The role of systematic reviews in pharmacovigilance planning and Clinical Trials Authorisation application: example from the SLEEPS trial.

Carrol Gamble,Catherine Spowart,Andrew Wolf,Paula Williamson,Ian Sinha,German Malaga

doi:10.1371/journal.pone.0051787

Abstract

BackgroundAdequate sedation is crucial to the management of children requiring assisted ventilation on Paediatric Intensive Care Units (PICU). The evidence-base of randomised controlled trials (RCTs) in this area is small and a trial was planned to compare midazolam and clonidine, two sedatives widely used within PICUs neither of which being licensed for that use. The application to obtain a Clinical Trials Authorisation from the Medicines and Healthcare products Regulatory Agency (MHRA) required a dossier summarising the safety profiles of each drug and the pharmacovigilance plan for the trial needed to be determined by this information. A systematic review was undertaken to identify reports relating to the safety of each drug.Methodology/Principal FindingsThe Summary of Product Characteristics (SmPC) were obtained for each sedative. The MHRA were requested to provide reports relating to the use of each drug as a sedative in children under the age of 16. Medline was searched to identify RCTs, controlled clinical trials, observational studies, case reports and series. 288 abstracts were identified for midazolam and 16 for clonidine with full texts obtained for 80 and 6 articles respectively. Thirty-three studies provided data for midazolam and two for clonidine. The majority of data has come from observational studies and case reports. The MHRA provided details of 10 and 3 reports of suspected adverse drug reactions.Conclusions/SignificanceNo adverse reactions were identified in addition to those specified within the SmPC for the licensed use of the drugs. Based on this information and the wide spread use of both sedatives in routine practice the pharmacovigilance plan was restricted to adverse reactions. The Clinical Trials Authorisation was granted based on the data presented in the SmPC and the pharmacovigilance plan within the clinical trial protocol restricting collection and reporting to adverse reactions.

Highlights

Adequate sedation is crucial to the management of children requiring assisted ventilation on the Paediatric Intensive Care Unit (PICU)
The aim of this paper is to describe the systematic review of safety data included within the Clinical Trials Authorisation application associated with the continuous infusion of midazolam or clonidine as sedation for neonates, infants and older children requiring mechanical ventilation and to illustrate how this informed the pharmacovigilance plan for the SLEEPS trial
The adverse effects were subsequently categorised into those relating to cardiovascular effects, withdrawal effects, and any other effects; Assessment of methodological quality For each randomised controlled trials (RCTs) and observational study we evaluated how rigorously the adverse event data were ascertained by assessing whether adverse effects were actively or passively monitored

Summary

Introduction

Adequate sedation is crucial to the management of children requiring assisted ventilation on the Paediatric Intensive Care Unit (PICU). Most critically ill children will require potent analgesic and sedative drugs to facilitate artificial ventilation, alleviate pain, prevent discomfort from procedures, and to prevent distress from the presence of unfamiliar personnel and from the high level of background noise, which can disturb natural sleeping patterns [4]. The SLEEPS trial (www.controlled-trials.com/ ISRCTN02639863), a prospective multi-centre randomised, double-blind, equivalence study was designed to compare clonidine and midazolam as intravenous sedative agents in critically ill children requiring mechanical ventilation. For sedation of the critically ill child it is usually given in combination with an opioid by intravenous infusion at doses between 50–300 micrograms/kg/hr [7]. The evidence-base of randomised controlled trials (RCTs) in this area is small and a trial was planned to compare midazolam and clonidine, two sedatives widely used within PICUs neither of which being licensed for that use. A systematic review was undertaken to identify reports relating to the safety of each drug

Objectives

Methods

Results

Conclusion