FDA issues draft guidances targeting GERD-related conditions

The US Food and Drug Administration (FDA) on Tuesday issued two draft guidances for the development of treatments for adults with symptomatic nonerosive gastroesophageal reflux disease (sGERD) and erosive esophagitis (EE), both of which are types of GERD.

GERD is caused by the reflux of acidic stomach contents into the esophagus and is part of a group of acid-related disorders known as gastroesophageal reflux disease (GERD). Patients with this condition often experience symptoms such as heartburn and regurgitation, with females being affected more frequently than males. If left untreated, complications can include tooth decay and the progression to erosive esophagitis.

sGERD

The draft guidance on sGERD outlines general considerations for studies involving these medications. It includes criteria for patient eligibility, details on trial design, evaluations of effectiveness, and assessments of safety. FDA notes that the draft does not address the treatment of erosive esophagitis, Barrett’s esophagus, pathological hypersecretory conditions (such as Zollinger-Ellison syndrome), peptic ulcer disease, or GERD in pediatric patients.

The guidance recommends that trials evaluating these drugs should enroll subjects who experience heartburn as their primary symptom and have a history of heartburn episodes for six months or longer. Subjects who test positive for Helicobacter pylori should be excluded from the trial, and FDA states that aside from protocol-specified rescue medications, the use of acid-reducing drugs, such as proton pump inhibitors, should be allowed.

The guidelines recommend a randomized, double-blind, placebo-controlled trial design for these trials. To demonstrate superiority to an approved therapy, it recommends a randomized, double-blind, active comparator trial design.

The treatment period should be at least 8 to 12 weeks to assess the drug’s benefit. The guidance notes, however, that “the trial duration and timing of efficacy assessments should be guided by the mechanism of action of the drug, its expected onset of action, and the time frame in which a clinical benefit is expected to be observed in the intended population. Additionally, sponsors should consider the duration of exposure necessary to inform the safety profile of the drug for its intended use and durability of treatment effect.”

The primary efficacy endpoints should be the proportion of heartburn-free days during the assessment period.

Sponsors should consider the multiple potential risks identified with long-term acid suppression. These risks include Clostridioides difficile infections, osteoporosis-related bone fractures, and vitamin deficiencies, to evaluate the extent and duration of treatment.

The deadline for submitting comments is 17 November. Submit comments to docket number FDA-2025-D-0331.

Erosive esophagitis

The agency also released a draft guideline for developing drugs to treat EE. The guidance addresses eligibility criteria for clinical trials, trial design features, efficacy evaluations, and safety assessments.

Out of scope are drugs for treating symptomatic nonerosive gastroesophageal reflux disease, Barrett’s esophagus, pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome), peptic ulcer disease, or drugs for healing EE in pediatric patients.

EE is caused by reflux of acidic stomach contents into the esophagus and is included in the spectrum of acid-related disorders known as gastroesophageal reflux disease (GERD). EE is defined as the presence of superficial esophageal erosions in patients with or without the typical symptoms of GERD. Complications of untreated EE include the development of esophageal strictures, perforation, and progression to Barrett’s esophagus.

The goals of therapy are to heal erosions and maintain healed erosions. Pharmacologic therapy for EE consists of two phases: an initial treatment period to heal existing erosions, followed by ongoing treatment to ensure that healing is maintained.

Clinical trials evaluating drugs should enroll participants diagnosed with EE, as defined by the Los Angeles classification system during the initial endoscopy. Subjects who test positive for Helicobacter pylori during screening should be excluded.

As with the sGERD guidance, the EE guidance states that subjects who test positive for Helicobacter pylori should be excluded from trials, and that the use of acid-reducing drugs, such as proton pump inhibitors, should not be allowed outside of protocol-specified rescue medications.

Sponsors should conduct a randomized, double-blind, active comparator trial design to demonstrate noninferiority or superiority compared to an approved therapy.

A primary efficacy endpoint should be the complete healing of the EE or the absence of erosions observed during endoscopic evaluation.

The trial duration and timing of efficacy assessments for healing of EE should be determined by the drug's mechanism of action and anticipated onset.

Sponsors developing these drugs should consider the various potential risks associated with long-term acid suppression. These include Clostridioides difficile enteric infections, osteoporosis-related bone fractures, and vitamin deficiencies. It is important for sponsors to consider these risks when determining the overall extent and duration of treatment in the program’s safety database.

The deadline for submitting comments is 17 November. Submit comments to docket number
FDA-2025-D-0346

Guidance on sGERD; Guidance on erosive esophagitis

FDA issues draft guidances targeting GERD-related conditions

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