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May 28, 2007
 |  BioCentury  |  Politics, Policy & Law

Political defibrillator

The circumstances surrounding the publication by the New England Journal of Medicine of a meta-analysis of safety data from studies of Avandia rosiglitazone and an accompanying commentary suggest that FDA critics on Capitol Hill have collaborated with whistleblowers in the agency and pharmaceutical industry critics in academia to create a controversy around Avandia safety in order to advance a political agenda.

Alarming headlines about Avandia last week served as a political defibrillator, shocking new life into congressional efforts to separate the assessment of drug efficacy and safety just weeks after they were defeated in the Senate and as the House Energy and Commerce Committee is set to begin debate on drug safety legislation.

In this context, it is largely irrelevant that the articles have contributed little to the scientific understanding of the drug's risks and benefits (see "Deconstructing Data," A6).

In remarks on the floor of Congress and in press releases, Sen. Chuck Grassley (R-Iowa), Rep. Henry Waxman (D-Calif.) and several of their colleagues have portrayed Avandia as the quintessential "what did they know and when did they know it" Washington scandal, complete with a maverick outsider who exposes wrong-doers and alerts congressional guardians of the public health.

The core contention is that FDA and Avandia's manufacturer, GlaxoSmithKline plc (LSE:GSK; GSK, London, U.K.), suppressed and failed to act on information about serious safety problems caused by Avandia.

Avandia, a peroxisome-proliferator-activated receptor gamma (PPAR gamma) agonist, is widely used as an insulin sensitizer to treat Type II diabetes. It is marketed as monotherapy and in combinations with metformin (Avandamet) and glimepride (Avandaryl).

If it has been hiding information, GSK has been doing so by placing it in clear view. Steven Nissen, chairman of the Cleveland Clinic's department of cardiovascular medicine, googled a GSK website to find the data for the meta-analysis he and Kathy Wolski published in NEJM.

Nissen's conclusions are similar to an integrated trial analysis that GSK posted on its clinical trial registry website and submitted to FDA and EMEA in August 2006.

The data reflected in GSK's pooled analysis prompted EMEA in September 2006 to add a warning to Avandia's label about the risk of cardiac ischemic events, accompanied by a caution against discontinuing treatment with the drug.

In fact, Nissen's paper and the GSK analysis are not nearly the first public alerts about possible cardiovascular problems with Avandia. Earlier signals led FDA and the EMEA to request the addition of a number of safety warnings to the label since Avandia was first approved in 1992 (see "Avandia Labeling History").

Indeed, GSK launched the 4,400-patient RECORD study of death or hospitalization from cardiovascular effects in 2000 in response to a request from the CHMP. Results are expected in 2009.

In the meantime, the pharma company submitted a proposed label change to FDA in August 2006, Anne Phillips, VP clinical for North America cardiovascular-metabolic, told BioCentury. She declined to describe the proposal or to say why the label had not yet been changed.

What they knew when

There has been a debate within FDA for several years over the merits of elevating to black box status the existing label warning that patients with congestive heart failure (CHF)...

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