Tea Leaves: Predicting Risk and Benefit in Translation

Every early phase trial begins with a series of predictions: that a new drug will show clinical utility down to road, that risks to study volunteers will be manageable, and perhaps, that patients in trials will benefit. Make a bad prediction here, and people potentially get hurt and resources wasted. So how good a job do we do with these predictions?

Hard to know, but given the high rate of failure in clinical translation, there are grounds for believing that various stakeholders go into early phase trials with an excess of optimism. In the current issue of PLoS Medicine, Alex London and I posit two problems with the way decision-makers make predictions in early phase trials. First, they underattend frequent and systematic flaws in the preclinical evidence base. Secondly, they draw on an overly narrow evidence base (what we call "evidential conservatism") that obscures an assessment of whether preclinical studies in a given research area are a reliable indicator of agent promise.

As an open access journal, readers are invited to view our article here. The article has garnered a decent amount of press- digestible summaries can also be found at the Scientist and Pittsburgh Gazette. Also check out a commentary commissioned by the journal editors. (photo credit: canopic 2010)

Dirty Windows of Drug Development

Think of clinical trial data as a window on the efficacy and safety of a drug. Think of data protection and trade secrecy as soot. The above picture? This is the public view on drug safety and efficacy.

According to a recent report in Nature Biotechnology (Feb 2011), medicine may be getting some soapy water and a squeegee, thanks to several policy initiatives at drug regulatory authorities. In Europe, the main drug regulatory authority, EMA, recently issued a policy that will make publicly available "full clinical trial reports"-- even for drugs that are not approved for licensure.

The reforms roughly parallel a series of proposed policies at FDA under the FDA Transparency Initiative. Among the proposed items that would be publicly accessible: when an application has been submitted to the agency (or withdrawn); whether a significant safety issue triggered withdrawal, and reasons why the agency turned down an application.

Disclosure of such information carries some risk. Contrary to common belief, information disclosure does not level all power and influence, as some parties are better equipped to aggregate, analyze, and act on information. No doubt, such transparency will be used by various parties to harangue FDA for otherwise enlightened regulatory decisions.

However, what the public sees of safety and efficacy information- to mix metaphors- is merely the tip of the iceberg. The Nature Biotechnology report, for example, describes the case of Pfizer's SSRI drug Edronax. Published trials included data on 1600 patients, but in actuality, trials involved 4600 patients. When complete data sets were obtained and reviewed, the drug turned out to be no better than placebo, and possibly unsafe (read more here). [[Yet one more reason to wonder what Canadian Institute of Health Research was thinking when it appointed Medical Director of Pfizer Canada to its Governing Council.)]]

Any transparency reforms would provide a much better basis for a) circumventing ethically suspect information practices so that healthcare systems can assess the totality of evidence on drug safety and efficacy, and b) getting a better understanding of the drug development process- warts and all. (photo credit: Lulu Vision 2007).