Ranges for SpO 2 During Usual Care Lower Limits 100 (% NICUs) Oxygen Saturation (%) 95 (10%) Lower limit of 90 targeted SpO 2 (80%) ranges varied 85 from 80%-95% (10%) 80 Hagadorn JI Pediatrics 2006;118(4):1574, Anderson CG Journal of Perinatology 2004;24(3):164, Nghiem TH Pediatrics 2008;121(5):e1039 – 46, Claure N Pediatrics 2011;127(1):e76 – 83, Hallenberger A Pediatrics 2014;133(2):e379 – 85, Schmid MB Archives of Disease in Childhood Fetal and Neonatal Edition 2013;98(5):F392 – 8, Quine D Archives of Disease in Childhood Fetal and Neonatal Edition 2008; 93(5):F347 – 50, Urschitz MS AJRCCM. 2004;170(10):1095 – 100, Ahmed SJ Pediatrics 2010; 125(1):e115 – 21, Bhandari V Pediatrics 2009;124(2):517 – 26, Bizzarro MJ Journal of Perionatology 2014;34(1):33 – 8, Clucas L. Pediatrics 2007;119(6):1056 – 60, Deulofeut R. Journal of Perinatology. 2006;26(11):700 – 5, Laptook AR Journal of Perinatology 2006;26(6):337 – 41, Lim K The Journal of Pediatrics 2014;164(4):730 – 6 e1, Mills BA. Journal of Paediatrics and Child Health. 2010;46(5):255 – 8, Sink DW Archives of Disease in Childhood Fetal and Neonatal Edition . 2011; 96(2):F93 – 8, van der Eijk AC Acta Paediatrica 2012;101(3):e97 – 104, Tin W Archives of Disease in Childhood Fetal and Neonatal Edition . 2001;84(2):F106 – 10.
Ranges for SpO 2 During Usual Care 100 What were the Oxygen Saturation (%) upper limits? 95 90 85 80 Hagadorn JI Pediatrics 2006;118(4):1574, Anderson CG Journal of Perinatology 2004;24(3):164, Nghiem TH Pediatrics 2008;121(5):e1039 – 46, Claure N Pediatrics 2011;127(1):e76 – 83, Hallenberger A Pediatrics 2014;133(2):e379 – 85, Schmid MB Archives of Disease in Childhood Fetal and Neonatal Edition 2013;98(5):F392 – 8, Quine D Archives of Disease in Childhood Fetal and Neonatal Edition 2008; 93(5):F347 – 50, Urschitz MS AJRCCM. 2004;170(10):1095 – 100, Ahmed SJ Pediatrics 2010; 125(1):e115 – 21, Bhandari V Pediatrics 2009;124(2):517 – 26, Bizzarro MJ Journal of Perionatology 2014;34(1):33 – 8, Clucas L. Pediatrics 2007;119(6):1056 – 60, Deulofeut R. Journal of Perinatology. 2006;26(11):700 – 5, Laptook AR Journal of Perinatology 2006;26(6):337 – 41, Lim K The Journal of Pediatrics 2014;164(4):730 – 6 e1, Mills BA. Journal of Paediatrics and Child Health. 2010;46(5):255 – 8, Sink DW Archives of Disease in Childhood Fetal and Neonatal Edition . 2011; 96(2):F93 – 8, van der Eijk AC Acta Paediatrica 2012;101(3):e97 – 104, Tin W Archives of Disease in Childhood Fetal and Neonatal Edition . 2001;84(2):F106 – 10.
Ranges for SpO 2 During Usual Care Upper Limits (% NICUs) Upper limit of 100 targeted SpO 2 ranges (~25%) Oxygen Saturation (%) varied from 92-100% 95 (~75%) 90 85 80 Hagadorn JI Pediatrics 2006;118(4):1574, Anderson CG Journal of Perinatology 2004;24(3):164, Nghiem TH Pediatrics 2008;121(5):e1039 – 46, Claure N Pediatrics 2011;127(1):e76 – 83, Hallenberger A Pediatrics 2014;133(2):e379 – 85, Schmid MB Archives of Disease in Childhood Fetal and Neonatal Edition 2013;98(5):F392 – 8, Quine D Archives of Disease in Childhood Fetal and Neonatal Edition 2008; 93(5):F347 – 50, Urschitz MS AJRCCM. 2004;170(10):1095 – 100, Ahmed SJ Pediatrics 2010; 125(1):e115 – 21, Bhandari V Pediatrics 2009;124(2):517 – 26, Bizzarro MJ Journal of Perionatology 2014;34(1):33 – 8, Clucas L. Pediatrics 2007;119(6):1056 – 60, Deulofeut R. Journal of Perinatology. 2006;26(11):700 – 5, Laptook AR Journal of Perinatology 2006;26(6):337 – 41, Lim K The Journal of Pediatrics 2014;164(4):730 – 6 e1, Mills BA. Journal of Paediatrics and Child Health. 2010;46(5):255 – 8, Sink DW Archives of Disease in Childhood Fetal and Neonatal Edition . 2011; 96(2):F93 – 8, van der Eijk AC Acta Paediatrica 2012;101(3):e97 – 104, Tin W Archives of Disease in Childhood Fetal and Neonatal Edition . 2001;84(2):F106 – 10.
Ranges for SpO 2 During Usual Care Upper Limits (% NICUs) 100 (~25%) Oxygen Saturation (%) 95 (~75%) 90 U.S. surveys of 120 NICUs in 85 2001 and 40 in 2004, showed that upper limits of targeted 80 SpO 2 ranges were always ≥92% Nghiem TH, Pediatrics . 2008; 121(5):e1039 – 46. Anderson CG. Journal of Perinatology . 2004; 24(3):164 – 8.
Did bedside caregivers adhere to intended targeted SpO 2 ranges? The AVIOx Study in 2004 Hagadorn JI. Pediatrics 2006; 118(4):1574 – 82.
Ranges for SpO 2 During Usual Care AVIOx Study Prescribed SpO 2 Ranges 100 Oxygen Saturation (%) 95 90 85 80 N L J G F M K D E B C I A H AVIOx study centers (A-N) Cortés-Puch I. PLoS One 2016;11(5):e0155005. Hagadorn JI. Pediatrics 2006; 118(4):1574 – 82.
Ranges for SpO 2 During Usual Care AVIOx Study Prescribed SpO 2 Ranges 100 Oxygen Saturation (%) 95 All 14 NICUs followed the 92% upper 90 limit rule 85 80 N L J G F M K D E B C I A H AVIOx study centers (A-N) Cortés-Puch I. PLoS One 2016;11(5):e0155005. Hagadorn JI. Pediatrics 2006; 118(4):1574 – 82.
Ranges for SpO 2 During Usual Care AVIOx Study Achieved SpO 2 Ranges 100 Oxygen Saturation (%) Median and Interquartile 95 Ranges for Achieved SpO 2 Ranges 75 th percentile 90 Median 25 th percentile 85 80 N L J G F M K D E B C I A H AVIOx study centers (A-N) Cortés-Puch I. PLoS One 2016;11(5):e0155005. Hagadorn JI. Pediatrics 2006; 118(4):1574 – 82.
