D EPARTMENT OF HEALTH AND H UMAN SERVICES 
OFFICE OF INSPECTOR GENERAL 
WASHINGTON, DC  20201 
SEP  15  2014 

TO:  Jerry Menikoff, M.D., J.D. 
Director 

Office for Human Research Protections 

FROM:  Suzanne MUrri:r} 
Deputy Insjl.OCtur <,Jefieral 
for Evatuatiorvand Inspections 
SUBJECT: 	 Memorandum Report:  The Office for Human Research Protections' 
Evaluation ofthe Surfactant, Positive Pressure, and Oxygenation 
Randomize d Trial, OEI-0 1-14-00560 
This memorandum report provides information about the review by the Department of 
Health and Human Services (HHS) Office of Inspector General to determine whether the 
Office for Human Research Protections (OHRP) followed its procedures in its 
compliance evaluation ofthe Surfactant, Positive Pressure, and Oxygenation Randomized 
Trial (SUPPORT).  OIG reviewed relevant SUPPORT and compliance evaluation 
documents and conducted interviews to assess OHRP's response to an allegation 
re garding the use of informed consent in SUPPORT.  Specifically, OIG's objectives 
were: 
(1) to ensure that OHRP followed procedures and exercised reasonable discretion in 
the compliance evaluation of SUPPORT; and 
(2) to provide specific recommendations for how OHRP or HHS can strengthen its 
review, approval, and monitoring procedures if any violation is found. 
We conducted this analysis in 2013 at the request of a Member of Congress, and we 
shared our findings with the requestor and with HHS.  We are issuing this report to 
present our findings publicly. 
SUMMARY 
We found that OHRP followed its procedures and exercised discretion throughout its 
evaluation of SUPPORT.  Generally, OHRP sees its role as educational and sees such 
evaluations as opportunities to strengthen human subjects protections in future research. 
The events following OHRP's determination in SUPPORT have raised important  Page 2  Jerry Menikoff, M.D., J.D. 
 
questions about the protection of human subjects in research that compares treatments 
within the current standard of care.   
 
BACKGROUND 
 
OHRP  
Section 491 of the Public Health Service Act (42 U.S.C.  289) authorizes the Secretary 
to establish a process to respond to alleged violations of human subjects protection in 
research conducted or supported by HHS. The Secretary has delegated this authority to 
OHRP.1  Pursuant to this authority, when OHRP receives allegations of violations it may 
conduct for-cause compliance evaluations.2    
 
OHRP has developed an 11-step procedure for conducting a for-cause compliance 
evaluation. In general, OHRPs process involves notifying the institution and requesting 
that it investigate the allegation, provide a written response with supporting documents, 
and develop a corrective action plan if any noncompliance is revealed.  OHRP evaluates 
the institutions response and issues a determination letter addressing the allegations of  
noncompliance.  If OHRP identifies noncompliance with human subjects protections 
regulations, it can (1) require the institution to take corrective measures, such as 
developing a corrective action plan or improving institutional policies; (2) restrict or 
suspend research at the institution; and/or (3) recommend that an institution or 
investigator be debarred from receiving Federal funds for research.   
 
OHRP has considerable discretion in this process.  For example, OHRP is able to 
determine whether to conduct a for-cause compliance evaluation; how to assess the 
institutions investigation; whether to consult with experts; and what, if any, are 
appropriate corrective actions. 
 
SUPPORT 
SUPPORT was a randomized multisite study that enrolled about 1,300 premature infants 
between 2005 and 2009. The National Institute of Child Health and Human 
Development (NICHD) within the National Institutes of Health (NIH) funded SUPPORT.  
The University of Alabama, Birmingham (UAB) was the lead coordinating institution of 
the 23 sites in the study.3  Research Triangle Institute (RTI) was the data-coordinating 
center responsible for collecting, storing, and analyzing study data for all sites.   
 
                                                 
1 65 Fed. Reg. 3713637  (June 13, 2000). 

2 OHRP also conducts  not-for-cause evaluations in the absence of allegations  or indications  of  

noncompliance.  OHRP selects institutions for not-for-cause evaluations on the basis of a range of factors, 

including volume of supported research, history  of low-level reporting to  OHRP, and geographic location.
 
