The US Food and Drug Administration (FDA) on Thursday issued draft guidance detailing clinical considerations for drugmakers looking to develop products to treat pediatric gastroesophageal reflux disease (GERD).
FDA says the draft is meant to be a starting point for discussions between the agency, drugmakers, academia and the public and sets out the agency's current thinking on potential study populations, endpoints and clinical pharmacology issues related to dosing.
Sponsors should discuss the details of their pediatric study plans with the agency "as early as feasible," FDA says, as sponsors are required to submit those plans within 60 days of the end-of-Phase II meeting.
According to FDA, clinicians should distinguish gastroesophageal reflux (GER) from GERD, which is described as "the presence of troublesome symptoms caused by the reflux of gastric contents and by the absence of mucosal breaks observed during endoscopy." GERD can be caused by a number of factors including transient lower esophageal sphincter relaxation, impaired esophageal clearance and delayed gastric emptying. In some patients, the condition can progress to erosive GERD (eGERD) or erosive esophagitis.
In the guidance, FDA lays out specific considerations for four pediatric age groups (neonates, infants, children and adolescents) and makes recommendations for stratifying patients into age cohorts and the appropriateness of pediatric extrapolation for each of those cohorts.
The agency details three potential approaches to dose finding, pharmacokinetic (PK) and efficacy; PK and pharmacodynamic (PD); or PK-only, describing when each approach is applicable and providing recommendations for carrying out the studies required under each approach.
For clinical trial designs, FDA provides specific recommendations for products intended to treat erosive GERD and symptomatic GERD.
For erosive GERD, FDA emphasizes that all patients participating in the trial should be confirmed to have esophageal erosions as a result of GERD and notes that infants should generally be excluded from clinical trials for eGERD as the condition is difficult to accurately diagnose in neonates and is often related to viral or bacterial infections.
FDA says that the primary endpoint in clinical trials for eGERD should be the healing of erosions assessed at 8 to 12 weeks after starting treatment and notes that a "primary endpoint of symptom improvement alone is not acceptable."
For symptomatic GERD, FDA says that "obtaining an indication for GERD in children is potentially problematic because of the variety of working definitions" for the disease.
As such, FDA recommends that sponsors select a definition that includes "signs and symptoms [of GERD] without erosions seen on endoscopy … because this allows the potential extrapolation from adult data unless the sponsor can adequately justify not using it."
FDA also recommends that sponsors use patient reported outcome (PRO) measures and observer-reported outcome (ObsRO) measures as a primary endpoint for studies of symptomatic GERD.
"Given the central role of symptoms in GERD, the ability of a drug to improve symptoms is critical to its approval. Consequently, the primary endpoint should include a PRO measure that measures signs and symptoms for older children and an ObsRO measure in infants and younger children," FDA writes, adding that if an alternative is selected for the primary endpoint, a PRO/ObsRO should be included as a secondary endpoint.