Bucking his superior at the FDA, a senior regulator is questioning the safety of the top-selling class – ARBs (angiotensin receptor blockers) – of blood pressure drugs.

Patients take these medicines daily in hopes of reducing their risk of heart attack, stroke and heart failure. ARBs on the market in the U.S. include candesartan (Atacand), eprosartan (Teveten), irbesartan (Avapro), telmisartan (Micardis), valsartan (Diovan), losartan (Cozaar), and olmesartan (Benicar).

Dr. Thomas A. Marciniak of the FDA is seeking stronger warnings about these drugs, according to internal documents reviewed by The Wall Street Journal and printed in that publication Saturday.

Dr. Marciniak argues that the drugs – which generated $7.6 billion in U.S. sales in 2012 – may be linked to higher cancer rates. He is not alone in his view, but a top FDA official disagrees, saying evidence does not support a link.

The ARB debate makes one wonder whether the FDA devotes enough effort examining the safety of blockbusters as it focuses on new drugs. Dr. Marciniak has clashed with his bosses on this issue, desiring to spend more of his time on ARB safety and less on new-drug applications.

Dr. Marciniak’s chief in the drug-evaluation division, Dr. Ellis Unger, has called Marciniak’s complaints a “diversion.” He said in an interview, “We have no reason to tell the public anything new.”

According to the WSJ: “In a 2010 study published in Lancet Oncology, Ilke Sipahi and colleagues at University Hospitals in Cleveland looked at five studies involving 68,402 patients and found that people taking ARBs had an 11% greater risk of new cancer overall and a 25% greater risk of new lung cancer, compared with patients who didn’t get the drugs.

Nevertheless, the FDA gave the all-clear signal within a year, saying its own analysis found “no increase in risk” from taking ARBs. Europe’s drug regulator also dismissed the cancer concerns.

But Dr. Marciniak wasn’t persuaded because he didn’t agree with the design of the initial studies which the FDA examined. In its meta-analysis, the FDA combined different studies to look at more patients, multiplying its statistical power to find possible side effects from the drugs. But if the original studies have flaws (as Marciniak believes in this case), then meta-analyses can simply compound the problem.

“Garbage in, garbage out,” wrote Dr. Marciniak, who warned others in the agency that taking results tabulated by companies with vested interests in safety outcomes was likely to produce unreliable results.

For one example, Dr. Marciniak said in an internal analysis the Journal viewed that the FDA meta-analysis didn’t count cases of “lung carcinomas” as lung cancers, which they are. This is only one such way analyzers can skew results if favor of more favorable safety outcomes.

FDA reviewers seldom speak as Dr. Marciniak has in this case, bringing internal disputes into the public eye, but in 2008, nine employees in the FDA’s device division wrote to members of Congress saying the division’s leaders were ignoring safety issues when approving devices. And in 2004, a courageous 20-year FDA scientist named David Graham rocked the pharmaceutical industry when he spoke to the U.S. Senateout about the problems of Vioxx and other Cox-2 inhibitors raising the risks of heart attack and stroke, and about the secret life inside the FDA. His testimony exposed tragic public health consequences stemming from a legalized conflict of interest: the FDA is one of the few government agencies whose funding depends largely on the success of products of the industry it regulates.

After the FDA’s 2011 verdict dismissing ARB cancer concerns, Dr. Marciniak decided to go through the raw data – patient by patient – of the drug studies. By March 2013, he concluded that lung-cancer risk increased by nearly 25% in ARB patients, compared with those taking a placebo or other drugs. He found that in 10 of 11 studies he examined, more lung cancer cases appeared in the ARB-treated patients than in the control group.

“The FDA needs to inform patients and physicians about the ARB lung-cancer risks. The FDA must act now,” he wrote in a memo to senior FDA officials.

FDA division chief Dr. Unger said in the interview that he didn’t agree. He said Dr. Marciniak’s use of raw data from patients could include as cancers some patient-reported ailments that doctors might not agree are cancers, making the FDA’s own research more credible.

The Wall Street Journal reported that Daiichi-Sankyo, Merck, Sanofi and Bristol-Myers said they haven’t seen Dr. Marciniak’s data and couldn’t comment. Novartis said it performed an “initial analysis” of its Diovan and found “no increased risk.” Other drug makers didn’t respond to WSJ requests for comment.

Dr. Marciniak’s analysis didn’t include data from trials on some ARB drugs, including Benicar, but he concluded:  “[T]hat the increased incidence of lung cancers with ARB use is likely a class effect of ARBs” and that it would be “inappropriate” to classify specific ARBs as safe due to a “lack of adequate studies.”

Dr. Marciniak specialized in cancer during his residency at the Mayo Clinic and spent ten years at the National Cancer Institute before coming to the FDA.

The debate he has triggered over ARBs has been accompanied by a dispute with his superior, Dr. Unger over how Dr. Marciniak should spend his time.

Writing to Dr. Marciniak last August, Dr. Unger dismissed the importance of 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 [cardio-renal] division at this point,” he wrote, “or that you will be doing this mostly after-hours.”

Dr. Marciniak responded pointedly on Aug. 31: “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?” He went forward 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 retorted, “Astonishingly, you would ignore a 30% increase in cancer rates for any drug, much less drugs for which there are many alternatives?”

Dr. Unger said in the interview he meant that if the 30% cancer increase weren’t convincingly proven, the FDA wouldn’t act.

So it would appear Dr. Marciniak has his work cut out for him with so much resistance in his own agency if he wishes to ascertain the safety of ARBs. Given that he feels the studies done are questionable at best (“garbage in, garbage out,” he said), it appears he has his work cut out for him.

by Matthews & Associates