May 5, 2016 - University of Nebraska Medical Center

Ernest Prentice, PhD
Associate Vice Chancellor for Academic Affairs
University of Nebraska Medical Center
Office of Regulatory Affairs
University of Nebraska Medical Center
987830 Nebraska Medical Center
Omaha, NE 68198-7810

Human Research Protections Under Federalwide Assurance FWA-2939

Research Project: Echocardiography guided hemodynamic management for elderly surgical patients

Principal Investigator: Sasha K. Shillcutt, MD

HHS Protocol Number: R03 AG045103 01A1

Dear Dr. Prentice:
Thank you for your January 29, 2015 report in response to our December 18, 2014 request that University of Nebraska Medical Center (UNMC) evaluate allegations of noncompliance with Department of Health and Human Services (HHS) regulations for the protection of human research subjects (45 CFR part 46).  Based on review of your response, we make the following determinations:
A. Determinations regarding the above-referenced research
1) The complainant alleged that subjects were being informed that the procedures that are being performed during the research protocol are part of standard of care, when they are not.  The HHS regulations at 45 CFR 46.116(a)(1) require, in part, that when seeking informed consent, subjects be provided with a description of the procedures to be followed, and identification of any procedures which are experimental. 
Based on the documentation provided in your January 29, 2015 correspondence, we make no finding regarding this allegation. Your response indicated that the echo sonographer technician named by the complainant as having witnessed the interaction between the principal investigator and this subject (or other subjects) was unable to substantiate the allegation and the principal investigator denied the allegation. Your response also indicated that the principal investigator asserted that though the research protocol called for performance of trans-esophageal echocardiography (TEE) in all subjects (both experimental and control), most patients who would have been eligible for this research (age > 70 years, with grade I-III LVDD undergoing major vascular surgery), would have had a TEE performed as part of standard clinical intraoperative monitoring independent of their participation in the research. However, we note that the protocol states, “Routine echocardiography in this study deviate[s] from Standard of Care at UNMC.”
2) The complainant alleged and we have determined that informed consent was not documented for some subjects by a written consent form signed by subjects (or their legally authorized representatives) prior to their involvement in this research, as required by 45 CFR 46.117(a), and that there was no IRB waiver of this requirement as permitted by HHS regulations at 45 CFR 46.117(c).  In specific, we note the following:
a. Your response indicated that a compliance subcommittee was formed to conduct the investigation into the allegations.
b. Based upon the information (particularly the informed consent documents) reviewed by the subcommittee, it was determined that the principal investigator clearly did not comply with the HHS regulations and the institutional requirement for documentation of consent (specifically, a signature of the subject or the subject’s legally authorized representative on the consent form).
Corrective Action:   
UNMC is implementing the following corrective actions to address this determination: informed consent will be obtained by the principal investigator until the training of two recently hired Research Nurse Coordinators (RNCs) is completed; a check list will be implemented to ensure that all elements of the consent have been completed; random audits of the process of informed consent will be completed until the problem has been rectified; the principal investigator and entire study staff must undergo mandatory re-training on the process of consent and the requirements for the documentation of informed consent; the IRB Education Coordinator must observe the consent process for a minimum of three subjects; the study coordinators will only be involved in the process of consent, but will not be responsible for documenting consent; all members of the Department of Anesthesiology who are involved in research must participate in mandatory IRB training on obtaining of informed consent with the IRB Education Coordinator; and the study remains on hold until the mandatory education is completed. These corrective actions adequately address the determination.
3) The complainant alleged that a subject was enrolled who was ineligible for the trial, due to the patient requiring cardiopulmonary bypass in an effort to save his life.  The HHS regulations at 45 CFR 46.103(b)(4)(iii) require that the IRB review and approve all proposed changes in a research activity, during the period for which IRB approval has already been given, prior to initiation of such changes, except when necessary to eliminate apparent immediate hazards to the subjects. Based on the documentation provided in your January 29, 2015 correspondence, we have determined that this allegation of noncompliance is unproven.  Your response indicated that no evidence was found that the patient was ineligible for the research prior to the surgery (at the time consent would have been obtained). There is also no evidence that the patient was enrolled when he was undergoing “cardiopulmonary bypass in an effort to save his life.”
4) The complainant alleged that the protocol stated that the Data Safety Monitoring Board (DSMB) would meet in the event of the death of a subject and that this did not occur. OHRP notes that the protocol does not require this, but does require the DSMB to meet every six months. In emails dated January 6, and February 12, 2016, UNMC indicated that the DSMB did not meet at all the first 3 years of the study, a deviation from the protocol not approved by the IRB.  We have determined that failure of the DSMB to meet every six months is contrary to the regulations at 45 CFR 46.103(b)(4)(iii) described above.  
Corrective Action:
UNMC will revise and expand the questions in its continuing review application.   The question regarding DSMB for the study will be revised to: “Does the IRB application indicate there would be a Data and Safety Monitoring Board (DSMB) for this study?  If the investigator answers “yes”, he or she will be asked “Has the DSMB been established?”  If they answer “no,” he or she will be asked to explain why it has not been established.  If they answer “yes” they will be asked “Has the DSMB met according to the timeline described in the IRB Application”.  If they answer “no” they will be asked to explain why they have not met.
The corrective actions adequately address the determinations.  At this time, there should be no need for further involvement by our office in this matter.  Please notify us if you identify new information which might alter this determination.
We appreciate the continued commitment of your institution to the protection of human research subjects.  Please do not hesitate to contact me should you have any questions. 

Kristina C. Borror, Ph.D.
Director, Division of Compliance Oversight
1101 Wootton Parkway, Suite 200
Rockville, Maryland  20852
Telephone: 240-453-8132
FAX:    240-453-6909
E-mail: [email protected]

Ms. Gail Paulsen, IRB Administrator III, UNMC
Dr. Bruce Gordon, IRB Chair, UNMC IRBs
Dr. Sasha K. Shillcutt, UNMC
Dr. Joanne Less, FDA 
Ms. Bridget A. Foltz, FDA
Dr. Richard J. Hodes, Director, National Institute on Aging
Dr. Sherry Rodgers, Director Office of Extramural Programs, National Institutes of Health (NIH) 
Dr. Michelle Bulls, Director of OPERA, Office of Extramural Research, NIH
Ms. Sarah Carr, Office of Science Policy, NIH 
Content created by Office for Human Research Protections (OHRP)
Content last reviewed