Infant's Death Raises Alarms On Who's Used In Drug Trials

"Little did we know that Gage was basically a guinea pig." 

A second look at the death of a 9-month-old Munhall boy has put the spotlight on a federally-approved practice of using children in clinical drug trials. Gage E. Stevens, a participant in a Children's Hospital study on the use of the drug Propulsid for gastroesophageal reflux, died asleep in his crib on Nov. 24. 

Finding no indications of drug overdoses or foul play, Dr. Cyril Wecht, Allegheny County coroner, initially determined that the infant had died of Sudden Infant Death Syndrome, or SIDS. Gage had been part of the Propulsid trial conducted by Children's gastroenterologist Dr. Susan Orenstein. While Propulsid, which also is known as cisapride, had not been approved by the Food and Drug Administration for use in treating infants and young children, it had been approved for adults. 

Orenstein had run the clinical trial with 100 children since 1994. Wecht said that toxicology reports initially sent up no red flags, but after a review of the case, he ruled yesterday that the cause of death was cardiac arrhythmia, a noted Propulsid side effect. 

A month ago, Janssen Pharmaceutica, the Titusville, N.J.-based manufacturer, announced it would pull the drug from the market this summer, and that use of it as of May 1 would be limited to those who met strict clinical guidelines. Gage is the only child in the clinical trial from this area to have died. 

The study at Children's is one of several around the country; the FDA reported that 19 children under the age of 19 who were treated with Propulsid have died. "This drug has been widely prescribed by pediatricians and pediatric specialists for the treatment of gastroesophageal reflux in children and infants due to its efficacy and presumed safety based on the adult data," Children's Hospital said in the statement. 

Maybe so, said the baby's mother, Gretchen Stewart, 27, "but little did we know that Gage was basically a guinea pig, and they never told us that [Propulsid] causes dangerous side effects, or there had been deaths." Stewart, a cardiac nurse at Mercy Hospital, said she was never comfortable with the SIDS ruling. She and her husband, Scott Stevens, accepted it, however, until two months ago when she read an Associated Press story in the Pittsburgh Post-Gazette that described the frightening health issues raised by parents whose children were prescribed Propulsid for reflux. 

Stewart called the FDA. She called the coroner's office. She kept asking questions. In the meantime, the FDA sent out an advisory acknowledging the "known risk of rare -- but serious --cardiac events associated with the drug." The FDA said it would hold a public advisory committee meeting this month to discuss the drug's safety.

The meeting was never held because Janssen said it would voluntarily pull Propulsid from the market. Gage, who weighed 5 pounds, 7 ounces at birth, had shown signs of reflux within a month of his birth. A symptom of reflux, which occurs when stomach acid backs up into the esophagus, is excessive throwing up. While not a life-threatening condition in and of itself, reflux can lead to malnourishment or cause permanent damage to the esophagus. Doctors say that most babies outgrow the problem by their first birthday. But Stewart said that Orenstein was adamant that Propulsid was the best treatment for their child. 

The drug acts as a peristalsis, helping propel food through the system. "They told us they were doing a study to see how effective the drug was," she said. The FDA-approved double-blind study, which ultimately included 100 children, meant that some children received a placebo; others, Propulsid only; a third group, Tagamet, or cimetidine, which inhibits the production of stomach acids; and a fourth group, Propulsid and Tagamet. Gage was a part of the fourth group. 

Canada recently warned on its drug labels that there is a contraindication in the use of Tagamet and Propulsid together. Stewart and Stevens, 31, a computer programmer, said they were unaware of any major problems and signed the consent form for their son's participation. 

The consent form said that Propulsid was FDA-approved for use in infants. That was wrong. "The language was added because, at the time, it was widely believed by pediatric gastroenterologists around the country that cisapride approval was imminent because of the manufacturer's sponsorship of pediatric studies and the apparent efficacy and safety," Children's Hospital said in a statement. "The consent form did, however, set forth the potential side effects and risks associated with cisapride, including death." 

Stewart said that if they had known of the previous deaths, they never would have consented. "Dredging this up is so hard," she said, "but we want to see that there is legislation so children can't be in studies. We want to make sure that parents are aware to research thoroughly the medications their children are put on." 

Two weeks before Gage's death, his parents took him to the pediatrician three times. "He was lethargic, wouldn't eat right and wouldn't sleep right," Stewart said. "He had diarrhea. They said it was the flu and it would go away. I thought that at the time. It made sense at the time." 

The day before Gage died, Stewart had a foot operation, so her mother-in-law, Bonnie Stevens, took care of her grandchild in her West Homestead home. Bonnie Stevens put him down for a nap. When she checked on him, sometime between 6 and 6:30 p.m., he was dead. 

Children's Disputes Conclusion on Death

 Hospital Says Infant in Propulsid Study Did Not Show the Irregular Heartbeat Found by Coroner

The Children's Hospital medical director and Allegheny County coroner agree on one thing: It is impossible to prove that the drug Propulsid caused the death in November of a Munhall baby enrolled in a federally-approved drug study. But that didn't keep them from coming to diametrically opposed conclusions on the cause of death of 9-month-old Gage E. Stevens, who had been a participant in a Children's study on using Propulsid to counter stomach acid reflux. 

The coroner, Dr. Cyril Wecht, determined initially that the infant had died of Sudden Infant Death Syndrome, or SIDS, but on Tuesday, he changed the death certificate to say that the cause of death was cardiac arrhythmia, an irregular heartbeat, which is a known Propulsid side effect. "Can we scientifically say that [the child] died of arrhythmia? No we can't," Wecht said at a news conference yesterday afternoon. Still, he said, "we're satisfied that this case fits this criteria." 

