The document summarizes the landmark 1954 polio vaccine trial led by Jonas Salk. It discusses: - The urgency to develop an effective polio vaccine due to rising polio cases - Debate over trial design, with some opposing randomization on ethical grounds - Unprecedented scale of trial involving 1.8 million children across 44 states - Results showing the inactivated polio vaccine was safe and effective at preventing paralytic polio - Trial's impact in accelerating vaccine development and approval, and establishing the importance of randomized controlled trials in medicine

1. Hiding in plain sight: Lessons from landmark clinical trials Steve Goodman, MD, PhD

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25. The ECMO controversy When tough cases don’t make good trials

26. The ECMO Circuit

28. Bartlett Article

29. Bartlett: Play-the-Winner Design ECMO Survived CMT Died 10 ECMO: survived 1 CMT: died

31. The ECMO Controversy “ Children’s Hospital made a serious error .” - Office for Protection from Research Risks, NIH

32. The Harvard Neonatal ECMO Trial Randomized newborns with PPHN to conventional therapy versus ECMO Conventional Therapy NICU: 7th Floor Neonatologists No patients had ever been offered ECMO Anti-ECMO ECMO PICU: 5th Floor Anesthesiologists & Surgeons Already had experience with ECMO for newborns with CDH Pro-ECMO

36. The Response to the ECMO Trial The hospital IRB “made decisions that rightfully belonged to the parents. They really blew it.” Charles McCarthy, Director of OPRR The NIH Office for Protection from Research Risks (OPRR) reprimanded the hospital: The doctors “were doing exactly what physicians did before we had a doctrine of informed consent - making decisions for parents.” George Annas, Boston University

37. A Justification

39. The Problem of “Randomized Consent” "It's clear to me they did not ask consent because it would be hard to get a control group otherwise. Properly informed parents would say 'No thank you.’ ” - Richard M. Royall, Johns Hopkins School of Public Health “ [Seeking consent from those randomized to the conventional medical treatment] would impose unacceptable psychological burdens on the parents of children not included in the ECMO arm of the study.” - Dr. Peter H. Wolff , Chair of Children’s Hospital IRB

40. The Problem of Adaptive Randomization "The clear expectation was that more patients would die on conventional therapy. So the question is whether having an excess of deaths balances the worth of information gained . Since I believe such information is available without randomizing, my answer is a resounding no.” - Donald A. Berry, University of Minnesota "The Harvard study was informed by the slightly hysterical view that we must immediately stop a study as soon as we have an idea which treatment might be better. If we're not careful, we will soon have a system in which we can establish nothing. ” - Paul Meier, University of Chicago

46. Lantos and Fader, NEJM, 1991

55. Women’s Health Initiative 1993 - 2002

57. Previous systematic review showed increased risk of cardiovascular events with HRT

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62. Endpoints in WHI trial 06/06/09

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69. WHI DSMB recommendation 06/06/09

70. NIH Letter #1 06/06/09

74. Comparison of Total Mastectomy and Lumpectomy With or Without Radiation (NSABP B-06) 1976-1984 National Surgical Adjuvant Breast and Bowel Project Bernard Fisher, MD Chairman and Scientific Director, NSABP Carol K. Redmond, ScD Director, NSABP Biostatistics Center

86. ImpACT Staff Emily Evans Gila Neta* Alison Brown Sara Lowther* Olaide Odelola

88. Project leaders Harry Marks Karen Robinson