July 13, 2022 – Biomedical Research Alliance of New York (BRANY)

Dear Ms. Hart:

The Office for Human Research Protections (OHRP) conducted a site evaluation of the IRB Services at the Biomedical Research Alliance of New York (BRANY) IRB from April 5 to April 15, 2021. The evaluation was conducted as part of OHRP’s program to evaluate Human Research Protections Programs (HRPPs) of institutions and institutional review boards (IRBs) that review research receiving Department of Health and Human Services (HHS) support for compliance with 45 CFR Part 46.

This evaluation was conducted by OHRP and involved a review of study files for approximately 50 of 262 active HHS-funded studies, IRB written procedures and checklists, IRB meeting minutes, and reliance agreements. Two IRB meetings were observed on April 8th and April 12th. OHRP was pleased to observe that continuing education was provided during the IRB meetings. In addition, during meetings staff were very accessible and promptly responsive to the needs of the IRB members.

OHRP conducted multiple interviews with BRANY’s IRB officials, IRB Chairs, IRB members, Quality Assurance staff and other support staff with a variety of responsibilities. Those we interviewed displayed a sincere commitment to the work of BRANY’s IRB and viewed themselves as providing a valuable service in the IRB’s process.

Based on review of the documents you provided and your responses to the questions and concerns outlined in our letter dated February 22, 2022, OHRP makes the following determinations:

Determinations:

1.   For protocol U-001 entitled, “Single-Center Phase II Efficacy and Safety study utilizing Utepreva, a new endometrial sampling device, as compared to standard sampling techniques,” OHRP questioned whether the IRB appropriately considered several of the 45 CFR 46.111 approval criteria.

According to your responses, BRANY IRB agreed with OHRP’s concerns. The following details OHRP’s determinations regarding this study:

a.   A description of the criteria the study would use to evaluate the safety of the experimental sampling device was not found in the study documents. No data and safety monitoring plans were evident; however, the protocol stated that an analysis of the data will be conducted once 50% of study subjects have been enrolled. OHRP determines that this did not meet the criteria of 45 CFR 46.111(a)(6) which requires an IRB to ensure, when appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects.

b.   No information was apparent regarding any prior use of the experimental device to suggest it was safe or effective. OHRP determines that insufficient information was provided regarding whether the device was safe and effective and, thus, the IRB did not have sufficient information to evaluate the risk-benefit ratio of the study as required by 45 CFR 46.111(a)(2).

The consent form did not clearly state that subjects would be required to have an additional biopsy taken for research purposes. The consent form stated that the biopsy taken with the experimental device will be compared to the one taken with the FDA-approved device but does not explicitly state that the subjects will have an additional biopsy. The portion of the consent form describing the risks of the study only discussed the risk of the biopsy procedure in general, not the risks associated with the additional biopsy performed with the experimental device. Further, the protocol erroneously stated that subjects in this study will not be exposed to additional risk from interventional procedures, because the procedures used are the standard of clinical practice for these patients. OHRP determines that risks specific to research procedures were omitted from the consent document, which did not meet the requirement that the consent form contain “a description of any reasonably foreseeable risks or discomforts to the subject” (45 CFR 46.116(b)(2)).

In addition, the consent form stated, “There is no guarantee that the Utepreva device will benefit you, but it is hoped that it will promote the early detection of uterine cancer for patients in the future.” OHRP determines this general statement did not provide enough information to subjects as it remained unclear if the research would offer subjects the potential for direct benefit, the possible type or types of benefit, and the likelihood of such benefits occurring. This general statement did not meet the requirement that the consent form includes “a description of any benefits to the subject or to others that may reasonably be expected from the research” (45 CFR 46.116(b)(3)).

In light of the above facts, OHRP determines that these statements in the consent form about the risks and possible benefits of the research did not provide information necessary to satisfy the requirement that the “informed consent as a whole must present information in sufficient detail relating to the research, and must be organized and presented in a way that does not merely provide lists of isolated facts, but rather facilitates the prospective subject’s or legally authorized representative’s understanding of the reasons why one might or might not want to participate” (45 CFR 46.116(a)(5)(ii)).