Ranges for SpO 2 During Usual Care AVIOx Study Achieved SpO 2 Ranges 100 Oxygen Saturation (%) 50% of time 95 achieved SpO 2 kept above the targeted range 90 85 80 N L J G F M K D E B C I A H All centers/patients combined AVIOx study centers (A-N) Cortés-Puch I. PLoS One 2016;11(5):e0155005. Hagadorn JI. Pediatrics 2006; 118(4):1574 – 82.
Ranges for SpO 2 During Usual Care SUPPORT Study 100 Oxygen Saturation (%) 95 90 Low targeted range 85-89% 85 80 N L J G F M K D E B C I A H All centers/patients combined AVIOx study centers (A-N) Cortés-Puch I. PLoS One 2016;11(5):e0155005. Carlo WA. NEJM 2010;362(21):1959 – 69.
Ranges for SpO 2 During Usual Care SUPPORT Study 100 Oxygen Saturation (%) 95 Within AAP 90 target range Low targeted range for SpO 2 85-89% 85 80 N L J G F M K D E B C I A H All centers/patients combined AVIOx study centers (A-N) Cortés-Puch I. PLoS One 2016;11(5):e0155005. Carlo WA. NEJM 2010;362(21):1959 – 69. American Academy of Pediatrics, American College of Obstetricians and Gynecologists. Guidelines for perinatal care 6th ed. American Academy of Pediatrics. 2007; Elk Grove Village (IL): AAP; Washington, DC: ACOG.
Ranges for SpO 2 During Usual Care SUPPORT Study 100 Oxygen Saturation (%) 95 Usual care: SpO 2 upper limit ≥ 92% 90 Low targeted range 85-89% 85 80 N L J G F M K D E B C I A H AVIOx study centers (A-N) Cortés-Puch I. PLoS One 2016;11(5):e0155005. Anderson CG. Journal of Perinatology . 2004; 24(3):164 – 8. Nghiem TH, Pediatrics . 2008; 121(5):e1039 – 46. Carlo WA. NEJM 2010;362(21):1959 – 69.
Ranges for SpO 2 During Usual Care SUPPORT Study 100 Oxygen Saturation (%) 95 NO U.S. NICU 90 reported Low targeted range upper limit as low as 89% 85-89% 85 80 N L J G F M K D E B C I A H AVIOx study centers (A-N) Cortés-Puch I. PLoS One 2016;11(5):e0155005. Anderson CG. Journal of Perinatology . 2004; 24(3):164 – 8. Nghiem TH, Pediatrics . 2008; 121(5):e1039 – 46. Carlo WA. NEJM 2010;362(21):1959 – 69.
Ranges for SpO 2 During Usual Care SUPPORT Study 100 Oxygen Saturation (%) 95 90 SUPPORT low Low targeted range range below or at the bottom half of 85-89% 85 prescribed in these 14 NICUs 80 N L J G F M K D E B C I A H AVIOx study centers (A-N) Cortés-Puch I. PLoS One 2016;11(5):e0155005. Hagadorn JI. Pediatrics 2006; 118(4):1574 – 82. Carlo WA. NEJM 2010;362(21):1959 – 69.
Ranges for SpO 2 During Usual Care SUPPORT Study 100 Oxygen Saturation (%) 95 90 SUPPORT low Low targeted range range below achieved SpO 2 in 85-89% 85 these 14 NICUs 80 N L J G F M K D E B C I A H AVIOx study centers (A-N) Cortés-Puch I. PLoS One 2016;11(5):e0155005. Hagadorn JI. Pediatrics 2006; 118(4):1574 – 82. Carlo WA. NEJM 2010;362(21):1959 – 69.
Ranges for SpO 2 During Usual Care SUPPORT Study 100 Low targeted SpO 2 range (85-89%) in Oxygen Saturation (%) SUPPORT below those commonly used 95 in U.S. and E.U. 90 Low targeted range 85-89% 85 80 N L J G F M K D E B C I A H AVIOx study centers (A-N) Cortés-Puch I. PLoS One 2016;11(5):e0155005. Hagadorn JI. Pediatrics 2006; 118(4):1574 – 82. Carlo WA. NEJM 2010;362(21):1959 – 69.
Ranges for SpO 2 During Usual Care SUPPORT Study 100 Oxygen Saturation (%) 95 High targeted range 91-95% 90 85 80 N L J G F M K D E B C I A H All centers/patients combined AVIOx study centers (A-N) Cortés-Puch I. PLoS One 2016;11(5):e0155005. Carlo WA. NEJM 2010;362(21):1959 – 69.
Ranges for SpO 2 During Usual Care SUPPORT Study 100 Oxygen Saturation (%) 95 High targeted range 91-95% Within AAP target range 90 for SpO 2 85 80 N L J G F M K D E B C I A H All centers/patients combined AVIOx study centers (A-N) Cortés-Puch I. PLoS One 2016;11(5):e0155005. Carlo WA. NEJM 2010;362(21):1959 – 69. American Academy of Pediatrics, American College of Obstetricians and Gynecologists. Guidelines for perinatal care 6th ed. American Academy of Pediatrics. 2007; Elk Grove Village (IL): AAP; Washington, DC: ACOG.
Ranges for SpO 2 During Usual Care SUPPORT Study 100 Upper limit of the high targeted range consistent with current practice Oxygen Saturation (%) 95 High targeted range Usual care: 91-95% SpO 2 upper limit ≥ 92% 90 85 80 N L J G F M K D E B C I A H AVIOx study centers (A-N) Cortés-Puch I. PLoS One 2016;11(5):e0155005. Anderson CG. Journal of Perinatology . 2004; 24(3):164 – 8. Nghiem TH, Pediatrics . 2008; 121(5):e1039 – 46. Carlo WA. NEJM 2010;362(21):1959 – 69.
Ranges for SpO 2 During Usual Care SUPPORT Study 100 Oxygen Saturation (%) 95 SUPPORT high High targeted range targeted range 91-95% consistent with prescribed in 90 these 14 NICUs 85 80 N L J G F M K D E B C I A H AVIOx study centers (A-N) Cortés-Puch I. PLoS One 2016;11(5):e0155005. Hagadorn JI. Pediatrics 2006; 118(4):1574 – 82. Carlo WA. NEJM 2010;362(21):1959 – 69.
Ranges for SpO 2 During Usual Care SUPPORT Study 100 Oxygen Saturation (%) SUPPORT high 95 targeted range High targeted range consistent with 91-95% achieved SpO 2 values in these 90 14 NICUs 85 80 N L J G F M K D E B C I A H AVIOx study centers (A-N) Cortés-Puch I. PLoS One 2016;11(5):e0155005. Hagadorn JI. Pediatrics 2006; 118(4):1574 – 82. Carlo WA. NEJM 2010;362(21):1959 – 69.
