Drugmaker Rebuffed Call to Monitor Users
By Kevin McCoy
The maker of Accutane, a controversial acne medication, disregarded a company doctor's recommendation that users of the drug be monitored for signs of depression and that a warning to that effect be added to the drug's U.S. label, allegations in a federal court case show.
Picture: Six weeks after Amanda Callais, 21, started taking Accutane, she tried to kill herself.
The Florida lawsuit against the drugmaker, Hoffmann-La Roche, charges that the Swiss drug giant omitted the warning after its marketing officials argued that such an alert could cost the firm sales or prompt lawsuits. The doctor's recommendation and the marketing debate sketched in legal filings have not been previously publicized.
There has been no official finding that links Accutane to depression or other psychiatric illnesses. Roche says the drug is effective when used properly. Nonetheless, a senior Roche official, testifying in a pretrial deposition for the Florida case, said the firm's internal analysis showed Accutane "probably caused" depression and other psychiatric illnesses in some patients, according to a summary of the deposition in a court brief.
The internal debate alleged in the case comes to light after a U.S. Food and Drug Administration researcher last month told a Senate panel Accutane was one of five drugs that should be studied for possible withdrawal from the market. The FDA has since moved to tighten safeguards against the major side effect: birth defects in children whose mothers took Accutane while pregnant.
The alleged internal corporate debate over an Accutane warning, which emerged from a USA TODAY review of Accutane lawsuits, also comes as the recent withdrawal of another drug, Merck's pain reliever Vioxx, has intensified scrutiny of both drug companies and the FDA's oversight of the industry.
Accutane made its U.S. debut in 1982 as a prescription drug that provided relief to many who have a severe form of acne that fails to respond to other treatments. Although still widely used, the drug has been the focus of more than 20 years of medical and regulatory controversy.
Roche is a target of about 70 lawsuits for alleged adverse reactions that include suicides, depression, birth defects and gastrointestinal injuries.
Among those lawsuits is the Florida case filed by relatives of Charles Bishop, a 15-year-old who committed suicide in 2002 by stealing a small plane and crashing it into a Tampa skyscraper. His family alleges that Accutane, which Bishop began taking for acne eight months before he died, was responsible.
Similarly, Debbie Banner, a 33-year-old Virginia mother of two, contends the drug nearly incapacitated her with depression and caused severe birth defects in her first child.
And the family of Amanda Callais, 21, alleges in a New Jersey lawsuit that Accutane triggered the depression that caused the young Louisiana woman to try to commit suicide in 1997.
Higher rates of depression
Court records filed in the Bishop case show that Martin Huber, Roche's global head of drug safety, answered questions about reports of Accutane psychiatric effects as he testified in a pretrial deposition. Huber said the company's internal assessments showed Accutane "probably caused" depression and other psychiatric ailments in some users, according to the court file summary of his deposition.
The FDA and Roche consultants had told company officials the rate of depression among Accutane users was 1.5 times higher than among non-users, the summary shows Huber testified.
Daniel Zabrowski, Roche's global head of drug regulatory affairs, testified separately that Peter Schifferdecker, a company doctor based at the Basel, Switzerland, headquarters, in 1997 studied data on depression and other adverse psychiatric events reported by Accutane patients.
A summary of Zabrowski's deposition testimony filed in a court brief shows that Schifferdecker wrote a report that recommended changes in the drug's U.S. label and core data sheet — the internal company document used by Roche to ensure consistency of the firm's products worldwide.
According to legal summaries of depositions by Zabrowski and other Roche officials, Schifferdecker recommended that Accutane's U.S. label warn that users "should be supervised for signs of depression during therapy and, if necessary, referred for appropriate treatment."
Warning label fears?
The company modified the core data sheet to reflect Schifferdecker's recommendation, records in the Bishop case state. But Zabrowski testified Roche's marketing division feared that placing the monitoring warning on the drug's U.S. label could hurt Accutane sales, the summary of his deposition shows.
Ulf Wiegand and John McLane, medical consultants in the marketing department, revised Schifferdecker's report to remove the reference to monitoring, and the firm sent the edited report to the FDA, Zabrowski testified, according to the summary of his deposition. The FDA declined to comment.
