Even as the US Food and Drug Administration (FDA) begins implementing sweeping new powers granted last year by Congress for drug safety oversight, including requiring manufacturers to conduct additional post-marketing clinical trials, the agency is coming under renewed congressional scrutiny into the standards for clinical trials required for new drug approvals.
The potential impact on manufacturers is significant: If the FDA toughens its requirements for clinical trials, the cost of bringing a new drug to market could increase by hundreds of millions of dollars and the length of time could stretch by several years. “If you’re looking at a decade-long trial, you may not have sufficient incentive … to pursue that drug,” Alan Goldhammer, deputy vice president of the Pharmaceutical Research and Manufacturers of America (PhRMA) told the Wall Street Journal in January.
The most recent congressional foray into the FDA’s operations was triggered by a January announcement from Schering-Plough Corp. that a clinical study showed its blockbuster cholesterol drug Vytorin (ezetimibe/simvastatin) was no more effective than cheaper generic simvastatin alone in slowing the progress of cardiovascular disease. Vytorin was, however, more effective in reducing LDL-cholesterol. Vytorin and its cousin Zetia (ezetimibe) are jointly marketed by Schering-Plough and Merck & Co., and have combined annual sales of more than $5 billion.
Members of Congress and the New York attorney general’s office are investigating whether Schering-Plough and Merck improperly withheld results of the study, called ENHANCE, which was completed in April 2006. They also want to determine whether the companies engaged in improper “aggressive marketing” with or without FDA’s approval, and whether company insiders sold stock properly in advance of the announcement. Both companies have denied any wrongdoing and “strongly object to mischaracterizations” about the trial.
“While the ENHANCE trial was time-consuming and took longer than originally anticipated to complete, our companies acted with integrity and good faith in connection with the trial,” said Thomas Koestler, PhD, president of the Schering-Plough Research Institute.
Unknown is the extent to which FDA’s reliance on biomarkers for drug approval will be impacted by the Vytorin and other recent controversies, including Avandia (rosiglitazone), GlaxoSmithKline PLC’s (GSK) blockbuster for type 2 diabetes. Potentially significant increased cardiovascular risks were identified last year in long-term use of Avandia even though other published and unpublished data from long-term clinical trials provided contradictory evidence.
FDA approvals of Avandia and Vytorin were based, in part, on data from surrogate endpoints, which have the advantage of being obtained more cheaply and quickly than larger population studies, but which may not be wholly accurate or detect important side effects. At worse, the use of surrogate endpoints may fail to pick up a drug’s long-term harmful effects, as has been alleged with Avandia. “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,” said Sen. Chuck Grassley (R-IA), who opened a probe into Vytorin.
House Energy and Commerce Committee leaders Reps. Bart Stupak and John Dinglell, both Democrats of Michigan, also announced probes into Vytorin. “People taking Vytorin are doing so because they believe it will reduce their risk of heart attack,” Stupak said. “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.”
So far, the FDA is taking the middle road. In a statement in January, the agency said it “will be considering what, if any, impact [the ENHANCE] study will have on our standards for approval of cholesterol-lowering drugs and may seek outside input at a future public meeting.” In an “early communication” on the ENHANCE study, the agency was careful to say that it was “not advising health care professionals to discontinue prescribing these products,” and noted it “has not reached a conclusion about whether this information warrants any regulatory action.”
Don’t publish or perish?
While the FDA normally is given access to all clinical trials data, several major drug manufacturers chose to withhold from publication studies that found their drugs were less than effective. Manufacturers of 12 antidepressant agents, including Eli Lilly and Co. (Prozac), GSK (Paxil), Pfizer Inc. (Zoloft), and Wyeth (Effexor) conducted 74 registered trials to win FDA approval. However, they did not publish 31% of these studies, mainly those that had negative or questionable results, according to a report published in the New England Journal of Medicine (NEJM) on Jan. 17, 2008.
Erick H. Turner, MD, a psychiatrist at Oregon Health & Science University, and his colleagues found that about 94% of trials of antidepressants published between 1987 and 2004 conveyed positive outcomes. A total of 37 out of 38 studies that the FDA viewed as having positive results were published, compared to only three out of 36 trials that were negative or questionable. Eleven of the negative or questionable studies were published in a way that conveyed positive outcomes, they reported.
PhRMA’s Goldhammer said the NEJM study failed to mention that industry has voluntarily decided to post all clinical trial data, and that new Federal laws require this information to be made public. “This is all based on data from before 2004, and since then we’ve put to rest the myth that companies have anything to hide,” he told the New York Times.
While making clinical trial data public may be a public benefit, it is unlikely to make blacks in the US more comfortable about participating in these studies. A recent survey found that blacks are 60% as likely as whites to participate in clinical trials largely because they distrust physicians and are concerned they could be harmed.
The survey, published online in Medicine (Jan. 14, 2008) by Neil Powe and colleagues at Johns Hopkins University, found 58% of blacks thought their doctors would willingly give them experimental drugs without their consent compared to 28% of whites. Powe, an epidemiologist, associated the deep mistrust among blacks to past unethical medical treatments, such as the notorious Tuskegee syphilis experiment.
“So long as the legacy of Tuskegee persists, African-Americans will be left out of important findings about the latest treatments for diseases, especially those that take a greater toll on African-Americans and consequently may not have ready or equal access to the latest medicines,” Powe said.
About the Author
Contributing editor Ted Agres, MBA, is a veteran science writer in Washington, DC. He writes frequently about the policy, politics, and business aspects of life sciences.
This article was published in Drug Discovery & Development magazine: Vol. 11, No. 3, March, 2008, pp. 10-12.