October 23, 2009

Data Missing On US Drug Labels

U.S. drug labels often omit key information about a medicine's effectiveness and the severity of its side effects, according to a commentary written by two doctors in the New England Journal of Medicine.

Such omission of data can result in some medicines appearing safer and more effective than they actually are, wrote Drs. Lisa Schwartz and Steven Woloshin of the Dartmouth Institute for Health Policy and Clinical Practice in Hanover, New Hampshire.

"The most direct way that the FDA communicates the prescribing information that clinicians need is through the drug labels," they wrote.

"To ensure that labels do not exaggerate benefits or play down harms, Congress might have required that the FDA or another disinterested party write them. But it did not. Drug labels are written by drug companies, then negotiated and approved by the FDA."

As a result, "much critical information that the Food and Drug Administration has at the time of approval may fail to make its way into the drug label and relevant journal articles," they said.

"How can I decide if the potential harms of this drug are worth the risk if I don't know how well the drug works, and vice versa?" asked Woloshin during an interview with Reuters.

Drs. Schwartz and Woloshin noted the case of Sepracor's sleep drug Lunesta, which the company heavily promoted with a $750,000 per day advertising campaign in 2007. 

Although the drug's label says Lunesta was superior to a placebo, test results submitted to the FDA showed that in the largest and longest study, "Lunesta patients still met criteria for insomnia and reported no clinically meaningful improvements in next-day alertness or functioning," the doctors wrote.

Sepracor generated sales of $600 million last year, and on Tuesday became a wholly owned subsidiary of Dainippon Sumitomoto Pharma Co.

A Reuters report quoted Sepracor as saying that more detailed information about its products, beyond what the FDA requires, is always available to healthcare providers who request it.

Drs. Schwarz and Woloshin also cited Takeda Pharmaceutical Co.'s drug Rozerem (ramelteon), which was approved in 2005 for chronic insomnia and was aggressively promoted to consumers.  The drug's label omitted key laboratory data showing that it took 31 minutes for adults over the age of 64, and 24 minutes for younger adults, to fall asleep once they took the drug "“ compared with 38 minutes for those taking a placebo.

Furthermore, "there were no subjective improvements in total sleep time, sleep quality, or the time it took to fall asleep," the doctors wrote.

"Two phase 3 outpatient trials confirmed that people didn't notice much benefit from Rozerem. In a trial involving younger adults, Rozerem had no effect on any subjective sleep outcome; in one involving older adults, the drug reduced reported time to fall asleep by 7 minutes but did not reduce the proportion of cases meeting the definition of insomnia (taking more than 30 minutes to fall asleep). Nor did it improve any of the secondary outcomes: falling back asleep, number of awakenings, total sleep time, or sleep quality."

"Sometimes what gets lost is data on harms," the doctors wrote.

For instance, the Novartis cancer drug Zometa (zoledronic acid) was approved in 2001 for use in patients with hypercalcemia of malignancy.  

The approval was based on the results of two trials in which 287 cancer patients were randomly assigned to receive either 4-mg or 8-mg doses of Zometa or Aredia (pamidronate), the standard of care.

According to the label, 8 mg of Zometa was no more effective than 4 mg in reducing calcium levels, but had greater renal toxicity. 

But "the numbers quantifying the renal-toxicity data for the 8-mg dose did not appear in the label, as they did for the 4-mg dose," the doctors said.

The data did appear in the 98 pages of FDA medical and statistical reviews.

"Surprisingly, the reviews also noted that the 8-mg dose was associated with a higher rate of death from any cause than the 4-mg dose," wrote Drs. Schwarz and Woloshin.

But that mortality data did not appear in the label, they said, nor did it appear in the journal article reporting on these studies, which recommended the 8-mg dose for refractory cases.

Seven years passed before the label was changed to explicitly inform doctors not to use the higher dose.  The new label now reads: "Renal toxicity may be greater in patients with renal impairment. Do not use doses greater than 4 mg."

The mortality data remains missing.

Woloshin said he and his colleagues have developed a better format that would clarify the scope of the risks and benefits to consumers. The FDA's Risk Advisory Committee voted unanimously last year to endorse the approach.


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