January 7, 2016 - Tulane University

Dear Dr. Levy and Mr. Lunn:

Thank you for your September 21, 2013, April 2014, and January 6, 2015 reports in response to our August 12, 2013, April 11, 2014, and November 25, 2014 requests for information relating to human subjects protection programs at Tulane University (Tulane) to evaluate compliance with Department of Health and Human Services (HHS) regulations for the protection of human research subjects (45 CFR part 46).  This is part of our not-for-cause evaluation program at OHRP.  We reviewed 29 informed consent documents, minutes of the most recent IRB meetings, written IRB policies and procedures, IRB guidelines for investigators involved in human subjects research, and other documents.  Based on our review of your response, we make the following determinations regarding the proposed corrective actions, describe other concerns that have been resolved, and make further recommendations:

A. Determinations

1) In our November 25, 2014 letter we expressed concern that the informed consent document for study #140759 “Rituximab for the Treatment of Inhibitors in Congenital Hemophilia A (The RICH Study)” provided in your response did not appear to include an adequate explanation of the purposes of the research.  We note that the informed consent document states, “The primary purpose of this study is to determine [if] Rituximab is effective in decreasing the production of inhibitors in patients with severe congenital hemophilia A and high levels of inhibitors.”  The consent form does not explain what “inhibitors” are and why they are significant.  

We have determined that the informed consent document for The RICH Study  did not include an adequate explanation of the purposes of the research in language understandable to the subject or representative, as required by HHS regulations at 45 CFR 46. 116 and 116(a)(1). We note that of the 29 consent documents that we reviewed, only the consent form for the RICH Study lacked this information.

Corrective Action:  Tulane proposed and is carrying out the following corrective actions: the Tulane University Human Research Protection Office (HRPO) has revised its Biomedical Consent Form Template as follows: (1) to outline a clearer delineation of the study purpose; (2) to include information regarding the necessity to simplify medical terminology in an 8th grade language level by not using technical jargon; and (3) updated the HRPO website to include the revised Biomedical Consent Template with a description of the requirements necessary for the “purpose” statement, that is consistent with the regulatory requirements at 45 CFR part 46.  In addition, the Tulane University research community will be provided with additional instruction through a variety of channels including: email blasts, the Tulane Human Research Protection Program (HRPP) website (http://tulane.edu/asvpr/irb), the Tulane University institutional review board (IRB) Newsletter, and in upcoming training sessions.  The Tulane University IRB members will be re-educated through a variety of channels including: the Tulane HRPP website (http://tulane.edu/asvpr/irb), the Tulane University IRB Newsletter, and in the upcoming bi-weekly IRB meetings.  As a quality assurance measure, targeted audits of IRB-approved informed consent documents and appropriate follow-up will be conducted for six (6) months to ensure compliance regarding language clarity and reading-level appropriateness.  We note that the “RICH” study closed in 2014, therefore these corrective actions are not required for that study. These corrective actions were also intended to respond to determination #2, which follows.  

These corrective actions adequately address the determination.

2) In our November 25, 2014 letter we expressed concern that the informed consent document for the study #280550 “Regulation of skeletal muscle metabolism and regenerative potential in skeletal muscle of patients diagnosed with advance[d] Heart Failure (HF) as compared to a group of patients who do not have CHF” [Congestive Heart Failure]” did not appear to describe the risks of the muscle biopsy done for research purposes in control group subjects.  Regarding the risks of the muscle biopsy, the informed consent document merely stated “Risks associated with the surgical procedure and anesthesia will be outlined for you in the consent forms provided by the surgeon…” A January 9, 2015 email from Roxanne Johnson acknowledged that such biopsies are not standard of care for the control group.

We have determined that that the informed consent document for this study does not describe the risks of the muscle biopsy done for research purposes in control group subjects, as required by HHS regulations at 45 CFR 46.116(a)(2), which require that informed consent include a description of any reasonably foreseeable risks and discomforts.

Corrective Actions:  Tulane proposed and is carrying out the following corrective actions: the Tulane HRPO has updated its Biomedical Consent Form Template, to be clearer with definite language to better outline the necessity for the proper notice of risks. This is available to the Investigators through IRBnet, and the general public at http://tulane.edu/asvpr/irb/guidance.cfm.  In an effort to strengthen the monitoring plan and ensure enhanced compliance, an outside consultant will conduct semi-annual documentation review. This process has already been implemented and will continue going forward.  We note that study #280550 closed in 2014, therefore these corrective actions are not required for that study.

These corrective actions, as well as pertinent corrective actions outlined in item #1, adequately address the determination.

B. Resolved concerns

The following concerns we expressed in our November 25, 2014 letter have been adequately addressed by Tulane.

