Infant GERD Studies For PPIs Need Narrower Populations, Advisory Committee Says

FDA's Gastrointestinal Drugs Advisory Committee reaches broad agreement that the pathophysiology of GERD is not the same in infants as it is in adults, although a few are vocal that it is in fact the same.

Future clinical trials of proton pump inhibitors or other drugs to treat infant gastroesophageal reflux disease in patients aged 1 to 12 months should focus on narrower populations of infants instead of the broader populations that were enrolled in previous studies which showed no benefit, an FDA advisory panel agreed.

The Gastrointestinal Drugs Advisory Committee gathered Nov. 5 to discuss why studies of AstraZeneca's Prilosec (omeprazole) and Nexium (esomeprazole), Pfizer's Protonix (pantoprazole) and Takeda's Prevacid (lansoprazole) had failed to show efficacy in infants suffering from GERD, whether further studies are necessary, and if so, how they should be done.

In background materials prepared before the meeting, FDA suggested that there may be inherent reasons for these failures, such as the fact that stomach acid seems to play a smaller role in infant GERD than lower esophageal sphincter function, while the sponsors suggested that narrower populations and different trial designs might be the answer (Also see "PPIs For Infants: FDA Summons Advisory Panel, But Industry Unenthusiastic" - Pink Sheet, 3 Nov, 2010.).

There was broad agreement on the committee that the pathophysiology of GERD is not the same in patients ages one month to less than one year as it is in adults, although a minority was very vocal in its insistence that it is in fact the same. Committee chair Jean-Pierre Raufman, University of Maryland School of Medicine, counted four such dissenters, along with three abstainers.

PK/PD Studies Hold Promise

There was more complete agreement on another question from FDA: Whether studies in pediatric patients ages one month to less than one year should be required when acid suppressing agents are approved for symptomatic GERD in adults. Raufman counted 19 members who supported this position, one who disagreed and one abstention, although he noted that the agency had not asked for a formal vote on any of the questions it posed.

However, there is no need and arguably no ethical justification for repeating the failed broad-spectrum trials of recent years, most on the committee agreed.

"Based upon knowledge of the pathophysiology, available studies and clinical experience, it seems reasonable to treat infants with endoscopically diagnosed erosive esophagitis without another etiology with PPIs," panel member Colin Rudolph, Children's Hospital of Wisconsin, said in a presentation he made to the committee before the discussion started.

Additional placebo-controlled trials to formally settle this point "are difficult to justify," he added. "The remaining questions for new PPIs or formulations and treatment strategies in infants are pharmacokinetics and pharmacodynamics, acceptability and stability, comparable side effects with other PPIs, length of therapy in otherwise normal infants and high-risk groups, and optimal dosing to limit risks while promoting healing."

Expanding on the point during the discussion period, Rudolph said that further trials are necessary, "but not efficacy studies in those populations - PK/PD and safety studies."

Jill Sklar, Beaumont Hospitals, the committee's consumer representative, said that due to the many unknowns about PPIs in infants and the potential for side effects, "I would hesitate to have these studies done on all children."

However, Raufman said, "if there's going to be an indication in this age group, [a drug] should be studied in this age group."

Committee Identifies Some Sub-populations

The question then became what subgroups of infants with GERD would be most likely to benefit from participating in new clinical trials. Raufman wondered "whether it would be practical to limit a study to infants with erosive esophagitis."

Patients with trachoesophageal fistulae who have yet to undergo surgery would be one population worth studying, especially because they are likely to be treatment-naive, Jenifer Lightdale, Children's Hospital Boston, said. Infants with cystic fibrosis, who suffer from a variety of gastrointestinal elements, could also benefit, she said.

"I would broaden the scope to consider adding children with airway-related issues," Richard Martin, Rainbow Babies & Children's Hospital, Cleveland, said. Other members suggested infants in intensive care with microaspiration, patients with neurological problems or those with erosive esophagitis.

"An effectively designed bridging study can help you," Gregory Kearns, Children's Mercy Hospitals and Clinics, Kansas City, Mo., said. "You know a lot about the [PPI] molecule in adults and how it works; it's perfectly fine to demonstrate in a target population that it works for a given amount of time. You don't need to expose lots of kids."

The answers the advisory panel came up with did not seem definitive, which may have been inevitable given FDA's unwillingness to hold formal votes, but matters definitely seemed to have advanced since the last time an advisory committee addressed this issue, back in June 2002.

At that time, the Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee said that PPI efficacy could not be extrapolated from adults or older children to infants, that two age subgroups should be studied separately - one to six months and six to 12 months - and that efficacy should be evident after four to eight weeks (Also see "PPI Efficacy Studies In Certain Infants May Be Needed, Cmte. Says" - Pink Sheet, 17 Jun, 2002.). The Nexium, Protonix and Prevacid infant studies all were conducted since then.

-Martin Berman-Gorvine ([email protected])