WASHINGTON, DC, 21 Oct 2004—After months of facing criticism about whether drug regulators are warning the public quickly enough about risks associated with some medications, FDA on October 15 announced that manufacturers of antidepressants must include a black-box warning in drug labeling to alert prescribers that youngsters using the medications have an increased risk of suicidal thoughts and behavior, often referred to suicidality.
An FDA advisory panel on September 14 voted 15–8 to add the warning to all antidepressants.
Even though fluoxetine is the only antidepressant with FDA-approved labeling for the treatment of major depressive disorder in children and adolescents, the agency is calling on makers of all antidepressants to warn prescribers considering the use of the medications for pediatric patients to balance the risk of suicidality with the clinical need for the drug.
"In other words, these drugs should not be used casually," said Sandra Kweder, FDA's acting director of the office of new drugs, at an October 15 press conference.
The agency's recommended boxed warning also directs prescribers to closely observe patients for clinical worsening, suicidality, or unusual changes in behavior and inform families and caregivers about the need to monitor patients using antidepressants and communicate with the prescriber.
Regulators, in following the FDA advisory panel's advice, are also asking pharmaceutical companies to package antidepressants in unit-of-use containers and include a medication guide that describes drug-labeling information in lay language.
Agency officials said the guide would be included in or attached to the unit-of-use packages, which, they said, would ensure that patients receive the guides.
Robert Temple, FDA's director of medical policy, argued that the agency lacks confidence in pharmacists' ability to distribute the guides if they were not included in the manufacturer-provided packaging.
Why the black-box warning? The controversy about antidepressant safety intensified in September when lawmakers during two congressional hearings demanded answers from agency officials about why regulators refused in February to release an analysis that found that children and adolescents taking antidepressants have an increased risk of suicidality.
An FDA scientist confirmed those findings at the agency's September advisory committee meeting, leaving lawmakers and families whose loved ones committed suicide while taking the medications asking why the agency waited seven months to validate the earlier analysis by Andrew Mosholder, an epidemiologist with the agency's division of drug risk evaluation in the office of drug safety.
"There is something terribly rotten at the FDA," exclaimed Representative Peter Deutsch (D-Florida), ranking member on the House Energy and Commerce Subcommittee on Oversight and Investigations, which convened the September 23 congressional hearing.
Bart Stupak (D-Michigan) said he was "appalled, but frankly not surprised, by the systematic efforts of the FDA to suppress information that could have prevented the senseless deaths of too many children."
But during his testimony, Temple was steadfast that regulators have worked in the best interest of the public by not acting too quickly to impose warnings that could scare physicians from prescribing antidepressants and patients from using the medications.
He argued that even though several studies have found antidepressants, other than fluoxetine, to be ineffective in children and adolescents for treating depression, "it does not mean there is no efficacy" for pediatric patients.
Temple stated that the agency in February "lacked confidence" in Mosholder's findings because some adverse events reviewed for the analysis may have been inappropriately classified.
FDA hired Columbia University last year to reclassify 400 case descriptions from 25 pediatric trials of antidepressants.
Columbia's reclassification and the reanalysis of the studies by Tarek A. Hammad, senior medical reviewer for FDA's division of neuropharmacological drug products, supported Mosholder's conclusions.
Hammad told the panel that about 2–3% of children taking antidepressants "experience increases in suicidality due to short-term treatment."
Patients in the studies he reviewed had taken the medications 4–16 weeks, he said.
A cover-up? Lawmakers, some even accusing FDA of a cover-up, asked officials why regulators tried to conceal from Congress an internal criminal investigation about who leaked information to the San Francisco Chronicle for a February 1 article that revealed that agency officials had pulled Mosholder's presentation about his analysis from the next day's scheduled advisory committee meeting.
Mosholder told the subcommittee that he was a subject of the agency's internal criminal investigation but that he was not the Chronicle's informant.
Big Brother. With his bosses sitting inches behind him, Mosholder testified that he was asked by FDA officials to alter an affidavit that he prepared for the agency's office of internal affairs, which was being sought by Senator Charles Grassley (R-Iowa), chairman of the Senate Finance Committee.
Grassley wanted a copy of the affidavit as part of an investigation his committee had initiated about why Mosholder was barred in February from presenting his analysis.
In a May 4, 2004, e-mail to Mosholder, Donna Katz of FDA's office of the chief counsel said she did not "think it's necessary to indicate that this document represents a version of the earlier one by noting that things have been omitted; that simply invites the committee to ask further questions about what was omitted" from the affidavit.
Katz wanted Mosholder to delete from the affidavit his account of when he and several other FDA employees, including Anne Trontell, deputy director of the agency's office of drug safety, were contacted by a Chronicle reporter in January.
After seeking the advice of his personal attorney, Mosholder informed Katz that he was uncomfortable concealing from the Finance Committee that he would be providing essentially a new document.
