GlaxoSmithKline’s diabetes drug Avandia (rosiglitazone) will be under the microscope at an important joint meeting of two advisory committees to the US Food and Drug Administration next week. The drug agency’s advisers are weighing up whether the blockbuster drug’s heart attack, heart failure and stroke risks – laid out most recently in studies in the Journal of the American Medical Association and in Archives of Internal Medicine – outweigh its benefits in effectively controlling blood sugar in Type II diabetes.
The elephant of a question that will be in the room with the advisers next week: Should Avandia be pulled from the market altogether, especially given the existence of an equally effective but safer competitor? (That drug is Actos (pioglitazone), made by Takeda Pharmaceutical of Osaka, Japan.) The question was given additional urgency late last month, when the JAMA and Archives papers were published. Nature wrote about them here.
(In response, GSK issued this statement, which it reiterated today in this USA Today editorial. It argues that the combined results of six clinical trials completed since 2007 show no increase in heart attack, stroke or death. “We look forward to participating in a rigorous scientific discussion of the data on the cardiovascular safety of rosiglitazone with the FDA Advisory Committees on 13 and 14 July,” the company added.)
In preparation for the meeting, the FDA in April asked a committee of the Institute of Medicine to study the ethical issues raised by studying the safety of already-approved drugs like Avandia. The post-market ethics issue is a relatively new one for the agency, which was given substantial powers to require post-market safety studies only in a 2007 law.
The IOM’s first response, timed to offer guidance to the meeting, comes in the form of a 25-page letter which was issued today.
It articulates general principles and recommendations in response to the question: “What are the ethical and informed consent issues that must be considered when designing randomized clinical trials to evaluate potential safety risks?” in marketed drugs.
The IOM committee’s recommendations are sensible and generalizable, saying, for instance, that FDA should in the first place determine that there is a “substantial public health question about the nature or acceptability of [a drug’s] risks….a question that requires a policy decision from FDA.”
It adds that it’s appropriate for FDA to require a randomized clinical trial in this kind of case only when there is substantial uncertainty about the risk-benefit balance of a marketed drug. The uncertainty needs to be large enough that a responsible policy decision cannot be made based on either the existing evidence, or on evidence from new observational trials.
The report doesn’t as much as mention the word Avandia. It remains to be seen how difficult it will be for FDA’s advisers to move from the IOM’s dispassionate guidelines through the charged particulars of this real-life case.
A more detailed IOM report comprehensively addressing FDA’s questions about the ethics of post-market clinical trials will be completed in the spring of 2011.