The SUPPORT, BOOST II, and COT Trials You Must Understand Usual Care To Safeguard Patients and Make Firm Conclusions

Transcription

1 The, BOOST II, and COT Trials You Must Understand Usual Care To Safeguard Patients and Make Firm Conclusions Charles Natanson M.D. Critical Care Medicine Department Clinical Center National Institutes of Health Clinical Center

2 Outline Facts Usual care at time of trials Outcomes Informed consent

3 Outline Facts Usual care at time of trials Outcomes Informed consent Controversy Criticism Defense Deficiency in the Common Rule?

4 Timeline Study conceived enrollment (2006 BOOST II and COT enrollment begin) study published OHRP investigation begins BOOST II Trial stopped early for harm Published follow-up study published 2013 March April May June July August 22 nd COT study published JAMA

5 , BOOST II and COT Trials For babies born at <28 wks gestation Within the AAP s recommended SpO 2 range, does targeting the top or bottom half produce the best outcomes for retinopathy of prematurity, neurologic damage, and death? AAP = American Academy of Pediatrics

6 Ranges for SpO 2 During Usual Care Oxygen Saturation (%) SpO 2 target range recommended by the American Academy of Pediatrics (AAP) 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

7 Ranges for SpO 2 During Usual Care Oxygen Saturation (%) Retinopathy of prematurity, blindness SpO 2 target range recommended by the American Academy of Pediatrics (AAP) Neurologic damage, death Risks 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

8 Ranges for SpO 2 During Usual Care Oxygen Saturation (%) Retinopathy of prematurity, blindness SpO 2 target range recommended by the American Academy of Pediatrics (AAP) Neurologic damage, death Unknown where risks begin or end 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

9 Oxygen Saturation (%) Ranges for SpO 2 During Usual Care SpO 2 target range recommended by the American Academy of Pediatrics (AAP) Hagadorn JI Pediatrics 2006;118(4):1574, Anderson CG Journal of Perinatology 2004;24(3):164, Nghiem TH Pediatrics 2008;121(5):e , 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): , 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): , 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):F

10 Oxygen Saturation (%) Ranges for SpO 2 During Usual Care 100 What was usual care? Hagadorn JI Pediatrics 2006;118(4):1574, Anderson CG Journal of Perinatology 2004;24(3):164, Nghiem TH Pediatrics 2008;121(5):e , 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): , 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): , 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):F

11 Ranges for SpO 2 During Usual Care Oxygen Saturation (%) What was usual care? Neonatologists picked ranges within the AAP recommended range Hagadorn JI Pediatrics 2006;118(4):1574, Anderson CG Journal of Perinatology 2004;24(3):164, Nghiem TH Pediatrics 2008;121(5):e , 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): , 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): , 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):F

12 Oxygen Saturation (%) Ranges for SpO 2 During Usual Care What was usual care? Upper limit 90 Range 85 Lower limit 80 Hagadorn JI Pediatrics 2006;118(4):1574, Anderson CG Journal of Perinatology 2004;24(3):164, Nghiem TH Pediatrics 2008;121(5):e , 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): , 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): , 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):F

13 Oxygen Saturation (%) Ranges for SpO 2 During Usual Care What were the lower limits? Hagadorn JI Pediatrics 2006;118(4):1574, Anderson CG Journal of Perinatology 2004;24(3):164, Nghiem TH Pediatrics 2008;121(5):e , 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): , 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): , 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):F

14 Ranges for SpO 2 During Usual Care Oxygen Saturation (%) Lower Limits (% NICUs) (10%) (80%) (10%) Lower limit of targeted SpO 2 ranges varied from 80%-95% 80 Hagadorn JI Pediatrics 2006;118(4):1574, Anderson CG Journal of Perinatology 2004;24(3):164, Nghiem TH Pediatrics 2008;121(5):e , 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): , 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): , 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):F

15 Oxygen Saturation (%) Ranges for SpO 2 During Usual Care What were the upper limits? Hagadorn JI Pediatrics 2006;118(4):1574, Anderson CG Journal of Perinatology 2004;24(3):164, Nghiem TH Pediatrics 2008;121(5):e , 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): , 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): , 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):F

16 Oxygen Saturation (%) Ranges for SpO 2 During Usual Care Upper Limits (% NICUs) (~25%) (~75%) Upper limit of targeted SpO 2 ranges varied from % Hagadorn JI Pediatrics 2006;118(4):1574, Anderson CG Journal of Perinatology 2004;24(3):164, Nghiem TH Pediatrics 2008;121(5):e , 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): , 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): , 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):F

17 Oxygen Saturation (%) Ranges for SpO 2 During Usual Care 100 Upper Limits (% NICUs) (~25%) 95 (~75%) U.S. surveys of 120 NICUs in 2001 and 40 in 2004, showed that upper limits of targeted SpO 2 ranges were always 92% Nghiem TH, Pediatrics. 2008; 121(5):e Anderson CG. Journal of Perinatology. 2004; 24(3):164 8.

