The New York Times
June 11, 2007
By GARDINER HARRIS
Safety and speed are the yin and yang of drug regulation. Patients want immediate access to breakthrough medicines but also want to believe the drugs are safe.
These goals can be incompatible. Race a drug to market and much is likely to remain unknown when patients take it. Test a drug thoroughly to assess all possible risks and its release may be delayed by years.
A series of drug-safety scandals has led many on Capitol Hill to question whether the Food and Drug Administration has failed to strike the right balance between speed and safety. A clear sign of this imbalance, these critics say, is the increasing number of F.D.A. drug-safety officers who say they have been punished or ignored after uncovering dangers of popular medicines.
The latest to suffer this fate is Dr. Rosemary Johann-Liang, 42, who recommended more than a year ago that the diabetes drug Avandia carry the agency’s strongest possible safety warning for its effects on the heart.
Dr. Johann-Liang spent Friday sadly winding down her nearly seven-year career at the F.D.A. She turned in her BlackBerry, laptop and office key, and she went to the agency library to make sure she had no overdue books. She wished her colleagues well.
A pediatrician and expert in infectious diseases, Dr. Johann-Liang joined the agency in December 2000 and rose through the ranks. For four years, she reviewed drug applications as a medical officer and then team leader.
Two years ago she became a deputy division director in the agency’s office of surveillance and epidemiology, the group that examines the safety of already-marketed drugs.
In February 2006, one of her safety reviewers, Lanh Green, went to her with a problem. The agency’s Office of New Drugs had asked Ms. Green to determine whether eye problems that sometimes resulted from taking Avandia and a similar drug, Actos, were a serious issue. But Ms. Green noted that visual deficits were just one part of a drug-induced swelling problem that could lead to weight gain, ankle swelling and, if left untreated, heart failure.
Alerts about some of these problems were scattered throughout the two drugs’ labels. Ms. Green suggested consolidating them and highlighting the heart risks with a boxed warning, the agency’s most severe. After a weeklong review, Dr. Johann-Liang agreed.
“There’s no doubt these problems are caused by these drugs, and there’s no doubt that patients are continuing to suffer bad outcomes,” Dr. Johann-Liang said.
A week later, top officials from the new drug office walked by Dr. Johann-Liang’s office and into the office of her boss, Dr. Mark Avigan, she said. Nearly an hour later, she said, the door opened, the officials left and Dr. Avigan called her in.
“Mark told me that they were upset with our recommendation,” Dr. Johann-Liang recalled. “They decided to act like the review never happened.”
Dr. Avigan took over the supervision of the safety review of Avandia and Actos and told Dr. Johann-Liang that she could no longer approve strong safety recommendations without his say-so, she said. Over the next year, she was increasingly excluded from crucial safety reviews and meetings, which contributed to her decision to leave the agency on Friday, she said.
In an interview, Dr. Avigan said that he did not intend to punish Dr. Johann-Liang.
“My view was simply that when there were conversations going on about important safety issues that were likely to garner a lot of attention, that I needed to be in the loop,” he said.
On Wednesday, the F.D.A. commissioner, Andrew C. von Eschenbach, announced that the agency had asked for boxed warnings on Avandia and Actos, more than a year after Dr. Johann-Liang’s recommendation.
At least four other F.D.A. safety reviewers in recent years have been punished or discouraged after uncovering similar drug dangers, according to Congressional investigations. Among them:
¶In 2003, Dr. Andrew Mosholder discovered that antidepressants led some children to become suicidal. When his findings were leaked to a reporter, the agency began a criminal investigation. Dr. Mosholder was prevented from speaking to an advisory committee about his analysis, and the agency hired Columbia University researchers to reanalyze the data; they concluded a year later that Dr. Mosholder had been right.
¶In 2006, Dr. David Ross became increasingly concerned about reports of serious illness and death from patients taking the antibiotic Ketek. Dr. Ross met with top agency officials and pleaded with them to take action. Nothing happened, he said. A month later, Dr. Ross complained privately to Congressional investigators. After articles about Ketek’s safety problems appeared in The Wall Street Journal and The New York Times, the agency and Ketek’s maker, Sanofi-Aventis, agreed to take actions.
After the articles were published, Dr. von Eschenbach held a meeting with Dr. Ross, Dr. Johann-Liang and other safety officials in which he urged them to keep their disagreements “inside the locker room,” Drs. Ross and Johann-Liang said. Those who discussed issues with outsiders would be “traded from the team,” Dr. Eschenbach said, according to Drs. Ross and Johann-Liang.
Dr. Ross left the agency in November for the Department of Veterans Affairs. Dr. von Eschenbach later told a Congressional panel that he had intended his remarks to Dr. Ross and others to encourage scientific debate.
Senator Charles E. Grassley, Republican of Iowa, said Drs. Johann-Liang, Mosholder and Ross were part of a pattern demonstrating the need for reforms at the F.D.A.
Heidi Rebello, an F.D.A. spokeswoman, said that the “F.D.A. is not aware of any kind of retaliation,” and that staff members “are committed to respecting all legal rights and protections of our employees.”
In interviews, safety reviewers said problems at the agency could be traced back to a deal struck in 1992.
In the 1980s, the F.D.A. took nearly three years to approve most drugs. The AIDS crisis demonstrated that such long delays could condemn to death patients who might have been helped by recent scientific breakthroughs. F.D.A. managers said they did not have enough people to assess reviews more quickly.
So in 1992, Congress helped the F.D.A. and the drug industry reach a deal. Companies agreed to pay millions of dollars in fees, and the F.D.A. guaranteed that drug reviews would be completed within a year or as little as six months for a life-saving medicine.
At the time, it seemed a good solution. But the deal’s fine print soon came to haunt the agency. Drug makers refused to let their money pay for the routine monitoring of drugs’ safety once they were on the market. As the agency began to depend more and more on industry fees, those parts of the agency slowly withered.
Perhaps even more important, the culture at the F.D.A. shifted toward valuing speed over safety. The 1992 deal required annual reports to Congress listing review times, but no such reports were demanded of the agency’s assessments of the safety of drugs already on the market.
Managers are now largely judged on how quickly their employees make a decision on new drug applications, safety officials say. Questions about the safety of already-marketed drugs are increasingly seen as sand in the gears, they say.
Drs. Johann-Liang, Ross and two other safety officials said Congress should require the F.D.A. to make regular public assessments of the safety of approved medicines, act on reports of drug problems within a month or two, and require regular reports on the agency’s adherence to these goals. Such requirements would lead to the promotion of safety-conscious managers, not just speed-conscious ones, they said.
The Senate last month passed a bill to overhaul the F.D.A. that includes more money for drug-safety assessments and requires an advisory committee to meet twice yearly to consider safety issues. The House will hold hearings on the legislation this week.
The safety officials say the bill does not go far enough, because it does not require clear timelines for a response to safety issues. It also does not require regular public disclosure of F.D.A. safety reviews.
“If managers were held accountable on safety issues, they’d pay more attention to them,” said Dr. Victoria Hampshire, who was disciplined and investigated criminally in part because of her work to uncover the dangers of a heartworm medicine that killed at least 500 dogs.
Dr. Hampshire, who still works at the F.D.A., said employees in Dr. Johann-Liang’s former office were “very demoralized.”
“There’s a feeling of fear,” she said.