3 Other institutions involved in SUPPORT were Case Western Reserve University, Duke University, 

Wake Forest University, Women and Infants Hospital of Rhode Island, Brown  University, the University of 
 
Utah, the University of Cincinnati, Tufts Medical Center, the University of Texas Southwestern Medical 

Center, Emory University, the University of  Rochester, Indiana University, Stanford University, the 

University of Miami, Wayne State University, the University of Iowa, Yale University, the University of 

California, Sharp Mary Birch Hospital for  Women & Newborns, and the University of New Mexico. 
 
OHRPs Evaluation of SUPPORT (OEI-01-14-00560)  Page 3  Jerry Menikoff, M.D., J.D. 
 
One purpose of the study was to determine the appropriate levels of oxygen saturation in 
infants with extremely low birth weights by comparing those receiving lower levels of  
oxygen saturation to those receiving higher ones.  Enrolled infants were randomized into 
two groups and maintained in one of two oxygen saturation target ranges (8589 percent 
or 9195 percent).4  At the time of the study, the standard of care was to treat premature 
infants within an oxygen saturation range of 8595 percent.  In practice, clinicians adjust 
oxygen saturation levels within that range according to an infants individual needs and 
characteristics.5   
 
One objective of the study was to test the hypothesis that a lower target range of oxygen 
saturation compared to a higher range would reduce the incidence of severe retinopathy 
of prematurity (a disease that causes abnormal blood vessel growth in the eye, leading to 
blindness and other visual impairments) or death among infants with extremely low birth 
weights. A second objective of the study was to compare two ventilation treatments in 
such infants. 
 
Allegation of Violation and OHRPs Determination Letter. In May 2011, OHRP received 
an email about SUPPORT alleging that (1) the study design was unethical because some  
infants received severely reduced oxygen and (2) the researchers had not obtained 
informed consent.  In response, OHRP conducted a for-cause compliance evaluation of 
SUPPORT at UAB (see Attachment: Chronology of OHRPs Evaluation of SUPPORT).  
OHRP issued a determination letter to UAB in March 2013 stating that the conduct of 
this study was in violation of the regulatory requirements for informed consent, stemming 
from the failure to describe the reasonably foreseeable risks of blindness, neurological 
damage and death.      
 
METHODOLOGY 
 
We reviewed how OHRP conducted its for-cause compliance evaluation of SUPPORT.  
We assessed how OHRP followed its 11 procedural steps and how the agency exercised 
its discretion. 
 
We reviewed the following documents provided by OHRP:  
 
   the emailed allegation regarding SUPPORT;  
   emails and written communication of relevant OHRP staff involved in the 
SUPPORT compliance evaluation, including communication among staff from  
OHRP, NIH, other HHS offices, UAB, and RTI; 
                                                 
4 SUPPORT Study  Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, Target 
Ranges of Oxygen Saturation  in  Extremely Preterm Infants.  The New England Journal  of Medicine, 2010; 
362:  19591969, May 27, 2010. 

5 J.M. Drazen et al., Informed Consent and SUPPORT.   The New England Journal  of Medicine, 2013; 

368:  19291930, May 16, 2013.  
OHRPs Evaluation of SUPPORT (OEI-01-14-00560)  Page 4  Jerry Menikoff, M.D., J.D. 
 
   the study documents that OHRP requested from UAB as part of its evaluation, 
including SUPPORTs Data Safety Monitoring Committee (DSMC) documents 
and approved informed-consent documents;6 and 
   a summary report of previous OHRP investigations or actions involving UAB. 
 
We also reviewed the minutes for both open and closed DSMC meetings and adverse 
event data provided by RTI. In addition, we conducted structured interviews with OHRP 
and NIH staff involved with SUPPORT. 
 
We did not review the appropriateness of OHRPs determination or actions in its 
SUPPORT evaluation. 
 
This study was  conducted in accordance with the Quality Standards for Inspection and 
Evaluation issued by the Council of the Inspectors General on Integrity and Efficiency. 
 
