This review concluded that there was a large body of evidence on use of proton pump inhibitors in children with gastro-oesophageal disease and these data could be used to avoid unnecessary trials. Limitations in the conduct of the review and the size and nature of included studies mean that the authors’ conclusions need to be treated with some caution.

To review the evidence for use of proton pump inhibitors (PPIs) in gastro-oesophageal reflux disease (GORD) in children to ascertain if further indications might be licensed.

A preliminary search was made to determine the regulatory status of approved PPIs. This was followed by a search of the MEDLINE and EMBASE databases (January 1990 to June 2008).

All clinical trials on off-label use of PPIs for treatment of GORD in children 0 to 17 years were eligible for inclusion in the review. Analysis was restricted to patients’ age ranges not already included in approved European Union indications.

The authors stated neither how studies were selected for the review nor how many reviewers performed the selection.

Across the studies five PPIs were investigated (omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole). Trials were conducted in infants and children up to 17 years of age. Study duration varied from five days to 12 weeks.

The authors did not state that they assessed validity.

A data extraction form was defined a priori. The safety profile of each drug was evaluated through a comparison of adverse events for adults listed in summaries of product characteristics documents versus adverse events reported in paediatric trials.

The authors stated neither how data were extracted nor how many reviewers were involved in data extraction.

On the basis of retrieved evidence, a classification of the appropriateness of off-label use of PPIs in children with GORD was carried out. Each drug was rated as having high, moderate or scarce appropriateness according to three predefined criteria (not stated) when administered in children. A narrative synthesis was carried out, grouped by drug.

Nineteen clinical trials were included in the review (n=782). There were six trials of omeprazole (n=151), six of lansoprazole (n=282), four of esomeprazole (n=257), two of pantoprazole (n=68) and one of rabeprazole (n=24).

Off-label use of omeprazole, lansoprazole and esomeprazole in children was found to be highly appropriate given the consistency between pharmacokinetics, efficacy and safety. Moderate appropriateness was attributed to pantoprazole due to a lack of pharmacokinetic data and insufficient efficacy trials. No adequate evidence was found for rabeprazole and so its off-label use was not considered to be appropriate in children. All compounds gave rise to a safety profile in children that was comparable to adults. However, in omeprazole adverse events of the respiratory system were reported more frequently in children aged up to two years of age.

There was a large body of evidence on use of proton pump inhibitors in children that could be used to avoid unnecessary trials for the purposes of regulation.

Inclusion criteria for the review were broadly defined for participants and intervention and less well-defined for study design and outcomes. A search for efficacy was based on two databases. It was unclear whether foreign language or unpublished material was eligible for inclusion, thus opening up a possibility of language and publication biases. Study validity was not assessed, which made evaluation of the appropriateness of evidence less reliable. It was unclear whether more than one reviewer was involved in the selection of studies and data extraction, so these processes may be open to bias and error. A narrative synthesis was appropriate given the heterogeneity of the studies. The reliability of the adverse event data was difficult to ascertain due to a lack of detail on its provenance. Given these problems and limitations of the small included studies, the authors’ conclusions need to be treated with some caution.

Practice: The authors stated that different regulatory authorities should share more information on the regulatory decision-making process for paediatric drugs. They stated that omeprazole, esomeprazole and lansaprazole showed a satisfying level of clinical evidence for paediatric use in the age ranges not covered by a formal indication. The drugs fulfilled all the criteria for a high appropriateness for administration in children.

Research: The authors stated that analysing available clinical data before conducting trials could help overcome practical and ethical considerations of drug trials in children. Even when data were insufficiently robust, further testing could be limited only to missing information. Due to the amount of information on omeprazole, further drug trials in this class were deemed useless and unethical unless within comparative trials. Regulatory bodies should promote and support the conduct of large well-designed trials rather than smaller and weaker designs.

No funding.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.