The (cisa) pride before the fall

The forgotten horror story of how Pharma's pursuit of profits led to deaths of children and jeopardized countless while FDA hand-wrung and played the blame game. Have things changed much since then?

Prologue

Scott Stevens and Gretchen Stewart of Munhall, Pennsylvania, took their 3-month-old son, Gage, to Pittsburgh Children’s Hospital specialist because he didn’t respond to their family pediatrician’s treatment. Gage suffered from heartburn and diarrhea, and frequently cried and vomited. The specialist said the problem was acid reflux, and enrolled Gage in a study she was conducting on the heartburn drug Cisapride (Trade name: Propulsid). Six months later Gage died in his sleep on thanksgiving morning of 1999.

His parents were told it was Sudden Infant Death Syndrome (SIDS). They weren’t told that cisapride had been linked to dozens of deaths including that of at least one other baby—from cardiac arrhythmia—a side effect of the drug known to its manufacturer, Johnson & Johnson before Gage even got his first dose. Shortly after Gage died, cisapride was pulled from the market. By then the drug had been linked to more than 300 deaths.

The drug Cisapride (Trade name: Propulsid) was approved by the FDA for the treatment of nocturnal heartburn on July 29, 1993 and its approval hailed as a revolutionary treatment for gastrointestinal motility disorders,

In the seven year span from approval till it was taken off the market on July 14, 2000, a whopping 30 million prescriptions had been written for it. That’s a mind-boggling 4285715 prescriptions a year, or 11741 prescriptions a day. In 1999 sales of Propulsid had reached approximately $950 million. At peak, it was a blockbuster drug, generating approximately $1 billion in revenue. By the time the drug was taken off the market, it had caused over 300 deaths and over 200 cases of irregular heart beat and other assorted disturbances of heart rhythm.

This is the stomach churning story of how Big Pharma ignored warning signals in pursuit of massive profits, how the medical establishment and regulatory agencies turned a blind eye to catastrophic injury and death leading to a scandal erased from public memory.

Birth: Danger signals present at the very start

Cisapride worked by stimulating the release of acetylcholine in the gastrointestinal tract. Based on data from clinical trials, cisapride was approved by the Food and Drug Administration (FDA) only for the treatment of nocturnal heartburn caused by gastroesophageal reflux disease (GERD). However, even prior to approval in mid-1993 the FDA was aware of its potential to cause disturbances of cardiac rhythm.

According to journalist David Willman, FDA medical officer Andre Dubois noted that 48 of 1,993, or 2.4%, of the patients who took Propulsid in U.S. studies experienced “heart rate and rhythm disorders.” And while I wasn’t able to personally verify the numbers cited in his LA times expose, the cardiovascular safety signal showing increased cardiac rhythm abnormalities from cisapride in the screenshot below is from the FDA’s own cisapride (propulsid) safety review document.

Dubois found that the drug’s chemical makeup could disturb cardiac function. But he agreed with drug maker Janssen/Johnson & Johnson that the deaths in the studies could be attributable to other causes. He recommended approval along with disclosure in the label of potential cardiac effects. “The risk seems very low,” he wrote.

Dubois, however, worked in a division that focuses on drugs for the gastrointestinal tract.

According to David Willman, no one at the FDA consulted with the agency’s division of cardiac specialists before approving Cisapride (Propulsid) on July 29, 1993. Therefore, FDA officials failed to notice what should have been another warning flag: Electrocardiograms showed that cisapride prolonged patients’ “QT interval,” the time during which the heart’s main pumping chambers contract and then relax. By early 1990, QT prolongation was already known to be a risk factor for cardiovascular arrhythmia and death. In fact, 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 the end, the FDA approved cisapride with a label that advised doctors of “rare cases” of increased heartbeats. The labeling said Propulsid’s role in the events “was not clear.”

Rise to fame, unheeded warnings and the fall

Shortly following approval, cisapride’s off-label use exploded to include the treatment of a wide range of motility disorders ranging from gastroparesis and pseudo-obstruction to colonic inertia. Despite clinical trials in gastroparesis not showing a consistent relationship between symptom improvement and an enhanced gastric emptying rate, cisapride came to be regarded as the drug of choice for the treatment of this problem among both diabetics and non-diabetics.

