Sparks Fly Within FDA Over Longstanding ARB-Cancer Controversy: WSJ

June 01, 2013

NEW YORK, NY — Emails and other documents reviewed by the Wall Street Journal (WSJ)[1] provide an unusual look at a sometimes-volatile dispute within the US Food and Drug Administration regarding the agency's oversight of angiotensin-receptor blocker (ARB) safety, specifically with respect to a simmering controversy: is there a link between chronic use of the drugs and cancer risk?

A story today from WSJ reporter Thomas M Burton shows sparks flying between senior FDA official Dr Thomas A Marciniak and his superiors at the agency over his efforts to place stronger warnings about a possible cancer risk into ARB labeling. Marciniak, echoing others in the scientific community, point to evidence in studies suggesting that the drugs, widely used for hypertension and heart failure, may in fact pose such a risk. Both the FDA and the European Medicines Agency concluded in 2011 that there likely isn't such a risk.

Marciniak has previously appeared in heartwire coverage taking the RECORD trial of rosiglitazone (Avandia, GlaxoSmithKline) to task for what he saw as unreliable safety data and questioning the completeness of outcomes data for rivaroxaban (Xarelto, Bayer Healthcare/Janssen Pharmaceuticals) in ATLAS ACS 2 TIMI 51 .

 
You would ignore a 30% increase in cancer rates for any drug, much less drugs for which there are many alternatives?
 

The WSJ story details Marciniak's review of patient-level data from ARB trials, in contrast to the meta-analysis approach the FDA relied on to reach its view on ARB safety, and in balanced fashion points out strengths and weaknesses of both approaches. And it shows how the dispute fits in with much broader controversy about whether the agency's efforts are aimed in the best directions.

"The debate over ARBs highlights the question of whether the US drug-safety agency devotes enough effort to examining the safety of long-marketed blockbusters as it focuses on new drugs," Burton writes. "In a rare rebellion by an FDA reviewer, Dr Marciniak has clashed with his bosses over his desire to spend time on ARB safety, instead of just on new drug applications."

For example, the story tells how the chief of Marciniak's division, Dr Ellis Unger, wrote to him to "discourage a safety investigation of the ARB drugs. 'This would represent a lot of man-hours, so I have to assume that there is a paucity of work in the [cardiorenal] division at this point,' [Unger] wrote, "or that you will be doing this mostly after hours.'"

Marciniak's reply, as quoted in the story: "You are faced with a serious, unanswered question of whether drugs taken by millions of Americans increase cancer rates, and you're concerned about 62 to 93 man-days for my entire plan?" Marciniak, Burton writes, "went ahead with his inquiry."

"In another email exchange, Dr Unger wrote that even if Dr Marciniak 'found an increased cancer risk of [30%], I doubt there would be much enthusiasm for basing a regulatory decision (labeling or otherwise) on that.' Dr Marciniak shot back, 'Astonishingly, you would ignore a 30% increase in cancer rates for any drug, much less drugs for which there are many alternatives?'"

Explaining his remark to the WSJ in an interview, Unger said "he meant that if the 30% cancer increase weren't convincingly proven, the FDA wouldn't act."

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