FDA Scientist Lays Out Case on Naproxen

By Thomas M. Burton 

SILVER SPRING, Md.--An epidemiologist with the Food and Drug Administration on Monday laid out why the anti-inflammatory pain drug naproxen may carry lower cardiovascular risks than comparable drugs.

The epidemiologist, Dr. Andrew D. Mosholder, made the remarks at a pivotal FDA advisory committee meeting here to determine whether the agency will let drug makers differentiate the pain drugs' labels based on their safety risks. Aleve is Bayer AG's brand name for naproxen.

The FDA, based on Dr. Mosholder's work, has asked the panel whether Aleve and generic naproxen should get a new label highlighting lower heart risk than other drugs in the class like Celebrex and ibuprofen, which go by brand names including Advil and Motrin.

Dr. Mosholder, a reviewer in the FDA Division of Epidemiology, said such heart risks are relatively lower with over-the-counter versions of the drugs, compared to prescription versions, but that the risks still are "observable" in some studies of OTC drugs.

He called the medical literature on the topic "a mile wide and an inch deep," raising questions about whether the FDA can properly differentiate among the medicines.

Dr. Mosholder also remarked that even naproxen in some studies has been linked to small increases in cardiac events. "The results across these studies are not uniform in all cases," he said.

Also at issue in the hearings is whether an FDA-ordered study called Precision--which measures naproxen, ibuprofen and Celebrex in seriously ill heart patients--will continue.

FDA-written analyses had suggested this study may no longer be ethical in its current form if in fact naproxen truly is safer than the other drugs.

After the 2005 hearings, the FDA asked Pfizer to sponsor Precision, and about 22,000 patients had been enrolled as of December 2013. The study is expected to be finished by next year. It isn't considered ethical in medicine to randomly assign patients to a treatment known less safe than others.

Dr. Steven E. Nissen, the principal investigator of Precision and chairman of cardiovascular medicine at the Cleveland Clinic, said the total number of cardiac events in his study "will dwarf everything that has come before."

Referring to the data presented to the panel by the FDA, he told the panel, "Most of what you looked at this morning were small numbers of events." Thus, he said, if Precision is allowed by the FDA to go to completion, it will likely lead to that a more definitive answer about the relative safety of the drugs. The study is expected to be completed by the end of 2015.

One study the FDA has focused on in a so-called meta-analysis, or study of studies, from Oxford University in England.

"We're talking about relatively small hazards" with all the drugs, said Oxford's Dr. Colin Baigent. "What we can't do is say there's no risk with naproxen."

Pfizer, maker of Celebrex and Advil; and Johnson & Johnson, Motrin's maker, said they are safe when used as directed and that current labeling already reflects any cardiac risk the medicines carry. Irene Laurora, a vice president in Bayer's consumer affairs division, said naproxen "does not increase the risk" of heart attack and stroke.

Write to Thomas M. Burton at [e-mail]

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