title: The role of systematic reviews in pharmacovigilance planning and Clinical Trials Authorisation application: example from the SLEEPS trial.
abstract: BACKGROUND
  Adequate 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.
  
  
  RESULTS
  The 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
  No 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.
authors.affiliation: Clinical Trials Research Centre, University of Liverpool, Liverpool, Merseyside, United Kingdom. c.gamble@liv.ac.uk
authors.forename: Carrol
authors.initials: C
authors.lastname: Gamble
authors.forename: Andrew
authors.initials: A
authors.lastname: Wolf
authors.forename: Ian
authors.initials: I
authors.lastname: Sinha
authors.forename: Catherine
authors.initials: C
authors.lastname: Spowart
authors.forename: Paula
authors.initials: P
authors.lastname: Williamson
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003000:Clonidine / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000009:adverse effects / Q000627:therapeutic use*; D007223:Infant; D008297:Male; D008874:Midazolam / Q000009:adverse effects / Q000627:therapeutic use*; D060735:Pharmacovigilance; D016032:Randomized Controlled Trials as Topic; D013565:Sympatholytics / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D006993:Hypnotics and Sedatives; D013565:Sympatholytics; D003000:Clonidine; D008874:Midazolam
references.citation: J Health Serv Res Policy. 2007 Apr;12(2):101-3
references.pmid: 17407660
references.citation: Crit Care Med. 2008 Aug;36(8):2479-80
references.pmid: 18664814
references.citation: BMJ. 2010 Feb 15;340:c365
references.pmid: 20156912
references.citation: Crit Care Med. 1999 Jan;27(1):196-9
references.pmid: 9934916
references.citation: Crit Care Med. 2008 Aug;36(8):2427-32
references.pmid: 18596622
references.citation: Anesthesiology. 1990 Oct;73(4):661-70
references.pmid: 2221435
references.citation: Crit Care Med. 2000 May;28(5):1569-71
references.pmid: 10834713
references.citation: Pediatrics. 2006 Mar;117(3 Pt 2):S9-S22
references.pmid: 16777824
references.citation: Intensive Crit Care Nurs. 1997 Aug;13(4):181-8
references.pmid: 9355422
references.citation: Paediatr Anaesth. 1997;7(2):143-53
references.pmid: 9188116
references.citation: Artif Organs. 1997 Jan;21(1):21-3
references.pmid: 9012901
references.citation: Anesth Analg. 1993 Dec;77(6):1207-14
references.pmid: 8250314
references.citation: Clin Trials. 2005;2(3):260-4
references.pmid: 16279149
references.citation: Intensive Care Med. 2000 Oct;26(10):1454-61
references.pmid: 11126256
references.citation: J Burn Care Rehabil. 2001 Mar-Apr;22(2):150-3
references.pmid: 11302604
references.citation: J Burn Care Rehabil. 2004 May-Jun;25(3):262-5
references.pmid: 15273467
references.citation: Clin Pharmacol Ther. 1981 Aug;30(2):239-45
references.pmid: 7249508
references.citation: Eur J Pediatr. 1991 Sep;150(11):784-8
references.pmid: 1959542
references.citation: J Clin Epidemiol. 2010 Sep;63(9):983-91
references.pmid: 20573483
references.citation: J Pediatr. 1991 Oct;119(4):644-9
references.pmid: 1919899
references.citation: Intensive Care Med. 1991;17 Suppl 1:S15-9
references.pmid: 1774407
references.citation: Arch Pediatr Adolesc Med. 1999 Apr;153(4):331-8
references.pmid: 10201714
references.citation: J Clin Pharm Ther. 2005 Oct;30(5):479-85
references.pmid: 16164495
