May 7, 2015 - Howard UniversityMay 7, 2015
Thomas Obisesan, M.D.
Associate Vice President for Regulatory and Research Compliance
Howard University Research Building 1
1840 7th Street, N.W.
Washington, DC 20001
Dear Dr. Obisesan:
The Office for Human Research Protections (OHRP) conducted an on-site evaluation of the human research subject protections program at Howard University (Howard) on July 25, 2013 and from September 4–6, 2013. The evaluation was conducted as part of a follow-up to a compliance oversight evaluation of that program in 2009, and to assess the implementation of corrective actions from that 2009 review as stated in the letters OHRP sent you dated January 29, 2010 and April 30, 2010. The concerns at those times were as follows:
Numerous protocols were approved, even though the IRB had substantive questions about how the research would be conducted, before the IRB received information it would have needed in order to make the determinations required under Department of Health and Human Services (HHS) regulations at 45 CFR § 46.111.
The IRB failed to conduct continuing review of research at least once per year for numerous studies and research was conducted after expiration of IRB approval, contrary to what is required by 45 CFR § 46.109(e).
Howard University did not have written IRB procedures that adequately describe the process the IRB will follow for determining which projects need verification from sources other than the investigators that no material changes have occurred since previous IRB review, as required by HHS regulations at 45 CFR § 46.103(b)(4). OHRP noted that the written procedures did state that such verification will occur, but did not state how projects needing such verification will be identified.
An investigator initiated human subjects research without either (1) having obtained legally effective informed consent of subjects or (2) the IRB appropriately waiving this requirement in accordance with 45 CFR § 46.116. An unanticipated problem involving risks to subjects or others was not reported to OHRP, as required by HHS regulations at 45 CFR § 46.103(a) and § 46.103(b)(5). To be specific, the complainant alleged that a research assistant for a study obtained personal information about a subject in the study and harassed her by phone. In addition, the research assistant shared identifiable private information about the subject with persons not associated with the research.
The on-site evaluations in 2013 were followed by on-site training by OHRP at Howard on February 6, 2014. We issued a question and concern letter dated August 4, 2014 related to some of the issues we had discovered in our 2009/2010 evaluation, along with new issues. We received reports from Howard dated October 1 and 22, 2014 responding to our August 4, 2014 letter. We apologize for the delay in responding to your October 2014 reports.
Based on the documents provided to us prior to, during, and after the on-site evaluation, and information gathered from interviews conducted during the on-site evaluation, we make the following determinations:
Determinations regarding your institution's system for protecting human subjects
1. In our August 4, 2014 letter, we expressed a concern that the IRB, when reviewing research study applications, sometimes appeared to lack sufficient information to make the determinations required for approval of research under HHS regulations at 45 CFR § 46.111. We noted that many expedited review files did not appear to have sufficient information. In particular, all chart review studies are submitted on form B-1 (Howard University Institutional Review Board Application for Chart Review Request), which has no section for gathering information regarding the obtaining and documentation of informed consent or waiver of informed consent. We note that HHS regulations at 45 CFR § 46.111 require that in order to approve research the IRB must determine, among other things, that informed consent will be sought from each prospective subject or the subject's legally authorized representative, or else waived, in accordance with, and to the extent required by 45 CFR § 46.116, and that informed consent will be appropriately documented, in accordance with, and to the extent required by, 45 CFR § 46.117.
It appears that as a result of the inadequacies of form B-1, the IRB failed to receive this information for some chart review studies. For example, in research study 13-CMED-42, “Identifying the Common Organisms Causing Sepsis in African American Patients with Co-Morbid Illnesses Admitted to Medical ICU, Likely Source of Sepsis, Risk Factors and the Outcome,” and in research study 13-CMED-36, “Tricuspid Annular Plane Diastolic Excursion and Morphology: A Marker of Right Ventricle Diastolic Function,” there was no information in the application to the IRB regarding informed consent being obtained or being waived.
We have determined that the IRB, when reviewing chart review research study applications, sometimes lacked sufficient information to make the determinations required for approval of research under HHS regulations at 45 CFR § 46.111.