Ranges for SpO 2 During Usual Care SUPPORT Study 100 Oxygen Saturation (%) SUPPORT high 95 targeted range High targeted range consistent with 91-95% achieved SpO 2 values in these 90 14 NICUs 85 High targeted SpO 2 range in SUPPORT indistinguishable from 80 N L J G F M K D E B C I A H usual care before and during study AVIOx study centers (A-N) Cortés-Puch I. PLoS One 2016;11(5):e0155005. Hagadorn JI. Pediatrics 2006; 118(4):1574 – 82. Carlo WA. NEJM 2010;362(21):1959 – 69.
Ranges for SpO 2 During Usual Care AVIOx Study Achieved SpO 2 Ranges 100 Oxygen Saturation (%) 95 90 85 80 N L J G F M K D E B C I A H All centers/patients combined AVIOx study centers (A-N) Cortés-Puch I. PLoS One 2016;11(5):e0155005. Hagadorn JI. Pediatrics 2006; 118(4):1574 – 82.
Median Achieved SpO 2 Values for 14 NICUs During Usual Care 100 Individual 99 Median achieved oxygen usual care 98 center 97 Saturation (%) 96 Mean 95 94 93 Median 92 91 90 89 88 Centers with Centers with lower limit ≤88% lower limit ≥90% AVIOXs study centers Cortés-Puch I. PLoS One 2016;11(5):e0155005.
Median Achieved SpO 2 Values for 14 NICUs During Usual Care Compared to the Low and High SpO 2 Arms in Clinical Trials 100 Individual 99 Median achieved oxygen usual care 98 center or 97 study arm Saturation (%) 96 Mean 95 94 93 Median 92 91 90 89 88 Low SpO 2 High SpO 2 Centers with Centers with lower limit ≤88% lower limit ≥90% arms arms Randomized clinical trial arms and AVIOXs study centers Cortés-Puch I. PLoS One 2016;11(5):e0155005.
Median Achieved SpO 2 Values for 14 NICUs During Usual Care Compared to the Low and High SpO 2 Arms in Clinical Trials 100 Individual 99 Median achieved oxygen usual care 98 center or 97 study arm Saturation (%) 96 Mean 95 94 93 Median 92 91 90 89 88 Low SpO 2 High SpO 2 Usual care Usual care arms arms centers with centers with lower limit ≤88% lower limit ≥90% Randomized clinical trial arms and AVIOXs study centers Cortés-Puch I. PLoS One 2016;11(5):e0155005.
Median Achieved SpO 2 Values for 14 NICUs During Usual Care Compared to the Low and High SpO 2 Arms in Clinical Trials 100 Individual 99 Median achieved oxygen usual care 98 Achieved SpO 2 in the low center or 97 arm significantly lower study arm Saturation (%) 96 than both usual care and Mean 95 the high SpO 2 arm 94 93 Median 92 91 90 89 88 Low SpO 2 High SpO 2 Usual care Usual care arms arms centers with centers with lower limit ≤88% lower limit ≥90% Randomized clinical trial arms and AVIOXs study centers Cortés-Puch I. PLoS One 2016;11(5):e0155005.
Time (%) Spent Below Indicated SpO 2 Cutoff for Targeted Ranges 40 below the indicated SpO 2 cutoff Percentage of time spend 30 20 Usual care 10 centers n = 45 patients 0 <85% <85% Lower limit of (Actual SpO 2 ) (Actual SpO 2 ) intended range Median = 88% (IQR 85-88%) Cortés-Puch I. PLoS One 2016;11(5):e0155005.
Time (%) Spent Below Indicated SpO 2 Cutoff for Targeted Ranges 40 below the indicated SpO 2 cutoff Percentage of time spend 30 Low SpO 2 20 arms Usual care 10 High SpO 2 centers arms n = 1618 n = 1634 n = 45 patients patients patients 0 <85% <85% Lower limit of (Actual SpO 2 ) (Actual SpO 2 ) intended range Median = 88% (IQR 85-88%) Cortés-Puch I. PLoS One 2016;11(5):e0155005.
Time (%) Spent Below Indicated SpO 2 Cutoff for Targeted Ranges 40 below the indicated SpO 2 cutoff Percentage of time spend p = 0.04 30 Low SpO 2 20 arms Usual care 10 High SpO 2 centers arms n = 1618 n = 1634 n = 45 patients patients patients 0 <85% <85% Lower limit of (Actual SpO 2 ) (Actual SpO 2 ) intended range Median = 88% (IQR 85-88%) Cortés-Puch I. PLoS One 2016;11(5):e0155005.
Time (%) Spent Below Indicated SpO 2 Cutoff for Targeted Ranges 40 below the indicated SpO 2 cutoff Percentage of time spend p = 0.04 30 p < 0.0001 Low SpO 2 20 arms Usual care 10 High SpO 2 centers arms n = 1618 n = 1634 n = 45 patients patients patients 0 <85% <85% Lower limit of (Actual SpO 2 ) (Actual SpO 2 ) intended range Median = 88% (IQR 85-88%) Cortés-Puch I. PLoS One 2016;11(5):e0155005.