"Had Dr. Mosholder not acted to thwart the submission of an altered document to a bona fide congressional investigation, a criminal act of obstruction of justice would have occurred," Deutsch charged. "As it was, the FDA and its lawyers are only guilty of attempting to obstruct justice."
The Florida congressman accused senior FDA officials of a "witch-hunt" that was "not about information but rather intimidation."
"It was a warning to Dr. Mosholder and other dedicated epidemiologists in the office of drug safety," he said.
Grassley scolded Department of Health and Human Services Secretary Tommy G. Thompson and FDA Acting Commissioner Lester Crawford in a June 3 letter for "chilling the free exchange of information by and between congressional staff members and FDA employees" after the Iowa senator discovered that 40 agency personnel had been warned in an e-mail not to speak directly to Finance Committee staff members.
"It is apparent, based on our interviews to date, that this e-mail effectively frightened and intimidated many FDA staff members," Grassley admonished.
FDA employees, he reminded Thompson and Crawford, have the right to speak directly to Congress or to a congressional committee "without interference."
Crawford defended the agency's actions in a September 30 letter to the Washington Post, stating that it is FDA's "long-standing government policy" that it does not confirm or deny the existence of an internal investigation until it is completed.
Crawford contended that Katz had "followed all relevant procedures" and that the agency did not censor Mosholder but rather "fully supported him in his efforts to comply with congressional investigators."
Energy and Commerce Committee Chairman Joe Barton (R-Texas) reminded senior agency officials at the hearing that the "mission of the FDA is not to protect the FDA but to promote and protect the public health by helping safe and effective products reach the market by monitoring for safety and by disclosing accurate, science-based information."
Drug regulators, he said, are "entrusted with being guardians of our safety."
"The FDA serves the American people. We are the client," he proclaimed.
Gone missing. Legislators pursued questions about why regulators waited for at least six years to investigate antidepressant safety in pediatric patients after an FDA drug reviewer, James F. Knudsen, in 1996 noted reports of suicidal ideation and behavior in children and adolescents exposed to sertraline.
Thomas P. Laughren, team leader of psychiatric drug products for FDA's division of neuropharmacological drug products, disputed Knudsen's 1996 findings about sertraline and told the subcommittee that when he reviewed the same data months later, he did not find a signal of risk for suicidality for either adults or children.
But lawmakers continued to focus questions on why a 1996 letter to Pfizer, sertraline's maker, from Knudsen, which discussed the reports of suicidality, mysteriously went missing from the agency's files.
The subcommittee obtained a copy of Knudsen's letter from a "third party," a congressional lawyer said in an interview, and, after requesting a copy from Pfizer, lawmakers were given two different versions of the letter—one, apparently a draft that was filled with spelling errors, that was faxed to Pfizer at 10:18 a.m. on March 19, 1996, and a second "cleaned-up" version faxed to the company two hours later.
Knudsen testified that he could not remember writing the letter, which bore his signature, but added that it "does not mean that I did not; I simply do not recall."
Temple acknowledged to lawmakers that there is no law or regulation requiring the agency to keep records associated with new drug applications.
He said the agency has "policies" about keeping records, but he could not be specific about the language in those policies.
Two weeks earlier, during a September 9 hearing, Barton had questioned whether FDA's lack of providing requested documents "in a timely fashion on a matter that involves the safety of our children" was an attempt by the agency to stonewall or just "plain incompetency."
He acknowledged at the September 23 hearing that there had been "some improvement" in FDA's cooperation with the subcommittee.
But Democratic Floor Whip Diana DeGette (Colorado) noted that her office and other legislators were still having trouble obtaining documents and answers from the agency and had not received copies of Mosholder's and Temple's written opening statements from FDA officials until after 7 p.m. the night before the hearing, which, she said, made it difficult for her to prepare her questions.
Clinical trial results kept secret. At the September 9 hearing, legislators sought answers from pharmaceutical companies and FDA officials about why clinical trial results that showed antidepressants to be ineffective in children and adolescents had been withheld from the public.
Barton noted that 12 of 15 antidepressant clinical trials showed no efficacy in pediatric patients and that only the 3 studies with the positive results had been published in peer-reviewed journals.
"Many people want to know what was in the other 12 studies," he said. "What do these studies show? Why haven't these 12 studies been published in peer-reviewed journals? Was there sufficient information available to the public about these unpublished studies to make informed decisions?"
Legislators called for the government to develop a database that provides information and results about all clinical drug trials.
The Food and Drug Administration Modernization Act of 1997 requires pharmaceutical makers to submit information to a government-run database about clinical trials conducted under an investigational new drug application for drugs to treat a serious or life-threatening disease or condition.
But drug companies are not required to submit the studies' results to the database.
The pharmaceutical industry on October 1 launched an online database, www.clinicalstudyresults.org, that contains results from controlled clinical trials.
However, noted Caroline Loew, vice president of scientific and regulatory affairs for the Pharmaceutical Research and Manufacturers of America, during her September 9 testimony before Congress, the program is voluntary for drug companies.
