Risk Assessment and the FDA

The March 1, 2006 issue of Genetic Engineering News features a column by Shep Bentley under the heading of FDA News & Analysis titled:  Finding a Balance in Assessment of Risk. The essential question impacting the drug industry is who should decide when a product is unsafe, and by what standards ?  The most critical problem appears to be the absence of  any remotely standardized expression of benefit within the paradigm of risk/benefit analysis. Value ascribed to  a drug or a process may be vaguely inferred, but rarely clearly stated and quantified.

This "biomedical" analysis differs from risk assessment involving toxicological and analytical chemistries, although both are forced to address inherent uncertainties. In the latter, the ever lower threshold of instrumental detection limits has often left uncertainty factors to the imagination (and potential manipulation) of the beholder.  In the medical realm, the "First Do No Harm" principle runs the risk of being extrapolated into a precautionary principle that may  preclude the accommodation of reasonable (calculated) risk.

Probably under-appreciated is the reality that the common denominator for evaluating risk is society's values. A pain-averse society uses a quality of life measurement that teeters on a delicate balance of function and comfort. Pre-market drug submission that includes less risk-related data and more quantitative expression of product benefit would be the new paradigm. But the fact is that although risk mitigation is a zero-sum exercise, there is always some residual risk.

More information can be found at www.genengnews.com.

Microdosing and the Vanishing Zero

The July 2005 issue of Drug Discovery News featured an interesting editorial (p. 8) by Randall Willis on the topic of microdosing in the "nether region between preclinical and clinical testing - Phase 0."  To some who have been alerted to the WSJ article of July 25, 2005 (posted here elsewhere), the regimen involved here may appear to intersect the conditions being used to study the effects on human health of ultra trace agents in the environment, namely parts per billion or smaller.  Microdosing simply involves the administration of sub-pharmacological or sub-therapeutic doses - micrograms - of a drug candidate to humans.  At least one study seems to indicate that microdose data are largely predictive of therapeutic dose response.            

Mainstream chemists interested in the nuances of chemical analysis would appreciate the fact that these protocols are only possible because of the technical advances in instrument detection limits that allow "almost single molecule detection."  Greater complexity comes from a realization that "sub-dosing" involves microgram quantities of chemical agents, similar to many environmental exposure levels (ppb).  Compare that to therapeutic dosages of an agent like perchlorate (historically used in treatment of Graves' disease) that has been administered at dosages of hundreds of milligrams per day, thousands of times higher than environmental exposure levels.  Small wonder that uncertainty drives many an environmental debate.

More on the topic:  www.drugdiscoverynews.com.