Summary • The Low SpO 2 arm (85-89%) of SUPPORT was below the commonly targeted range • Bedside caregivers, outside of the three trials routinely skewed SpO 2 toward the high end of NICU target ranges • Babies randomized to the low SpO 2 arm of SUPPORT spent significantly more time below an O 2 saturation of 85%
Pulse Oximeters in SUPPORT, BOOST II and COT • Health care providers blinded • Calibration error in pulse oximeters offset to return false readings to maintain blinding
Pulse Oximeters in SUPPORT, BOOST II and COT • SpO 2 values between 85% to 95% were offset up to 3% to maintain and blind randomized group assignment • Displays reverted to true values for O 2 saturations ≤84% or ≥96%
Masimo Pulse Oximeters Used in the Trials: Calibration Error Masimo calibration curve from 2002 to 2009 Upper calibration curve adjusted 100 upward for fetal hemoglobin Oxygen Saturation (%) Artificial data used to 95 connect two separate calibration curves 90 85 Lower calibration curve not adjusted upward for fetal 80 hemoglobin 75 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 Light Ratio
Mortality Calibration Favors Trial and Country algorithm Low High SpO 2 arm SpO 2 arm BOOST II All three studies used Australia Original Revised the same modified New Zealand Original pulse oximeters United Kingdom Original Revised COT Original Revised SUPPORT Original 0.5 1.0 1.5 2.0 2.5 Odds Ratio (± 95% CI)
Mortality Calibration Favors Trial and Country algorithm Low High SpO 2 arm SpO 2 arm BOOST II BOOST II was done in Australia Original Revised Australia, New Zealand, New Zealand Original and United Kingdom United Kingdom Original Revised COT Original Revised SUPPORT Original 0.5 1.0 1.5 2.0 2.5 Odds Ratio (± 95% CI)
Mortality Calibration Favors Trial and Country algorithm Low High SpO 2 arm SpO 2 arm BOOST II Australia Original Revised New Zealand Original United Kingdom Original Revised COT was conducted COT Original primarily in Canada Revised SUPPORT Original 0.5 1.0 1.5 2.0 2.5 Odds Ratio (± 95% CI)
Mortality Calibration Favors Trial and Country algorithm Low High SpO 2 arm SpO 2 arm BOOST II Australia Original Revised New Zealand Original United Kingdom Original Revised COT Original SUPPORT was conducted Revised in US and started one year SUPPORT Original before BOOST II and COT 0.5 1.0 1.5 2.0 2.5 Odds Ratio (± 95% CI)
Mortality Calibration Favors Trial and Country algorithm Low High SpO 2 arm SpO 2 arm BOOST II Australia Original Revised New Zealand Original SUPPORT and BOOST II United Kingdom Original in New Zealand used Revised only the original COT Original Revised calibration algorithm SUPPORT Original 0.5 1.0 1.5 2.0 2.5 Odds Ratio (± 95% CI)
Mortality Calibration Favors Trial and Country algorithm Low High BOOST II (Australia and SpO 2 arm SpO 2 arm BOOST II Australia Original United Kingdom) and COT Revised started with the original New Zealand Original calibration algorithm, but United Kingdom Original Revised changed to the revised algorithm halfway COT Original Revised through enrollment SUPPORT Original 0.5 1.0 1.5 2.0 2.5 Odds Ratio (± 95% CI)
Mortality Calibration Favors Trial and Country algorithm Low High SpO 2 arm SpO 2 arm BOOST II Australia Original Revised New Zealand Original Solid white boxes are odds ratios of United Kingdom Original survival; horizontal Revised lines are 95% COT Original confidence intervals Revised SUPPORT Original I 2 Summary (n=) p-value All studies (8) 33% 0.17 0.5 1.0 1.5 2.0 2.5 Odds Ratio (± 95% CI)
Mortality Calibration Favors Trial and Country algorithm Low High SpO 2 arm SpO 2 arm BOOST II Australia Original Revised No effect line; 95% confidence intervals New Zealand Original crossing this line = no United Kingdom Original significant effect Revised COT Original Revised SUPPORT Original I 2 Summary (n=) p-value All studies (8) 33% 0.17 0.5 1.0 1.5 2.0 2.5 Odds Ratio (± 95% CI)
Mortality Calibration Favors White boxes on this Trial and Country algorithm Low High side indicate better SpO 2 arm SpO 2 arm BOOST II survival in high arm Australia Original Revised New Zealand Original United Kingdom Original Revised COT Original Revised SUPPORT Original I 2 Summary (n=) p-value All studies (8) 33% 0.17 0.5 1.0 1.5 2.0 2.5 Odds Ratio (± 95% CI)
Mortality Calibration Favors Trial and Country algorithm Low High SpO 2 arm SpO 2 arm BOOST II Australia Original Revised New Zealand Original United Kingdom Original Revised COT Original Revised SUPPORT Original I 2 Summary (n=) p-value All studies (8) 33% 0.17 0.5 1.0 1.5 2.0 2.5 Odds Ratio (± 95% CI)
Mortality Calibration Favors Trial and Country algorithm Low High SpO 2 arm SpO 2 arm BOOST II Australia Original Revised New Zealand Original United Kingdom Original Revised COT Original Revised SUPPORT Original I 2 Summary (n=) p-value (No summary, I 2 >30%) All studies (8) 33% 0.17 0.5 1.0 1.5 2.0 2.5 Odds Ratio (± 95% CI)
Mortality Calibration Favors Trial and Country algorithm Low High SpO 2 arm SpO 2 arm BOOST II Australia Original New Zealand Original United Kingdom Original COT Original SUPPORT Original I 2 Summary (n=) p-value Original (5) 19.5% 0.29 p = 0.80 0.5 1.0 1.5 2.0 2.5 Odds Ratio (± 95% CI)
Mortality Calibration Favors Trial and Country algorithm Low High SpO 2 arm SpO 2 arm BOOST II Australia Revised United Kingdom Revised COT Revised I 2 Summary (n=) p-value Revised (3) 0% 0.65 p = 0.002 0.5 1.0 1.5 2.0 2.5 Odds Ratio (± 95% CI)
Mortality Calibration Favors Trial and Country algorithm Low High SpO 2 arm SpO 2 arm BOOST II Australia Original Revised New Zealand United Kingdom Original Revised COT Original Revised SUPPORT I 2 Summary (n=) p-value Original (studies with p = 0.54 revised data) (3) 0% 0.44 Interaction p = 0.01 p = 0.002 Revised (3) 0% 0.65 0.5 1.0 1.5 2.0 2.5 Odds Ratio (± 95% CI)
Mortality Targeting the bottom half of the AAP recommended Calibration Favors SpO 2 range can increase mortality, but this effect Trial and Country algorithm Low High SpO 2 arm SpO 2 arm was variably influenced by the calibration algorithm BOOST II Australia Original Revised New Zealand United Kingdom Original Revised COT Original Revised SUPPORT I 2 Summary (n=) p-value Original (studies with p = 0.54 revised data) (3) 0% 0.44 Interaction p = 0.01 p = 0.002 Revised (3) 0% 0.65 0.5 1.0 1.5 2.0 2.5 Odds Ratio (± 95% CI)
Necrotizing Enterocolitis Favors Calibration Trial and Country algorithm Low High SpO 2 arm SpO 2 arm BOOST II Original Australia Revised New Zealand Original United Kingdom Original Revised COT Original/Revised SUPPORT Original Summary (n=) I 2 p-value p=0.01 All studies (7) 0% 0.95 0.5 1.0 1.5 2.0 2.5 3.0 4.0 Odds Ratio (± 95% CI)
Necrotizing Enterocolitis Favors Calibration Trial and Country algorithm Low High SpO 2 arm SpO 2 arm BOOST II Original Australia Revised New Zealand Original United Kingdom Original Revised COT Original/Revised SUPPORT Original Summary (n=) I 2 p-value p=0.01 All studies (7) 0% 0.95 0.5 1.0 1.5 2.0 2.5 3.0 4.0 Odds Ratio (± 95% CI)
