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WARNING LETTER

Larkin Community Hospital Institutional Review Board MARCS-CMS 638146 —


Delivery Method:
VIA UNITED PARCEL SERVICE
Product:
Drugs

Recipient:
Recipient Name
Sima Marzban, M.D.
Recipient Title
Vice President for Research and Academic Affairs
Larkin Community Hospital Institutional Review Board

7031 Southwest 62nd Avenue
South Miami, FL 33143-4701
United States

Issuing Office:
Center for Drug Evaluation and Research | CDER

United States


WARNING LETTER

January 11, 2023

FDA Ref. No.: 23-HFD-45-01-01

Dear Dr. Marzban:

This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection conducted between November 12 and November 19, 2021, of the Larkin Community Hospital Institutional Review Board (IRB). Investigator Richard A. Lyght, representing FDA, conducted the inspection to determine whether the IRB’s procedures for the protection of human subjects complied with FDA regulations contained in Title 21 of the Code of Federal Regulations (CFR), parts 50 and 56. These regulations apply to clinical investi-gations of products regulated by FDA.

This inspection is a part of FDA’s Bioresearch Monitoring Program, which includes inspections designed to evaluate the conduct of research and to help ensure that the rights, safety, and welfare of human subjects have been protected.

At the conclusion of the inspection, Investigator Lyght presented and discussed with you Form FDA 483, Inspectional Observations. We acknowledge receipt of the IRB’s December 6, 2021, written response to the Form FDA 483.

From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and the IRB’s December 6, 2021, written response, it appears that the IRB did not adhere to applicable statutory requirements in the Federal Food, Drug, and Cosmetic Act (FD&C Act) and FDA regulations governing the protection of human subjects.

We wish to emphasize the following:

1. The IRB failed to review proposed research at convened meetings at which a majority of the members of the IRB are present, including at least one member whose primary concerns are in nonscientific areas [21 CFR 56.108(c)].

Under 21 CFR 56.108(c), except when an expedited review procedure is used, the IRB may review proposed research only at convened meetings at which a majority of the IRB members are present, including at least one member whose primary concerns are in nonscientific areas. The IRB failed to adhere to this requirement.

Specifically, the IRB reviewed and approved FDA-regulated research at convened IRB meetings where a majority of the IRB members, including at least one nonscientist member, were not present.

IRB meeting minutes for meetings held on April 24, 2020; August 3, 2020; September 11, 2020; November 16, 2020; and February 15, 2021, indicate that the following members were present, and that no member whose primary concerns are in nonscientific areas attended:

  • IRB meeting held on April 24, 2020: Gerardo Ferrer (physician), (b)(6) (pharmacist), (b)(6) (physician), and (b)(6) (pharmacist)
  • IRB meeting held on August 3, 2020: Gerardo F. Ferrer (physician), (b)(6) (pharmacist), (b)(6) (physician), and (b)(6) (pharmacist)
  • IRB meeting held on September 11, 2020: Gerardo F. Ferrer (physician), (b)(6) (pharmacist), (b)(6) (physician), (b)(6) (physician), and (b)(6) (pharmacist)
  • IRB meeting held on November 16, 2020: (b)(6) (pharmacist), (b)(6) (physician), (b)(6) (physician), and (b)(6) (pharmacist)
  • IRB meeting held on February 15, 2021: Gerardo F. Ferrer (physician), (b)(6) (pharmacist), (b)(6) (physician), (b)(6) (physician), and (b)(6) (pharmacist)

The IRB should not have reviewed or approved the proposed research because the IRB did not have a member present whose primary concerns are in nonscientific areas at these IRB meetings in which FDA-regulated research was reviewed.

During the inspection, the IRB chair, Gerardo F. Ferrer, M.D., indicated that (b)(6) acted as the nonscientific IRB member. However, Ms. (b)(6) resigned on April 24, 2020, and was not in attendance at any of the above-mentioned IRB meetings. Furthermore, no other nonscientific member appears to have been identified or attended any of the above-mentioned IRB meetings.