Based on initial safety data the drug was marketed to medical professionals as “remarkably safe” with diarrhea, abdominal pain, nausea or vomiting, headache and constipation being the most frequently reported side effects. (Of course with the perfunctory “rare cases of increased heart beats” on the prescribing label that no one ever reads)

Unsurprisingly, the first signs of trouble emerged soon after cisapride was approved. By January 1995, the FDA had received reports of 18 patients with serious heart arrhythmias; one patient, an infant, had died. According to a New York Times expose, FDA officials held a private meeting with Johnson & Johnson executives shortly after these reports began surfacing and told them the drug was causing life-threatening arrhythmias.

As evidence of cisapride’s dangerous side-effects continued to mount, the FDA added its first "black-box" warning on the cisapride label in 1995 contraindicating its use in patients taking drugs that affected cisapride metabolism and the manufacturer sent a "Dear Health Care Professional" letter. By then, the Food and Drug Administration (FDA) had received 34 cases of torsade de pointes and 23 of prolonged QT interval in cisapride users, including 4 deaths. However, the black box warning did absolutely nothing to dampen the drug’s soaring popularity and prescriptions continued to skyrocket.

By March 1998, less than five years after approval, dozens had died and more than 100 patients had suffered serious heart problems after taking cisapride. Infants, given the drug to treat acid reflux, seemed particularly at risk. Federal officials told Propulsid's manufacturer, Johnson & Johnson that the drug might have to be banned for children, or even withdrawn altogether. Instead, the government and the company negotiated new warnings for the drug's label - though not nearly as tough as regulators had wanted.

In June 1998, the FDA issued another black-box warning contraindicating cisapride for patients taking medications that could prolong the QT interval or in patients with heart disease or cardiac arrhythmias. The FDA circulated a press release and the manufacturer of cisapride distributed a Dear Health Care Professional letter informing practitioners of the revised label. But the drug continued to stay on the market.

Cisapride had little to no substantial pediatric data prior to approval. Its safety and efficacy in children younger than 16 years of age was not established for any indication. Despite this startling lack of data, cisapride was widely prescribed off-label to children, with over 36 million children receiving it worldwide. However, so heinously tone-deaf was the medical community to the accumulating evidence of the drug’s harm that, in 1999, just one year before it was taken off the market, a consensus statement by the European Society of Pediatric Gastroenterology, Hepatology and Nutrition recommended cisapride as the drug of first choice, claiming "the potential benefits far outweigh the potential risks and provide strong justification for its continued use."

Despite the rising crescendo of the drug’s undeniable and egregious harms, cisapride (Propulsid) continued to smash all records and surpassed $1 billion in sales. Johnson & Johnson continued to promote its use in children. A survey that year found that about 20 percent of babies in neonatal intensive care units were being given the drug.

As reports of heart injuries and deaths mounted, Johnson & Johnson continued defending the safety of cisapride, but then abruptly pulled it from the market on July 14, 2000, prior to meeting with FDA and a panel of outside experts. This meeting, unlike the others at which cisapride’s safety record was to be discussed, was going to be open to the public.

The Post Mortem

In 2005, The New York Times published a stunning expose documenting cisapride manufacturer Johnson & Johnson’s half-decade long malfeasant cover-up of warning signs, lack of efficacy data in children, their systematic stonewalling of regulator concerns and the FDA’s utter ineffectuality at protecting citizens that bordered on complicity.

NYT journalists Gardiner Harris and Eric Koli reviewed records from corporate and government sources and discovered documents from lawsuits against Johnson & Johnson showing the company did not conduct safety studies urged by federal regulators and their own consultants that could have revealed cisapride's danger early on. The F.D.A., moreover, did not disclose company research that cast doubt on Propulsid's effectiveness against digestive disorders it was being used to treat, since the studies are considered trade secrets.

Despite supposedly warning the public and prescribers about the dangers of cisapride through so-called “black box warnings” (that went largely unheeded), the conversation between the company and regulators was kept private allowing the drug to thrive. With evidence mounting that cisapride could interfere with the heart's electrical system, government regulators became increasingly confrontational with Johnson & Johnson executives.

But physicians were never made aware of the full depth of the agency's concerns. And even though cisapride was never proved effective in children, the company helped finance programs that encouraged the drug's pediatric use, according to internal company documents.

You see, Johnson & Johnson had previously conducted pediatric studies of cisapride that failed to demonstrate the drug was effective. In January 1995, the F.D.A. warned the company that without studies showing that the drug worked in children it would not be approved for pediatric use. In order to circumvent the lack of FDA approval, Johnson and Johnson began promoting the drug’s off-label use under the guise of educational programs for doctors. Johnson & Johnson financed pediatric gastroenterologist Dr. Paul Hyman and put him on its Propulsid advisory board. When he edited a textbook on pediatric digestive diseases that recommended Propulsid, the company paid for the press run of 10,000 copies and distributed them to doctors. In December 1997, he also made a 15-minute presentation at a Johnson & Johnson seminar where 240 doctors were trained to speak to health care professionals about the drug.