Necrotizing Enterocolitis increased in babies Necrotizing Enterocolitis randomized to the bottom half of the SpO2 range Favors Calibration Trial and Country algorithm Low High recommended by AAP SpO 2 arm SpO 2 arm BOOST II Original Australia Effect consistent across all three studies, five Revised countries and the two monitor calibrations used New Zealand Original United Kingdom Original Revised COT Original/Revised SUPPORT Original Summary (n=) I 2 p-value p=0.01 All studies (7) 0% 0.95 0.5 1.0 1.5 2.0 2.5 3.0 4.0 Odds Ratio (± 95% CI)
Retinopathy of Prematurity Calibration Favors Trial and Country algorithm Low High SpO 2 arm SpO 2 arm BOOST II Australia Original Revised New Zealand Original United Kingdom Original Revised COT Original and Revised SUPPORT Original I 2 Summary (n=) p-value (No summary, I 2 >30%) All studies (7) 55% 0.04 0.5 1.0 1.5 2.0 Odds Ratio (± 95% CI)
Retinopathy of Prematurity Calibration Favors Trial and Country algorithm Low High SpO 2 arm SpO 2 arm BOOST II Australia Original New Zealand Original United Kingdom Original SUPPORT Original I 2 Summary (n=) p-value (No summary, I 2 >30%) Original (4) 53% 0.09 0.5 1.0 1.5 2.0 Odds Ratio (± 95% CI)
Retinopathy of Prematurity Targeting the bottom half of the AAP SpO 2 range Calibration Favors Trial and Country algorithm Low High inconsistently prevented retinopathy of prematurity SpO 2 arm SpO 2 arm BOOST II Australia Original (ROP) Revised New Zealand Original Variability in results suggests that unknown United Kingdom Original cofactor(s) other than the SpO 2 range affected the Revised occurrence of ROP COT Original and Revised SUPPORT Original I 2 Summary (n=) p-value All studies (7) 55% 0.04 Original (4) 53% 0.09 Revised (2) 51% 0.15 0.5 1.0 1.5 2.0 Odds Ratio (± 95% CI)
Retinopathy of Prematurity SUPPORT 2 year follow-up: “although eye surgery Calibration Favors was significantly less frequent in the Trial and Country algorithm Low High lower…than...higher -oxygen-saturation group, there SpO 2 arm SpO 2 arm BOOST II Australia Original were no significant differences … (in) rates of Revised New Zealand Original unilateral and bilateral blindness, nystagmus, United Kingdom Original strabismus, or use of corrective lenses.” Revised N Engl J Med 2012; 367:2495-2504 COT Original and Revised SUPPORT Original I 2 Summary (n=) p-value All studies (7) 55% 0.04 Original (4) 53% 0.09 Revised (2) 51% 0.15 0.5 1.0 1.5 2.0 Odds Ratio (± 95% CI)
Summary Targeting the low SpO 2 range of 85 to 89%: • Increased Necrotizing Enterocolitis • Increased Mortality under some conditions • Did not necessarily prevent ROP • After corrective eye surgery, vision differences were no longer present between study arms
Representative Excerpts from 10 of 21 SUPPORT Informed Consent Forms That Were Institutional Review Board Approved That Characterized the Oxygen Management Interventions. Institutions Are Blinded E “Keeping the level in either end of the normal range S “The oxygen saturation level currently used in the neonatal Q “There are also two oxygen support strategies: 1) O “ Routine neonatal intensive care will be M “Within the range of oxygen that we normally keep K “Both of these ranges are within the oxygen saturation I “… your baby will have his/her oxygen G “Within the range of oxygen which we normally A “Each of the 4 possible combinations of C “We will also be looking at the ranges of intensive care units at [institution S] is between 85% and range that is currently used for premature infants in the is routinely used in the NICU for premature babies.” babies in (85 to 95%), your baby will either be in the a low normal range (85 ‐ 89%) and 2) a high normal treatments is considered standard care by some use, your infant will either be on the high end of oxygen saturation that are currently being used provided during your baby's participation in the saturation level kept in the high or low part of the 94%, so both treatment groups (the group for whom the high end of normal or the low end of normal .” “Your NICU at [institution K].” “All of these treatments have “This will determine if your baby will have his/her oxygen normal or the low end of normal. ” “…each of the 4 range (91 ‐ 95%).” “Because all treatments proposed units in the United States.” “All of the treatments normal oxygen saturation range .” with these same babies.” “All of these saturations study.” “Each of the study treatments is already target for oxygen saturation levels will be 85 ‐ 89% and the been carefully studied and all are used in Newborn baby will receive all standard care provided to any saturation level kept in the high or low part of the in this study are currently accepted standard of (CPAP in the delivery room, delivery room intubation possible combinations of treatments is currently being used by many doctors across the country, are considered normal ranges for premature group for whom the target for oxygen saturation levels will baby in the Neonatal Intensive Care.” “The procedures ICUs.” “All of these treatments are currently clinically normal oxygen saturation range .” “Your infant will used by some NICUs as their primary approach to plus surfactant, lower oxygen range, and higher care , there is no predictable increase in risk to your there is no predictable increase in risk for your infants.” “Sometimes higher ranges are used and be 91 ‐ 95%) will be treated with oxygen in a manner that is accepted , but haven’t been compared with each other have al [sic] usual care for infants born before 28 that are being used are standard (routine) treatments treating premature infants.” “Because all of the oxygen range) proposed in this study are standard baby.” “… because all of the treatments proposed in very similar to that currently used at both hospitals” “The sometimes lower ranges are used. All of them baby.” used in neonatal intensive care. … To the best of our weeks gestation.” “The oxygen saturation ranges to be in this manner …” “For this study, there will be no of care at various hospitals like [institution F] in the this study are currently accepted as standard of treatments proposed in this study are standard of ranges used in this study are in common use in NICU’s are acceptable ranges.” used are currently used for usual care in premature change in the oxygen saturation range from the one that understanding, there will be no more risks for the baby across the country.” “Because all of the treatments proposed United States, so there are no predictable increases care , there is no unpredictable increase [in risk] care , there is no expected increase in risk for your infants in the NICU.” is currently used in the NICU at [institution K].” in this study than are possible for any ill premature baby in this study are standard of care , there is no predictable in risk for your baby.” expected.” infant” needing intensive care.” increase in risk for your baby.”