18 Did bedside caregivers adhere to intended targeted SpO ranges? 2 The AVIOx Study in 2004 Hagadorn JI. Pediatrics 2006; 118(4):

19 Oxygen Saturation (%) Ranges for SpO 2 During Usual Care AVIOx Study Prescribed SpO 2 Ranges 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):e Hagadorn JI. Pediatrics 2006; 118(4):

20 Oxygen Saturation (%) Ranges for SpO 2 During Usual Care AVIOx Study Prescribed SpO 2 Ranges All 14 NICUs followed the 92% upper limit rule 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):e Hagadorn JI. Pediatrics 2006; 118(4):

21 Oxygen Saturation (%) Ranges for SpO 2 During Usual Care AVIOx Study Achieved SpO 2 Ranges Median and Interquartile Ranges for Achieved SpO 2 Ranges 75 th percentile Median 25 th percentile 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):e Hagadorn JI. Pediatrics 2006; 118(4):

22 Oxygen Saturation (%) Ranges for SpO 2 During Usual Care AVIOx Study Achieved SpO 2 Ranges % of time achieved SpO 2 kept above the targeted range 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):e Hagadorn JI. Pediatrics 2006; 118(4):

23 Oxygen Saturation (%) Ranges for SpO 2 During Usual Care 100 Study Low targeted range 85-89% 80 N L J G F M K D E B C I A H AVIOx study centers (A-N) All centers/patients combined Cortés-Puch I. PLoS One 2016;11(5):e Carlo WA. 2010;362(21):

24 Oxygen Saturation (%) Ranges for SpO 2 During Usual Care 100 Study Low targeted range 85-89% Within AAP target range for SpO 2 80 N L J G F M K D E B C I A H All centers/patients combined Cortés-Puch I. PLoS One 2016;11(5):e AVIOx study centers (A-N) Carlo WA. 2010;362(21): 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.

25 Oxygen Saturation (%) Ranges for SpO 2 During Usual Care 100 Study Low targeted range 85-89% Usual care: SpO 2 upper limit 92% 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):e Anderson CG. Journal of Perinatology. 2004; 24(3): Nghiem TH, Pediatrics. 2008; 121(5):e Carlo WA. 2010;362(21):

26 Oxygen Saturation (%) Ranges for SpO 2 During Usual Care 100 Study Low targeted range 85-89% NO U.S. NICU reported upper limit as low as 89% 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):e Anderson CG. Journal of Perinatology. 2004; 24(3): Nghiem TH, Pediatrics. 2008; 121(5):e Carlo WA. 2010;362(21):

27 Oxygen Saturation (%) Ranges for SpO 2 During Usual Care 100 Study Low targeted range 85-89% low range below or at the bottom half of 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):e Hagadorn JI. Pediatrics 2006; 118(4): Carlo WA. 2010;362(21):

28 Oxygen Saturation (%) Ranges for SpO 2 During Usual Care 100 Study Low targeted range 85-89% low range below achieved SpO 2 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):e Hagadorn JI. Pediatrics 2006; 118(4): Carlo WA. 2010;362(21):

29 Oxygen Saturation (%) Ranges for SpO 2 During Usual Care Study Low targeted SpO 2 range (85-89%) in below those commonly used in U.S. and E.U Low targeted range 85-89% 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):e Hagadorn JI. Pediatrics 2006; 118(4): Carlo WA. 2010;362(21):

30 Oxygen Saturation (%) Ranges for SpO 2 During Usual Care 100 Study High targeted range 91-95% 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):e Carlo WA. 2010;362(21):

31 Oxygen Saturation (%) Ranges for SpO 2 During Usual Care 100 Study High targeted range 91-95% Within AAP target range for SpO 2 80 N L J G F M K D E B C I A H All centers/patients combined Cortés-Puch I. PLoS One 2016;11(5):e AVIOx study centers (A-N) Carlo WA. 2010;362(21): 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.

32 Oxygen Saturation (%) Ranges for SpO 2 During Usual Care 100 Study Upper limit of the high targeted range consistent with current practice High targeted range 91-95% Usual care: SpO 2 upper limit 92% 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):e Anderson CG. Journal of Perinatology. 2004; 24(3): Nghiem TH, Pediatrics. 2008; 121(5):e Carlo WA. 2010;362(21):

33 Oxygen Saturation (%) Ranges for SpO 2 During Usual Care 100 Study High targeted range 91-95% high targeted range consistent with prescribed in these 14 NICUs 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):e Hagadorn JI. Pediatrics 2006; 118(4): Carlo WA. 2010;362(21):

34 Oxygen Saturation (%) Ranges for SpO 2 During Usual Care 100 Study High targeted range 91-95% high targeted range consistent with achieved SpO 2 values in these 14 NICUs 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):e Hagadorn JI. Pediatrics 2006; 118(4): Carlo WA. 2010;362(21):

35 Oxygen Saturation (%) Ranges for SpO 2 During Usual Care 100 Study High targeted range 91-95% high targeted range consistent with achieved SpO 2 values in these 14 NICUs 85 High targeted SpO 2 range in indistinguishable from 80 N L J G F M K D E B C I A H usual care AVIOx before study centers and (A-N) during study Cortés-Puch I. PLoS One 2016;11(5):e Hagadorn JI. Pediatrics 2006; 118(4): Carlo WA. 2010;362(21):

36 Oxygen Saturation (%) Ranges for SpO 2 During Usual Care AVIOx Study Achieved SpO 2 Ranges 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):e Hagadorn JI. Pediatrics 2006; 118(4):

