The Wall Street Journal-20080125-Politics - Economics- FDA Procedures Draw Scrutiny- Vytorin- Avandia Rekindle Debate Over Drug-Approval Process
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Politics & Economics: FDA Procedures Draw Scrutiny; Vytorin, Avandia Rekindle Debate Over Drug-Approval Process
Controversies about cholesterol drug Vytorin and diabetes drug Avandia are reigniting debate over what evidence the Food and Drug Administration requires to approve drugs -- and may generate pressure on the agency to raise its bar.
The FDA's system for approving drugs has been criticized as scrutiny grows about Vytorin, marketed by Schering-Plough Corp. and Merck & Co., in the wake of a study that raised questions about whether the widely advertised blockbuster worked better than a cheaper generic.
Yesterday, Democratic Reps. John Dingell and Bart Stupak, both of Michigan and leaders of the House Energy and Commerce Committee, sent the latest in a volley of letters about the drug to Merck, Schering- Plough and two medical groups, the American Heart Association and the American College of Cardiology.
Sen. Charles Grassley (R., Iowa), who has led several investigations of the FDA and the drug industry, yesterday opened his own probe into Vytorin. Both Messrs. Stupak and Grassley said they were concerned about the issue of FDA approval standards and what studies the agency required after a drug went on the market.
A shift by the FDA toward tougher scrutiny of new drugs could add hundreds of millions of dollars to the cost of developing a drug at a time when some big drug makers are struggling to replenish product pipelines.
In addition, any preapproval holdup eats into the manufacturer's crucial time to sell the drug before protective patents expire and generic competition leaps in. "If you're looking at a decade-long trial, you may not have sufficient incentive . . . to pursue that drug," says Alan Goldhammer, a deputy vice president at the Pharmaceutical Research and Manufacturers of America, a trade group.
The lawmakers' interest is the latest sign that the flap over Vytorin, in addition to a recent controversy about the safety of GlaxoSmithKline PLC's Avandia, is adding new fuel to a long-running debate over FDA approval standards -- and, specifically, a mechanism known as "surrogate markers."
Vytorin and Avandia went on the market based largely on evidence that they helped control patients' cholesterol and blood sugar, respectively. These lab measures were believed to reflect important clinical benefits, such as reducing the risk of heart attacks. Thus, the measures serve as proxy markers, or surrogates, for the drug's broader and more important effect on the body. Using surrogates helps speed drug approvals, because studies can generally be shorter, smaller and cheaper.
But the proxy markers can be misleading. Sometimes a drug works on a proxy but doesn't deliver the promised benefit for the primary health problem. Or a drug can have side effects that don't surface during initial proxy-marker studies but end up outweighing its benefit.
"There are inherent risks in using surrogate markers," said Clifford Rosen, a senior scientist at the Maine Medical Center Research Institute who, after leading an FDA panel on Avandia, wrote a piece in the New England Journal of Medicine that questioned whether the surrogate endpoint was enough for its approval.
In the case of Vytorin, the new study showed the drug didn't slow the progression of heart disease better than a cheaper generic, even though Vytorin did have a bigger effect on so-called LDL, or "bad" cholesterol.
Robert Califf, director of Duke University's Translational Medicine Institute, says using surrogate endpoints is a reasonable strategy for allowing drugs to come on the market. But he said that for major chronic ailments such as cardiovascular disease, the large-scale, long-term studies needed to show benefits against heart attacks and other events should begin immediately after a drug is approved. Direct-to-consumer advertising shouldn't be permitted until those results are in, he said. Finally, prescribing information, or labels, for such medicines should clearly reflect the uncertainty of the long- term benefit until the data are in.
For Zetia, one of the ingredients in Vytorin, Merck and Schering- Plough didn't launch a major long-term study until 2006, four years after the drug was approved. Data aren't expected until about 2011. Combined sales of Zetia and Vytorin hit $5 billion in 2007 in part because of aggressive advertising.
In the case of Avandia, after concerns emerged about a potential link between the drug and a heightened risk of heart attacks, some researchers suggested the FDA should have demanded more data on the drug's cardiovascular impact. Cardiovascular problems are common among diabetes patients.
"The FDA needs to have more teeth," says John Buse, a professor at the University of North Carolina at Chapel Hill and a president of the American Diabetes Association. "They need to demand hard endpoint studies at the time of approval and they need to have some system for monitoring progress" after the drugs are on the market. Dr. Buse said he wasn't speaking for the ADA.
Mr. Grassley said yesterday that "in light of what's happened with Avandia and Vytorin, maybe the FDA needs to re-examine when it's appropriate to use surrogate endpoints. . . . These two cases also highlight the importance of vigilant postmarketing surveillance and the need for more postmarketing studies to address important safety questions."
Mr. Stupak said that requiring clinical endpoint studies for all drugs before approval would delay their marketing. But, he added, "people taking Vytorin are doing so because they believe it will reduce their risk of heart attack. It would make sense for FDA to require manufacturers to conduct an endpoint study to determine whether Vytorin just reduces cholesterol or if it also reduces heart attacks."
The FDA has indicated only that it will look at the issue. In a statement about the Vytorin study, the agency said its officials "will be considering what, if any, impact this new study will have on our standards for approval of cholesterol lowering drugs and may seek outside input at a future public meeting." FDA officials also wrote to the New England Journal of Medicine to defend the use of blood sugar as a basis for approval, saying that requiring long-term cardiovascular benefits would slow new drugs and might make developing them impossible.
The FDA has long struggled with when to use surrogate markers. In one marked example of their limits, a study published in 1991 showed that drugs that had been approved to prevent deaths from a form of heart arrhythmia were actually tied to a higher rate of death in certain patients who had extra heartbeats. The medications had been approved, though for a different patient population, based partly on the surrogate marker of reducing extra heartbeats.
But starting in the late 1980s, the use of surrogate markers helped speed the flow of drugs to fight AIDS. "It's an incredible advance for AIDS drug approval," says Scott Hammer, a professor at Columbia Medical School.