Corrective actions: OHRP acknowledges that BRANY concurred with these concerns and provided several corrective actions to address them. The following corrective actions were taken by BRANY:

1.   Training was provided to the IRB Chairs, IRB members and IRB staff on the requirements for ensuring that there is sufficient information to be able to determine all the criteria for IRB approval have been satisfied including, but not limited to those noted by OHRP. These included the following:

a.   Ensuring the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects, as applicable, as required by 45 CFR 46.111(a)(6)

b.   Ensuring the IRB has sufficient information to evaluate the risk-benefit ratio of the study as required by 45 CFR 46.111(a)(2)

c.   Ensuring that the consent form clearly describes the risks associated with the research procedures

d.   Ensuring the consent form includes a description for the benefits to the subjects or to others that may reasonably be expected from the research, if any, as required by 45 CFR 46.116(b)(3).

e.   Ensuring the consent form presents information in sufficient detail relating to the research and is organized and presented in a way that facilitates the prospective subject’s understanding of the reasons why one might or might not want to participate, as required by 45 CFR 46.116(a)(5)(ii).

2.   An additional training session with the IRB staff took place to review submission pre-screening processes and use of internal submission screening checklists to ensure all required information and documentation is received to facilitate review by the IRB.

3.   The Quality Assurance department will conduct an IRB file review focused on examining a sample of studies to confirm that the IRB consistently has sufficient information to determine that criteria for IRB approval are met in accordance with regulatory requirements.

According to your response, this study closed in October 2021.

2.   For the protocol entitled, “Skin Barrier Abnormalities and Oxidative Stress Response in the Skin of Atopic Dermatitis Patients with Food Allergy, ADRN3 CRC” that was approved via expedited review category 3, OHRP questioned whether this study qualified for expedited review since it involves a skin punch biopsy which appeared to be invasive.

According to your response, BRANY IRB agreed this study did not qualify for review under an expedited procedure. OHRP determines that as this study did not meet the conditions of any of the expedited review categories, as required by 45 CFR 46.110(b)(1), and that the expedited review procedure was inappropriately applied.

Corrective actions: OHRP acknowledges that BRANY concurred with these concerns and provided several corrective actions to address them. BRANY re-reviewed and approved the study at the convened IRB. The IRB reviewed the protocol and the materials related to prior IRB reviews.

The following corrective action plan was implemented to prevent this type of oversight in the future:

1.   The IRB Chairmen, IRB members and IRB staff were provided with training to ensure that the correct level of review is always applied to each submission received by the IRB. The training included emphasis on expedited review categories 3 and 4, and the need to ensure procedures approved under these categories are noninvasive. Training materials were provided to all IRB members and IRB staff.

2.   The IRB updated its IRB reviewer checklist so that when expedited review category 3 or 4 is selected the reviewer must affirm that research procedures are not invasive. Instructions in the reviewer checklist also remind reviewers that when research involves invasive procedures the expedited review procedure cannot be utilized, and the reviewer must refer the research project for review by the convened IRB.

An internal quality assurance compliance review was also conducted. The review focused on examining the IRB records for studies reviewed and approved under expedited review categories 3 or 4. The goal of the review was to ensure that the research reviewed under these expedited review categories did not include invasive research procedures. A subsequent review will be scheduled for later in 2022 to ensure the effectiveness of the corrective actions.

Resolved Concerns:

The following are BRANY IRB’s responses to other questions raised by OHRP.

1.   During OHRP’s visit, BRANY noted they were piloting a new Local Research Context Form and OHRP inquired about the status of the new form.

Response: According to your response, the Local Research Context Form has been fully implemented and is now required for all applicable submissions. The form is completed by a representative of the local site’s HRPP and collects information including but not limited to local requirements, state or tribal laws that stipulate requirements for the conduct of the research, information regarding any history of audits and compliance findings, if applicable, as well as community or cultural norms. This ensures that local context is applied for each study site reviewed by the IRB.

