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WARNING LETTER

Dear Dr. Firn:

This Warning Letter informs you of objectionable conditions observed during a Food and Drug Administration (FDA) Remote Regulatory Assessment (RRA) of Massachusetts Institute of Technology (MIT) Committee on the Use of Humans as Experimental Subjects (COUHES) Institutional Review Board (IRB) conducted between May 30 and June 9, 2023. This RRA was conducted to determine if the MIT COUHES IRB’s activities and procedures for the protection of human subjects comply with federal regulations published in Title 21, Code of Federal Regulations (CFR) Part 50- Protection of Human Subjects, Part 56- Institutional Review Boards, and Part 812- Investigational Device Exemptions.

The FDA conducted this RRA under the Bioresearch Monitoring Program, which includes RRAs and inspections designed to review IRB operations for clinical investigations and to help ensure that the rights, safety, and welfare of human subjects are protected. At the end of the RRA, the FDA investigator presented a list of RRA Observations for your review and discussed the listed observations with you. We acknowledge receipt of the IRB’s June 30, 2023, written response to the RRA Observations.

Based on our review of the RRA Memo, the documents your firm provided to FDA as part of the RRA, and your written response dated June 30, 2023 to the RRA Observations, we determined that your IRB violated IRB regulations, as published in Title 21, Code of Federal Regulations (CFR) Part 56 (available at https://www.gpo.gov/fdsys/pkg/CFR-2018-title21-vol1/pdf/CFR-2018-title21-vol1- part56.pdf). The applicable provisions of the CFR are cited for each violation listed below. The violations include, but are not limited to the following:
 

1.    Failure to ensure that information given to subjects as part of informed consent is in accordance with 21 CFR 50.25 [21 CFR § 56.109(b)].

Your IRB failed to require that information given to subjects as part of informed consent is in accordance with 21 CFR 50.25 (elements of informed consent). For example:

A.    The IRB failed to ensure that IRB-approved informed consent forms (ICFs) for the following clinical investigations included a disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject, as required by 21 CFR 50.25(a)(4):
i.    The ICF for Protocol #211100051 was approved following full board review on 12/23/2021 and subsequently re-approved on 12/13/2022.

ii.    The ICF for Protocol #2211000807 was approved following full board review on 1/27/2023.

We reviewed your response to the RRA Observations dated June 30, 2023. In your response, you acknowledged that “some standard of care approach” could have been described as an alternative in the above-referenced ICFs. You proposed to contact investigators of the identified protocols and request amendments to revise the ICFs to include additional language, as well as to amend your ICF template for FDA-regulated research. However, your response fails to include a description of the standard of care approaches that will be added to the ICFs for the identified protocols. Based on our review, we have concluded that your response is not adequate.

B.    Your IRB failed to require that the ICFs for a clinical investigation involving more than minimal risk include an explanation as to whether any compensation is available if injury occurs and, if so, what it consists of, or where further information may be obtained as required by 21 CFR 50.25(a)(6).

For example, Protocol #2201000535 was classified as research involving more than minimal risk by the IRB on 4/4/2022. However, the ICF associated with this protocol, which was approved by your IRB on 4/4/2022 following full board review and subsequently reapproved on 1/19/2023, did not contain an explanation of whether any compensation would be available to subjects if injury occurs or where further information regarding such compensation may be obtained.

We reviewed your response to the RRA Observations dated June 30, 2023. In your response, you explained that Protocol #2201000535 was a collaborative research project with the (b)(4) Hospital. Your response states that both institutions' IRBs conducted full board reviews, but your institution’s role was limited to providing funding, core technology, and receiving and analyzing data. However, this justification is inadequate because your response did not include documentation of the responsibilities of each IRB involved in reviewing the collaborative research showing that your IRB was not responsible for review of the ICF. Additionally, we note that your IRB required changes to the ICF following full board review of Protocol #2201000535 on 2/17/2022 before the study received initial approval from your IRB on 4/4/2022 (indicating that your IRB did consider itself responsible for review of the ICF). The research was subsequently reapproved on 1/19/2023 by your IRB.

In your response, you proposed developing a template for a Memorandum of Understanding (MOU) that can be tailored to the degree of engagement by each collaborating institution. Your response also stated that you are in the process of revising the IRB’s Operational Policies and Procedures to specify the activities and responsibilities of each IRB involved in collaborative research where a single-IRB is not feasible or suitable and to specify that the activities and responsibilities of each IRB must be documented and agreed upon by all collaborating IRBs. However, without reviewing the approved MOU and the revised Operational Policies and Procedures mentioned in your plan, we are unable to perform an informed evaluation at this time. From our review, we have concluded that your response is not adequate.

C.    Your IRB failed to require that ICFs for the following clinical investigations include a statement that notes the possibility that the FDA may inspect the records, as required by 21 CFR 50.25(a)(5):

i.    The ICF for Protocol #2111000516; (b)(4) was approved following full board review on 12/23/2021 and subsequently re-approved on 12/13/2022.

ii.    The ICF for Protocol #2201000535; (b)(4) was approved following full board review on 4/4/2022 and was subsequently reapproved on 1/20/2023.

iii.    The ICF for Protocol #2211000807; (b)(4) was approved following full board review on 1/27/2023.

This is a repeated observation from inspections conducted in July of 2002 and September of 2012. We reviewed your firm’s response to the RRA Observations dated June 30, 2023. The proposed Corrective Action and Preventive Action (CAPA) mentioned in your firm’s response, which involves providing your staff with additional alerts for FDA-regulated studies, has been previously proposed in your response to the 2002 and 2012 inspection observations, however, this issue continues to persist, indicating that the proposed CAPA is not adequate to address this problem.

