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The Next Big Thing

By Ernie Bush

July 29, 2010 | Bush Doctrine | Although probably not the best topic for your next neighborhood barbecue, the question of which new technologies may contribute to developing safer medicines makes for interesting debate over a beer with professional colleagues. I find it particularly entertaining to ask the question: What happened to previous “Big Things” that appeared from prior beer summits one, five or ten years ago?

Perhaps the most talked about Big Thing of the recent 3-5 years has been biomarkers. The discovery and development of biomarkers has been promised to aid in the diagnosis and treatment of diseases as well as in monitoring and predicting safety outcomes.

When the FDA released its Critical Path Opportunities List in March 2006, one could be forgiven for concluding that it was all about biomarkers. Indeed, of the 76 targeted opportunities identified, nearly half referred to the identification and validation of new biomarkers. In fact, there was an initial flurry of activity that seemed to promise success, exemplified by the work of the Predictive Safety Testing Consortium of the C-Path Institute and its work in detecting early kidney damage.

Unfortunately, four years later we still have not seen any significant adoption of new biomarkers for tissue damage or safety evaluation either in clinical studies or pre-clinical safety assessment. Of course, validation of new clinical biomarkers has been more difficult than many would have guessed, but even those new preclinical biomarkers which have been ‘accepted’ by regulatory authorities, and for which commercial tests are available, are not used appreciably in routine GLP studies.

Before biomarkers, the Big Thing in safety assessment was undoubtedly toxicogenomics. It would be hard to overstate the hype surrounding the introduction of microarrays and their potential impact on toxicology and adverse event prediction. Toxicogenomics spawned many companies and soaked up hundreds of millions of dollars of R&D money from VC firms and big pharma companies.

A decade later, it is clear that toxicogenomics has evolved into a valuable mechanistic tool and may yet provide some value in terms of safety evaluation. But as the demise of all those toxicogenomics companies suggests, its value in safety prediction has not panned out.

Another Big Thing worth considering is the rise, fall and subsequent reappearance of exploratory or mechanistic toxicology groups. This movement stretches back into the late 1980’s. Even 20 years ago, the limitations of conducting safety evaluations in GLP animal studies were well recognized. Therefore and at least in part based on the success of the Aims type gene tox testing systems, there was a trend in pharma companies to establish in vitro toxicology functions/groups focused on creating the next generation of safety evaluation.

Unfortunately, these groups did not contribute much in terms of toxicology prediction. Interestingly, though, after a couple of decades of development and refinement, in vitro (and now in silico) safety testing is enjoying a re-emergence with most major pharma research groups establishing discovery safety functions and implementing new pre-GLP safety prediction tools.

What Have We Learned?

It is tempting to conclude that the biggest takeaway about next Big Things is to disregard the hype, and maybe even to ignore all new things, as most don’t work out as well as promised. Indeed, I would always advise a healthy (scientific) amount of skepticism about any claims for new technology promises or routine assay results.

But such simplistic conclusions miss the useful lessons from what our history is trying to teach us. These are:

1. The development AND implementation of new technologies are experimental sciences. If most of your experiments do not turn out as you expect, then you are probably not being creative or daring enough in your science.

2. Real advances in scientific practice, especially in safety prediction, take time. Although the vision for early safety evaluation stretches back more than 20 years, it took a full two decades for the science and the technology to catch up with that vision. I suspect that biomarkers and toxicogenomics will also one day play important roles in safety assessment, but that is probably another 5-10 years in the future.

3. New technologies in which success depends on catching really small fish in really big oceans are doomed to fail most of the time. If the new technology vision promises, “If we look at a large enough number of parameters across a large enough pool of patients/subjects/experiments, we will eventually find an answer,” then be prepared for a very long haul. Endeavors such as building toxicogenomics databases, finding the next biomarker from large patient databases, generating huge libraries of compounds through combinatorial chemistry, etc. all fail to acknowledge the nearly unimaginable diversity of chemistry and biology on Earth. The ocean of possibilities is really deep and even giant fishing expeditions have a slim chance of catching fish without some guide to where the fish are.

Ernie Bush is VP and scientific director of Cambridge Health Associates. He can be reached at:

This article also appeared in the July-August 2010 issue of Bio-IT World Magazine. Subscriptions are free for qualifying individuals. Apply today.

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