Later in the afternoon, however, Dr. Donald R. Fischer, Children's medical director and a pediatric cardiologist, countered Wecht's conclusion, saying that hospital officials never had any indication that the boy had an irregular heartbeat, and that an autopsy could not establish that he did. "I don't know whether we'll ever know what led to his death," Fischer said. Wecht said he did not consider changing the cause of death until he heard recently from the baby's parents, Gretchen Stewart, 27, and Scott Stevens, 31, who had been contacted by CBS News for a story on the boy's death, which aired Wednesday. 

Gage, who died in his crib at his grandmother's house the day before Thanksgiving, is one of 19 children nationwide reported by the Food and Drug Administration to have died while being treated with Propulsid, known generically as cisapride. He is believed to be the only child enrolled in an FDA-approved clinical trial who has died. The others were being treated separately by doctors. While Propulsid had been approved only for adult use, doctors prescribed the drug for children on a case-by-case basis.

Wecht said that immediately after Gage died, he did not know that the baby had been taking Propulsid, and that it was only "mentioned" that the baby also had been given Tagamet, or cimetidine, which inhibits the production of stomach acids. Gage had been prescribed both Propulsid and Tagamet in the FDA study, which was conducted by Children's gastroenterologist Susan Orenstein and had enrolled 100 children since 1994. Researchers were experimenting with using both drugs for reflux because Tagamet relieves stomach acid while Propulsid helps push food through the digestive system.

Since 1995, however, there have been reports that the drugs compete for the same enzymes as they are metabolized in the body, which can result in higher amounts of Propulsid being left in the bloodstream than if it were just used alone. "There is not an absolute contraindication" for using both drugs, Wecht said, but "it could not have helped" for the baby to have been taking both. 

Doctors and pharmacists at Children's pointed out that the medical literature shows no deaths associated with the use of Tagamet and Propulsid. Children's discontinued the Propulsid study a month ago when Janssen Pharmaceutica, the drug's Titusville, N.J.-based manufacturer, announced it would pull the drug from the market this summer. 

Wecht, who did not personally perform the autopsy on Gage Stevens, said that he received no notification of the boy's involvement in a clinical trial until a week after the death, when Janssen asked that a blood sample be sent to a laboratory for further examination. But Children's officials released a document dated Nov. 24, the day of Gage's death, in which the coroner's office asked Orenstein for all of Gage's hospital records. Fischer said Orenstein provided the information promptly, and that the hospital also notified the FDA and Janssen right away. 

Full Disclosure 

Patients (or their parents) need to know a drug's risks

No one will ever know with absolute certainty what killed 9-month-old Gage E. Stevens. But the fact that this baby was one of at least 80 people who died while taking the anti-heartburn drug Propulsid makes it reasonable to assume that the drug could have played a role. Coroner Cyril Wecht's decision to change the child's death certificate to indicate heart arrhythmia, a known side effect of the drug, rather than SIDS, seems equally reasonable. 

Children's Hospital, where the child had been enrolled in a clinical trial of Propulsid before his death last November, argues that there had been no evidence of arrhythmia. But as both Dr. Wecht and Children's Medical Director Donald R. Fischer agree, there is no way to prove what caused Gage
Stevens' death. 

What is most disturbing about the case is that the consent form that the parents signed allowing Gage to be part of the trial said, incorrectly, that the drug had been approved for infants. The hospital said that the claim was made because it believed the approval was imminent, but that is hardly an acceptable explanation. 

It's impossible to know whether Gage's parents, Scott Stevens and Gretchen Stewart of Munhall, would have agreed to Gage's participation had they known. But that shouldn't be a matter of conjecture. It is crucial that medical consent forms be clear, straightforward and honest. The risks must be precisely spelled out so that participants understand exactly what the possible cost is for what possible benefit. 

The problem is, people seeking relief from chronic pain or discomfort are frequently willing to overlook the danger posed to a tiny percentage of the population in the hope that the drug will work the miracles that will restore their quality of life. Doctors no doubt understand the psychological factors at play and must therefore be all the more scrupulous in presenting the facts. That is especially the case when the subject is a child. 

Gage's parents say they didn't realize the serious side effects that were associated with Propulsid when they agreed to allow Gage to be part of the study. The child had suffered from heartburn and chronic diarrhea, and he was taking the drug to see if it was effective and safe in treating acid reflux in children. 

No parent would risk seeing his child die in exchange for possibly alleviating troublesome but not
life-threatening symptoms. Gage's parents never considered the possibility that their son would be among the tiny percentage who would experience heart problems, even though the consent form indicated that heart abnormalities were a side effect. It is up to doctors to make sure that parents understand that even if the side effects are rare, they are still real. 

There is something of a Catch-22 in the whole process, however. If parents fully recognize the risks, they will be less likely to enroll their children, making it more difficult to conduct the trials. But doctors often prescribe drugs for purposes other than those for which they were approved and for populations on whom they weren't tested. 

Doctors sometimes just cut the dosage to accommodate the lower weight of children without fully
comprehending what effect a child's metabolism and body chemistry might have on how the drug works. At least 19 children died while taking Propulsid, for example, but Gage Stevens was the only one of those 19 who was part of a Food and Drug Administration approved drug study. That study was finally stopped in March, four months after Gage's death. 

It is impossible to completely eliminate risks in testing new drugs, and such tests remain essential. But despite the obstacles that full disclosure might present in the advancement of medical science, it is crucial that participants, or in this case their parents, understand exactly what they are getting into.