Additionally, the response fails to provide details on the implementation and validation process for the proposed alert system in the digital platform, and no description or documentation of staff training was included. You also proposed to amend all identified ICFs from the inspection, but your response fails to address how you plan to review and correct previously approved ICFs. The recurrence of failures signifies inadequate management oversight and control over the IRB review process. From our review, we have concluded that your response is not adequate.
 

2.    Failure to prepare and maintain adequate documentation of IRB activities [21 CFR 56.115].

Under 21 CFR 56.115(a), the IRB must prepare and maintain adequate documentation of IRB activities. This includes preparing and maintaining IRB meeting minutes in sufficient detail to show attendance at meetings; actions taken by the IRB; the vote on these actions (including the number of members voting for, against, and abstaining); the basis for requiring changes in or disapproving research; and a written summary of the discussion of controverted issues and their resolution (21 CFR 56.115(a)(2)).

Additionally, it requires preparing and maintaining a list of IRB members identified by name; earned degrees; representative capacity; indications of experience sufficient to describe each member's chief anticipated contributions to IRB deliberations; and any employment or other relationship between each member and the institution (21 CFR 56.115(a)(5)).

Your IRB failed to prepare and maintain adequate documentation of IRB activities, including in the following instances:

A.    Your IRB failed to prepare adequate meeting minutes, as required by 21 CFR 56.115(a)(2), for meetings involving FDA-regulated studies because the minutes contained discrepancies, including the following:

i.    The number of voting members documented in the meeting minutes as present does not match the number of members documented in the minutes as having voted on IRB actions during convened meetings. It is unclear from the meeting minutes when members entered the meeting, exited, or excused themselves or disconnected from the Zoom platform when remote meetings were held. For example, meeting minutes dated 6/16/2022, 9/8/2022, 10/20/2022, and 12/15/2022 included such discrepancies.
ii.    The meeting minutes from December 15, 2022, list (b)(4)(b)(6) as present as a member of the IRB at the meeting. The same minutes also list her as present as a Principal Investigator (PI) to discuss the initial approval for protocol #2209000746. However, none of the IRB membership records provided during the RRA list her as a member of the IRB.

B.    The IRB failed to prepare and maintain a list of IRB members, as required by 21 CFR 56.115(a)(5). For example:
i.    During the RRA, the IRB provided its four most recent membership rosters dated from August 2021 to August 2022. However, these lists did not include IRB members’ earned degrees, representative capacity, or indications of experience such as board certifications, licenses, etc., sufficient to describe each member’s chief anticipated contributions to IRB deliberations.
 
ii.    The IRB’s list of members was not updated with the most recent and current members. For instance, the meeting minutes on 1/19/2023 for Protocol #2211000807 indicated that IRB member (b)(6) was in attendance, but the most recent IRB roster provided during the RRA dated 8/30/2022 did not include this person as a member. This individual was listed as an active voting member from 9/14/2022 to 5/17/2023 according to screen shots of the IRB’s electronic platform database provided during the RRA for verification of active members as the roster dated 8/30/2022 was not updated with the most current members.

In your response, you acknowledge the discrepancies related to attendance records, meeting minutes, IRB rosters, and online databases, attributing these issues to the way software generates meeting minutes in PDF forms. Your response states that your IRB has taken corrective actions to improve attendance recording, including accounting for members leaving meetings, and updated the software to address complete and accurate meeting minutes.

We acknowledge these proposed corrective actions. However, your response is inadequate because it fails to address how the software you used caused these discrepancies or how the software update will be validated to ensure this will not happen in the future. Additionally, your proposal to prepare and append a roster of current members to each monthly meeting agenda is inadequate because this would not reflect the IRB membership at the time of the meeting; a roster of active members at the time of the meeting should be prepared and appended to the respective meeting minutes.

We reviewed previous Establishment Inspection Reports (EIRs) for FDA inspections of your IRB conducted in September 2012 and July 2002. Those EIRs note observations that are the same or similar to the deficiencies referenced above at 1(A) and 2(A). It therefore appears that previous corrective actions have not been adequate to prevent recurrence of these issues. This letter is not intended to be an all-inclusive list of deficiencies that may exist at your IRB. It is your responsibility to ensure compliance with the Federal Food, Drug, and Cosmetic Act (FD&C Act) and all applicable FDA regulations.

We request that you respond in writing within fifteen (15) working days from your receipt of this letter. In your response, please provide written documentation of additional actions you have taken or will take to correct the noted violations and to prevent the recurrence of similar violations in current and future studies for which you are the responsible IRB.

Failure to adequately address this matter may lead to regulatory action. Failure to respond to this letter and to take appropriate corrective action could result in FDA taking regulatory action without further notice to you. If you believe that you have complied with the FD&C Act and FDA regulations, please include your reasoning and any supporting information for our consideration.

This letter notifies you of our observations and provides you an opportunity to address the above deficiencies. You should investigate and determine the causes of any violations and take prompt actions to correct the violations to prevent the recurrence of similar violations in current and future studies that your IRB oversees.

Your response should be sent to me at the following address: U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, Document Control Center, 10903 New Hampshire Ave., WO71-G112, Silver Spring, MD 20993-0002. If you have any questions regarding this letter, please contact the Division of Inspections and Surveillance, CBER at 240-425-3201.

We also request that you send a copy of your response to the FDA Office listed below.

Sincerely,

/S/

Melissa J. Mendoza, JD
Director, Office of Compliance and Biologics Quality

Center for Biologics Evaluation and Research

cc:

Christine M. Smith, Acting Director FDA ORA-BIMO East