House Subcommittee Hearing Considers Issue of Clinical Trial Data Concealment
FDA has "repeatedly urged" drug makers not to disclose clinical study results showing their antidepressants are no more effective in children than placebos and has suppressed negative information "on the grounds that it might scare families and physicians away from the drugs," according to documents and testimony at a House Energy and Commerce Subcommittee on Oversight and Investigations hearing Thursday, the Washington Post reports (Vedantam, Washington Post, 9/10). The hearing was the "first of what are expected to be several hearings" on the issues of the use of antidepressants in children and FDA and drug companies' decisions not to disclose some negative study results, according to the Philadelphia Inquirer.
According to Rep. Greg Walden (R-Ore.), "[S]ix of the seven antidepressants tested in pediatric trials did not show efficacy in kids." Only one antidepressant, Eli Lilly's Prozac, has received FDA approval for use in children, but physicians frequently prescribe other drugs off-label to children. "In 2002 alone, more than 10 million kids in America were prescribed antidepressants, and the number is on the rise," Walden said (Mondics, Philadelphia Inquirer, 9/10).
Janet Woodcock, FDA's deputy commissioner for operations, maintains that FDA did not act more aggressively to curb prescriptions of the drugs in children because depression treatments for children are limited and "the jury is still out" on their effectiveness in children (Shogren, Los Angeles Times, 9/10). Woodcock said, "While there are findings among these data suggestive of an increased risk of suicidality for some of these drugs, there remai[n] inconsistencies in the results" (Carey, CQ Health Beat, 9/9).
For at least three medications, FDA has blocked drug makers' attempts to reveal negative study results on drug labels, according to evidence presented in the hearing (Washington Post, 9/10). Officials from Bristol-Myers Squibb, which makes Serzone, and Wyeth, which makes Effexor, testified that they had sought to include language on their drugs' labels indicating that they did not perform in clinical trials significantly better than placebos in children. However, FDA would not allow the label changes, they said.
In addition, Wyeth had sought to add a warning that Effexor may increase hostility and suicidal thoughts in children, but FDA asked the company to remove the precaution from the drug's label, according to a document released at the hearing (Wilde Mathews, Wall Street Journal, 9/10).
Although a new FDA analysis of antidepressant clinical trials supports Wyeth's original conclusion, FDA officials said they originally requested that the warning be removed because, at the time, they felt there was a "discrepancy" between the warning and FDA's position that no causal tie had been confirmed between antidepressants and suicidal tendencies (California Healthline, 9/8). An FDA letter said Wyeth's warning could be "confusing and potentially misleading" when paired with FDA's recommended label warning for all major antidepressants, which urges physicians to closely monitor patients using the drugs (Wall Street Journal, 9/10).
Subcommittee Chair Joe Barton (R-Texas) at the hearing accused FDA of "deliberately defying" the panel by withholding documents that detail the effects of antidepressants in children, the New York Times reports (Harris, New York Times, 9/10). In March, the committee requested from FDA 12 unpublished studies and interviews with key officials (Albanesius, CongressDaily, 9/10).
The studies were among the 15 trials of antidepressants that have been conducted on children. Of all the studies, 12 failed to show the drugs were effective, but only three of those had been published when the committee's investigation began this year. Several more of the studies have been made public since. Following the committee's request for information on the unpublished studies, an FDA official sent an e-mail to colleagues notifying them that they should not give Congress "draft documents, notes, memos to self or file or incoming contacts from non-FDA individuals."
While Woodcock said the message was sent because the agency has "legal restrictions of the kind of information we can disclose," Barton said the e-mail was evidence of FDA's "stonewalling, slow rolling and plain incompetency" (Los Angeles Times, 9/10). He added, "FDA's lack of cooperation ... leaves me wondering whether this is sheer ineptitude or something far worse" (CongressDaily, 9/10).
After the hearing, FDA spokesperson Jason Brodsky on Thursday denied accusations that the agency withheld information, saying, "We have provided all the information requested by the chairman's letter," which includes "thousands of pages" of documents (New York Times, 9/10). However, panel members said FDA and drug companies have provided "scant details" of antidepressant trials in children, and when the agency last month published five summaries of such trials it failed to include "crucial details, such as links between antidepressants and heightened suicidal thoughts among children," the AP/Las Vegas Sun reports (Henderson, AP/Las Vegas Sun, 9/10).
Reps. Edward Markey (D-Mass.) and Henry Waxman (D-Calif.) plan to introduce legislation that would expand a 1997 bill that requires trials involving life-threatening diseases to be registered on ClinicalTrials.gov but lacks an enforcement mechanism. As the law currently stands, "it is the equivalent of a voluntary system," Markey said. The proposed legislation would "include both federal-funded and privately funded clinical trials so that clinicians, patients and researchers will be able to know the universe of clinical trials on a particular drug and have access to the results of those trials," according to Markey. Failure to report trial results would result in civil penalties (CongressDaily, 9/10).