2.   During the record reviews, OHRP noted that the files in the IRB records seemed inconsistently named and the location of the files varied among study records, which made it a challenge to reconstruct a complete history of some IRB actions related to a protocol review.

Response: According to your response, BRANY IRB recognized that the way that the roles and permissions were set up in the electronic records needed to be revised to make documents more readily accessible during audits.

OHRP acknowledges that BRANY implemented several procedures to improve the accessibility, the format of the electronic IRB files and the labeling and visibility of documents and correspondence within the file.

To ensure that the above practices are being consistently implemented, BRANY’s Quality Assurance department will complete an initial quality assurance review in 6 months and then periodically thereafter.

3.   During the IRB meetings OHRP observed, it was unclear to the site visit team what study information the IRB members had access to in order to satisfy the approval criteria outlined in 45 CFR 46.111 for the research and at 45 CFR 46.116 for the informed consent.

a.   It was unclear to the OHRP site visit team what information IRB members received to evaluate research submissions to ensure that IRB approval criteria are met prior to granting approval. OHRP requested clarification regarding what information the IRB receives to conduct deliberations during convened meetings.

Response: According to your response, all members of the IRB are provided with the Research Applications, full protocols, informed consent/assent documents. A primary and secondary reviewer are assigned for each study and these reviewers are provided the same materials provided to all IRB members. In addition, the primary and secondary reviewer also receive the investigator brochure (when applicable), the curriculum vitae of the Principal Investigator and the protocol summary.

During convened meetings, IRB staff and IRB members access relevant agenda materials and IRB records through the e-IRB system to support the IRB review.

b.   It was unclear if the IRB had access to documents that included revisions to the protocol or consent form that were proposed by the primary or secondary IRB reviewers. Other IRB members seemed to rely on the primary and secondary reviewers’ oral description of their proposed changes to the protocol and consent form. The IRB did not appear to summarize the conditions for approval prior to taking a vote on whether to approve the research.

Response: According to your response, all IRB members are made aware of the changes required to secure approval during the discussion at the convened meeting facilitated by the IRB Chairman. All IRB Members are provided with access to checklists completed by the primary and secondary reviewers. These checklists guide the reviewer’s assessment of the study and document the reviewer’s recommendations for any changes to the research and the consent document. Reviewers attach a tracked changes version of the consent forms to their checklist. This information is available for all IRB members to view. To ensure all comments and changes are mentioned and clarified during the discussion at the meeting, during the presentation from the primary and secondary reviewers, the IRB Staff follow the review using the same checklists completed by the reviewers including the tracked changes provided by the reviewer.

If the discussions during the convened meeting change the determinations or change the modifications recommended by the reviewers or documented on the reviewer’s checklist, those changes are stated at the meeting and captured in the meeting minutes. IRB staff confirm that the reviewer checklist is appropriately updated or annotated to reflect the IRB’s final determination.

Once the IRB Chair confirms that all deliberations are complete, and all changes or determinations required by the IRB to secure approval have been discussed, the IRB will take the vote and make its final determination. The deliberations and vote are recorded in the IRB meeting minutes.

The IRB staff then combine the changes provided by the assigned reviewers, add any additional revisions that were summarized during the meeting discussion, and provide the researcher with a conditional approval decision notice. The conditional approval decision notice enumerates any clarifications requested by the IRB and provides tracked changes versions of consent forms or other documents that resulted from the IRB discussion.

To improve how required changes are delineated, BRANY IRB adopted a process whereby during convened meetings, IRB staff will display changes or requested clarifications discussed by the committee for the informed consent, protocol, application, or other materials prior to the vote.

c.   For studies reviewed at a convened meeting when the IRB required changes to secure approval, it was unclear who verified the required changes were made if the changes did not require review by the convened IRB. It was unclear how BRANY IRB designated individuals with the appropriate expertise or qualifications to review responsive materials from the investigator.

Response: According to your response, when research is approved by the convened IRB with conditions (minor modifications or clarifications required), an expedited review of responsive materials may be performed unless the convened IRB states during the meeting that responsive materials must return to the convened IRB for reconsideration.