37 Median achieved oxygen Saturation (%) Median Achieved SpO 2 Values for 14 NICUs During Usual Care Centers with lower limit 88% Centers with lower limit 90% AVIOXs study centers Individual usual care center Mean Median Cortés-Puch I. PLoS One 2016;11(5):e

38 Median achieved oxygen Saturation (%) Median Achieved SpO 2 Values for 14 NICUs During Usual Care Compared to the Low and High SpO 2 Arms in Clinical Trials Low SpO 2 arms High SpO 2 arms Centers with lower limit 88% Centers with lower limit 90% Randomized clinical trial arms and AVIOXs study centers Individual usual care center or study arm Mean Median Cortés-Puch I. PLoS One 2016;11(5):e

39 Median achieved oxygen Saturation (%) Median Achieved SpO 2 Values for 14 NICUs During Usual Care Compared to the Low and High SpO 2 Arms in Clinical Trials Low SpO 2 arms High SpO 2 arms Usual care centers with lower limit 88% Usual care centers with lower limit 90% Randomized clinical trial arms and AVIOXs study centers Individual usual care center or study arm Mean Median Cortés-Puch I. PLoS One 2016;11(5):e

40 Median achieved oxygen Saturation (%) Median Achieved SpO 2 Values for 14 NICUs During Usual Care Compared to the Low and High SpO 2 Arms in Clinical Trials Achieved SpO 2 in the low arm significantly lower than both usual care and the high SpO 2 arm Low SpO 2 arms High SpO 2 arms Usual care centers with lower limit 88% Usual care centers with lower limit 90% Randomized clinical trial arms and AVIOXs study centers Individual usual care center or study arm Mean Median Cortés-Puch I. PLoS One 2016;11(5):e

41 Percentage of time spend below the indicated SpO 2 cutoff Time (%) Spent Below Indicated SpO 2 Cutoff for Targeted Ranges Usual care centers 0 <85% (Actual SpO 2 ) <85% (Actual SpO 2 ) n = 45 patients Lower limit of intended range Median = 88% (IQR 85-88%) Cortés-Puch I. PLoS One 2016;11(5):e

42 Percentage of time spend below the indicated SpO 2 cutoff Time (%) Spent Below Indicated SpO 2 Cutoff for Targeted Ranges Low SpO 2 arms 10 High SpO 2 arms Usual care centers 0 n = 1618 patients <85% (Actual SpO 2 ) n = 1634 patients <85% (Actual SpO 2 ) n = 45 patients Lower limit of intended range Median = 88% (IQR 85-88%) Cortés-Puch I. PLoS One 2016;11(5):e

43 Percentage of time spend below the indicated SpO 2 cutoff Time (%) Spent Below Indicated SpO 2 Cutoff for Targeted Ranges 40 p = Low SpO 2 arms 10 High SpO 2 arms Usual care centers 0 n = 1618 patients <85% (Actual SpO 2 ) n = 1634 patients <85% (Actual SpO 2 ) n = 45 patients Lower limit of intended range Median = 88% (IQR 85-88%) Cortés-Puch I. PLoS One 2016;11(5):e

44 Percentage of time spend below the indicated SpO 2 cutoff Time (%) Spent Below Indicated SpO 2 Cutoff for Targeted Ranges 40 p = p < Low SpO 2 arms 10 High SpO 2 arms Usual care centers 0 n = 1618 patients <85% (Actual SpO 2 ) n = 1634 patients <85% (Actual SpO 2 ) n = 45 patients Lower limit of intended range Median = 88% (IQR 85-88%) Cortés-Puch I. PLoS One 2016;11(5):e

45 Summary The Low SpO 2 arm (85-89%) of 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 spent significantly more time below an O 2 saturation of 85%

46 Pulse Oximeters in, BOOST II and COT Health care providers blinded Calibration error in pulse oximeters offset to return false readings to maintain blinding

47 Pulse Oximeters in, 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%

48 Oxygen Saturation (%) Masimo Pulse Oximeters Used in the Trials: Calibration Error Masimo calibration curve from 2002 to Upper calibration curve adjusted upward for fetal hemoglobin Artificial data used to connect two separate calibration curves Lower calibration curve not adjusted upward for fetal hemoglobin Light Ratio

49 Trial and Country BOOST II Australia New Zealand United Kingdom COT Calibration algorithm Mortality Favors Low SpO 2 arm High SpO 2 arm All three studies used the same modified pulse oximeters Odds Ratio (± 95% CI)

50 Trial and Country BOOST II Australia New Zealand United Kingdom COT Calibration algorithm Mortality Favors Low SpO 2 arm High SpO 2 arm BOOST II was done in Australia, New Zealand, and United Kingdom Odds Ratio (± 95% CI)

51 Trial and Country BOOST II Australia New Zealand United Kingdom COT Calibration algorithm Mortality Favors Low SpO 2 arm High SpO 2 arm COT was conducted primarily in Canada Odds Ratio (± 95% CI)

52 Trial and Country BOOST II Australia New Zealand United Kingdom COT Calibration algorithm Mortality Favors Low SpO 2 arm High SpO 2 arm was conducted in US and started one year before BOOST II and COT Odds Ratio (± 95% CI)