Corrective Action: Howard has implemented new safeguards to ensure that the investigator provides the informed consent document and information about the informed consent process, when appropriate, to the IRB. Checklists ensure that the IRB finds and documents specific criteria when reviewing such applications. These include consideration for the waiver or alteration of some or all of the required elements of informed consent as required by HHS regulations at 45 CFR 46.111 and 45 CFR 46.116. Specifically, the form B-1 has been revised to include an informed consent checklist, with questions about waiver of informed consent and documentation of informed consent and the involvement of any vulnerable population. In addition, Howard provides a checklist to each IRB reviewer along with meeting materials, and requests that the primary reviewer complete the checklist while other members of the IRB are encouraged to act similarly. Howard will not approve a waiver of informed consent or informed consent documents lacking the required elements without a justified waiver or alteration of the informed consent requirements in accordance with the regulations. This corrective action adequately addresses the determination and is appropriate under your assurance.
2. In our August 4, 2014 letter, we expressed a concern that the IRB did not appear to always make the required findings when reviewing research involving children. For example, there were no 45 CFR part 46 Subpart D findings for studies involving children in research protocols 13‐PNAH‐15, “Physical Therapy Division of Allied Health Sciences” and 13‐MED‐03, “Inhibition of HIV‐1 Sickle Cell Disease.” We note your October 1, 2014 response that children were not involved in 13‐MED‐03, and that you acknowledge the lack of evidence that the protocol IRB-13-PNAH-15 received adequate consideration on the inclusion of children, and that the review of the protocol may not have complied with 45 CFR §§ 46.404-409.
We have determined that the IRB did not always make the required findings when reviewing research involving children, as required by regulatory requirements at 45 CFR §§ 46.404-409 which require specific findings on the part of the IRB for approval of research involving children.
Corrective Action: Howard has implemented a new procedure to safeguard the interest and welfare of vulnerable populations enrolled in research. When reviewing protocols that will enroll children, IRB members must address the additional regulatory requirements outlined in Subpart D. Each IRB member must assess all proposed research to determine whether any fits into one of the allowable categories at 45 CFR §§ 46.404-46.409. To assist IRB members with making the specific findings, the Office of Regulatory Research Compliance (ORRC) has created reviewer worksheets and supplemental forms for all vulnerable populations, one of which clearly specifies the criteria for approval and additional considerations for research involving children. This corrective action adequately addresses the determination and is appropriate under your assurance.
3. In our August 4, 2014 letter, we expressed a concern that the IRB failed to meet the quorum requirement for certain IRB meetings. Thus, any actions taken at these meeting that required a quorum were not valid under the HHS regulations at 45 CFR § 46.108(b). For example, in the IRB meeting held on April 27, 2011, there was no quorum for the entire meeting and the IRB approved research during that meeting.
We expressed a concern that the minutes of IRB meetings appeared to sometimes lack sufficient detail to show attendance at the meetings, and the votes on any IRB actions, including the number of members voting for, against, and abstaining, as required by HHS regulations at 45 CFR § 46.115(a)(2). While we found no evidence of conflict of interest for the initial and continuing review of the referenced protocols, recusals of IRB members for conflict of interest are not consistently documented in the minutes, and the vote tally sometimes is not adjusted for those IRB members who have been recused. Examples can be found in 12-MED-04 (May 29, 2013 minutes); 06-MED-39 and 10-MED-40 (May 1, 2013 minutes); and 09-PED-07 and 10-MED-21 (May 15, 2013 minutes).
We have determined that the IRB failed to meet the quorum requirement for certain IRB meetings found in HHS regulations at 45 CFR § 46.108(b). We have determined that the minutes of IRB meetings were sometimes lacking in sufficient detail to show attendance at the meetings, and the votes on any IRB actions, including the number of members voting for, against, and abstaining, as required by HHS regulations at 45 CFR § 46.115(a)(2).
Corrective Actions: Howard has reviewed and revised the IRB Policy and Procedures to ensure compliance with the quorum requirements at 45 CFR 46.108(b). Documentation of the Howard IRB meetings is now enhanced with a new form intended to capture the important elements of the meeting, including but not limited to conflicts of interest and discussions of controverted issues. Further, the IRB chair and ORRC staff summarize IRB discussions prior to voting on all protocols. During this process, the IRB clearly indicates for the minutes any concerns that may prevent the Board’s approval of a protocol according to HHS regulations at 45 CFR 46.111 and, if applicable, subparts B, C, or D of 45 CFR part 46. These corrective actions adequately address the determination and are appropriate under your assurance.
