In Support of SUPPORT ??? A View from the NIH

Kathy L. Hud­son, Ph.D., Alan E. Guttmacher, M.D., and Fran­cis S. Collins, M.D., Ph.D.

June 5, 2013

Each year in the United States, nearly 500,000 infants — 1 in every 8 — are born pre­ma­turely, before 37 weeks of ges­ta­tion. Despite sub­stan­tial advances in their care, pre­ma­ture infants face a daunt­ing array of chal­lenges; they are at high risk for death in infancy and face severe and life­long health prob­lems if they sur­vive.1 The National Insti­tutes of Health (NIH) has a legal and moral respon­si­bil­ity to do research in part­ner­ship with sci­en­tists and fam­i­lies to opti­mize the care of these highly vul­ner­a­ble infants. In recent weeks, a major pub­lic debate has arisen regard­ing a study designed to do just that. And the ram­i­fi­ca­tions go well beyond this one study: the out­come of this debate could affect how we con­duct and com­mu­ni­cate about crit­i­cal research on inter­ven­tions that are within the stan­dard of care for all dis­eases and conditions.

The Sur­fac­tant, Pos­i­tive Pres­sure, and Oxy­gena­tion Ran­dom­ized Trial (SUPPORT), car­ried out at more than 20 sites between 2004 and 2009, sought to iden­tify, in infants born very pre­ma­turely at 24 to 27 weeks’ ges­ta­tion, the oxygen-saturation level within the range con­sid­ered the stan­dard of care that would min­i­mize the risk of retinopa­thy of pre­ma­tu­rity (ROP), a com­pli­ca­tion of oxy­gen ther­apy that can result in vision loss.2 When the study began, tar­get­ing an oxygen-saturation range of 85 to 95% was becom­ing stan­dard clin­i­cal prac­tice, and the Amer­i­can Acad­emy of Pedi­atrics (AAP) later rec­om­mended this range in its 2007 guide­lines. The SUPPORT researchers and insti­tu­tional review boards (IRBs), prac­tic­ing clin­i­cians, and the AAP had no sci­en­tific evi­dence to expect a dif­fer­ence in mor­tal­ity between the two treat­ment groups in SUPPORT — one with the oxy­gen sat­u­ra­tion tar­get of 85 to 89%, the other with the tar­get of 91 to 95%.

An impor­tant find­ing of the study was a reduced inci­dence of ROP in the lower oxygen-saturation range. How­ever, con­trary to what was known at the time, the study also showed a slightly but sig­nif­i­cantly increased inci­dence of death — 19.9% ver­sus 16.2% (P=0.04) — among infants assigned to the lower as com­pared with the upper range. As a result, last year the AAP amended its guide­lines, cit­ing SUPPORT, and physi­cians treat­ing very pre­ma­ture infants are start­ing to use higher sat­u­ra­tion rates to reduce the risk of death, even with the poten­tially higher risk of ROP at these lev­els. Stud­ies such as SUPPORT that com­pare two alter­na­tives, both within cur­rent stan­dard clin­i­cal prac­tice, often lead to crit­i­cal improve­ments in med­ical care.

The fed­eral Office for Human Research Pro­tec­tions (OHRP), which is charged with pro­vid­ing lead­er­ship in the pro­tec­tion of the rights, wel­fare, and well-being of per­sons involved in research con­ducted or sup­ported by the U.S. Depart­ment of Health and Human Ser­vices (DHHS), asserted in March 2013, on the basis of its own exam­i­na­tion of the evi­dence, that the SUPPORT researchers failed to pro­vide prospec­tive par­ents suf­fi­cient infor­ma­tion about the risks posed by the study. After a detailed review of the pro­to­col, the rel­e­vant con­sent doc­u­ments, and the research lit­er­a­ture, we respect­fully dis­agree with the con­clu­sions of the OHRP, which we believe resulted from a fun­da­men­tal dif­fer­ence in inter­pre­ta­tions of how the reg­u­la­tions should apply to the state of sci­en­tific under­stand­ing when the SUPPORT study com­menced. More­over, there is a larger issue here: how risks should be con­veyed in the informed-consent process when research is com­par­ing inter­ven­tions that are all con­sid­ered to be the stan­dard of care.

