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Search, Bias, Flotsam and False Positives in Preclinical Research

Photo credit: RachelEllen 2006)

Photo credit: RachelEllen 2006

If you could change one thing- and only one thing- in preclinical proof of principle research to improve its clinical generalizability, what would it be? Require larger sample sizes? Randomization? Total data transparency?

In the May 2014 issue of PLoS Biology, my co-authors Uli Dirnagl and Jeff Mogil offer the following answer: clearly label preclinical studies as either “exploratory” or “confirmatory” studies.

Think of the downed jetliner Malaysia Airlines Flight 370. To find it, you need to explore vast swaths of open seas, using as few resources as possible. Such approaches are going to be very sensitive, but also prone to false positives.   Before you deploy expensive, specialized ships and underwater vehicles to locate the plane, you want to confirm that the signal identified in exploration is real.

So it is in preclinical research as well. Exploratory studies are aimed at identifying strategies that might be useful for treating disease- scanning the ocean for a few promising treatment strategies. The vast majority of preclinical studies today are exploratory in nature. They use small sample sizes, flexible designs, short study durations, surrogate measures of response, and many different techniques to demonstrate an intervention’s promise. Fast and frugal, but susceptible to bias and random variation.

Right now, the standard practice is to go right into clinical development on the basis of this exploratory information. Instead, we ought to be running confirmatory studies first. These would involve prespecified preclinical designs, large sample sizes, long durations, etc.   Such studies are more expensive, but can effectively rule out random variation and bias in declaring a drug promising.

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.