references.citation: Br J Anaesth. 2005 Jun;94(6):821-4
references.pmid: 15764627
references.citation: Paediatr Anaesth. 2006 Oct;16(10):1063-7
references.pmid: 16972837
references.citation: Pediatr Crit Care Med. 2005 Sep;6(5):562-7
references.pmid: 16148818
references.citation: J Cardiothorac Vasc Anesth. 1993 Apr;7(2):148-53
references.pmid: 8477017
references.citation: Intensive Care Med. 1988;14(1):55-9
references.pmid: 3125236
references.citation: Paediatr Anaesth. 2007 Jul;17(7):675-83
references.pmid: 17564650
references.citation: Crit Care Med. 1996 Jun;24(6):932-9
references.pmid: 8681594
references.citation: Anaesth Intensive Care. 1987 Nov;15(4):440-4
references.pmid: 3122596
references.citation: Pediatr Emerg Care. 2004 Mar;20(3):162-165
references.pmid: 15094573
references.citation: Plast Reconstr Surg. 2003 Jan;111(1):150-6; discussion 157-8
references.pmid: 12496575
references.citation: Br J Anaesth. 2003 Dec;91(6):850-6
references.pmid: 14633757
references.citation: Dev Pharmacol Ther. 1992;19(4):191-5
references.pmid: 1364197
references.citation: Eur J Emerg Med. 1994 Sep;1(3):111-4
references.pmid: 9422150
references.citation: Anaesthesia. 2007 Jan;62(1):18-22
references.pmid: 17156222
references.citation: BMC Med Res Methodol. 2007 Jul 05;7:32
references.pmid: 17615054
references.citation: Br J Anaesth. 1995 Nov;75(5):593-7
references.pmid: 7577287
references.citation: Pharmacotherapy. 1995 Sep-Oct;15(5):665-8
references.pmid: 8570440
references.citation: Paediatr Anaesth. 2000;10(2):195-9
references.pmid: 10736084
references.citation: J Korean Med Sci. 2007 Aug;22(4):693-7
references.pmid: 17728512
references.citation: Intensive Crit Care Nurs. 2004 Dec;20(6):344-51
references.pmid: 15567675
references.citation: Clin Intensive Care. 1994;5(5 Suppl):17-21
references.pmid: 10150550
references.citation: Crit Care Med. 1999 Feb;27(2):417-21
references.pmid: 10075070
references.citation: Anesth Analg. 1995 Jun;80(6):1076-82
references.pmid: 7762832
references.citation: Clin Toxicol (Phila). 2005;43(3):207-9
references.pmid: 15902797
references.citation: Cochrane Database Syst Rev. 2000;(2):CD002052
references.pmid: 10796280
references.citation: J Burn Care Rehabil. 2003 Nov-Dec;24(6):356-60
references.pmid: 14610418
references.citation: J Burn Care Res. 2006 Mar-Apr;27(2):206-10
references.pmid: 16566567
references.citation: Lancet. 1994 Sep 3;344(8923):628-9
references.pmid: 7915342
references.citation: Intensive Crit Care Nurs. 2005 Jun;21(3):179-86
references.pmid: 15907670
references.citation: Crit Care Med. 1996 Feb;24(2):222-8
references.pmid: 8605792
references.citation: Intensive Care Med. 1994 Aug;20(7):504-7
references.pmid: 7995868
references.citation: Eur J Anaesthesiol. 1991 Jan;8(1):21-7
references.pmid: 1678701
references.citation: Arch Dis Child. 1997 Jan;76(1):57-61
references.pmid: 9059164
references.citation: Eur J Clin Pharmacol. 2006 Oct;62(10):823-7
references.pmid: 16896787
references.citation: Mov Disord. 2007 Apr 15;22(5):712-5
references.pmid: 17373722
references.citation: Intensive Care Med. 2007 Aug;33(8):1396-406
references.pmid: 17541548
references.citation: J Intensive Care Med. 2007 May-Jun;22(3):173-9
references.pmid: 17569173
references.citation: Br J Anaesth. 2007 Aug;99(2):252-61
references.pmid: 17578905
references.citation: Lancet. 2010 Jul 3;376(9734):20-1
