Regulatory Decision Summary for Micro+ TE Pediatric

This New Drug Submission (NDS) was filed on December 04, 2020 to seek market authorization for Micro+ TE Pediatric for use as a pediatric supplement to intravenous solutions given for Total Parenteral Nutrition (TPN) to help maintain plasma zinc, copper, manganese, selenium, and iodide levels, and to prevent depletion of endogenous stores of these elements and development of subsequent deficiency symptoms.

A Notice of Deficiency (NOD) was issued on December 20, 2021. The Response to NOD was filed on April 05, 2022 by the Sponsor and reviewed as part of this submission.

Health Canada considers that the benefit-harm-uncertainty profile of Micro+ TE Pediatric (5 trace elements) is favourable for use as a pediatric supplement to intravenous solutions given for Total Parenteral Nutrition (TPN) for patients requiring supplementation with all five trace elements, to help maintain plasma zinc, copper, manganese, selenium and iodide levels in these patients when oral or enteral nutrition is not possible, and to help prevent depletion of endogenous stores of these 5 trace elements and the development of subsequent deficiency symptoms. The submission used the Submissions Relying on Third-Party Data (SRTD) pathway.

This pediatric formulation was developed in response to the American Society for Parenteral and Enteral Nutrition (ASPEN; 2012) recommendations for changes to currently marketed multi-trace element products. Specifically for pediatric formulations, ASPEN recommended that the currently marketed multiple trace element products be modified to remove chromium, decrease manganese content administered to neonates to 1 mcg/kg/d, and to add 2 mcg/kg/d selenium in all pediatric/neonatal preparations. Thus, the Sponsor modified the currently marketed Micro+ 6 Pediatric Injection (DIN 02091100) as a formulation without chromium, with dosing recommendations in keeping with the ASPEN recommendations.

The submission complied with Health Canada’s guidance for an SRTD submission. The Sponsor’s systematic review of the literature yielded 16 unique studies for inclusion in the review that met the selection criteria outlined in the literature search protocol. No meta-analysis was conducted because of the wide range of study designs and doses administered.

The safety profile in the presented studies was limited; however, the trace elements in Micro+ TE Pediatric have been authorized for use as individual elements or in combination with no reported major safety risks in post-market safety reports. Further, as the trace elements in the proposed product are naturally present in the human body, they are not expected to cause significant safety risks at physiological levels. Levels above physiological levels are associated with a range of adverse health effects, including neurological and gastrointestinal effects.

Efficacy was measured as the ability of the proposed doses of the trace elements to bring the blood trace element concentrations to physiological levels and prevent or correct deficiency symptoms. The proposed recommended doses for the trace elements were based on the recommendations of ASPEN, whose recommendations drive the development and revisions to parenteral nutrition products. These recommendations were made based on an expert panel who reviewed parenteral requirements using literature and ASPEN research, as well as extensive clinical consultation. The available evidence from the Sponsor’s systematic review supports supplementation with zinc and copper at the recommended dose in maintaining normal physiological levels of these trace elements and preventing deficiencies. The recommended dose of zinc was also effective in increasing the plasma concentration of zinc and the ability to correct zinc deficiency and its symptoms. The available evidence was inconclusive for the ability of iodide at the recommended dose to maintain or increase normal physiological levels; however, the proposed dose is currently authorized for the proposed indicated population in Micro+ 6 Pediatric Injection. The available evidence was additionally inconclusive for the ability of selenium or manganese at the proposed doses to maintain or increase physiological levels of these trace elements; however, these doses are based on the recommendations of ASPEN. Taken as a whole, although the publicly available studies curated by the Sponsor as part of the systematic review do not demonstrate efficacy for iodide, selenium, and manganese, the availability of recommendations from ASPEN can be considered to outweigh the evidence from the submitted literature studies.

Overall, the anticipated benefits of Micro+ TE Pediatric are expected to outweigh the risks under the conditions of use recommended in the Product Monograph at this time. Therefore, a Notice of Compliance (NOC) is recommended.

For further details about Micro+ TE Pediatric, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.