BRANY noted that in the future, when modifications to research are requested by the IRB as a condition of approval, the IRB will in all cases specify how the verification procedure will be completed. A prompt has been added to the IRB reviewer’s checklist to ensure the process for verification (expedited or convened) is specified. The checklist that is used by the IRB staff for tracking meeting determinations has also been updated to include a prompt to record the process for verification specified by the committee. These determinations will be documented in the meeting minutes.

4.   The 2018 Common Rule requires that consent forms include a statement about the future use of the collected identifiable private information or identifiable biospecimens (45 CFR 46.116(b)(9)). OHRP requested that BRANY clarify how it ensures that this regulatory requirement is met. In addition, OHRP requested clarification regarding the statement in the reviewer checklist that this regulatory requirement may be satisfied by including it in the HIPAA authorization.

Response: According to your response, IRB members and IRB staff were trained on the regulatory changes that took place with the 2018 Common Rule. Reviewer checklists, consent form templates and standard operating procedures were updated and included the requirement to add to the consent form statements about future use of collected identifiable private information or identifiable biospecimens (45 CFR 46.116(b)(9)).

The consent form template includes guidance to researchers to include statements about future use of collected identifiable private information or identifiable biospecimens as required by the 2018 Common Rule. In addition, the reviewer checklist requires that reviewers confirm this consent element is present in the consent form.

The comment in the IRB reviewer checklist indicated, “Sometimes this language is embedded in the HIPAA authorization section of the consent form (if there is one).” This text is “help text” and there was no intent to imply that language in the HIPAA authorization replaced the need for this required statement. The “help text” has been removed from the reviewer checklist to avoid confusion.

With implementation of the Revised Common Rule requirements in 2019, the IRB took proactive measures to conduct quality assurance reviews in 2020 of the additional consent elements required by the 2018 Requirements. This included the required statement about future use of collected identifiable private information or identifiable biospecimens. The results confirmed that the consent forms consistently contained this required element.

5.   For the study entitled, “Online System for Identifying and Addressing Teen Depression in Primary Care” the protocol describes two phases of the research, and it was unclear to the OHRP site visit team how the waiver of consent or waiver of documentation of consent were applied and to which phase.

For Phase 1, it was indicated that the investigators planned to seek waiver of documentation of informed consent from child-subjects' parents, but also stated that participants provide "implicit consent," by agreeing to participate in the focus groups. From the IRB approval letter, it appeared that the IRB approved a waiver of documentation of consent for the focus groups, but the IRB approval letter does not specify that the IRB approved a waiver of consent applicable to this phase of the study. OHRP requested that BRANY clarify whether oral consent was obtained for this phase of the research.

For Phase 2, the investigator indicated that a waiver of consent and assent should be permissible for parents and teens completing the questionnaires since the CHADIS questionnaires administered in the study are "standard of care." From the IRB approval letter, it appeared that the IRB waived consent for this portion of the study. It was unclear if the waiver criteria were met for this portion of the study. Also, it was unclear as to why "the research could not practicably be carried out without the requested waiver or alteration" (45 CFR 46.116(f)(3)(iii)).

Additionally, the study was approved via expedited review and OHRP was unable to ascertain the rationale for how the expedited reviewer's determinations were made regarding these waivers. It appears that the IRB reviewer's determinations were not documented in the review cycle other than by their inclusion in the final approval letter sent to the investigator.  OHRP requested that BRANY clarify to which portion(s) of the study these waivers apply and how this was documented in the review cycle.

OHRP also requested clarification regarding whether the key information was presented first during the oral consent, in accordance with the requirements of 45 CFR 46.116(a) and (a)(5)(i).

Response: According to your response, Phase 1 included focus groups with practitioners, focus groups with teens, and the pilot study. Phase 2 included the standard care/enhanced standard care activity. There were several phone calls and email conversations that occurred during the IRB review cycle with the researcher and the IRB staff, as well as between the IRB reviewer and IRB staff. Each phase was carefully considered and the regulations regarding informed consent were carefully applied to each phase and subgroup.