RESULTS  
 
We found that OHRP followed its for-cause compliance evaluation procedures, 
which are broadly drawn and provide the office with substantial discretion.  
OHRPs activities to ensure institutions compliance are not codified in Federal statute or 
regulations; rather, they appear in compliance procedures issued by OHRP.  These 
procedures give OHRP considerable discretion in how it conducts such evaluations.7   
OHRP specifies 11 steps in a for-cause compliance evaluation; we found that after 
receiving the allegation, OHRP followed its procedures for each step.  Below, we list 
each step and describe the actions OHRP took and how it exercised its discretion.  
 
 Step 1: OHRP determines whether it has jurisdiction to evaluate allegations. 
 
After receiving the emailed allegation on May 24, 2011, OHRP reviewed the published 
results of SUPPORT in a New England Journal of Medicine article referenced in the 
allegation and determined that the study fell within its jurisdiction.8  The article stated 
that SUPPORT was an NIH-funded study; OHRP confirmed this fact by contacting NIH.  
OHRP has the authority to evaluate allegations pertaining to human subject research that 
HHS conducts or supports.9  According to officials at OHRP, the agency receives 
between 80 and 100 allegations per year, of which 5 to 10 fall within its jurisdiction.10    
                                                 
6 A DSMC is an independent committee of experts responsible for reviewing clinical trial data on an 

ongoing  basis to ensure the safety of study subjects and  validity and integrity of the data.  

7 OHRP, Compliance Oversight Procedures for Evaluating  Institutions, October 14, 2009.  Accessed  at 

http://www.hhs.gov/ohrp/compliance/evaluation/  on July 23, 2013. 

8 SUPPORT Study  Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, Target 

Ranges of Oxygen Saturation  in Extremely Preterm Infants. The New England Journal of Medicine, 2010; 
 
362: 19591969, May 27, 2010. 

9  42 U.S.C.  289(b)(2);  65 Fed.  Reg.  .3713637 (June  13, 2000). 
  
10 In addition,  OHRP has authority to evaluate allegations when an institution is covered  by an applicable 

OHRP-approved Federalwide Assurance.  A Federalwide Assurance is a written document that commits 

the institution to  full compliance with  HHS regulations  whenever the institution is engaged in human 
 
subject research  that HHS conducts or supports. 

OHRPs Evaluation of SUPPORT (OEI-01-14-00560)  Page 5  Jerry Menikoff, M.D., J.D. 
 
 
Step  2: OHRP notifies complainant as to whether it will open an evaluation. 
 
On July 18, 2011, OHRP notified the complainant that it would be evaluating the 
allegations related to informed consent/parental permission.   
 
 Step 3: If OHRP chooses to conduct a for-cause compliance evaluation, OHRP sends an 
 inquiry letter to the institution. 
  
 Step 4: OHRP sends copies of the inquiry letter to the principal investigator(s) involved in 
 the research.  
 
OHRP sent an inquiry letter to UAB and RTI on July 18, 2011, copying the principal 
investigator for SUPPORT along with relevant individuals at NIH, NICHD, and the Food 
and Drug Administration (FDA).11  OHRPs inquiry letter included all required 
information outlined in its procedures.  It explained OHRPs compliance procedures, 
described the allegations, and requested that UAB investigate and respond in writing with 
corrective actions if the investigation revealed a violation.   
 
OHRP discretion in initiating the evaluation. Within 2 weeks of receiving the allegation, 
OHRP conducted a preliminary analysis to determine whether the allegation warranted an 
evaluation. OHRP first obtained from NIH the research protocol and the template for 
informed-consent documents.  OHRPs initial decision was that the template did not 
include all reasonably foreseeable risks.  OHRP staff told us that OHRP chose to initiate 
an evaluation even though enrollment in SUPPORT had ended and therefore the element 
of ongoing risk to human subjects was absent.  OHRP considered the evaluation to be 
important because NIH has increasingly funded research of similar design (i.e., involving 
human subjects who are assigned to receive different treatments within the current  
standard of care). OHRP staff reported that when they decide to initiate an evaluation, 
they consider primarily the level of risk to human subjects.  Because each compliance 
evaluation requires OHRP to commit significant human resources, new evaluations may 
require OHRP to reprioritize ongoing or planned evaluations.   
 