53 Trial and Country BOOST II Australia New Zealand United Kingdom COT Calibration algorithm Mortality Favors Low SpO 2 arm High SpO 2 arm and BOOST II in New Zealand used only the original calibration algorithm Odds Ratio (± 95% CI)

54 Trial and Country BOOST II Australia New Zealand United Kingdom COT Calibration algorithm Mortality Favors Low SpO 2 arm High SpO 2 arm BOOST II (Australia and United Kingdom) and COT started with the original calibration algorithm, but changed to the revised algorithm halfway through enrollment Odds Ratio (± 95% CI)

55 Trial and Country BOOST II Australia New Zealand United Kingdom COT Calibration algorithm Mortality Favors Low SpO 2 arm High SpO 2 arm Solid white boxes are odds ratios of survival; horizontal lines are 95% confidence intervals Summary All studies (n=) I 2 p-value (8) 33% Odds Ratio (± 95% CI)

56 Trial and Country BOOST II Australia New Zealand United Kingdom COT Calibration algorithm Mortality Favors Low SpO 2 arm High SpO 2 arm No effect line; 95% confidence intervals crossing this line = no significant effect Summary All studies (n=) I 2 p-value (8) 33% Odds Ratio (± 95% CI)

57 Trial and Country BOOST II Australia New Zealand United Kingdom COT Calibration algorithm Mortality Favors Low SpO 2 arm High SpO 2 arm White boxes on this side indicate better survival in high arm Summary All studies (n=) I 2 p-value (8) 33% Odds Ratio (± 95% CI)

58 Trial and Country BOOST II Australia New Zealand United Kingdom COT Calibration algorithm Mortality Favors Low SpO 2 arm High SpO 2 arm Summary All studies (n=) I 2 p-value (8) 33% Odds Ratio (± 95% CI)

59 Trial and Country BOOST II Australia New Zealand United Kingdom COT Calibration algorithm Mortality Favors Low SpO 2 arm High SpO 2 arm Summary All studies (n=) I 2 p-value (8) 33% 0.17 (No summary, I 2 >30%) Odds Ratio (± 95% CI)

60 Trial and Country BOOST II Australia Calibration algorithm Mortality Favors Low SpO 2 arm High SpO 2 arm New Zealand United Kingdom COT Summary (n=) I 2 p-value (5) 19.5% 0.29 p = Odds Ratio (± 95% CI)

61 Trial and Country BOOST II Australia Calibration algorithm Mortality Favors Low SpO 2 arm High SpO 2 arm United Kingdom COT Summary (n=) I 2 p-value (3) 0% 0.65 p = Odds Ratio (± 95% CI)

62 Trial and Country BOOST II Australia Calibration algorithm Mortality Favors Low SpO 2 arm High SpO 2 arm New Zealand United Kingdom COT Summary (n=) I 2 p-value (studies with (3) 0% 0.44 p = 0.54 revised data) (3) 0% 0.65 p = Interaction p = Odds Ratio (± 95% CI)

63 Calibration SpO Trial 2 and range Countrycan algorithm increase mortality, but this effect BOOST II Australia New Zealand Mortality Targeting the bottom half of the AAP recommended Favors Low SpO 2 arm High SpO 2 arm was variably influenced by the calibration algorithm United Kingdom COT Summary (n=) I 2 p-value (studies with (3) 0% 0.44 p = 0.54 revised data) (3) 0% 0.65 p = Interaction p = Odds Ratio (± 95% CI)

64 Trial and Country BOOST II Australia Necrotizing Enterocolitis Calibration algorithm Favors Low SpO 2 arm High SpO 2 arm New Zealand United Kingdom COT / Summary All studies (n=) I 2 p-value (7) 0% 0.95 p= Odds Ratio (± 95% CI)

65 Trial and Country BOOST II Australia Necrotizing Enterocolitis Calibration algorithm Favors Low SpO 2 arm High SpO 2 arm New Zealand United Kingdom COT / Summary All studies (n=) I 2 p-value (7) 0% 0.95 p= Odds Ratio (± 95% CI)

66 Necrotizing Enterocolitis increased in babies Trial and Country BOOST II Australia New Zealand Necrotizing Enterocolitis randomized to the bottom half Favors of the SpO2 range Calibration algorithm Low High recommended by AAP SpO arm SpO arm 2 2 Effect consistent across all three studies, five countries and the two monitor calibrations used United Kingdom COT / Summary All studies (n=) I 2 p-value (7) 0% 0.95 p= Odds Ratio (± 95% CI)

67 Trial and Country BOOST II Australia Retinopathy of Prematurity Calibration algorithm Low SpO 2 arm Favors High SpO 2 arm New Zealand United Kingdom COT and All studies Summary (n=) I 2 p-value (7) 55% 0.04 (No summary, I 2 >30%) Odds Ratio (± 95% CI)

68 Trial and Country BOOST II Australia Retinopathy of Prematurity Calibration algorithm Low SpO 2 arm Favors High SpO 2 arm New Zealand United Kingdom Summary (n=) I 2 p-value (4) 53% 0.09 (No summary, I 2 >30%) Odds Ratio (± 95% CI)

