 10 selling drugs. Muromonomag is a murine antibody but there has since been a movement towards either chimeric or humanised antibodies. The latter have 95% human sequence homology. More recently still fully humanised mAbs have been developed. These are thought to be less immunogenic than their predecessors. Our author looks ahead and discusses new ways to optimise therapeutic and diagnostic antibodies – “paving the way to better antibodies”. Finally, for what I think is the first time in these pages, we have article discussing the question of early access to drugs in clinical development for patients for whom no other treatment option is available. The Expanded Access Program in the US and Named Patient Programmes in other parts of the world already exist. They are, appropriately, closely regulated and must not be seen as a substitute for conventional clinical trials. However, useful data are generated and our author discusses ways in which managed access programmes could be organised to meet the needs of patients on a global basis in a regulated, ethical and transparent manner.

Dr Roger Brimblecombe PhD, DSc, FRCPath, FIBiol 7

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