While Dr. Hyman begrudgingly acknowledged that Propulsid had some potentially dangerous side effects, he said they were rare. Such a cisapride evangelist he was and claimed the drug so safe that he said it could be used to treat "happy spitters" - infants who frequently spit up but are not ill. "I was fairly vocal about how silly the whole death thing was, and how it was one in a million," he said.

Dr. Stephen B. Fredd, who oversaw Propulsid for the F.D.A., pleaded ignorance of Johnson & Johnson’s workaround financing the drug's off-label use in infants.

"I had no idea they were doing anything in any way to support off-label use in pediatrics," said Dr. Fredd, former director of the F.D.A.'s gastrointestinal and coagulation drugs unit. Instead, he said, "I wanted them to warn doctors that there were dangers in using the drug."

“A three-month-old female died while on Propulsid therapy," reads a July 3, 1998, report on F.D.A. MedWatch, the agency's Web site for posting potential safety problems and analogous to VAERS for vaccine side effects. Her parents reported that the child, who had undergone cardiac surgery, was sitting in her swing chair and was "fussy" at 7:50 a.m., the F.D.A. form says. "When the parents rechecked her at 8 a.m., the infant was unresponsive," it reads. "Attempts to revitalize her were futile." Three weeks later, the mother of an 11-week-old premature boy who had had stomach surgery and was taking Propulsid "noticed her son not breathing," another report said. Attempts were made to revive him. He was declared dead at the hospital.

Johnson & Johnson’s response to these alarming deaths was the callous conclusion that these cases "strongly suggested" other factors may have contributed to the infants' deaths. Of course they wouldn’t tell us what those other factors could have been.

As injuries mounted, concern inside Johnson & Johnson about side effects among the youngest patients was growing. Johnson & Johnson researchers and executives made plans to ban sales for premature infants in the United States, an action it had taken in some European countries, according to documents obtained by NYT.

But there was internal debate. On March 16, 1998, a Johnson & Johnson regulatory affairs director, Gaetan Rouleau, sent an e-mail message to other executives saying that Propulsid could be used for premature babies and that further discussion of its use in them be delayed until after an F.D.A. meeting that month on the drug's safety.

Dirk Reyn, a Johnson & Johnson executive, wrote back to support the decision to ban Propulsid for premature babies, saying, "We do have cases and there is a scientific rationale for this."

Mr. Rouleau, however, responded that if the company agreed to ban Propulsid in premature children, it might be forced to stop selling its cherry-flavored liquid form of the drug. Unless Johnson & Johnson could justify the use of Propulsid in premature babies, he wrote, "We have very little to support the use of the suspension in children at this time."

Ultimately, the drug was not banned for premature babies. In the March 1998 meeting between the F.D.A. and company representatives, regulators expressed increasing concern about Cisapride’s risks.

During a presentation, an FDA. official projected a slide that asked, "Is it acceptable for your nighttime heartburn medicine (i.e., something for which you could take Tums) to have the potential to kill you?"

Johnson & Johnson's minutes of the meeting stated: "In FDA's opinion, cisapride is only minimally efficacious therefore no safety risk is acceptable."

In May 1998, the F.D.A. proposed major changes to the label, including adding a paragraph stating, "Despite more than 20 clinical trials in pediatric patients, safety and effectiveness of cisapride (Propulsid) have not been demonstrated in pediatric patients for any indication."

An internal company memo examined 15 of the proposed label changes and estimated that they would cost over $250 million a year in lost sales.

Throughout these negotiations and label changes, the company kept up its aggressive financing of doctors and patient groups promoting the drug as safe for use in children.

During the late 1980's and the 1990's, Johnson & Johnson gave $1 million to the American Pseudo-Obstruction and Hirschsprung's Disease Society. The society began as a support group for parents of children with rare digestive diseases for which cisapride or propulsid was a treatment.

By 1996, with financing from Johnson & Johnson, the group's focus had shifted to common childhood acid reflux. Dr. Hyman was the chief medical adviser to the group, which helped to train speakers who, over three years, made presentations to 6,000 to 8,000 pediatric doctors and nurses about the treatment of reflux, recommending Propulsid, said the group's founder, Andrea Anastas, who later claimed the company had no influence over the group's activities.

