NEJM: Lost in Transmission — FDA Drug Information That Never Reaches Clinicians

[Jackpine Radical]

http://healthcarereform.nejm.org/?p=2126&query=TOC

When companies apply for drug approval, they submit the results of preclinical studies and usually at least two phase 3 studies — randomized clinical trials in patients with a particular condition. FDA reviewers with clinical, epidemiologic, statistical, and pharmacologic expertise spend as long as a year evaluating the evidence. FDA review documents (posted at www.accessdata.fda.gov/scripts/cder/drugsatfda/) record the reasoning behind approval decisions. Unfortunately, review documents are lengthy, inconsistently organized, and weakly summarized. But they can be fascinating, providing a sense of how reviewers struggled to decide whether benefits exceed harms. Yet in many cases, information gets lost between FDA review and the approved label.

Sometimes what gets lost is data on harms. For example, in 2001, Zometa (zoledronic acid, Novartis) was approved for use in patients with hypercalcemia of malignancy. Approval was based on the results of two trials,1 in which 287 patients with cancer 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 (see box on Zometa data). 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. But they 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 (P=0.03). These mortality data also did not appear in the label. Nor did they appear in the journal article reporting on these studies,2 which actually recommended the 8-mg dose for refractory cases. In 2008, the FDA approved an updated Zometa label with an explicit warning statement: “Renal toxicity may be greater in patients with renal impairment. Do not use doses greater than 4 mg.” Yet the mortality data are still missing from the label.



Sometimes, efficacy data get lost. Lunesta (eszopiclone) was approved in 2004 for chronic insomnia. Sepracor, its manufacturer, began an intense direct-to-consumer advertising campaign — spending more than $750,000 a day in 2007 — featuring a luna moth that transforms frustrated insomniacs into peaceful sleepers. Lunesta sales reached almost $800 million last year. Clinicians who are interested in the drug’s efficacy cannot find efficacy information in the label: it states only that Lunesta is superior to placebo (see box on Lunesta data).3 The FDA’s medical review provides efficacy data, albeit not until page 306 of the 403-page document. In the longest, largest phase 3 trial, patients in the Lunesta group reported falling asleep an average of 15 minutes faster and sleeping an average of 37 minutes longer than those in the placebo group. However, on average, Lunesta patients still met criteria for insomnia and reported no clinically meaningful improvement in next-day alertness or functioning.