OHRP discretion in defining the scope of the evaluation. OHRP reviewed the allegation 
and relevant study documents and chose to focus its evaluation on one institution, one 
study objective, and only the informed-consent issue. 
 
OHRP chose to focus its evaluation on the lead institution, UAB, rather than all of the 
institutions involved in the study.  OHRP staff told us that they expected the outcomes 
among the multiple sites would be similar, so focusing the review on the lead institution 
seemed appropriate.   
 
                                                 
11 OHRP staff indicated that they also included RTI because data-coordinating centers often have access to  
materials that the individual sites dont have.  OHRP later determined that RTI had limited involvement in  
the conduct of  SUPPORT and only collected, stored, and analyzed data for SUPPORT. OHRP 
communicated to RTI that it need  not  respond. 
OHRPs Evaluation of SUPPORT (OEI-01-14-00560)  Page 6  Jerry Menikoff, M.D., J.D. 
 
OHRP staff also explained that they chose to focus the evaluation on one of the two 
research objectives of SUPPORT because the allegation referred specifically to the 
comparison of different oxygen saturation ranges.12    
 
Lastly, OHRP focused its evaluation on the initial informed-consent document that UAB 
used, with the goal of determining whether that document appropriately described the 
research purpose and all reasonably foreseeable risks to human subjects.  OHRP did not 
assess whether any new risks were identified throughout the trial that should have been 
communicated to human subjects as required by 45 CFR 46.116(b).  According to OHRP 
staff, their concern was that known risks at the start of SUPPORT were not set out in the 
informed-consent document that UAB used.   
 
 
Step 5: OHRP evaluates the documentation submitted by the institution in response to its 
 
inquiry letter to determine whether additional information is needed.  
 
 
 
Step 6: OHRP engages external expert consultants as needed.  
 
 
 
Step 7: OHRP presents any questions and concerns in additional written correspondence to 
 
the institution. OHRP can conduct interviews and onsite visits at institutions if relevant. 
 
 
UAB responded to OHRPs inquiry letter on August 26, 2011, stating that it had 
reviewed the institutional review board (IRB) file for SUPPORT and had interviewed 
relevant study staff.  UAB found that its informed-consent document complied with 
45 CFR  46.116(a). Specifically, UAB stated that there were no data from  
evidence-based trials to indicate increased risk or benefits between the two ranges of 
oxygen saturations tested. It also stated that the DSMC had reviewed the study data 
several times and found no concerns with increased risk or benefit. 
 
OHRP started its review of UABs response in January 2012 when it assigned the case to 
a specific coordinator in its Division of Compliance Oversight.  OHRP did not engage 
experts external to HHS in its evaluation, but it did consult experts in NIH before issuing 
its inquiry letter to UAB.  OHRP did not conduct interviews or site visits in its evaluation 
of SUPPORT. OHRP requested additional information from both NICHD and UAB via 
email between January 2012 and April 2012.  OHRP requested informed-consent 
documents from all SUPPORT-involved sites to conduct a comparative analysis of all the 
documents.13  OHRP also requested additional DSMC documents from UAB after 
receiving only some of the open meeting minutes.  OHRP received no additional DSMC  
documents because UAB had none.  OHRP also requested clarification regarding 
oxygen-saturation practices for premature infants at UAB at the time of the study.   
 
OHRP discretion in prioritizing evaluations. Although OHRP received a response from  
UAB to its inquiry letter on August 26, 2011, it did not begin its review until 
                                                 
12 The other arm of the study compared different ventilation treatments. 

13 OHRPs analysis of all informed-consent documents found that  none of the documents listed death as a 
 
risk and that two listed  blindness as a risk. 

OHRPs Evaluation of SUPPORT (OEI-01-14-00560)  Page 7  Jerry Menikoff, M.D., J.D. 
 
January 2012. OHRP staff stated they were unable to commit resources in the interim 
because of ongoing evaluations and insufficient staffing.  In addition, SUPPORT had 
completed enrollment, results had been published, and the element of ongoing risk to 
human subjects was absent.  
 