The initial screening of the application raised questions about the reference to “implicit consent” in the protocol because the IRB staff recognized that “implicit consent” is not permitted by the IRB. An email provided to OHRP showed the conversation between the IRB staff and the study site to clarify what was meant by implicit consent in the protocol. The site confirmed their plan to review the study information with the participants but not obtain a signed consent form, which equates to a waiver of documentation of consent.

The reference to “implicit consent” was used to describe a plan to waive the signature, not fully waive consent. The protocol contains the following:

“Attendance and participation in the focus group will be considered implicit consent by the parents and implicit assent by the teens. We will be requesting a waiver of consent documentation.”

The reference to “implicit consent” in the excerpt above did not require a full waiver as is traditionally understood using this term, rather the IRB ensured the verbal consent script included all the required elements of a consent process and thus approved a waiver of documentation, not a full waiver.

The researcher confirmed that this phase of the study has been completed and that verbal consent/assent was obtained from practitioners and teens and their parents in the focus groups in accordance with the IRB approval. For the pilot study portion of Phase I, full consent was obtained via a digital, online process from all participants (practitioners, parents, and teens).

The IRB approval letter does not specify that the IRB approved a waiver of consent applicable to this phase of the study since the process of “implicit consent” represented a verbal consent procedure and thus required a waiver of documentation of consent, not a full waiver.

Regarding the presentation of key information at the start of the oral consent process, the brevity of the consent form enabled the text to meet the requirements of the key information and consent requirements together. This approach is supported by details provided in the preamble to the Revised Common Rule for brief consent forms. This is consistent with BRANY’s practice, but it is noted that the record did not document the determination.

IRB staff were provided with training on the requirements to clearly document discussions between the IRB and researchers. This training will also be reviewed with IRB members. Training materials will be provided to all IRB members and IRB staff.

6.   The study entitled, “Intervention Study in Overweight Patients with COPD” was expedited under category 9, but the category 9 determination was not documented in the IRB files.

Response: According to your response, BRANY IRB agreed that the documentation that was available to OHRP during the site visit was not clear.

This study was initially reviewed by another IRB and then transferred to the BRANY IRB. According to the initial approval letter, the original review was conducted by the convened IRB and included a determination that the research involves no greater than minimal risk and continuing review could be completed by expedited review category 9.

The BRANY IRB reviewer conducted an expedited continuing review at the time of transfer, confirmed the study was minimal risk, but identified an incorrect expedited review category in the records.

The following corrective action plan is being implemented to prevent this type of oversight in the future:

1.   This study was returned to a convened meeting for review. The IRB reviewed the study protocol and the materials related to prior IRB reviews. The committee considered the study’s risk level, and determined the study remains minimal risk and continues to qualify for Expedited Continuing Review under Category 9.

2.   The IRB Chairs, IRB members and IRB staff were provided with training on the applicability of expedited review categories.

The corrective actions that BRANY IRB has taken, and plans to implement, adequately address OHRP’s determinations of noncompliance. 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 that might alter this determination.

We appreciate your institution’s continued commitment to the protection of human research subjects. Please feel free to contact me if you have any questions.

Sincerely,
Amanda P. Sly, MS, CIP
Compliance Officer
Division of Compliance Oversight

cc:
Linda Reuter, MS, CIP, HPA, IRB Director, BRANY
Ms. Winifred Meeker-O’Connell, Director, Office of Clinical Policy, FDA
Dr. Quynh-Van Tran, Center for Drug Evaluation and Research, FDA
Dr. Michelle Bulls, Director, OPERA, Office of Extramural Research, NIH
Dr. Pamela Kearney, Director, Division of Human Subjects Research, Office of Extramural Research, NIH
Dr. Adam Berger, Director, Division of Clinical and Healthcare Research Policy, Office of Science Policy, NIH
Ms. Lydia Kline, Team Lead, Clinical Research Policy, Division of Clinical and Healthcare Research Policy, Office of Science Policy, NIH