In your December 6, 2021, written response to the Form FDA 483, you indicated that this observation has been noted and procedures are being initiated to correct this observation. In addition, you indicated that IRB meetings will only take place if a majority of the IRB members are available, including one nonscientific member. You also stated that the IRB minute agendas will document members’ affiliations to facilitate audit review designation.

We are unable to perform an informed evaluation of the IRB’s written response because you did not provide a corrective action plan that, if properly carried out, would prevent the recurrence of this type of violation in the future. Specifically, you did not provide sufficient details on the procedures you are initiating and how you will ensure that a majority of the IRB members, including at least one member whose primary concerns are in nonscientific areas, will be present at convened meetings when proposed FDA-regulated research is under review.

As an IRB, review of proposed research at convened meetings at which a majority of the IRB members is present, including at least one member whose primary concerns are in a nonscientific area, is important to ensure that the IRB’s review and approval of research is fair and equitable.

2. The IRB failed to prepare and maintain adequate documentation of IRB activities, including a list of IRB members [21 CFR 56.115(a)(5)].

Under 21 CFR 56.115(a), the IRB is required to prepare and maintain adequate documentation of IRB activities, including a list of IRB members identified by name; earned degrees; representative capacity; indications of experience such as board certifications, licenses, etc., sufficient to describe each member’s chief anticipated contributions to IRB deliberations; and any employment or other relationship between each member and the institution. The IRB failed to adhere to these requirements.

Specifically, the IRB failed to prepare and maintain a list of IRB members, in accordance with 21 CFR 56.115(a)(5), for the time period between July 2019 and March 2021. During the inspection, the IRB compiled a membership list for this time frame. However, this list is inadequate because it did not include all IRB members listed in minutes for IRB meetings convened during this time frame. Furthermore, for several listed IRB members, the list did not include each IRB member’s representative capacity, indications of experience sufficient to describe the member’s chief anticipated contributions to the IRB deliberations, or any employment or other relationship between the member and the institution. For example:

  • (b)(6), M.D., M.B.A., F.A.C.S., is not listed on this membership list, but is listed as a voting member in the minutes of the IRB meetings held on September 11, 2020; November 16, 2020; and February 15, 2021.
  • (b)(6), M.S., L.M.H.C., C.A.P., is not listed on this membership list, but is listed as an absent voting member in the minutes of the IRB meetings held on April 24, 2020; August 3, 2020; September 11, 2020; and February 15, 2021.
  • (b)(6), M.D., M.S.S., is listed on this membership list, but this IRB member’s representative capacity is missing.
  • (b)(6), Pharm.D., M.P.H., B.C.P.S., is listed on this membership list, but this IRB member’s representative capacity is missing.

In your December 6, 2021, written response to the Form FDA 483, you noted the observation and stated that it was difficult to acquire in full details the complete membership list because the prior IRB coordinator’s files were not easily accessible. You noted that a new roster of current members will be created, maintained, monitored annually, and adjusted when required. You also indicated that the membership list will include the full details of each member’s name, earned degrees, representative capacity, and indication of experience sufficient to describe the member’s chief anticipated contribution to IRB deliberations. However, we note that this membership list, as proposed, would not meet the regulatory requirements unless employment or other relationship between each member and the institution were to be included, as required under 21 CFR 56.115(a)(5).

We are unable to undertake an informed evaluation of the IRB’s written response because you did not provide a corrective action plan that, if properly carried out, would prevent the recurrence of this type of violation in the future. Specifically, you did not provide sufficient details on the actions that will be taken (for example, maintaining and monitoring the new membership list annually) to ensure that the IRB prepares and maintains a list of IRB members in accordance with the regulations at 21 CFR 56.115(a)(5). In addition, you did not provide documentation of a complete, updated membership list that includes the missing information described above. Please submit a current membership list that complies with 21 CFR 56.115(a)(5).