Records in the Bishop case also show that Angela Bylancik, another marketing staffer, wrote an e-mail stating that any decision "to add the proposed label change" should not be finalized "without full consideration of the enhancements to Dr. Schifferdecker's report." "It is important to the International Dermatology Marketing Team that the change not be made to the core data sheet without full consideration of all available data and the potential impact on marketing strategy and product liability," Bylancik also wrote in the e-mail, which was included in the Bishop case court files.
Michael Ryan, a Fort Lauderdale attorney who is co-lead counsel coordinating that lawsuit and other Accutane cases filed against Roche in federal and state courts, said in telephone interviews the Bishop case filings showed that "the company put profits over safety." In 1998, the FDA announced that Accutane packaging would be changed to warn that adverse reactions reported by some users included "depression, psychosis, and, rarely, suicidal ideation, suicide attempts and suicide." Roche sent alert letters to doctors advising of the change and telling them to monitor patients for any unexpected emotional shifts. But the FDA-prompted change, added to Accutane's label in 2000, was unrelated to Schifferdecker's monitoring recommendation.
Ryan argues that the exclusion serves as silent evidence that Roche's marketing division trumped the company's drug safety experts. "There is no good reason why that recommendation wasn't followed, other than profits," the attorney said.
Carolyn Glynn, a senior U.S. spokeswoman for Roche, said she could not comment on the matter because the company does not discuss pending litigation. Glynn, however, said Roche maintains "there is no causal relationship" that links Accutane to depression or other psychiatric illnesses.
In separate comments on Nov. 18, the day that FDA researcher David Graham told the Senate Finance Committee Accutane should be studied for possible withdrawal from the market, other Roche representatives said the drug was beneficial when used appropriately.
Long history of controversy
Despite those assurances, Accutane's record of controversy is even broader than the drug's extended warning label:
• In 1986, four years after Accutane's U.S. debut, Roche changed the drug's package insert for doctors to advise that some patients had reported depression. An FDA memo of a 1994 telephone conference with Roche showed the firm had reviewed reports of suicide and depression related to Accutane and had "concurred that there does appear to be a problem."
• Drug regulators in France required Roche to add suicide as a potential side effect to Accutane labels there in 1997. The FDA, which only learned of the action months later, reached its agreement with Roche on a similar label advisory in February 1998. Days later, the FDA sent Roche a warning letter over what regulators called "false or misleading" promotional material that suggested Accutane treated "psychosocial trauma" and "emotional suffering" associated with acne.
• Janet Woodcock, director of the FDA Center for Drug Evaluation and Research, told a House subcommittee in 2002 that the agency had received reports of 3,104 adverse psychiatric events involving Accutane. She said the FDA at the time knew of 173 suicide reports associated with Accutane.
• In 1988, Godfrey Oakley, director of the Division of Birth Defects and Developmental Disabilities at the Centers for Disease Control, wrote that "40 infants born alive after first trimester exposure to Accutane have died … because of the developmental errors that Accutane caused." Oakley argued that "we simply need to remove the drug from the market."
• In 1990, more than 14 years before his recent Senate testimony, Graham wrote that Accutane "cannot safely be given to women of childbearing age or potential" because the drug causes birth defects and results in abortions among women unwilling to give birth to children with deformities.
Graham, who calculated separately that the risk of severe adverse reactions from Accutane was roughly 3 per 100, "one to two orders of magnitude greater" than other drugs, concluded: "There is no alternative to immediate withdrawal of Accutane from the market. To delay only compounds the body count."
• Michael Hook, a Pensacola, Fla., attorney collaborating with Ryan on multiple Accutane lawsuits filed against Roche, said many of the cases allege the drug caused gastrointestinal illnesses. Accutane's label warns that the drug "has been associated with inflammatory bowel disease … in patients without a prior history of intestinal disorders."
Hook's clients include Adam Mason, a 28-year-old Florida resident unable to return to work as a welder since surgeons removed most of his colon to treat inflammatory bowel disease. In an interview last week, Mason said he's convinced that Accutane caused his illness. "I'm angry about what I have to go through every day of my life because someone didn't do their research properly," he said.
Motivated by concern about birth defects and other medical problems reported with Accutane, Public Citizen, a national consumer advocacy group, petitioned the FDA in 1988 for a ban on the drug. But the agency did not grant the petition or act on the recommendations that Accutane be pulled.