Controversy
Timeline 2001-2003 2005-2009 2010 2011 2012 SUPPORT SUPPORT enrollment SUPPORT OHRP BOOST II SUPPORT Study (2006 BOOST II and study investigation Trial stopped follow-up conceived COT enrollment published begins early for study begin) NEJM harm published Published NEJM NEJM 2013 “we determine, that the IRB …approved March April May June July August “ for over 50 years. …it was well recognized that informed consent documents … failed to 7 th changing a premature infant’s amount of exposure …adequately address the following HHS to oxygen could have an impact on… the …regulation (Common Rule) …: A description development of severe eye disease…; reduced neurologic development, …and could even lead to of any reasonably foreseeable risks and death .” discomforts.” Letter from OHRP to lead SUPPORT center
Timeline 2001-2003 2005-2009 2010 2011 2012 SUPPORT SUPPORT enrollment SUPPORT OHRP BOOST II SUPPORT Study (2006 BOOST II and study investigation Trial stopped follow-up conceived COT enrollment published begins early for study begin) NEJM harm published Published NEJM NEJM 2013 March April May June July August 7 th 10 th 15 th 18 th NYT editorial NYT NYT article opinion on SUPPORT letter Letter from OHRP to lead SUPPORT center
Timeline 2001-2003 2005-2009 2010 2011 2012 NEW YORK, WEDNESDSAY APRIL 10, 2013 SUPPORT SUPPORT enrollment SUPPORT OHRP BOOST II SUPPORT FRONT PAGE Study (2006 BOOST II and study investigation Trial stopped follow-up conceived COT enrollment published begins early for study begin) NEJM harm published Published NEJM Study of Babies Did Not NEJM Disclose Risks, U.S. Finds 2013 By SABRINA TAVERNISE March April May June July August “The risk the consent form did “the researchers had …information to know, 7 th 10 th before conducting the study, that participation mention was far less significant: might lead to differences in whether an infant NYT abrasion of the infants’ skin by survived, or developed blindness, in article on SUPPORT an oxygen monitoring device .” comparison to …had that child not been Letter from enrolled in the study .” OHRP to lead SUPPORT center
Timeline 2001-2003 2005-2009 2010 2011 2012 NEW YORK, MONDAY APRIL 15, 2013 SUPPORT SUPPORT enrollment SUPPORT OHRP BOOST II SUPPORT EDITORIAL Study (2006 BOOST II and study investigation Trial stopped follow-up conceived COT enrollment published begins early for study begin) NEJM harm published Published NEJM An Ethical Breakdown NEJM By THE EDITORIAL BOARD “The Department of Health and Human 2013 Services needs to investigate how this March April May June July August breakdown occurred. And if the 7 th 10 th 15 th institutions do not offer strong reforms, NYT editorial NYT the agency can suspend their ability to article on SUPPORT conduct federally financed research on Letter from OHRP to lead human subjects .” SUPPORT center
Timeline 2001-2003 2005-2009 2010 2011 2012 NEW YORK, THURSDAY APRIL 18, 2013 OPINION PAGES SUPPORT SUPPORT enrollment SUPPORT OHRP BOOST II SUPPORT Study (2006 BOOST II and study investigation Trial stopped follow-up conceived COT enrollment published begins early for study LETTER begin) NEJM harm published Published NEJM NEJM Consent Forms in a Clinical 2013 Trial of Premature Babies March April May June July August By 25 SUPPORT TRIAL INVESTIGATORS “When the study was planned, the best 7 th 10 th 15 th 18 th evidence showed that lower oxygen targets NYT — even lower than used in the study — editorial NYT NYT article resulted in less eye disease without a higher opinion on SUPPORT letter death rate. The finding of a higher death Letter from OHRP to lead rate in one study group was not anticipated” SUPPORT center
Pulse oximetry, severe retinopathy, and outcome at one year in babies of less than 28 weeks gestation March 2001 W Tin, D W A Milligan, P Pennefather, E Hey Vol 84 No 2, Pages F106-F110 “An examination of case notes of 295 babies in northern England 1990- 1994”
Pulse oximetry, severe retinopathy, and outcome at one year in babies of less than 28 weeks gestation March 2001 W Tin, D W A Milligan, P Pennefather, E Hey Vol 84 No 2, Pages F106-F110 “An examination of case notes of 295 babies in northern England 1990- 1994” “Staff always aimed to maintain saturation in the top half of the target range”
Pulse oximetry, severe retinopathy, and outcome at one year in babies of less than 28 weeks gestation March 2001 W Tin, D W A Milligan, P Pennefather, E Hey Vol 84 No 2, Pages F106-F110 “An examination of case notes of 295 babies Four target oxygen saturation ranges : in northern England 1990- 1994” “Staff always aimed to maintain saturation 88-98%, 85-95%, 84-94%, and 70-90% in the top half of the target range” One year No of One year Target One year survivors with babies survivors with O 2 saturation survivors threshold admitted cerebral palsy retinopathy 88 – 98% 123 65 (52.8) 11 (16.9) 18 (27.7) 85 – 95% 235 128 (54.5) 20 (15.6) 20 (15.6) 84 – 94% 84 37 (44.0) 6 (16.2) 5 (13.5) 70 – 90% 126 65 (51.6) 10 (15.4) 4 (6.2)
Pulse oximetry, severe retinopathy, and outcome at one year in babies of less than 28 weeks gestation March 2001 W Tin, D W A Milligan, P Pennefather, E Hey Vol 84 No 2, Pages F106-F110 “An examination of case notes of 295 babies Mortality was comparable over the in northern England 1990- 1994” four target oxygen saturation ranges: “Staff always aimed to maintain saturation 52.8%, 54.5%, 44%, and 51.6% in the top half of the target range” One year No of One year Target One year survivors with babies survivors with O 2 saturation survivors threshold admitted cerebral palsy retinopathy 88 – 98% 123 65 (52.8) 11 (16.9) 18 (27.7) 85 – 95% 235 128 (54.5) 20 (15.6) 20 (15.6) 84 – 94% 84 37 (44.0) 6 (16.2) 5 (13.5) 70 – 90% 126 65 (51.6) 10 (15.4) 4 (6.2)
Pulse oximetry, severe retinopathy, and outcome at one year in babies of less than 28 weeks Mortality reported here (1990 – gestation March 2001 W Tin, D W A Milligan, P Pennefather, E Hey Vol 84 No 2, Pages F106-F110 1994) was double that seen one “An examination of case notes of 295 babies in northern England 1990- 1994” decade later at the time of “Staff always aimed to maintain saturation in the top half of the target range” SUPPORT (15-25%) One year No of One year Target One year survivors with babies survivors with O 2 saturation survivors threshold admitted cerebral palsy retinopathy 88 – 98% 123 65 (52.8) 11 (16.9) 18 (27.7) 85 – 95% 235 128 (54.5) 20 (15.6) 20 (15.6) 84 – 94% 84 37 (44.0) 6 (16.2) 5 (13.5) 70 – 90% 126 65 (51.6) 10 (15.4) 4 (6.2)
Pulse oximetry, severe retinopathy, and outcome at one year in babies of less than 28 weeks gestation March 2001 W Tin, D W A Milligan, P Pennefather, E Hey Vol 84 No 2, Pages F106-F110 “An examination of case notes of 295 babies Targeting the lowest O 2 saturation range 70-90%, in northern England 1990- 1994” mortality was comparable, but ROP was less; “Staff always aimed to maintain saturation 6.2% vs. other 3 ranges (13.5, 15.6, and 27.7%) in the top half of the target range” One year No of One year Target One year survivors with babies survivors with O 2 saturation survivors threshold admitted cerebral palsy retinopathy 88 – 98% 123 65 (52.8) 11 (16.9) 18 (27.7) 85 – 95% 235 128 (54.5) 20 (15.6) 20 (15.6) 84 – 94% 84 37 (44.0) 6 (16.2) 5 (13.5) 70 – 90% 126 65 (51.6) 10 (15.4) 4 (6.2)