references.pmid: 20609983
references.citation: J Clin Anesth. 2002 Dec;14(8):564-70
references.pmid: 12565113
references.citation: Acta Paediatr. 1994 Nov;83(11):1194-9
references.pmid: 7841736
references.citation: J Paediatr Child Health. 1997 Aug;33(4):335-8
references.pmid: 9323623
references.citation: Lancet. 1994 Sep 3;344(8923):646-50
references.pmid: 7915348
references.citation: J Burn Care Rehabil. 1994 Nov-Dec;15(6):515-8
references.pmid: 7852455
references.citation: Paediatr Anaesth. 2006 Dec;16(12):1285-8
references.pmid: 17121562
references.citation: Clin Ther. 2005 Jun;27(6):877-99
references.pmid: 16117990
references.citation: Crit Care Med. 1989 Mar;17(3):301-2
references.pmid: 2920569
references.citation: Br J Anaesth. 1986 Oct;58(10):1104-8
references.pmid: 3533120
references.citation: South Med J. 2004 May;97(5):451-5
references.pmid: 15180019
references.citation: Paediatr Anaesth. 2007 Nov;17(11):1059-65
references.pmid: 17897271
references.citation: Eur J Clin Pharmacol. 1992;42(3):329-32
references.pmid: 1577053
references.citation: Am J Dis Child. 1983 Feb;137(2):171-4
references.pmid: 6849304
references.citation: J Neurotrauma. 1999 Sep;16(9):843-50
references.pmid: 10521143
references.citation: N Engl J Med. 1992 Jan 2;326(1):1-9
references.pmid: 1530752
references.citation: Crit Care Med. 2000 Jun;28(6):2122-32
references.pmid: 10890677
references.citation: Clin Pediatr (Phila). 1997 Aug;36(8):449-54
references.pmid: 9272318
references.citation: Br J Anaesth. 1986 Oct;58(10):1109-15
references.pmid: 3768222
references.citation: Neurocrit Care. 2007;7(2):124-7
references.pmid: 17846719
references.citation: Intensive Care Med. 1996 Mar;22(3):249-51
references.pmid: 8727440
references.citation: Pharmacotherapy. 2008 Jan;28(1):51-7
references.pmid: 18154474
references.citation: Can J Anaesth. 1997 Jun;44(6):629-35
references.pmid: 9187783
references.citation: Lancet. 1989 Sep 23;2(8665):704-9
references.pmid: 2570958
references.citation: Paediatr Anaesth. 1997;7(5):405-10
references.pmid: 9308065
references.citation: Paediatr Anaesth. 2003 Feb;13(2):147-51
references.pmid: 12562488
references.citation: Pediatr Clin North Am. 1994 Dec;41(6):1269-92
references.pmid: 7984386
references.citation: Crit Care Med. 2003 Mar;31(3):711-7
references.pmid: 12626974
references.citation: Indian Pediatr. 2001 Sep;38(9):967-72
references.pmid: 11568372
references.citation: Ann Pharmacother. 1993 May;27(5):579-81
references.pmid: 8347907
references.citation: Anesth Analg. 2001 Apr;92(4):882-90
references.pmid: 11273919
references.citation: Perfusion. 2005 May;20(3):139-43
references.pmid: 16038385
references.citation: Br J Anaesth. 2005 May;94(5):630-5
references.pmid: 15764631
references.citation: Curr Drug Targets. 2005 Nov;6(7):741-4
references.pmid: 16305451
references.citation: Pediatrics. 1999 Mar;103(3):E30
references.pmid: 10049986
references.citation: Anesth Analg. 1992 Jan;74(1):44-50
references.pmid: 1734797
references.citation: Br J Anaesth. 2005 Jun;94(6):805-9
references.pmid: 15833779
references.citation: PLoS Med. 2008 Apr 29;5(4):e96
references.pmid: 18447577
references.citation: Br J Anaesth. 2000 Jun;84(6):794-6
references.pmid: 10895758
references.citation: Biol Neonate. 2006;90(3):197-202
references.pmid: 16717443
references.citation: Pediatrics. 1996 Jul;98(1):135-40
references.pmid: 8668388