1) We expressed concern that in some cases IRB review and approval expired and that human subjects research was conducted after expiration of IRB approval, contrary to requirements at 45 CFR 46.109(e), which require that continuing review of research be conducted by the IRB at intervals appropriate to the degree of risk, but not less than once per year.
Institution Response:  Tulane indicated that for all the studies we expressed concern about, either approval did not lapse, or if approval did lapse, no research interactions or analyses of subjects’ identifiable private information occurred during the lapse(s).  Tulane also indicated that to assist investigators, an electronic system generates courtesy reminders to investigators, 60 days, 45 days, and 30 days in advance of the study expiration date so that investigators can submit timely Continuing Review Applications.  Upon study expiration, an expiration notice is automatically sent to the Principal Investigator, warning him/her that IRB approval has expired and that all research activities must be terminated immediately and that lapse in approval is considered non-compliance.  In addition, when a reviewer is assigned to review a protocol, part of the reviewer’s responsibilities is to check the protocol expiration date to ensure that no research has been conducted in a period of lapse. In an effort to strengthen Tulane’s monitoring program, the IRB is amending the Investigator’s Submission Checklist to include questions that ask the investigator to identify the expiration date and if that date has passed, to confirm that no new research has been conducted during the period of lapse in IRB approval.  As a quality assurance measure, targeted audits and appropriate follow-up will be conducted for six (6) months, to ensure that no research studies have incurred periods of lapse and if they have, that investigators have provided adequate assurance to the IRB that no research has been conducted during said lapsed periods.  We recommend that you clarify on the Investigator’s Submission Checklist for studies that have a lapse in IRB approval to confirm that no human subjects research of any kind has been conducted during the period of lapse in IRB approval (not just no new research). OHRP notes that no further action is required.

2) We expressed concern that some studies involve children but do not appear to include assent documents and whether this was consistent with the regulatory requirements at 45 CFR 46.404-406, which require, among other things, that adequate provisions are made for soliciting assent of the children and permission of their parents or guardians, as set forth in §46.408.  We requested assent documents or scripts and permission forms for these studies, or a description of why the IRB found that assent was not appropriate for these studies.

Institution Response: Appropriate assent and parental permission documents for each study were provided.

3) We expressed concern that it was not clear from the informed consent document for the IPFnet Biorepository what data about the subjects will be associated with any specimens donated to the biorepository.  We expressed concern as to whether this was consistent with the regulatory requirements at 45 CFR 46. 46.116(a)(5) which require that informed consent include a statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained.
Institution Response: You indicated that the investigator had properly disclosed to the participant what data about the subject would be associated with any specimen that would be donated to the biorepository.  The consent form states: “Maintaining confidentiality is important to the NIH/NHLBI. Your samples will be labeled with a code (rather than your name or any other unique identifier) prior to shipping to the repository. While this code will be linked to your unique study identification number, your age, gender, and ethnic background information in the IPFnet Data Coordinating Center database will not be transferred to the repository. Therefore the repository database will not include any information about you it will only include this code.”

C. Recommendations

We make the following recommendations regarding Tulane’s human subject protection program:

1) We note that the Standard Operating Procedures (SOP) for the Tulane Human Research Protection Program focus on the procedures for handling reporting of investigator noncompliance. We recommend that those procedures be revised to include more operational details regarding noncompliance by the IRB or other entities or people at Tulane, as required by HHS regulations at 45 CFR 46.103(b)(5).

2) We note that the Report Form for Unanticipated Problems indicates that the Form is due within 10 days of identifying an Unanticipated Problem.  We note that some events, such as an unanticipated death, may need to be reported more quickly.  For example, OHRP recommends, in the Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events, that  “[u]nanticipated problems that are serious adverse events should be reported to the IRB within 1 week of the investigator becoming aware of the event” in order to satisfy the requirement for prompt reporting.  In addition, the Guidance on Reporting Incidents to OHRP provides that “[t] he regulations at 45 CFR 46.103(a) and (b)(5) do not specify a time frame for reporting, except ‘promptly.’ For a more serious incident, this may mean reporting to OHRP within days. . . .” We recommend that the Form be revised to note that some events may need to be reported more quickly.

3) We note that the consent form for study 155389 “Memory Functioning in Children and Adolescents with Perinatal HIV Infection” is for subjects who are no longer minors, but the form states that one of the reasons subjects might be asked to leave the study includes “Discontinuation of participation in AMP before age 18” and there is a signature line for a Parent.  We recommend that these be deleted from the consent form as these items are unnecessary for adult subjects.

Your responses adequately addressed our remaining concerns. At this time, there should be no need for further involvement by our office regarding the determinations and resolved concerns.  Please notify us if you identify new information which might alter this conclusion.  Please feel free to contact me if you have any questions.

We appreciate your institution’s continued commitment to the protection of human research subjects.  

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]

cc:
Ms. Roxanne R Johnson, Human Research Protection Office, Tulane
Mr. Ryan Barbe, Quality Manager/IRB Coordinator, Tulane Hospital & Clinic
Ms. Roberta McDuffie, Chair, Tulane Health Science Center IRB #1 - Biomedical
Dr. Fred Buttell, Chair, Tulane-Uptown Campus IRB #1 - Social/Behavioral

Dr. Joanne Less, Food and Drug Administration
Ms. Bridget A. Foltz, FDA
Dr. Sherry Mills, National Institutes of Health (NIH)
Dr. Michelle Bulls, Director of OPERA, Office of Extramural Research, NIH
Ms. Sarah Carr, Office of Science Policy, NIH