69 Trial and Country New Zealand Retinopathy of Prematurity Targeting the bottom half offavors the AAP SpO 2 range Calibration algorithm Low High inconsistently BOOST II prevented retinopathy of prematurity SpO arm SpO arm 2 2 Australia and (ROP) Variability in results suggests that unknown United Kingdom cofactor(s) other than the SpO 2 range affected the COT occurrence of ROP All studies Summary (n=) I 2 p-value (7) 55% 0.04 (4) 53% 0.09 (2) 51% Odds Ratio (± 95% CI)

70 Retinopathy of Prematurity 2 year follow-up: although eye surgery Calibration Favors Trial and was Country significantly algorithm less Low frequent High in the BOOST II SpO 2 arm SpO 2 arm lower than...higher-oxygen-saturation group, there Australia were no significant differences (in) rates of New Zealand unilateral and bilateral blindness, nystagmus, United Kingdom COT strabismus, or use of corrective lenses. N Engl J Med 2012; 367: and All studies Summary (n=) I 2 p-value (7) 55% 0.04 (4) 53% 0.09 (2) 51% Odds Ratio (± 95% CI)

71 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

72 Representative Excerpts from 10 of 21 Informed Consent Forms That Were Institutional Review Board Approved That Characterized the Oxygen Management Interventions. Institutions Are Blinded C I O We Routine your will baby also neonatal will be looking have intensive his/her at the oxygen care ranges will of be A E G K M Q S Keeping Both Each Within There oxygen of of are these range saturation also level 4 ranges possible two of in of either level oxygen are combinations within currently end that support which of the we the used oxygen normally we strategies: of in normally the saturation keep range neonatal 1) treatments oxygen is use, saturation range babies provided a intensive low routinely your normal that care saturation (85 infant is level is used currently units during to considered range 95%), will in [institution kept your that either (85 your used in baby's NICU are the standard 89%) be for currently for S] high on participation premature will is the between or either care 2) high low a being high infants by end 85% part babies. some normal the and of the used in the units This will with NICU high 94%, end so these in at both [institution or of determine the normal treatment same United low K]. babies. end or States. if your groups the All of low baby normal. of (the these end will group All of of have treatments normal. for these each treatments his/her whom oxygen saturations of Your have the normal study. range (91 95%). Each oxygen of the saturation Because study all range. treatments is proposed already the 4 (CPAP saturation are possible been baby target will carefully for oxygen considered in receive combinations the level delivery studied kept saturation all standard the levels normal room, of high all treatments care ranges delivery or will used low provided be part 85 89% for is in room Newborn of the premature currently to and intubation any the being this study used are by currently many doctors accepted across standard the country, of group for whom the target for oxygen saturation levels will plus normal infants. used ICUs. baby surfactant, in by All oxygen some of Neonatal these saturation Sometimes NICUs lower treatments Intensive oxygen as range. higher their Care. range, Your ranges primary currently The and infant are approach procedures higher clinically will have al [sic] usual care for infants born before used 28 and to accepted, that there care, be 91 95%) there are is being no will is but predictable no be treated predictable with used haven t been standard increase oxygen increase compared (routine) a with risk in manner risk each treatments for to your that your is other oxygen treating baby. range) premature proposed infants. this Because study are all of standard the sometimes weeks in used baby. very similar because to this in manner gestation. neonatal lower that currently all of the intensive The For ranges used treatments this oxygen care. study, are saturation used. both hospitals proposed there To the will All ranges best of no them The in of our to be of treatments this ranges care study used are various proposed in this currently study hospitals in are this accepted in common study like [institution are as use standard NICU s F] in the of are used change understanding, acceptable are currently the oxygen there ranges. used will saturation for be usual no more range care risks from in premature for the the one baby that United care, across there States, country. is no so expected unpredictable Because there are all increase no of predictable the increase treatments risk [in increases for risk] proposed your infants is currently this study in the used than NICU. are in the possible NICU for at [institution any ill premature K]. baby infant expected. this risk study for your are standard baby. of care, there is no predictable needing increase intensive risk for your care. baby.

73 Controversy

74 Timeline Study conceived enrollment (2006 BOOST II and COT enrollment begin) study published OHRP investigation begins BOOST II Trial stopped early for harm Published follow-up study published March 7 th Letter from OHRP to lead center 2013 for we over determine, 50 years. that it the was IRB well approved recognized that changing informed a consent premature documents infant s amount failed of exposure to to adequately oxygen could address have an the impact following on the HHS development regulation of (Common severe eye Rule) : disease ; A reduced description neurologic of any reasonably development, foreseeable and could risks even and lead to death. discomforts. April May June July August

75 Timeline Study conceived enrollment (2006 BOOST II and COT enrollment begin) study published OHRP investigation begins BOOST II Trial stopped early for harm Published follow-up study published 2013 March April May June July August 7 th 10 th 15 th 18 th Letter from OHRP to lead center NYT article on NYT editorial NYT opinion letter

76 Timeline Study conceived NEW enrollment YORK, WEDNESDSAY APRIL OHRP 10, 2013 BOOST II (2006 FRONT BOOST II and study PAGE investigation Trial stopped COT enrollment published begins early for begin) harm Published Study of Babies Did Not follow-up study published March April May June July August 7 th Letter from OHRP to lead center 10 th NYT article on Disclose Risks, U.S. Finds By SABRINA TAVERNISE 2013 The the researchers risk the had consent information to did know, before mention conducting was far the study, less significant: that participation might lead to differences in whether an infant survived, abrasion or of developed the infants blindness, skin by comparison an oxygen to had monitoring that child device. not been enrolled in the study.