Some Democrats on the subcommittee also suggested modifying a law that offers drug companies incentives to test their drugs for use in children -- including a six-month patent extension that gives them market exclusivity for their drugs -- to include a requirement for clinical trial publication. "To get companies to do studies on children, we bribed them," Waxman said, adding that market exclusivity is "worth billions" to the industry. Some panel members suggested that the incentives should not be extended to drug makers unless they publish all clinical trial results. "Right now, drug makers can cherry pick which studies they publish and which they don't," Rep. Bart Stupak (D-Mich.) said (CQ Health Beat, 9/9).
However, Rep. Cliff Stearns (R-Fla.) said that if drug makers were required to publish all trial information, it could be used against them in major lawsuits "based on specious information" (CongressDaily, 9/10). Markey said, "I understand when companies are concerned about how bad news might lead their stockholders to suffer a monetary loss, but the alternative is that patient health suffers as doctors, researchers and sick people proceed on the basis of false assumptions" (CQ Health Beat, 9/9).
Representatives from seven drug companies said in testimony that they support a Pharmaceutical Research and Manufacturers of America proposal unveiled this week to promptly publicize all clinical trials on a collective Web site (New York Times, 9/10).
PhRMA on Tuesday presented plans to launch on Oct. 1 a voluntary Web site that would include summary results from most of its members' studies. Trial results would be published within a year of their conclusion; feature only summaries of unpublished studies; exclude some data, such as early-stage studies and unfinished trials; include trials not published in medical journals; and contain only trials completed after Oct. 1, 2002. The site also would not publish trials that are still enrolling patients or details from trials on drugs that fail to receive FDA approval. PhRMA said that along with recent actions from GlaxoSmithKline, Merck and Lilly, which recently announced they are creating separate trial registry Web sites, all major drug companies have now committed to making public trial information (California Healthline, 9/8). The Web site will be located at www.clinicalstudyresults.org (Los Angeles Times, 9/10).
Drug company representatives said that summaries of clinical trials would be sufficient because releasing entire reports would be "so unwieldy that it could confuse doctors and patients," the AP/Sun reports. According to Dr. John Hayes, a product team leader at Lilly, a single report can number more than 400,000 pages. Including 120,000 clinical trials on the Web site could "dilute the usefulness of the information," Dr. David Wheadon, senior vice president of regulatory affairs for GSK, said, the AP/Sun reports (AP/Las Vegas Sun, 9/10).
A group of 12 medical journal editors who belong to the International Committee of Medical Journal Editors on Wednesday announced that they will refuse to publish research from drug companies' clinical trials unless the studies are listed with a national registry accessible to the public at no charge. While the plan did not specify an existing registry, the editors said it would have to be electronically searchable and managed by a not-for-profit organization. Each study on the registry would be described in detail, from its primary and secondary outcome measures to its funding source, and would be registered at or before patient enrollment.
The registry must include the purpose of the study, how its goals were initially defined, its commencement date, its anticipated length and its sponsor company. Companies will not be required to register Phase I preliminary trials, which are used to examine biological activity and toxicity. The editors said that the only current database template that would meet their requirements is ClinicalTrials.gov, operated by NIH's National Library of Medicine. The requirement would apply to any trials that begin after June 1, 2005. Trials that were in progress before that date must be registered by September 2005 to be considered for publication (California Healthline, 9/9).
Several broadcast programs reported on the hearing:
- NPR's "All Things Considered": The program on Thursday discussed the hearing with NPR's Joanne Silberner (Siegel, "All Things Considered," NPR, 9/9). The complete segment is available online in RealPlayer.
- NPR's "Morning Edition": The program on Friday reported on the hearing. The segment includes comments from Dr. Catherine Clary, a vice president at Pfizer; Walden; Waxman; and Woodcock (Prakash, "Morning Edition," NPR, 9/10). The complete segment is available online in RealPlayer.
- NPR's "Talk of the Nation/Science Friday": The program on Friday will include an interview with Catherine DeAngelis, editor of the Journal of the American Medical Association, about the new publication policy (Flatow, "Talk of the Nation/Science Friday," NPR, 9/10). The complete segment will be available online in RealPlayer after 6 p.m. ET.
- PBS' "NewsHour with Jim Lehrer": The program on Thursday reported on the "growing controversy" over the disclosure of clinical trial results. The segment includes comments from Joseph Camardo, senior vice president at Wyeth; Dr. Lawrence Diller, a pediatrician in California; and Waxman (Dentzer, "NewsHour with Jim Lehrer," PBS, 9/9). The program on Thursday also included interviews with Kay Dickersin, director of the U.S. Cochrane Center and a professor of community health at Brown Medical School, and PhRMA spokesperson Alan Goldhammer (Suarez, "NewsHour with Jim Lehrer," PBS, 9/9). The complete transcript of the segments is available online. The complete segment is available online in RealPlayer.