OHRP discretion in engaging experts.   According to OHRP staff, OHRPs review of 
SUPPORT was based on information included in the SUPPORT protocol and 
informed-consent documents written by the principal investigators themselves and no 
external expert was needed.  OHRP staff explained that they rarely consult outside 
experts during an evaluation, but often contact NIH or FDA to obtain more information 
about specific research and related clinical practices, medical devices, or drugs.  OHRP 
discussed handling the SUPPORT allegation in a manner similar to that of past 
allegations by identifying experts at NICHD who could discuss the trial and by 
requesting a copy of the protocol and model parental permission form.  In addition, 
OHRP staff told us that OHRP had in-house expertise and was familiar with the science 
and debate regarding retinopathy and premature infants.   
 
OHRP discretion in conducting interviews or site visits.  According to OHRP staff, 
OHRP conducts site visits when it has concerns of systemic issues at an institution; when 
certain events occur, such as an unexpected death of a study subject; or when 
correspondence with the institution has been difficult.  None of these issues were 
applicable in OHRPs evaluation of SUPPORT. 
    
 
Step 8: On the basis of the institutions responses and any relevant information received 
 
  from the complainant or other sources, OHRP issues its determination letter(s) to the  
  institution pertaining to the allegations and the institutions program for protecting human 
  subjects.   
 
OHRP issued a determination letter to UAB and RTI on February 11, 2013.  RTI 
contacted OHRP and requested that OHRP remove it from the determination letter 
because of its limited involvement in the trial.  OHRP removed RTI from the letter and 
reissued it on March 7, 2013. In its determination letter, OHRP copied UABs principal 
investigator on SUPPORT along with the principal investigators at each institution in the 
multisite trial.   
 
OHRPs determination letter addressed in detail the specific noncompliance with Federal 
regulations at 45 CFR 46.11(a)(2) that require a description in the informed-consent 
document of any reasonably foreseeable risks and discomforts to the subject.  According 
to OHRP staff, the determination letter included significant detail so that it could serve as 
a resource for the research community. 
 
OHRPs procedures specify eight possible outcomes for evaluations, ranging from  
identifying no issues of noncompliance to recommending suspension and debarment of 
an institution or investigator.  The determination letter to UAB aligns with one possible 
outcome that OHRP described in its procedures, i.e., a determination that the research  
OHRPs Evaluation of SUPPORT (OEI-01-14-00560)  Page 8  Jerry Menikoff, M.D., J.D. 
 
project as conducted was out of compliance with one or more requirements of the Federal 
regulations. OHRP procedures require that in such an instance the institution develop  
and implement corrective actions.  Specifically, OHRP required UAB to provide a plan to 
its IRB to ensure that its approved informed-consent documents include the elements of 
45 CFR  46.116(a). 
 
OHRP discretion in copying all institutions. OHRP conducted its evaluation at the lead 
institution only, but OHRP copied all institutions involved in the study to educate them 
regarding the issues it examined.  OHRP staff told us that OHRPs determination letters 
are commonly reviewed by the broader research community. OHRP staff reported that 
the agencys primary purpose in overseeing federally funded research is educational 
rather than punitive.  Furthermore, staff referenced OHRPs common practice of limiting 
evaluations to one or two institutions in multisite studies and copying the others.  They 
said that conducting one evaluation and making one determination is more efficient and 
achieves the same impact as the alternativein this case, conducting 23 separate but 
similar evaluations.   
  
OHRP discretion in focusing on one regulatory concern.  In its original inquiry letter, 
OHRP listed two concerns with SUPPORTs informed-consent documents not 
adequately addressing two basic elements required by Federal regulations:  
(1) a description of any reasonably foreseeable risks and discomforts and 
(2) an explanation of the purposes of the research.  OHRP staff reported that the agency 
chose to focus its determination letter on the failure to describe in the informed-consent 
document any reasonably foreseeable risks and discomforts.  The staff stated that they  
made this decision because they thought it would be confusing to address both concerns.  
OHRP staff explained that OHRP letters tend to focus on the central regulatory issue, and 
in this case, they believed that the issue was that human subjects were not adequately 
informed of the risks of participating in the study.  
 