77 Timeline Study conceived NEW YORK, MONDAY APRIL 15, OHRP 2013 EDITORIAL study investigation published begins enrollment (2006 BOOST II and COT enrollment begin) An Ethical Breakdown BOOST II Trial stopped early for harm Published follow-up study published March April May June July August 7 th Letter from OHRP to lead center 10 th NYT article on By THE EDITORIAL BOARD The Department of 2013 Health and Human Services needs to investigate how this 15 breakdown th occurred. And if the NYT institutions editorial do not offer strong reforms, the agency can suspend their ability to conduct federally financed research on human subjects.

78 Timeline Study conceived 7 th Letter from OHRP to lead center 10 th enrollment NEW YORK, THURSDAY APRIL 18, OHRP 2013 (2006 BOOST II and COT enrollment begin) study published investigation begins NYT editorial NYT article NYT on opinion OPINION PAGES LETTER BOOST II Trial stopped early for harm Published Consent Forms in a Clinical Trial of Premature 2013 Babies letter death rate. The finding of a higher death follow-up study published March April May June July August By 25 TRIAL INVESTIGATORS When 15 th 18 the study was planned, the best th evidence showed that lower oxygen targets even lower than used in the study resulted in less eye disease without a higher rate in one study group was not anticipated

79 Pulse oximetry, severe retinopathy, and outcome at one year in babies of less than 28 weeks gestation W Tin, D W A Milligan, P Pennefather, E Hey March 2001 Vol 84 No 2, Pages F106-F110 An examination of case notes of 295 babies in northern England

80 Pulse oximetry, severe retinopathy, and outcome at one year in babies of less than 28 weeks gestation W Tin, D W A Milligan, P Pennefather, E Hey March 2001 Vol 84 No 2, Pages F106-F110 An examination of case notes of 295 babies in northern England Staff always aimed to maintain saturation in the top half of the target range

81 Pulse oximetry, severe retinopathy, and outcome at one year in babies of less than 28 weeks gestation W Tin, D W A Milligan, P Pennefather, E Hey March 2001 Vol 84 No 2, Pages F106-F110 An examination of case notes of 295 babies in northern England Four target oxygen saturation ranges : Staff always aimed to maintain saturation in the top half of the target range 88-98%, 85-95%, 84-94%, and 70-90% Target O 2 saturation No of babies admitted One year survivors One year survivors with cerebral palsy One year survivors with threshold retinopathy 88 98% (52.8) 11 (16.9) 18 (27.7) 85 95% (54.5) 20 (15.6) 20 (15.6) 84 94% (44.0) 6 (16.2) 5 (13.5) 70 90% (51.6) 10 (15.4) 4 (6.2)

82 Pulse oximetry, severe retinopathy, and outcome at one year in babies of less than 28 weeks gestation W Tin, D W A Milligan, P Pennefather, E Hey March 2001 Vol 84 No 2, Pages F106-F110 An examination of case notes of 295 babies in northern England Mortality was comparable over the four target oxygen saturation ranges: Staff always aimed to maintain saturation in the top half of the target range Target O 2 saturation 52.8%, 54.5%, 44%, and 51.6% No of babies admitted One year survivors One year survivors with cerebral palsy One year survivors with threshold retinopathy 88 98% (52.8) 11 (16.9) 18 (27.7) 85 95% (54.5) 20 (15.6) 20 (15.6) 84 94% (44.0) 6 (16.2) 5 (13.5) 70 90% (51.6) 10 (15.4) 4 (6.2)

83 Pulse oximetry, severe retinopathy, and outcome at one year in babies of less than 28 weeks gestation Mortality reported here (1990 W Tin, D W A Milligan, P Pennefather, E Hey Target O 2 saturation No of babies admitted One year survivors One year survivors with cerebral palsy March 2001 Vol 84 No 2, Pages F106-F ) was double that seen one An examination of case notes of 295 babies in northern England decade later at the time of Staff always aimed to maintain saturation in the top half of the target range (15-25%) One year survivors with threshold retinopathy 88 98% (52.8) 11 (16.9) 18 (27.7) 85 95% (54.5) 20 (15.6) 20 (15.6) 84 94% (44.0) 6 (16.2) 5 (13.5) 70 90% (51.6) 10 (15.4) 4 (6.2)

84 Pulse oximetry, severe retinopathy, and outcome at one year in babies of less than 28 weeks gestation W Tin, D W A Milligan, P Pennefather, E Hey March 2001 Vol 84 No 2, Pages F106-F110 An examination of case notes of 295 babies in northern England Targeting the lowest O 2 saturation range 70-90%, mortality was comparable, but ROP was less; 6.2% vs. other 3 ranges (13.5, 15.6, and 27.7%) Staff always aimed to maintain saturation in the top half of the target range Target O 2 saturation No of babies admitted One year survivors One year survivors with cerebral palsy One year survivors with threshold retinopathy 88 98% (52.8) 11 (16.9) 18 (27.7) 85 95% (54.5) 20 (15.6) 20 (15.6) 84 94% (44.0) 6 (16.2) 5 (13.5) 70 90% (51.6) 10 (15.4) 4 (6.2)