As an IRB, you are required to prepare and maintain a complete list of IRB members in compliance with 21 CFR 56.115(a)(5) to ensure that the IRB has adequate representation, experience, and expertise to promote complete and adequate review of the institution’s research activities.

3. The IRB failed to ensure that information given to subjects as part of informed consent is in accordance with 21 CFR part 50.25 [21 CFR 56.109(b)].

Under 21 CFR 56.109(b), the IRB must require that information given to subjects as part of the informed consent process is in accordance with 21 CFR 50.25 (elements of informed consent). The IRB failed to ensure that the IRB-approved informed consent documents (ICDs) for the following two clinical trials, which meet the definition of an “applicable drug clinical trial”1, contained the statement2 notifying the subject that clinical trial information has been or will be submitted for inclusion in the clinical trial registry databank, as required by 21 CFR 50.25(c):

  • Protocol LCH-2-112020, “Impact of GSE and Xylitol (Xlear) in Symptoms and time to PCR negativisation of patients with Acute COVID-19 Infection”
  • Protocol LCH-3-082020, “A Randomized Placebo Control Trial to Evaluate the Efficacy of Xylitol Nasal Sprays vs. Placebo for Acute COVID-19 Infection”

In your December 6, 2021, written response, you noted the observation and stated that actions were in motion to establish best practices. You also indicated that the formatted informed consent will contain the statement for clinical trials, as required by 21 CFR 50.25(c).

We acknowledge your written response, indicating that “actions are in motion to establish best practice” and that ICDs will contain the required information. However, we are unable to perform an informed evaluation of the IRB’s written response because you did not provide a corrective action plan that, if properly carried out, would prevent the recurrence of this type of violation in the future. Specifically, you did not provide sufficient details on the best practices you are establishing and how you will ensure that the ICDs will contain the statement, as required by 21 CFR 50.25(c), when appropriate.

Failure to ensure that IRB-approved informed consent documents for applicable clinical trials contain the statement notifying subjects that clinical trial information has been or will be submitted for inclusion in the clinical trial registry databank may result in subjects not being provided appropriate human subject research protections or pertinent information about the clinical investigation.

For more information on this element, please see “Guidance for Sponsors, Investigators, and Institutional Review Boards: Questions and Answers on Informed Consent Elements, 21 CFR § 50.25(c)” at the following URL: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM291085.pdf.

This letter is not intended to be an all-inclusive list of deficiencies related to the IRB’s procedures or the review and approval by the IRB of protocols and informed consent documents. It is the IRB’s responsibility to ensure adherence to each requirement of the law and relevant FDA regulations.

This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. Within 15 business days of your receipt of this letter, you should notify this office in writing of the actions the IRB plans to take or has taken to address any violations and to prevent recurrence of similar violations in the future. Failure to adequately address this matter may lead to regulatory action. If you believe you have complied with the FD&C Act and relevant regulations, please include your reasoning and any supporting information for our consideration.

We recommend that the IRB visit the following FDA Web page for information on human subject protections that may assist the IRB in its efforts to come into compliance with FDA regulations: http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/default.htm.

If the IRB has any questions, please call Miah Jung, Pharm.D., M.S., at 240-402-3728. Alternatively, you may e-mail FDA at [email protected]. The IRB’s written response and any pertinent documentation should be addressed to:

Miah Jung, Pharm.D., M.S.
Branch Chief
Compliance Enforcement Branch
Division of Enforcement and Postmarketing Safety
Office of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
Building 51, Room 5352
10903 New Hampshire Avenue
Silver Spring, MD 20993

Sincerely yours,
/S/

David C. Burrow, Pharm.D., J.D.
Director
Office of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
U.S. Food and Drug Administration

__________________________

1 See 42 USC 282(j)(1)(A) and 42 CFR 11.10 for the definition of “applicable drug clinical trial.”

2 “A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.”

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