Instead, the FDA over several years considered establishing a mandatory registry for doctors who prescribe Accutane, pharmacists who dispense the drug and patients who take it. The registry proposal was aimed at strengthening efforts to keep pregnant women from taking Accutane. Regulators also considered using the registry for adverse psychiatric problems associated with the drug. The FDA didn't take final action until last month, when it announced formal plans for an Accutane pregnancy registry. Under the move, a negative pregnancy test will be a prerequisite for a woman who's prescribed the drug. Refills will require a new pregnancy test.
Internal Roche documents uncovered by congressional investigators for the 2002 House subcommittee hearing show the company officials listed the absence of immediate FDA action on the proposed Accutane registry on an internal list of corporate "successes." Other records found by the investigators include an October 2001 e-mail written by Cynthia Dinella, a Roche vice president of drug regulatory affairs. The message, addressed to Roche U.S. CEO George Abercrombie and other company officials, said the firm should "CELEBRATE" the FDA's non-action at the time. Noting that a registry might have "alienated" dermatologists who prescribe Accutane, Dinella wrote that "the outcome could have been drastically different" but for Roche's efforts.
Lawsuits claim tragic results
Debbie Banner says her life would have been drastically different if she hadn't taken Accutane. A doctor prescribed it for the Virginia Beach resident in 1995, when Banner was a 24-year-old student at Old Dominion University and worked as a part-time aerobics instructor and coffee shop employee.
"From the beginning, I developed severe headaches and nausea," Banner said in an interview. Within weeks, Banner said, she also found herself "constantly thinking about dying."
"Suicidal thoughts just came out of nowhere. It was very scary," she said.
A friend who noticed the behavior changes took her to a psychiatrist, who Banner said advised her to stop using the drug. Banner said her symptoms cleared up. But not before potential harm of the fetus she learned she was carrying — the result of what Banner described as unprotected sex during Accutane-caused depression.
Banner said she rejected doctors who recommended an abortion. She said her son, now 8, was diagnosed with cerebral palsy and other severe defects at birth. Today, he requires a feeding tube to help with nutrition, suffers continuing seizures and bowel accidents and attends a special education program.
"He has a very difficult time doing anything for himself," Banner said. "He's going to need help all his life."
Banner and her husband sued Roche, but lost in a New Jersey court ruling that said Accutane's label adequately warned of the risks of taking the drug while pregnant. A state appeals court is weighing the case, in part on grounds that some internal Roche documents about Accutane weren't disclosed for the lower court proceeding.
Testifying at an FDA hearing this year, Banner detailed her son's injuries and urged the agency to impose tougher, mandatory safeguards to prevent pregnant women from taking Accutane.
In her words, "To leave this decision to patients who may be in denial and cannot protect themselves is to guarantee more birth defects and abortions."
Key dates in Accutane's history
1971: Roche develops Roaccutane, called Accutane in the USA.
1982: Food and Drug Administration approves Accutane to treat severe acne that is unresponsive to other treatments.
1986: Roche changes Accutane's package insert to say some users had reported symptoms of depression.
1988: Public Citizen petitions the FDA for a ban on Accutane.
1997: French regulators require Roche to list suicide as a potential side effect. A Roche doctor studies data on depression in Accutane patients, leading him to recommend users be supervised for signs of depression, and if necessary referred for treatment.
Feb. 1998: FDA says Accutane packaging will include a warning that some users have reported adverse reactions including depression, psychosis, and "rarely, suicidal ideation, suicide attempts and suicide."
March 1998: Health regulators in Britain and Ireland require warnings of Accutane's risk of psychiatric disorders.
December 1999: Roche prepares a "Psychiatric Disorder Issue Work-Up" for the FDA, concluding that none of the 168 reports of suicidal behavior can be directly linked to Accutane.
May 2000: Roche changes Accutane's package warning label to include possible side effects involving depression, rare suicidal thoughts, suicide attempts and suicide.
September 2000: During an FDA dermatology committee meeting, the agency confirms that Accutane patients were linked to 147 suicides and hospitalizations for depression from 1982 to May 2000 and concludes more research is needed to assess the drug's risks of birth defects.
June 20, 2002: Accutane's label is changed to warn of "depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors."
Nov. 18, 2004: FDA scientist David Graham tells a Senate committee the drug should be studied for possible withdrawal.
Nov. 23: FDA announces registry of prescribers, patients and pharmacies for Accutane, requires women test negative for pregnancy before getting prescription.
Sources: FDA, Roche, USA TODAY research by Kelly Barry