Half of the 21 drugs pulled from the market in the U.S. for safety reasons since 1995 involved heart complications, a finding that is spurring Congress and doctors to call for closer government review of side effects.
The products were on the market from 11 months to 30 years, based on a review of Food and Drug Administration data obtained by Bloomberg.
GlaxoSmithKline Plc’s (NYSE: GSK) diabetes drug Avandia, marketed for 11 years, narrowly avoided a recall last week when the FDA restricted its use as a result of a link to heart ailments only uncovered after the drug was in wide use. The agency is now reviewing heart risks for Abbott Laboratories’ (NYSE: ABT) diet pill Meridia, sold since 1997.
Sen. Charles Grassley, an Iowa Republican, said the data supports his recommendation to create an FDA center that would independently study drug safety, saying early warnings within the agency are now sometimes ignored. Doctors say heart risks can best be found in large controlled studies before or after a drug is released, as opposed to an FDA system that depends largely on voluntary reports from doctors and patients.
“The question is whether there are more drugs that should be on the list, and are not,” Grassley said in a statement, after he was supplied with the recall data. Grassley is working with Rep. Rosa DeLauro, a Connecticut Democrat, on a bill to create the new FDA center.
Janet Woodcock, head of the FDA Center for Drug Evaluation and Research, said the agency has already instituted new safety tests to weigh possible heart risks in the case of drugs, such as Avandia, that are used over a long period of time for chronic conditions. “It’s an ongoing process,” she said in a telephone interview.
Heart’s electrical system
Woodcock pointed to studies now required with most new drugs to determine the effect on the heart’s electrical system. The guidelines were issued in 2005 after drugs were withdrawn in the 1990s because they caused dangerous changes to heart rhythm.
It “doesn’t make sense” to test all drugs for heart risks in large controlled studies, Woodcock said. Some drugs are taken for only a short time and others are more likely to cause negative effects on other body systems because of how they work, she said.
The FDA has also started a post-market surveillance network called the Sentinel Initiative that will allow the agency to track reports of drug complications in insurance claims, electronic health-care records and patient registries. The agency is also requiring drugmakers to develop formal plans to educate doctors and patients about potential side effects with new treatments.
These risk-management tools help identify and track safety concerns while keeping medicines available for patients who need them, Woodcock said.
The Grassley-DeLauro bill would separate the safety reviewers in the Office of Surveillance and Epidemiology to reduce clashes with the Office of New Drugs, which is responsible for deciding which products to approve and when changes are needed to medicines that are already on the market.
It’s hard to tell if a heart attack or stroke is caused by a medicine without strictly monitoring patients, said Alastair Wood, a drug-safety expert who spent almost 30 years as medical professor at Vanderbilt University. Cardiovascular disease is the leading cause of death in the United States with an estimated 831,272 people dying from that cause in 2006, or one in every three deaths, according to the American Heart Association.
‘Impossible to detect’
“It’s virtually impossible to detect CV problems, like heart attacks, in a spontaneous reporting system where there is no control,” said Wood, now a managing director at Symphony Capital LLC in New York, in a telephone interview. “If you see six patients with a heart attack on the same drug, it means nothing.”
Avandia concerns prompted the FDA in December 2008 to ask companies for more heart data from new diabetes medicines. Drugs submitted for approval must be able to rule out an 80 percent increased risk of cardiovascular side effects in clinical trials. Drugmakers should conduct additional testing after their products are on the market when an increased risk of 30 percent to 80 percent can’t be eliminated.
“If you were to require cardiac outcomes studies on every type of drug that comes along, I’m afraid it would basically grind the system to a halt,” said Ira Loss, an analyst at Washington Analysis who has followed the FDA for three decades. “Companies wouldn’t want to make investments,” he said.
Posicor, Hismanal, Vioxx
The drugs recalled since 1995 because of heart risks include Roche Holding AG’s blood-pressure treatment Posicor in 1998, Johnson & Johnson’s (NYSE: JNJ) antihistamine Hismanal in 1999, and Merck & Co.’s (NYSE: MRK) painkiller Vioxx in 2004. The average time to recall was eight years, according to data compiled by Bloomberg.
Posicor was withdrawn after 11 months because of signs of low heart rhythm in patients. Basel, Switzerland-based Roche won FDA approval in July 1997 and added warnings to its prescribing information late that year about irregular heart rhythm and the risk of potential muscle injury seen when the drug was combined with certain cholesterol pills. Analysts had estimated that the drug would become one of Roche’s top sellers.
Hismanal was approved in 1988 and the FDA warned four years later that rare cases of serious heart complications and deaths had been reported with higher-than-recommended doses. The agency added cautions to the drug’s prescribing information in 1998 about deadly changes to heart rhythm, allergic reactions and interactions with other medicines. J&J, of New Brunswick, N.J., withdrew the allergy drug after 11 years of marketing after the safety concerns and newer products eroded sales.
Vioxx, used to treat arthritis, was recalled by Whitehouse Station, N.J.-based Merck after five years of marketing when a study suggested the drug doubled the risk of heart attacks after 18 months of treatment. An earlier study published in 2000 suggested the medicine posed heart risks and led to calls for further research into the drug’s side effects.
Avandia, once the world’s best-selling diabetes drug, was linked to a 43 percent higher risk of heart attacks in an analysis released in 2007, eight years after its approval. Glaxo, of London, said last week that it would stop promoting the drug as a result of new FDA restrictions and European regulators’ decision to withdraw the product completely.
Meridia, a 13-year-old diet pill, was tied to 16 percent more major cardiovascular complications in a six-year study of 10,000 patients released this month. Abbott Park, Ill.-based Abbott no longer promotes the drug in the United States.
One reason for having a separate drug-safety center is that there are often disagreements between the offices now under Woodcock’s Center for Drug Evaluation and Research. The Office of Surveillance has been prevented from acting on safety concerns because it is “under the thumb of the office that put the drug on the market in the first place,” Grassley said.
David Graham, a reviewer in the surveillance office and 26-year veteran of the FDA, told Congress of Meridia’s risks in 2004 while calling for a recall of Vioxx. Graham also urged Avandia to be pulled at a 2007 FDA advisory panel meeting. The head of the surveillance office, Gerald Dal Pan, said in documents released by the FDA last week he still believes the diabetes drug should be withdrawn from the market. John Jenkins, head of the Office of New Drugs, recommended against any restrictions to Avandia or changes to its prescribing information during the FDA’s review, the agency’s documents show.