After the June 1998 label changes, the North American Society for Pediatric Gastroenterology Hepatology and Nutrition, a medical group for pediatric gastroenterologists, announced that it was going to study whether pediatricians should continue using Propulsid.

Johnson & Johnson sent the group a confidential report conceding that placebo-controlled studies, many of them never published by the company, failed to show it was effective in treating children for reflux disease. The company, which had begun financing the group before the study was announced, eventually donated $450,000 to the society. The group report, released in May 1999, concluded that Propulsid "has a place in pediatric therapeutics."

Dr. Robert Shulman, a professor at the Baylor College of Medicine and the lead author of the report, said Johnson & Johnson's money had no influence on the group's conclusions, although he said that he regretted that its financial support was not disclosed in the paper.

Asked how his group's recommendation squared with the company's admission that the drug had not been proved effective in infants and children, Dr. Shulman said his group understood acid reflux in children better. "We treat these kids every day," he said.

By January 2000, the number of deaths and serious heart problems in patients taking cisapride prompted the FDA to schedule a meeting with Johnson & Johnson to discuss its concerns with a panel of outside experts. This meeting, unlike the others at which Propulsid's safety record was discussed, was going to be public.

Preparing for the hearing, Janice Bush, a Johnson & Johnson executive, wrote a note during what a company spokesman said was a "brainstorming" session: "Do we want to stand in front of world and admit that we were never able to prove efficacy!" The words "never able" were underlined.

Three weeks before the scheduled hearing, Johnson & Johnson announced it would stop selling Propulsid in the United States. The hearing was canceled.

Johnson & Johnson eventually agreed to pay up to $90 million to settle lawsuits that involved claims that 300 people died and as many as 16,000 were injured from taking Propulsid. But many of the documents relating to cisapride obtained by The New York Times were filed under seal in the lawsuits. The company declined repeated requests to make executives available to be interviewed by the New York Times. In written responses, Johnson & Johnson said that the marketing of the pill was appropriate and instead blamed the drugs withdrawal on physicians citing physicians prescribing it inappropriately despite repeated attempts by the company to warn them against it.

Have things really changed much since then?

First, lets examine how regulators responded in the aftermath of the cisapride tragedy. The greatest prognosticator of future outcomes is a system or individual’s ability to demonstrate earnest introspection and assume responsibility for their failures. And judging by their actions, they learned nothing.

Jason Brodsky, an FDA spokesman during the cisapride saga said the case was unique because doctors insisted on having access to the drug, despite its side effects, and because its label was unusually confusing. The FDA, which is in the business of deciding which drugs get approved and stay on the market blamed doctors for prescribing the drugs they approved to be on the market. Make it make sense.

Dr. Janet Woodcock, director of the FDA’s drug review center during cisapride said the danger associated with non-cardiac drugs that prolonged the QT interval “was not well appreciated” at the time cisapride was approved. Consequently, she said, this “was not identified as a concern” by the gastrointestinal division. This is absoultely not true. Two allergy drugs, Seldane, and later Hismanal, both prolonged the QT interval and therefore posed a significant risk for cardiac arrhythmia, were withdrawn by the FDA in 1990 and 1999. In fact, Dr. Raymond J. Lipicky, director of FDA’s cardiology division wrote in the August 1993 issue of the American Journal of Cardiology that if a drug that prolonged the QT interval had a benefit that was “less than lifesaving . . . any risk of death would likely be considered unacceptable.”

“We simply tried a variety of measures,” Woodcock said in an interview. “We have to sort of walk that line: Where do we inform and where do we intervene by removing a drug from the market? That is a very draconian step. . . . And so, we do try to avoid that.” She said the FDA did not formally weigh the off-label use while deciding to keep the drug on the market. She acknowledged that it was prescribed widely for children but said she relied on pediatricians to make prudent decisions. Asked why the FDA did not immediately inform doctors and patients of the deaths of children, Woodcock told The Times: "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."

“They’re aware of the QT-prolongation issue,” Woodcock said. “This isn’t as if it’s some mystery. . . . They evaluated this and came to their own conclusions about the risks.”

Which is hilarious considering the FDA had no problems telling us that Ivermectin—an FDA approved drug for use in humans—was a horse pill that shouldn’t be used to treat COVID.