  Step 9:  If OHRP makes no determinations of noncompliance or determines that 
  noncompliance has been adequately addressed through corrective action, OHRP concludes 
  the evaluation and informs the institution of this final outcome in writing.   
 
OHRP issued a determination letter, so this step was not applicable.   
 
 
Step 10: OHRP informs the complainant in writing of OHRPs determinations and any 
 
corrective actions taken by the institution upon completion of the evaluation.   
 
 
At the time of our review (i.e., 2013), OHRPs evaluation of SUPPORT was not final and 
OHRP had not informed the complainant of its determination.  
   
OHRPs Evaluation of SUPPORT (OEI-01-14-00560)  Page 9  Jerry Menikoff, M.D., J.D. 
 
 
Step 11: An institution or complainant may request that the Director of OHRP reconsider 
 
any determinations resulting from a for-cause compliance oversight evaluation.  
 
No evidence exists that UAB asked the Director of OHRP to reconsider OHRPs 
determination.  Rather, UAB responded to OHRPs determination on March 22, 2013, 
with a list of corrective actions that the institution had implemented to ensure that  
approved informed-consent documents would include and would adequately address the 
basic elements of consent as required by Federal regulations.   These corrective actions  
included a revision to UABs template for informed-consent documents; the creation of a 
new protocol checklist; and a reminder to the UAB staff of the IRB that all risks must be 
described, even when treatment falls within the parameters of standard of care.    
 
OHRP discretion in maintaining its determination. In mid-April 2013, NIH contacted 
OHRP and raised concerns regarding OHRPs determination letter.  Later that month, 
NIH encouraged OHRP to reverse its determination.  OHRP maintained its determination 
but suspended all compliance actions against UAB.  In a followup letter to UAB on 
June 4, 2013, OHRP committed to providing guidance to address the appropriate way to 
communicate risks to human subjects enrolled in research involving different treatments 
within the standard of care. On August 28, 2013, HHS held a public meeting to discuss 
the protection of human subjects in such research.    
 
SUMMARY OF EVENTS FOLLOWING OHRPS DETERMINATION  
 
In the time since OHRP issued its determination letter in March 2013, additional 
important events and discussion have taken place.  On April 10, 2013, a consumer 
advocacy group brought the determination letter to the attention of the public by sending 
an open letter to HHS Secretary Kathleen Sebelius.  The group agreed with OHRPs 
finding that the informed-consent document was inadequate, but alleged that OHRP had 
failed to demand adequate and meaningful corrective actions by HHS, the medical 
centers that conducted this research, and the IRBs that reviewed and approved it. 
 
After the group released its letter, SUPPORT and OHRPs determination received 
significant attention in the popular media and in professional journals.  Prominent 
scholars, physicians, and bioethicists wrote to the editor of  The  New England Journal of 
Medicine expressing a range of views. Some argued that randomizing infants to different 
oxygen-saturation ranges within a standard of care may increase risk for study subjects. 14   
These individuals agreed with OHRP that the informed-consent documents used in 
SUPPORT were inadequate.  Others argued that treatments within a standard of care, by 
definition, cannot increase risk; that the risk of death in SUPPORT was not supported by 
current research; and that all premature infants have an increased risk of death as a result 
of their condition.15, 16  These individuals considered OHRPs determination regarding 
the informed-consent document to be inappropriate.17    
                                                 
14 R. Macklin et al., The OHRP and SUPPORTAnother View.   The New England Journal  of Medicine, 

2013; 369:  e3, June  26, 2013. 

15 J.M. Drazen et al., Informed Consent and SUPPORT.   The New England Journal  of Medicine, 2013; 

368:  19291930, May 16, 2013.   
OHRPs Evaluation of SUPPORT (OEI-01-14-00560)  Page 10  Jerry Menikoff, M.D., J.D. 
 