85 Timeline Study conceived enrollment (2006 BOOST II and COT enrollment begin) study published OHRP investigation begins BOOST II Trial stopped early for harm Published follow-up study published 7 th 10 th 15 th 18 th 16 th 2013 March April May June July August Letter from OHRP to lead center NYT article on NYT editorial NYT opinion letter Correspondence 3 articles published in defense of Editorial Perspective

86 Timeline Study conceived enrollment (2006 BOOST II and COT enrollment begin) study published May 16, 2013 OHRP investigation begins BOOST II Trial stopped early for harm Published CORRESPONDENCE Oxygen-Saturation Targets in follow-up study published March April May June July August 7 th 10 th 15 th 18 th 16 th 2013 Extremely Preterm Infants By CARLO WA et al The best evidence available when we planned the study was that oxygen saturations of 70 to 90% were associated with less retinopathy without an increase Death was included in the primary outcome because it competes with retinopathy, not because NYT editorial NYT a difference in mortality 3 articles was expected. The article on NYT opinion published in defense of letter Letter from OHRP to lead in Correspondence Perspective treatment mortality. groups had targets within that range. Editorial center American Academy of Pediatrics recommended oxygen-saturation levels of 85 to 95%, and both ADC Fetal & Neonatal Ed. Tin W et al. 2001;84:F106-F110

87 Timeline Study conceived enrollment (2006 BOOST II and COT enrollment begin) study published May 16, 2013 OHRP investigation begins EDITORIAL Informed Consent and BOOST II Trial stopped early for harm Published follow-up study published March April May June July August By Drazen JM et al 7 th 10 th 15 th 18 th 16 th NYT editorial NYT article NYT on opinion letter Letter from OHRP to lead Correspondence center Editorial 2013 there was no evidence to suggest an increased risk of death with oxygen levels in the lower end of a 3 range articles viewed by experts as published in acceptable, and defense thus of there was not a failure on the part of investigators to obtain appropriately informed consent Perspective

88 Timeline Study conceived enrollment (2006 BOOST II and COT enrollment begin) study published May 16, 2013 OHRP investigation begins PERSPECTIVE BOOST II Trial stopped early for harm Published Risk, Consent, and follow-up study published By MAGNUS D and CAPLAN AL The since OHRP all the reprimand study infants is would troubling receive both oxygen practice...because levels at it the incorrectly within time the the prevailing study suggests was standard that the of care, mounted, there was it is no not additional risk to being clear how enrolled in the trial. 3 articles (The trial) should have randomization, is equivalent published among to in the treatment risk of research options been eligible for defense a waiver of of documentation of informed involving consent... randomization to a novel Given that there was variation in clinical March April May June July August 7 th 10 th 15 th 18 th 16 th risk of comparative effectiveness research NYT editorial NYT article NYT on opinion letter Letter from OHRP to lead Correspondence center could have created novel risk over random physician intervention. preference. Perspective Editorial

89 Timeline Study conceived enrollment (2006 BOOST II and COT enrollment begin) study published OHRP investigation begins BOOST II Trial stopped early for harm Published follow-up study published 2013 March April May June July August 7 th 10 th 15 th 18 th 16 th 4 th Letter from OHRP to lead center NYT article on NYT editorial NYT opinion letter Correspondence 3 articles published in defense of Editorial Perspective Second letter from OHRP to lead center

90 Timeline Study conceived enrollment (2006 BOOST II and COT enrollment begin) study published OHRP investigation begins BOOST II Trial stopped early for harm Published follow-up study published 7 th 10 th public 15 th 18 th meeting 16 th on this topic. 4 th Letter from OHRP to lead center NYT editorial NYT article NYT on opinion Correspondence Editorial 2013 we have will put conduct hold all compliance open actions relating to the case, and plan to take no further action in (Held August 2013, 28 speakers) Second letter from OHRP to studies involving 3 articles similar from lead designs OHRP to until the published in lead center process of producing defense of appropriate center letter guidance is completed. March April May June July August Perspective

91 Timeline Study conceived enrollment (2006 BOOST II and COT enrollment begin) study published OHRP investigation begins BOOST II Trial stopped early for harm Published follow-up study published 2013 March April May June July August 7 th 10 th 15 th 18 th 16 th 4 th 20 th Letter from OHRP to lead center NYT article on NYT editorial NYT opinion letter Correspondence 3 articles published in defense of Editorial Perspective Second letter from OHRP to lead center 2 articles in defense of Perspective Correspondence

92 Timeline Study conceived enrollment (2006 BOOST II and COT enrollment begin) study published June 20, 2013 OHRP investigation begins PERSPECTIVE In Support of BOOST II Trial stopped early for harm Published follow-up study published March April May June July August 7 th Letter from OHRP to lead center 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. no...recent each treatment(s) scientific studies evidence showed to no 10 th 15 th 18 th 16 th 4 th 20 th expect increased considered a difference risk by of death some in mortality units to NYT Second letter editorial NYT between neurodevelopmental the 3 articles two treatment from impairment OHRP to article represent NYT published their in desired lead on opinion defense of center groups at saturation letterin levels as low as 2 articles in approach defense of 70%. Correspondence Perspective Editorial Perspective Correspondence