In a let­ter dated March 7, 2013, the OHRP asserted that the study’s con­sent form failed to con­vey that “the level of oxy­gen being pro­vided to some infants, com­pared to the level they would have received had they not par­tic­i­pated, could increase the risk of brain injury or death.”3 That find­ing was influ­enced by research con­ducted in the 1950s, but in our view, it failed to assign proper weight to stud­ies con­ducted in pre­ma­ture infants in the 2000s, which used more sophis­ti­cated oxygen-monitoring and oxygen-measurement devices, sim­i­lar to those used in SUPPORT.4 The more recent stud­ies showed no increased risk of death or neu­rode­vel­op­men­tal impair­ment at sat­u­ra­tion lev­els as low as 70%.5

Given these data, the inves­ti­ga­tors had no rea­son to fore­see that infants in one study group would have a higher risk of death than would those in the other group. The babies included in SUPPORT were, of course, fac­ing sub­stan­tial risks because of pre­ma­tu­rity — the same risks as pre­ma­ture babies who were not enrolled in the study — but their care was never com­pro­mised for the sake of the study. The sam­ple con­sent form for SUPPORT stated that each of the “pos­si­ble com­bi­na­tions of treat­ments is con­sid­ered by some units to rep­re­sent their desired approach” ( This state­ment describes the clin­i­cal equipoise at the time of the study, which was, in fact, the jus­ti­fi­ca­tion for con­duct­ing a clin­i­cal trial. Although the OHRP took issue with the con­sent form, it stated that the study design was eth­i­cal — a con­clu­sion worth empha­siz­ing. The increased risk of death was a sig­nif­i­cant and unex­pected find­ing of the study; if it had been known before the study began, stan­dard clin­i­cal care would not have encom­passed the lower oxy­gen range, and it would have been uneth­i­cal to con­duct the study.

The NIH is com­mit­ted to ensur­ing that prospec­tive research par­tic­i­pants — and the peo­ple who speak for and love them — are given clear, com­plete, and accu­rate infor­ma­tion about the risks and ben­e­fits of par­tic­i­pat­ing in research. We are strongly com­mit­ted to sup­port­ing crit­i­cal research stud­ies like SUPPORT, which inform clin­i­cal care by pro­vid­ing rig­or­ous evi­dence for use in daily prac­tice. This con­tro­versy has alarmed some of the par­ents of infants who were in the study, con­fused the bio­med­ical research com­mu­nity, and befud­dled IRBs. Sev­eral other stud­ies seek­ing new insights to improve care for these vul­ner­a­ble infants have been put on hold as the field tries to under­stand the OHRP findings.

But con­tro­ver­sies such as this are also an oppor­tu­nity to advance shared under­stand­ing, pro­vide clar­i­fi­ca­tion, and encour­age progress. The pub­lic debate sur­round­ing the SUPPORT study has set the stage for a sub­stan­tive national dia­logue with the research, advo­cacy, and ethics com­mu­ni­ties on how best to respect and pro­tect par­tic­i­pants in research stud­ies con­ducted within the stan­dard of care and how to define “rea­son­ably fore­see­able risks” in this set­ting. The tim­ing is crit­i­cal — the clin­i­cal research com­mu­nity, bioethi­cists, reg­u­la­tors, IRBs, and prospec­tive research par­tic­i­pants are pay­ing close atten­tion now. The NIH is happy to work with all stake­hold­ers to advance this impor­tant dia­logue and its trans­la­tion into clear guid­ance, in accor­dance with the plan just announced by the DHHS ( In addi­tion, a new let­ter to the Uni­ver­sity of Alabama at Birm­ing­ham from the OHRP, stat­ing its inten­tion to put all com­pli­ance actions on hold until the process of pro­duc­ing appro­pri­ate guid­ance is com­pleted, is avail­able now on the OHRP web­site (

Going for­ward, the NIH strongly and unequiv­o­cally sup­ports the impor­tance of the role of the OHRP in the over­sight of human sub­jects research. But the com­mu­nity will ben­e­fit from an explicit descrip­tion of the process the OHRP fol­lows for inves­ti­gat­ing com­plaints. For exam­ple, when ques­tions are raised about rea­son­ably fore­see­able risks and the state of the sci­ence rel­e­vant to a par­tic­u­lar clin­i­cal trial, appro­pri­ate inde­pen­dent experts might need to be con­sulted. Finally, we are pleased to see the DHHS plans to ensure that inves­ti­ga­tors and IRBs will have a fair and trans­par­ent process for appeal­ing OHRP find­ings and com­pli­ance actions, in those sit­u­a­tions in which rea­son­able peo­ple dis­agree about the actions taken.

The cir­cum­stances sur­round­ing the SUPPORT study have unques­tion­ably cre­ated con­tro­versy in the research com­mu­nity, but the sit­u­a­tion has cre­ated an oppor­tu­nity for a bet­ter under­stand­ing of the sci­en­tific and eth­i­cal issues that must be addressed when design­ing such stud­ies in the future. We look for­ward to work­ing with the OHRP, the research com­mu­nity, and patient advo­cates to improve the effec­tive­ness and eth­i­cal stan­dards of research involv­ing human participants.