NIH encouraged OHRP to withdraw its determination letter on SUPPORT, arguing that 
at the start of SUPPORT, researchers did not have scientific evidence to expect a 
difference in mortality between the two target ranges for oxygen saturation.  Furthermore, 
NIH acknowledged that OHRPs determination letter has raised a larger issue:  the 
question of how risks should be conveyed when the purpose of the research is to compare 
interventions that are all considered to be within the standard of care.  According to NIH 
officials, 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.18     
 
In response to the concerns of the research community and NIH, OHRP issued a 
followup letter to UAB on June 4, 2013. OHRP reaffirmed its decision that the 
informed-consent document was inadequate, but acknowledged the difficulty in defining 
reasonably foreseeable risks in research involving interventions considered to be within 
the standard of care. OHRP put on hold compliance actions against UAB relating to 
SUPPORT and committed to providing guidance on this topic.  
 
On June 26, 2013, HHS announced a public meeting to be held August 28, 2013, on how 
regulations on human subjects protections should be applied to research on interventions 
within the standard of care.  Issues for consideration included defining reasonably 
foreseeable risks and what should be disclosed to subjects in such research.19  The 
announcement also stated that HHS was considering changes to OHRPs compliance 
oversight procedures, including the use of experts during compliance reviews and the 
establishment of an administrative process for appealing OHRPs determinations.20  HHS 
held this public meeting to gather input as it considered developing guidance on the topic.  
Twenty-seven individuals, including SUPPORT subjects parents, bioethicists, 
physicians, and researchers, presented a range of views and provided feedback to OHRP 
on ways to improve oversight of human subjects protections.   
 
FURTHER DISCUSSION  
 
We offer the following observations based on this review and the events that have 
occurred since OHRP issued its determination letter in March 2013.  Our observations 
relate to the retrospective nature of OHRPs compliance review of SUPPORT, OHRPs 
flexibility in its procedures for conducting reviews, and research comparing treatments 
within the standard of care.   
   
 
                                                 
16 D. Magnus and A.L. Caplan, Risk, Consent, and SUPPORT.  The  New England Journal  of Medicine, 

2013; 368:  18641865, May 16, 2013. 

17 B.S. Wilfond et al., The OHRP and Support.  The New England Journal of Medicine, 2013;  368:  e36, 
 
June 20, 2013.  

18 K.L. Hudson et al., In Support of SUPPORTA View from the NIH.   The New  England Journal  of 
 
Medicine, 2013; 368:  23492351, June  20, 2013. 

19 78 Fed. Reg. 38343, 38345  (June 26, 2013). 

20 Ibid. 

OHRPs Evaluation of SUPPORT (OEI-01-14-00560)  Page 11  Jerry Menikoff, M.D., J.D. 
 
Retrospective nature of the SUPPORT review  
 
OHRPs ability to influence directly the informed-consent process for a particular study 
is limited.  Federal regulations rely on IRBs and research institutions, as well as the 
funders of research, to protect human subjects through initial determination of the ethics 
and merits of any particular study and through the informed-consent process.   
 
OHRP received the complaint about the SUPPORT trial 2 years after patient enrollment 
in the trial had concluded.  The study had been completed and the results had already 
been published. As a result, any actions that OHRP took could not have affected the 
course of the research, the informed-consent documents, or the enrollment of individual 
subjects in the study. Although OHRPs review of SUPPORT was retrospective, its 
determination letter addressed the institutions failure to include or adequately address 
reasonably foreseeable risks. The letter required the institution to provide a plan that its 
IRB will use to ensure and adequately address the basic elements of consent in future 
research involving human subjects, as required by Federal regulations.  OHRP shared this 
determination letter with the other 22 institutions involved in the research and posted it 
on its Web site to educate those institutions about expectations for this type of research. 
 
Flexibility in conducting compliance reviews 
 
OHRPs 11-step process for conducting evaluations and the considerable discretion 
provided therein allow it to prioritize and shape its reviews in response to the specific 
circumstances of each allegation.  OHRP can largely choose the specific allegations that 
it evaluates, as well as the content of any determination letters that it issues.  Its 
compliance activities are not codified in Federal statute or regulations; rather, they appear 
in procedures issued by the agency. 
 