Labeling changes. Lawmakers demanded to know why FDA asked some drug companies to drop language from antidepressant drug labeling that warned of suicidal thoughts or behavior.
Joseph Camardo, senior vice president of medical affairs for Wyeth Pharmaceuticals, testified that his company in August 2003 amended its label for the company's antidepressant drug venlafaxine to "notify health professionals about the reports of suicidal ideation, hostility, and self-harm."
The company, he added, sent a letter that month to 450,000 physicians and other health care professionals that disclosed information about the reports of suicidal ideation and hostility and reminded practitioners that the medication was not approved for pediatric patients or demonstrated to be effective in that group.
But on March 22, when FDA asked the makers of 10 antidepressants—fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram, bupropion, venlafaxine, nefazodone, and mirtazapine—to voluntarily add a warning in product labeling about the need to closely observe patients for "clinical worsening and suicidality," the agency asked Wyeth to drop its language about the known reports of suicidal ideation, Camardo testified.
FDA recommended instead for the labeling for venlafaxine and other antidepressants to include a statement that says "Although there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients, a causal role for antidepressants in inducing such behaviors has not been established."
But Mosholder's and Hammad's findings conflict with that statement.
Families appeal. Families of patients who committed suicide after taking antidepressants testified at the September advisory committee meeting that it was "the drugs and not the disease" of depression that killed their loved ones.
Several parents said that pediatricians and other physicians had prescribed antidepressants to their children for conditions other than depression or obsessive compulsive disorder.
"Why is it easier to have antidepressants prescribed to our children than antibiotics?" one mother asked.
She told the panel that her 9-year-old daughter had been prescribed sertraline after a physician had diagnosed her as having an eating disorder because the child had no appetite.
Marion Goth said that after her daughter's condition worsened, the physician changed the child's medication to a combination of paroxetine and olanzapine.
"These drugs did not help her," Goth said. "They made her suicidal and abusive to herself and to our family. We almost lost our child twice."
A blood test eventually revealed that Goth's daughter did not have an eating disorder but instead had Lyme disease, for which the child is now being treated with i.v. antibiotics, she said.
"Why are we turning to drugs before we truly understand the problem," she said, questioning why physicians do not rule out other conditions before prescribing antidepressants.
Other parents testified that antidepressants have saved their children's lives and urged FDA not to restrict use of the drugs.
Will a black-box warning limit access? Barbara G. Wells, professor and dean of the University of Mississippi's School of Pharmacy and one of only two pharmacists on the joint panel, voted against the black-box warning on antidepressant labeling, stating that she was concerned that the strong warning would "decrease access to too many patients who need to have the medications."
The other pharmacist on the panel, Steven Ebert, a pharmacist at Meriter Hospital in Madison, Wisconsin, agreed with Wells and also voted no.
But Wayne K. Goodman, chair of the Department of Psychiatry at the University of Florida's College of Medicine in Gainesville, argued that the black-box warning would not impede antidepressant prescribing or access.
"I anticipate there will be alarm from parents and the child, and I think that's worth that complication because it will raise the threshold to prescribing and force an engagement of the discussion not only about the risks but the potential benefits and alternatives," said Goodman, who chairs the psychopharmacologic drugs advisory committee.
Temple acknowledged in a September 14 press conference that studies have shown that black-box warnings do not affect prescribing.
He said that "hundreds" of medications carry black-box warnings in their labeling.
Patient education programs. Many on the panel expressed concern that black-box warnings are only seen by physicians and not by patients and families.
Some on the panel called for FDA to initiate a risk management program that requires patients or their guardians to sign informed-consent forms acknowledging that they have discussed the risks and benefits of antidepressants with their physician.
But FDA officials at the meeting warned advisory panel members that such programs restrict access for medications.
However, only thalidomide's risk management program was put forth by agency officials as an example for the advisory committee to consider during the two-day meeting in September. Other drug products with risk management programs, such as isotretinoin, which may have been more familiar to the pediatricians on the panel, were not discussed.
Kweder argued at the October 15 press conference that the conditions that antidepressants treat are very different than the acne for which isotretinoin is prescribed.
"We do not feel that a controlled-distribution system or that kind of rigid risk-management system would necessarily facilitate safer use of these products," she said.
More trials and results. Advisory panel members also called for more clinical trials of antidepressants and the release of results to the public.
"We need more efficacy data," said Goodman. "We need safety data in which one of the intended endpoints is assessing suicidality."
He also called for more long-term studies of antidepressants, including comparison trials.
Laurel K. Leslie, a pediatrician and research scientist at the Child and Adolescent Services Research Center at Children's Hospital in San Diego, California, also called for "unbiased" continuing medical education.
"It really bothers me that the majority of [continuing medical] education" about antidepressants is provided and funded by "pharmaceutical companies," she said. "I don't always feel that it is a fair perspective."