Timeline 2001-2003 2005-2009 2010 2011 2012 SUPPORT SUPPORT enrollment SUPPORT OHRP BOOST II SUPPORT Study (2006 BOOST II and study investigation Trial stopped follow-up conceived COT enrollment published begins early for study begin) NEJM harm published Published NEJM NEJM 2013 March April May June July August 7 th 10 th 15 th 18 th 16 th NYT NEJM editorial 3 articles NYT NYT published in article defense of opinion on SUPPORT letter SUPPORT Letter from OHRP to lead Correspondence Perspective SUPPORT Editorial center
Timeline 2001-2003 2005-2009 2010 2011 2012 SUPPORT SUPPORT enrollment SUPPORT OHRP BOOST II SUPPORT May 16, 2013 Study (2006 BOOST II and study investigation Trial stopped follow-up CORRESPONDENCE conceived COT enrollment published begins early for study begin) NEJM harm published Published NEJM NEJM Oxygen-Saturation Targets in 2013 Extremely Preterm Infants March April May June July August By CARLO WA et al “The best evidence available when we “Death was included in the primary outcome 7 th 10 th 15 th 18 th 16 th because it competes with retinopathy, not because planned the study was that oxygen NYT NEJM editorial a difference in mortality was expected. The 3 articles NYT saturations of 70 to 90% were associated NYT published in article American Academy of Pediatrics recommended defense of opinion on SUPPORT with less retinopathy without an increase letter SUPPORT oxygen-saturation levels of 85 to 95%, and both Letter from in mortality .” OHRP to lead treatment groups had targets within that range.” Correspondence Perspective Perspective SUPPORT Editorial ADC Fetal & Neonatal Ed. Tin W et al. 2001;84:F106-F110 center
Timeline 2001-2003 2005-2009 2010 2011 2012 SUPPORT SUPPORT enrollment SUPPORT OHRP BOOST II SUPPORT May 16, 2013 Study (2006 BOOST II and study investigation Trial stopped follow-up EDITORIAL conceived COT enrollment published begins early for study begin) NEJM harm published Published NEJM NEJM Informed Consent and 2013 SUPPORT March April May June July August By Drazen JM et al “…there was no evidence to suggest an 7 th 10 th 15 th 18 th 16 th increased risk of death with oxygen levels in the NYT NEJM editorial lower end of a range viewed by experts as 3 articles NYT NYT published in article acceptable, and thus there was not a failure on defense of opinion on SUPPORT letter SUPPORT the part of investigators to obtain appropriately Letter from OHRP to lead informed consent…” Correspondence Perspective SUPPORT Editorial center
Timeline 2001-2003 2005-2009 2010 2011 2012 SUPPORT SUPPORT enrollment SUPPORT OHRP BOOST II SUPPORT May 16, 2013 Study (2006 BOOST II and study investigation Trial stopped follow-up PERSPECTIVE conceived COT enrollment published begins early for study begin) NEJM harm published Published NEJM NEJM Risk, Consent, and SUPPORT By MAGNUS D and CAPLAN AL 2013 “The OHRP reprimand is troubling both “Given that there was variation in clinical “... since all the study infants would receive March April May June July August oxygen levels within the prevailing standard of practice at the time the study was ...because it incorrectly suggests that the 7 th 10 th 15 th 18 th 16 th care, there was no additional risk to being risk of comparative effectiveness research mounted, it is not clear how NYT NEJM enrolled in the trial. …(The trial) should have editorial 3 articles NYT …, is equivalent to the risk of research randomization among treatment options NYT published in article been eligible for a waiver of documentation of defense of opinion on SUPPORT could have created novel risk over random involving randomization to a novel informed consent...” letter SUPPORT Letter from intervention .” physician preference .” OHRP to lead Correspondence Perspective SUPPORT Editorial center
Timeline 2001-2003 2005-2009 2010 2011 2012 SUPPORT SUPPORT enrollment SUPPORT OHRP BOOST II SUPPORT Study (2006 BOOST II and study investigation Trial stopped follow-up conceived COT enrollment published begins early for study begin) NEJM harm published Published NEJM NEJM 2013 March April May June July August 7 th 10 th 15 th 18 th 16 th 4 th NYT NEJM Second letter editorial 3 articles NYT from OHRP to NYT published in article lead SUPPORT defense of opinion on SUPPORT center letter SUPPORT Letter from OHRP to lead Correspondence Perspective SUPPORT Editorial center
Timeline 2001-2003 2005-2009 2010 2011 2012 SUPPORT SUPPORT enrollment SUPPORT OHRP BOOST II SUPPORT Study (2006 BOOST II and study investigation Trial stopped follow-up conceived COT enrollment published begins early for study begin) NEJM harm published Published NEJM NEJM 2013 “…we will …conduct an open “…we have put on hold all compliance March April May June July August actions …relating to the SUPPORT case, public meeting on this topic .” 7 th 10 th 15 th 18 th 16 th 4 th 4 th and plan to take no further action in NYT (Held August 2013, 28 speakers) NEJM Second letter Second letter editorial from OHRP to studies involving similar designs until the 3 articles NYT from OHRP to lead SUPPORT NYT published in article lead SUPPORT center process of producing appropriate defense of opinion on SUPPORT center letter SUPPORT guidance is completed .” Letter from OHRP to lead Correspondence Perspective SUPPORT Editorial center
Timeline 2001-2003 2005-2009 2010 2011 2012 SUPPORT SUPPORT enrollment SUPPORT OHRP BOOST II SUPPORT Study (2006 BOOST II and study investigation Trial stopped follow-up conceived COT enrollment published begins early for study begin) NEJM harm published Published NEJM NEJM 2013 March April May June July August 7 th 10 th 15 th 18 th 16 th 4 th 20 th NYT NEJM Second letter editorial 3 articles NYT from OHRP to NYT published in article lead SUPPORT NEJM defense of opinion on SUPPORT center 2 articles in letter SUPPORT Letter from defense of OHRP to lead SUPPORT Correspondence Perspective SUPPORT Editorial Perspective Correspondence center
Timeline 2001-2003 2005-2009 2010 2011 2012 SUPPORT SUPPORT enrollment SUPPORT OHRP BOOST II SUPPORT June 20, 2013 Study (2006 BOOST II and study investigation Trial stopped follow-up PERSPECTIVE conceived COT enrollment published begins early for study begin) NEJM harm published Published NEJM In Support of SUPPORT – NEJM A View from the NIH 2013 By Kathy L. Hudson, Ph.D., Alan E. Guttmacher, M.D., and Francis S. Collins, M.D., Ph.D. “…each…treatment(s)… “...recent studies showed no “no scientific evidence to March April May June July August 7 th 10 th 15 th 18 th 16 th 4 th 20 th increased risk of death or expect a difference in mortality considered by some units to NYT NEJM Second letter editorial neurodevelopmental impairment 3 articles NYT from OHRP to between the two treatment represent their desired NYT published in article lead SUPPORT NEJM defense of opinion on SUPPORT center groups in SUPPORT ” at saturation levels as low as 2 articles in letter SUPPORT Letter from approach ” defense of OHRP to lead 70 %.” SUPPORT Correspondence Perspective SUPPORT Editorial Perspective Correspondence center