4. In our August 4, 2014 letter, we expressed a concern that unanticipated problems involving risks to subjects or others, and suspensions or terminations of IRB approval apparently were not always reported to OHRP, as required by HHS regulations at 45 CFR § 46.103(a) and § 46.103(b)(5). For example, in 11-MED-46, the April 18, 2012 minutes indicate an incorrect dosage of the study drug was given on February 22, 2012, with no indication of this event being reported to OHRP. In research study 09-MED-13, on October 26, 2011, the IRB suspended its approval of the research for issues involving confidentiality and changes in the consent form with no indication of this being reported to OHRP.
We have determined that unanticipated problems involving risks to subjects or others, and suspensions or terminations of IRB approval were not reported to OHRP, as required by HHS regulations at 45 CFR § 46.103(a) and § 46.103(b)(5).
Corrective Actions: Howard staff and IRB members are undergoing continuing education about IRB reportable events in accordance with 45 CFR § 46.103(a) and 45 CFR § 46.103(b)(5). In addition, new IRB policies and procedures that provide guidance on satisfying all HHS regulatory requirements outlined at 45 CFR 46.103(a) and 46.103(b)(5), and new minutes forms and documents, are now in place. Finally, Howard is currently working on developing an ongoing quality assurance monitoring program for IRB activities. These corrective actions adequately address the determination and are appropriate under your assurance.
5. In our August 4, 2014 letter, we expressed a concern that Howard applied an exemption to research activities that appear to be non-exempt human subjects research, in violation of HHS regulations at 45 CFR part 46. One example where there was not enough information in the file available to make an exemption decision is in 13-MED-31 “Detection of Methylation Targets in Advanced Adenoma in African Americans: Discovery of Colorectal Cancer Risk Markers.” In a review of the record, there was insufficient information in the submission to satisfy the exemption category of 45 CFR § 46.101(b)(4), which requires that existing information be publicly available or that existing information cannot be identified, directly or through identifiers linked to the subjects. We further note that there is some confusion on the part of those reviewing exemptions about the exempt categories. For example, protocol 12-EACS-03 was approved under exemption category 45 CFR § 46.101(b)(4), but it appears as if it could be exempt under 45 CFR § 46.101(b)(1) and not under exemption category 45 CFR § 46.101(b)(4).
We have determined that Howard applied an exemption to research activities that appear to be non-exempt human subjects research, in violation of HHS regulations at 45 CFR part 46.
Corrective Actions: To improve the accuracy of exemption determinations, new exempt application documents clearly delineating exempt criteria and reviewer checklists are now in place. Education of IRB staff, IRB members and the academic community is ongoing. This corrective action adequately addresses the determination.
6. In our August 4, 2014 letter, we expressed a concern that IRB approvals apparently lapsed before continuing review took place in several research studies. For example, in research studies 00-PED-04, 04-MED-03 and 12-MED-44, there were no continuing review approvals for periods of more than one year after the prior approval. Additionally, during our interviews, we heard from several people that they were aware of lapses in approval and that this was an issue that the ORRC staff were attempting to address.
We have determined that IRB approvals lapsed before continuing review took place in several research studies, in violation of HHS regulations at 45 CFR § 46.109(e).
Corrective Actions: ORRC communication with the principal investigator (PI) of protocols with lapses in approval will now include the requirement for cessation of non-exempt human subjects research until an approval is granted, unless such cessation may cause harm to research subjects. As a matter of Howard policy, PIs are reminded that any data inadvertently collected during this period are to be discarded. The IRB initiated a new protocol expiration dates tracking system to alert the IRB of protocols about to expire, necessitating the PIs to submit continuing review applications or closed-out requests as needed. As a courtesy to investigators, and to enhance compliance, the ORRC now sends the relevant PIs and administrative contacts email reminders at 60, 45, and 30 days prior to protocol expiration. This corrective action adequately addresses the determination and is appropriate under your assurance.
The corrective actions adequately address all of the determinations. Please notify us if you identify new information which might alter this conclusion. We anticipate conducting an on-site evaluation within the next two years to follow up on implementation of these corrective actions.
We appreciate the steps your institution has taken to respond to our determinations and for 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
Dr. Wayne Frederick, President
Dr. Robert L. Copeland, Jr., IRB Chairperson
Dr. Alfonso L. Campbell, Jr., IRB Chairperson
Dr. Joanne Less, FDA
Dr. Michelle Bulls, Director of OPERA, Office of Extramural Research, NIH
Ms. Sarah Carr, Office of Clinical Research and Bioethics Policy, Office of Science Policy, NIH
Content last reviewed on May 22, 2015