Whole-of-Life Inclusion in Bayesian Adaptive Platform Clinical Trials

Author:

Campbell Anita J.123,Anpalagan Keerthi23,Best Emma J.456,Britton Philip N.78,Gwee Amanda91011,Hatcher James1213,Manley Brett J.141516,Marsh Julie217,Webb Rachel H.4618,Davis Joshua S.192021,Mahar Robert K.222324,McGlothlin Anna25,McMullan Brendan2627,Meyer Michael2829,Mora Jocelyn30,Murthy Srinivas31,Nourse Clare3233,Papenburg Jesse3435,Schwartz Kevin L.3637,Scheuerman Oded3839,Snelling Thomas240,Strunk Tobias34142,Stark Michael4344,Voss Lesley6,Tong Steven Y. C.3045,Bowen Asha C.12, ,McQuilten Zoe46,Webb Steve46,Paterson David46,Heriot George46,Roberts Jason46,Scarborough Matthew46,Lye David46,Walls Genevieve46,Morpeth Susan46,Boyles Tom46,Bonten Marc46,Hensgens Marjolein P.M46,Daneman Nick46,Yahav Dafna46,Goodman Anna L46,Cheng Matthew46,Cosgrove Catherine46,Whiteway Lynda46,Van Hal Sebastian46,Lee Todd C.46,Lewis Roger J46,Robinson Owen46,Hardy Erica46,Malhamé Isabelle46

Affiliation:

1. Department of Infectious Diseases, Perth Children’s Hospital, Perth, Western Australia, Australia

2. Wesfarmers Centre of Vaccines and Infectious Diseases, Telethon Kids Institute, Perth, Western Australia, Australia

3. School of Medicine, University of Western Australia, Perth, Western Australia, Australia

4. Department of Paediatrics, Child and Youth Health, The University of Auckland, Auckland, New Zealand

5. The National Immunisation Advisory Centre, The University of Auckland, Auckland, New Zealand

6. Department of Infectious Diseases, Starship Children’s Hospital, Auckland, New Zealand

7. Sydney Medical School and Sydney Infectious Diseases, University of Sydney, Sydney, New South Wales, Australia

8. Department of Infectious Diseases and Microbiology, the Children’s Hospital at Westmead, Sydney, New South Wales, Australia

9. Department of General Medicine, The Royal Children’s Hospital, Melbourne, Victoria, Australia

10. Antimicrobials Group, Murdoch Children’s Research Institute, Melbourne, Victoria, Australia

11. Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, Australia

12. Department of Microbiology, Great Ormond Street Hospital for Children, London, United Kingdom

13. Infection, Immunity, and Inflammation Research Department, University College London, London, United Kingdom

14. The Royal Women’s Hospital, Melbourne, Victoria, Australia

15. The Department of Obstetrics, Gynaecology and Newborn Health, The University of Melbourne, Melbourne, Victoria, Australia

16. Murdoch Children’s Research Institute, Melbourne, Victoria, Australia

17. Centre for Child Health research, School of Medicine, University of Western Australia, Perth, Western Australia, Australia

18. Department of Paediatrics, Kidz First Children’s ‘Hospital, Auckland, New Zealand

19. Menzies School of Health Research, Charles Darwin Hospital, Darwin, Northern Territory, Australia

20. John Hunter Hospital, University of Newcastle, Newcastle, New South Wales, Australia

21. School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia

22. Clinical Epidemiology and Biostatistics, Murdoch Children’s Research Institute, Parkville, Victoria, Australia

23. Centre for Epidemiology and Biostatistics Unit, Melbourne School of Population and Global Health, University of Melbourne, Parkville, Victoria, Australia

24. Centre for Data Science, Queensland University of Technology, Brisbane, Queensland, Australia

25. Berry Consultants, Austin, Texas

26. Department of Infectious Diseases, Sydney Children’s Hospital, Randwick, Sydney, New South Wales, Australia

27. School of Clinical Medicine, University of New South Wales, Sydney, New South Wales, Australia

28. Neonatal Unit, Kidz First Middlemore Hospital Auckland, Auckland, New Zealand

29. Department of Paediatrics: Child and Youth Health University of Auckland, Auckland, Auckland, New Zealand

30. Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia

31. Division of Critical Care, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

32. Queensland Children’s Hospital, Brisbane, Queensland, Australia

33. Faculty of Medicine, University of Queensland, Queensland, Australia

34. Division of Pediatric Infectious Diseases, Department of Pediatrics, Montreal Children’s Hospital, McGill University Health Centre, Montreal, Quebec, Canada

35. Division of Microbiology, Department of Clinical Laboratory Medicine, McGill University Health Centre, Montreal, Quebec, Canada

36. Division of Infectious Diseases, St Joseph’s Health Centre - Unity Health Toronto, Toronto, Ontario, Canada

37. Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada

38. Pediatrics B and Pediatric Infectious Diseases Unit, Schneider Children Medical Center Israel, Petach Tikva, Israel

39. Tel Aviv University, Tel Aviv, Israel

40. School of Public Health, University of Sydney, Sydney, New South Wales, Australia

41. Neonatal Directorate Child and Adolescent Health Service, King Edward Memorial Hospital for Women, Subiaco, Western Australia, Australia

42. Telethon Kids Institute, Perth, Western Australia, Australia

43. The Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia

44. The Department of Neonatal Medicine, The Women’s and Children’s Hospital, Adelaide, South Australia, Australia

45. Victorian Infectious Diseases Service, The Royal Melbourne Hospital, the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia

46. for the Staphylococcus aureus Network Adaptive Platform Paediatric and Youth (SNAP-PY) working groupSNAP Global Trial Steering Committee

Abstract

ImportanceThere is a recognized unmet need for clinical trials to provide evidence-informed care for infants, children and adolescents. This Special Communication outlines the capacity of 3 distinct trial design strategies, sequential, parallel, and a unified adult-pediatric bayesian adaptive design, to incorporate children into clinical trials and transform this current state of evidence inequity. A unified adult-pediatric whole-of-life clinical trial is demonstrated through the Staphylococcus aureus Network Adaptive Platform (SNAP) trial.ObservationsBayesian methods provide a framework for synthesizing data in the form of a probability model that can be used in the design and analysis of a clinical trial. Three trial design strategies are compared: (1) a sequential adult-pediatric bayesian approach that involves a separate, deferred pediatric trial that incorporates existing adult trial data into the analysis model to potentially reduce the pediatric trial sample size; (2) a parallel adult-pediatric bayesian trial whereby separate pediatric enrollment occurs in a parallel trial, running alongside an adult randomized clinical trial; and (3) a unified adult-pediatric bayesian adaptive design that supports the enrollment of both children and adults simultaneously in a whole-of-life bayesian adaptive randomized clinical trial. The SNAP trial whole-of-life design uses a bayesian hierarchical model that allows information sharing (also known as borrowing) between trial age groups by linking intervention effects of children and adults, thereby improving inference in both groups.Conclusion and RelevanceBayesian hierarchical models may provide more precision for estimates of safety and efficacy of treatments in trials with heterogenous populations compared to traditional methods of analysis. They facilitate the inclusion of children in clinical trials and a shift from children deemed therapeutic orphans to the vision of no child left behind in clinical trials to ensure evidence for clinical practice exists across the life course. The SNAP trial provides an example of a bayesian adaptive whole-of-life inclusion design that enhances trial population inclusivity and diversity overall, as well as generalizability and translation of findings into clinical practice.

Publisher

American Medical Association (AMA)

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