In its review of SUPPORT, OHRP exercised its discretion to focus the evaluation on 
risks known at the start of the trial and on whether those risks had been communicated in 
the initial informed-consent document.  Furthermore, in focusing its evaluation on the 
initial informed-consent documents, OHRP exercised its discretion not to review other 
aspects, such as whether any new risks were identified during the trial that should have 
been communicated to human subjects.  Such risks might be found, for example, by the 
DSMC, which reviews data that might not be available to the funders of the research or to 
OHRP.21  
 
Differing views on research comparing treatments within the standard of care  
 
Finally, the discussions about SUPPORT have drawn attention to the protection of human 
subjects in research that compares treatments within the current standard of medical care.  
The goal of such research is to improve current knowledge and practice by determining 
the more effective intervention for diseases and conditions.  OHRPs evaluation and 
                                                 
21  In our review, we became aware that OHRP may not have access to the minutes and records from the 
closed DSMC meetings.  We are following  up  with  OHRP to seek clarification  on its authority to  obtain  all 
DSMC records when needed.    
OHRPs Evaluation of SUPPORT (OEI-01-14-00560)  Page 12  Jerry Menikoff, M.D., J.D. 
 
determination made public fundamental differences on this topic, not just within the 
research and patient advocacy community, but also among government agencies that fund 
and oversee this research. 
 
For example, in an article published in The  New England Journal of Medicine, NIH 
leadership wrote:  [W]e 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 SUPPPORT 
study commenced.22  Given the differing perspectives of NIH and OHRP, HHS is 
reexamining this issue to better ensure that appropriate protections of human subjects are 
in place, while not discouraging progress in scientific research.  
 
CONCLUSION 
 
Our review of OHRPs for-cause compliance evaluation of SUPPORT found that it 
followed its published procedures in conducting that evaluation.  Those procedures are 
broad, meaning that the office has substantial discretion in how it carries out any one 
evaluation. 
 
This report is being issued directly in final form because it contains no recommendations.  
If you have comments or questions about this report, please provide them within 60 days.  
Please refer to report number OEI-01-14-00560 in all correspondence. 
 
 
Attachment 
 
  
 
                                                 
22 K.L. Hudson et al., In Support of SUPPORTA View from the NIH.   The New  England Journal  of  
Medicine, 2013; 368:2349-2351, June 20, 2013. 
OHRPs Evaluation of SUPPORT (OEI-01-14-00560)       Attachment:   
     Chronology of OHRPs Evaluation of SUPPORT   
        (from OHRPs 5/24/11 receipt of complaint to UABs 3/22/13 response  
        to OHRPs determination letter) 
2011  May 24 OHRP receives an email complaint alleging that SUPPORT was 
unethical and researchers did not obtain informed consent from 
participants. 
May 25 OHRP confirms SUPPORT is funded by Eunice Kennedy Shriver 
National Institute of Child Health (NICHD) Neonatal Research Network  
and that OHRP has jurisdiction to conduct an evaluation. 
May 31  OHRP responds to the complainant acknowledging that the complaint 
was received and is under review. 
June 6    OHRP receives the SUPPORT protocol and informed-consent template 
from NICHD and conducts a preliminary review.  OHRP identifies some 
preliminary concerns with the informed-consent document. 
July 7    OHRP initiates a conference call with NICHD to discuss the complaint. 
July 18  OHRP opens an evaluation by sending an inquiry letter to UAB (the lead 
institution of SUPPORT) and RTI (the SUPPORT data-coordinating 
center).   
  OHRP informs the complainant of its action the same day. 
Aug. 26 UAB responds to OHRPs inquiry letter, stating that it found no 
violations during its investigation.   
 
2012  Jan.  OHRP requests additional information from UAB, such as DSMC 
documents and clarification on aspects of SUPPORT. 
June  OHRP drafts its determination letter to UAB.  OHRP asks for additional 
information from UAB and redrafts a few versions before finalizing. 
 
2013  Feb. 11  OHRP sends its final determination letter to UAB and RTI.  
Mar. 7  In response to RTIs request, OHRP removes RTI from the determination 
letter and reissues it. 
Mar. 22  UAB responds to OHRPs determination letter with corrective actions.