93 Timeline Study conceived enrollment (2006 BOOST II and COT enrollment begin) study published June 20, 2013 OHRP investigation begins BOOST II Trial stopped early for harm Published CORRESPONDENCE The OHRP and follow-up study published 7 th 2013 Signed By MORE THAN 40 PROMINENT SCIENTISTS, ETHICISTS, AND CLINICIANS OHRP...(should) withdraw notification There... infants is nothing were to randomly indicate March April May June July August 10 th to the 15 institutions 18 th 16 th involved in 4 the NYT NYT editorial article NYT on opinion Letter from letter OHRP to lead Correspondence center 20 th institutional assigned to oxygen-saturation bodies responsible Surfactant, Positive Pressure, and Oxygenation for targets...consistent Randomized failed with Trial the standard () factors clinical required care that at they the by failed participating the to Common meet regulatory informed-consent requirements 3 articles Second letter from OHRP to published in lead defense of center 2 articles in defense of Perspective Editorial Perspective Correspondence Rule institutions. approving the study...

94 Timeline Study conceived enrollment (2006 BOOST II and COT enrollment begin) study published OHRP investigation begins BOOST II Trial stopped early for harm Published follow-up study published 2013 March April May June July August 7 th 10 th 15 th 18 th 16 th 4 th 20 th 1 st Letter from OHRP to lead center NYT article on NYT editorial NYT opinion letter Correspondence 3 articles published in defense of Editorial Perspective Second letter from OHRP to lead center Perspective 2 articles in defense of Online only A correspondence critical of Correspondence

95 Timeline Common Rule Study conceived March April May June July August 7 th (Four Components August for 1, 2013 Informed Consent) 10 th enrollment (2006 BOOST II and COT enrollment begin) NYT NYT editorial article NYT on opinion Letter from letter OHRP to lead Correspondence center study published 2013 OHRP investigation begins BOOST II Trial stopped early for harm Published CORRESPONDENCE Signed By MORE THAN 40 PROMINENT SCIENTISTS, ETHICISTS, AND CLINICIANS The U.S. Code of Federal Regulations (45CFR Common Rule ) 15includes th 18 th the following 16 th requirements for 4 th informed consent: 20 th A statement that the study involves research, an explanation of the purposes of the research,... a description of the procedures to be followed, and identification of any procedures which are experimental ; a description of any reasonably foreseeable risks or discomforts to the subject ; and a disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject. follow-up study published A statement description disclosure that of of appropriate any the procedures study reasonably involves alternative to foreseeable be research, an procedures followed, risks explanation or The discomforts and OHRP or identification courses of the and to purposes of the treatment, subject of any of the procedures if research any, that might which Another be are advantageous experimental View to the subject 3 articles Second letter from OHRP to Online only published in lead A correspondence defense of center critical of 2 articles in defense of Perspective Editorial Perspective Correspondence 1 st

96 Timeline Study conceived enrollment (2006 BOOST II and COT enrollment begin) study published August 1, 2013 OHRP investigation begins BOOST II Trial stopped early for harm Published CORRESPONDENCE The OHRP and follow-up study published March April May June July August 7 th Letter from OHRP to lead center Another View 2013 Signed By MORE THAN 40 PROMINENT SCIENTISTS, ETHICISTS, AND CLINICIANS a potential differential in the risks that The () consent 10 th 15 th 18 th 16 th 4 th 20 were being tracked (death, retinopathy th of forms failed in each of the NYT Second letter prematurity, and neurologic impairment) editorial NYT 3 articles from OHRP to Online only article elements NYT published in lead A correspondence was reasonably described foreseeable, since above. on opinion defense of center critical of letter 2 articles in determining differential risk was the (of the Common Rule) defense very of Correspondence Perspective purpose of the Editorial study. Perspective Correspondence 1 st

97 Timeline Study conceived March enrollment (2006 BOOST II and COT enrollment begin) study published OHRP investigation begins BOOST II Trial stopped early for harm Published Nearly 4 years, and no compliance action or guidance has been provided follow-up study published by OHRP to resolve this controversy 2013 April May June July August 7 th 10 th 15 th 18 th 16 th 4 th 20 th 1 st 28 th Letter from OHRP to lead center NYT article on NYT editorial NYT opinion letter Correspondence 3 articles published in defense of Editorial Perspective Second letter from OHRP to lead center Perspective 2 articles in defense of Online only A correspondence critical of Correspondence HHS meeting

98 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

99 Summary Understanding Usual care, 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 were not germane to either the trial design or concerns about consent documents

100 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

101 How to Characterize Usual care Literature search Observational studies RCTs Surveys of usual care Chart reviews Range of therapy at enrolling hospitals Patient characteristics that determine treatment approach Prospective studies Practice surveys Observational cohorts

102 Science is simply common sense at its best, that is, rigidly accurate in observation, and merciless to fallacy in logic. Thomas H. Huxley English Scientist

103

104 Critical Care Studies of Commonly Used Therapies Most of these studies cannot be defined as Comparative Effectiveness Research Controls can be protocolized, but need to closely reflect contemporary practices Comparing two experimental treatments or a commonly used intervention in two novel ways compromises safety monitoring

105 Misconceptions Comparative Effectiveness Research In Critical No experimental Care, commonly therapies used therapies meeting No novel Comparative approach Effective to administering Research a requirements commonly used are not therapy common Interchangeable Comparable Risks Therapy 1 Therapy 2