February 11, 2001-FDA, Drug Maker Haggled As Children Died
In mid-1993, officials with the Food and Drug Administration prepared to approve Propulsid, a drug that eased nighttime heartburn. But a sign of danger loomed. FDA medical officer Andre Dubois noted that 48 of 1,993, or 2.4 percent, of the patients who took Propulsid in U.S. studies experienced 'heart rate and rhythm disorders.' In addition, eight children age 6 or younger who were given Propulsid had died.
Dubois found that the drug's chemical makeup could disturb cardiac function. But he agreed with drugmaker Janssen Pharmaceutica, a Johnson & Johnson Co. subsidiary, that the deaths in the studies were attributable to other causes. He recommended approval along with disclosure in the label of potential cardiac effects. 'The risk seems very low,' he said.
Dubois, however, worked in a division that focuses on drugs for the gastrointestinal tract. No one at the FDA consulted with the agency's division of cardiac specialists before approving Propulsid on July 29, 1993, according to physicians familiar with the matter. By not tapping their expertise, FDA officials failed to notice what should have been another warning flag: Electrocardiograms showed that Propulsid prolonged patients' 'QT interval,' the time during which the heart's main pumping chambers contract and then relax. If the QT interval -- typically about four-tenths of a second -- is extended even slightly, it can trigger a disruption or cessation of the heartbeat. Called an arrhythmia, it can result in sudden death. FDA officials outside the gastrointestinal division had already warned publicly on June 11, 1990 that two allergy drugs, Seldane and Hismanal, prolonged the QT interval and therefore posed lethal risk. Both drugs were later withdrawn.
In approving Propulsid, the FDA agreed to labeling that advised doctors of 'rare cases' of increased heartbeats. The labeling said Propulsid's role in the events 'was not clear.' In response to written questions, Janet Woodcock, director of the FDA's drug review center, said the danger associated with noncardiac drugs that prolonged the QT interval 'was not well appreciated' at the time Propulsid was approved. Consequently, she said, this 'was not identified as a concern' by the gastrointestinal division. By early 1995, Propulsid's danger to the heart was certainly identified as a concern within the gastrointestinal division, agency records show.
On Jan. 25, 1995, a senior FDA medical officer, Stephen B. Fredd, told Janssen executives that recent adverse-reaction reports showed their drug was prolonging the QT interval, perhaps resulting in deaths. According to the meeting summary, 'It was the firm's position that the cases cited by Fredd were not 'clean' cases, thus making it difficult to attribute the effect to [Propulsid].' Fredd responded that 'unequivocal evidence' of Propulsid's culpability was unlikely to be captured outside of a controlled study. But within a month, the FDA and the company agreed to the first of five safety-labeling changes that would help keep the drug on the market over the next five years. Meanwhile, a significant market for Propulsid emerged in the treatment of children.
Propulsid was never proved effective or safe for infants, yet it became the drug of choice for pediatricians in treating gastric reflux, a common disorder that is usually outgrown by age 1. Reflux can impede infants' digestion and, due to their crying, disrupt their parents' sleep.
On Aug. 15, 1996, the FDA informed the Johnson & Johnson subsidiary that Propulsid was 'not approvable' for children. The rejection, in keeping with FDA practice, was not made public. In private correspondence a year later, on Aug. 19, 1997, Lilia Talarico, FDA's gastrointestinal drugs division director, cited 'at least' three recently reported deaths among child patients. Asked why the FDA did not immediately inform doctors and patients of the deaths, Woodcock said: 'Labeling changes [advising of infant deaths] were requested by FDA in August of 1997 but were not agreed to by the company until June of 1998.'
That revised label did acknowledge 'several pediatric deaths' but left physicians guessing whether Propulsid was the culprit. Parents of children who died after taking Propulsid said in interviews that they had no inkling of danger. 'If I had known that this drug caused cardiac arrhythmias, I would never have given it to him,' said Tina Englebrick, the mother of 3-month-old Scott, who died in October 1997. The Kansas health department identified Scott's cause of death as sudden infant death syndrome.
Had the parents of Gage Stevens, the deceased 9-month-old, 'been informed of a risk of sudden death, they would not have administered the medication to their son,' according to a lawsuit they filed in a Pennsylvania court on Sept. 10 against the manufacturer and the doctor and hospital who treated him. Gage, who had reflux, was given Propulsid within a pediatric study that was approved by the FDA and performed by researchers at the University of Pittsburgh. On March 23, 2000, the FDA announced that Propulsid would be taken off the market as of July as a normally prescribed drug because of scores of confirmed heart-rhythm deaths. Overall, Propulsid has been cited as a suspect in 302 deaths.
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