Dr. Woodcock is the currently the FDA’s Principal Deputy Commissioner. On January 27, 2021 a coalition of 28 public health groups and opioid crisis organizations sent a letter to the Biden Administration regarding Woodcock's position as Acting Commissioner of the FDA. The letter said in part that "as the Director of the FDA’s Center for Drug Evaluation and Research (CDER) for more than 25 years, Dr. Woodcock presided over one of the worst regulatory agency failures in U.S. history."

FDA's Dr. Florence Houn was one of the few voices of refreshing candor "We've had a seven-year history with this drug where it's a very rich opportunity for us to learn. One of the things we have learned is the approved indication for a drug really needs to [justify] the serious and life-threatening" side effects. In comments to an FDA advisory committee, Houn added, "The labeling probably was not effective.”

Since the cisapride tragedy culminating in its withdrawal in 2000, there have been at least 19 FDA approved drugs that have been pulled from the US market. The most famous ones are:

• Troglitazone (2000) withdrawn for liver damage

• Sparfloxacin (2001) withdrawn in 2001 for QT prolongation (like cisapride)

• Rofecoxib or Vioxx (2004) and Valdecoxib or Bextra (2004) both with stories remarkably similar to cisapride. During early development of rofecoxib, scientists at Merck were concerned the drug might cause cardiac toxicity. Merck covered up the safety signal, conducted inadequate follow-up studies, stonewalled regulators and obscured the risk through cherry-picked data. Just as with cisapride, Merck strongly promoted its drug by purchasing nearly 1 million reprints of biased publications to circulate to doctors and other health professionals, and academic journals charged with peer review turned a blind eye in exchange for revenue. In the end more than 30,000 patients suffered cardiovascular side-effects as a result of taking Vioxx. If you’d like to understand how academic journals are complicit in pharmaceutical fraud, consider reading my essay “Bad Medicine: How hidden incentives and opaque conflicts dictate what you read in medical journals”

• Gatifloxacin (2006) an antibiotic closely related to ciprofloxacin that caused horrendous side-effects leading to its eventual withdrawal from the market. I’ve written a very long and detailed piece on ciprofloxacin’s toxicity and the utter tone-deafness or part of of drug regulators. It took over 20 years from ciprofloxacin’s approval in 1987 to the appearance of the first fluoroquinolone black box warning in 2008. Two decades. Five fluoroquinolones, including gatifloxacin, were pulled off the US market for safety concerns before ciprofloxacin’s 2008 first black box warning. In total, the FDA issued 5 black box warnings. I highly encourage you to read my essay “The rise and fall of Ciprofloxacin (and other fluoroquinolones)” to understand how repeated appeals by public health advocacy groups went unheeded before the FDA took notice.

As long as we have a system designed to be opaque, accountable to no one, more obsessed with their own survival than that of the people they serve, and key players guaranteed to fail upward, I regret to inform you that there will be more Cisaprides and Vioxxes.

The Pharmaceutical company at the heart of the Cisapride tragedy, Johnson and Johnson, has a checkered past overflowing at the brim with controversy and corruption that includes prescription opiates, talcum powder, COVID vaccines and so much more. If you’d like to learn more, read this fantastic twitter thread by Josh Walkos:

https://x.com/JoshWalkos/status/1626334423896522752

If past is prologue, the single most important question, one that must be conclusively and unequivocally answered is “Does the FDA have the ability to monitor and regulate pharmaceuticals effectively once they are on the market?”

And a question of tremendous urgency it is. Because the mass deployment of diagnostics, vaccines and therapeutics during the COVID-19 pandemic was predicated on using Emergency use authorizations, which, by default, favor speed over scrutiny and a lowered bar of regulatory diligence. Historically the FDA takes upwards of five to ten years to acknowledge the presence of a safety signal after a drug is approved. To suppose they will act expediently the one time the process was politically charged, tainted with perverse incentives and they continue to turn a blind eye to the exploding number of reports in the VAERS database or traces of DNA contamination, is naivete bordering on moribund stupidity. You can read Maryanne Demasi’s reporting on the DNA contamination issue here.

To better understand how EUA was explicitly engineered to incentivize big pharma profits at the expense of the safety of citizens, I urge to read my most recent installment in the “anatomy of the pandemic state” series. You won’t be disappointed. Disgusted, maybe. But not disappointed.

Anatomy of the Pandemic state

It would come as no surprise if a few years from now a public catastrophe of unimaginable magnitude arising from regulatory lack of due diligence during COVID were to become unearthed. In fact, it would be more shocking if this eventuality didn’t come to fruition.

Thank you for reading. The best compliment a writer can get is to have more people read his work. If you enjoyed this, your help in increasing my viewership would be greatly appreciated.