Timeline 2001-2003 2005-2009 2010 2011 2012 SUPPORT SUPPORT enrollment SUPPORT OHRP BOOST II SUPPORT June 20, 2013 Study (2006 BOOST II and study investigation Trial stopped follow-up CORRESPONDENCE conceived COT enrollment published begins early for study begin) NEJM harm published Published NEJM NEJM The OHRP and SUPPORT Signed By MORE THAN 40 PROMINENT SCIENTISTS, ETHICISTS, AND CLINICIANS 2013 “There is nothing to indicate “... infants … were randomly “OHRP...(should) withdraw … notification March April May June July August to the institutions involved in the …institutional bodies responsible 7 th 10 th 15 th 18 th 16 th 4 th 20 th assigned to oxygen-saturation Surfactant, Positive Pressure, and NYT for… SUPPORT failed the NEJM Second letter targets...consistent with standard editorial 3 articles NYT from OHRP to Oxygenation Randomized Trial NYT published in article lead SUPPORT factors required by the “Common NEJM clinical care at the participating defense of opinion on SUPPORT center (SUPPORT) that they failed to meet 2 articles in letter SUPPORT Letter from defense of regulatory informed- consent requirements” Rule” in approving the study ...” institutions .” OHRP to lead SUPPORT Correspondence Perspective SUPPORT Editorial Perspective Correspondence center
Timeline 2001-2003 2005-2009 2010 2011 2012 SUPPORT SUPPORT enrollment SUPPORT OHRP BOOST II SUPPORT Study (2006 BOOST II and study investigation Trial stopped follow-up conceived COT enrollment published begins early for study begin) NEJM harm published Published NEJM NEJM 2013 March April May June July August 7 th 10 th 15 th 18 th 16 th 4 th 20 th 1 st NYT NEJM NEJM Second letter editorial 3 articles Online only NYT from OHRP to NYT published in A correspondence article lead SUPPORT NEJM defense of critical of opinion on SUPPORT center 2 articles in letter SUPPORT SUPPORT Letter from defense of OHRP to lead SUPPORT Correspondence Perspective SUPPORT Editorial Perspective Correspondence center
Timeline Common Rule Common Rule Common Rule Common Rule 2001-2003 2005-2009 2010 2011 2012 (Four Components for Informed Consent) (Four Components for Informed Consent) (Four Components for Informed Consent) (Four Components for Informed Consent) SUPPORT SUPPORT enrollment SUPPORT OHRP BOOST II SUPPORT August 1, 2013 Study (2006 BOOST II and study investigation Trial stopped follow-up CORRESPONDENCE conceived COT enrollment published begins early for study “A description of any reasonably foreseeable “A disclosure of appropriate alternative “A description of the procedures to be “A statement that the study involves research, begin) NEJM harm published Published NEJM The OHRP and SUPPORT – an explanation of the purposes of the research” risks or discomforts to the subject” NEJM followed, and identification of any procedures procedures or courses of treatment, if any, that Another View which are experimental” might be advantageous to the subject” 2013 Signed By MORE THAN 40 PROMINENT SCIENTISTS, ETHICISTS, AND CLINICIANS March April May June July August “The U.S. Code of Federal Regulations (45CFR46.116 ‘Common Rule’) includes the following requirements for informed consent: ‘A 7 th 10 th 15 th 18 th 16 th 4 th 20 th 1 st statement that the study involves research, an explanation of the NYT purposes of the research, . . . a description of the procedures to be NEJM NEJM Second letter editorial 3 articles Online only NYT from OHRP to followed, and identification of any procedures which are NYT published in A correspondence article lead SUPPORT experimental’; ‘a description of any reasonably foreseeable risks or NEJM defense of critical of opinion on SUPPORT center discomforts to the subject’; and ‘a disclosure of appropriate 2 articles in letter SUPPORT SUPPORT Letter from defense of alternative procedures or courses of treatment, if any, that might be OHRP to lead SUPPORT Correspondence advantageous to the subject .’” Perspective SUPPORT Editorial Perspective Correspondence center
Timeline 2001-2003 2005-2009 2010 2011 2012 SUPPORT SUPPORT enrollment SUPPORT OHRP BOOST II SUPPORT August 1, 2013 Study (2006 BOOST II and study investigation Trial stopped follow-up CORRESPONDENCE conceived COT enrollment published begins early for study begin) NEJM harm published Published NEJM The OHRP and SUPPORT – NEJM Another View 2013 Signed By MORE THAN 40 PROMINENT SCIENTISTS, ETHICISTS, AND CLINICIANS “ The (SUPPORT) consent March April May June July August “a potential differential in the risks that 7 th 10 th 15 th 18 th 16 th 4 th 20 th 1 st were being tracked (death, retinopathy of forms… failed in each of the NYT prematurity, and neurologic impairment) NEJM NEJM Second letter editorial 3 articles Online only NYT from OHRP to elements described above .” was reasonably foreseeable, since NYT published in A correspondence article lead SUPPORT NEJM defense of critical of opinion on SUPPORT center 2 articles in determining differential risk was the very letter SUPPORT SUPPORT Letter from defense of (of the Common Rule) OHRP to lead SUPPORT purpose of the study .” Correspondence Perspective SUPPORT Editorial Perspective Correspondence center
Timeline 2001-2003 2005-2009 2010 2011 2012 SUPPORT SUPPORT enrollment SUPPORT OHRP BOOST II SUPPORT Study (2006 BOOST II and study investigation Trial stopped follow-up Nearly 4 years, and no compliance conceived COT enrollment published begins early for study begin) NEJM harm published action or guidance has been provided Published NEJM NEJM by OHRP to resolve this “controversy” 2013 March April May June July August 7 th 10 th 15 th 18 th 16 th 4 th 20 th 1 st 28 th NYT NEJM NEJM Second letter editorial 3 articles Online only NYT from OHRP to NYT published in A correspondence article lead SUPPORT NEJM defense of critical of opinion on SUPPORT center 2 articles in letter SUPPORT SUPPORT Letter from defense of HHS OHRP to lead SUPPORT Correspondence meeting Perspective SUPPORT Editorial Perspective Correspondence center
Summary • After the NY Times editorial, the controversy became more important than resolving valid concerns about consent documents • The focus became winning public opinion, protecting federally funded neonatal research and having OHRP retract its determinations
Summary Understanding Usual care • SUPPORT, BOOST II and COT Trials – RCT of two SpO 2 ranges – High arm consistent with usual care (control) – Low arm experimental – Most comments made by both defenders and critics of SUPPORT were not germane to either the trial design or concerns about consent documents
Potential Solutions • Clarify Common Rule – Distinguish between commonly used and novel or experimental – Commonly used therapy, given in a new manner, is experimental • Guidance for studies reported as “Usual Care” – Provide data defining usual care to IRBs – Determine whether or not a commonly used therapy might be given in a novel or experimental manner
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