- Delivery Method:
- VIA UNITED PARCEL SERVICE AND VIA E-MAIL
- Reference #:
- 24-HFD-45-12-02
- Product:
- Drugs
- Recipient:
-
Recipient Name
Jeffrey W. Taub, M.D.
- Jeffrey W. Taub, M.D./Children's Hospital of Michigan
3901 Beaubien Street
Detroit, MI 48201-2119
United States
- Issuing Office:
- Center for Drug Evaluation and Research | CDER
United States
Secondary Issuing Offices
WARNING LETTER
Dear Dr. Taub:
This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection conducted at your clinical site between September 23, 2022, and October 12, 2022. Investigators Jennifer A. Kemp and Andrace Deyampert, representing FDA, reviewed your conduct of the following clinical investigations, performed for (b)(4):
- Protocol (b)(4), “(b)(4),” of the investigational drug (b)(4)1
- Protocol (b)(4), “(b)(4),” of the investigational drugs (b)(4)
This inspection was conducted as 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, Investigators Kemp and Deyampert presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your October 27, 2022, and January 10, 2023, written responses to the Form FDA 483.
From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your written responses dated October 27, 2022, and January 10, 2023, it appears that you did not adhere to the applicable statutory requirements in the Federal Food, Drug, and Cosmetic Act (FD&C Act) and applicable regulations contained in Title 21 of the Code of Federal Regulations, part 312 [21 CFR 312], governing the conduct of clinical investigations and the protection of human subjects. We wish to emphasize the following:
1. You failed to ensure that the investigation was conducted according to the investigational plan [21 CFR 312.60].
As a clinical investigator, you are required to ensure that your clinical studies are conducted in accordance with the investigational plan. The investigational plan for Protocol (b)(4) included three main treatment phases: (1) Remission Induction (and Early Intensification); (2) Consolidation; and (3) Continuation Treatment, during which subjects were assigned to treatment based on risk group [low-risk, standard-risk, and high-risk (b)(4)] and cell type ((b)(4)).
During the Continuation Treatment phase, subjects at standard risk or high risk with either a (b)(4). Subjects at low risk were to stop (b)(4) pulses after Week 49 of Continuation Treatment.
You failed to adhere to these requirements. Specifically, Subject (b)(6) was a pediatric subject (6 years old) with (b)(4) Continuation Treatment. However, this subject continued to receive (b)(4) treatment through Week 61. As a result, this subject received three additional doses of (b)(4), on Week 53 ((b)(6)), Week 57 ((b)(6)), and Week 61 ((b)(6)), and three additional five-day cycles of (b)(4) during Weeks 53, 57, and 61. Subjects administered (b)(4) are exposed to a risk of certain serious toxicities, including but not limited to neurologic and hematologic toxicity. Since Subject (b)(6) received additional doses of (b)(4) that were not required by the protocol, this subject was exposed to an increased risk of these toxicities.
In your October 27, 2022, written response to the Form FDA 483, you acknowledged that the subject received additional study treatments of (b)(4). You stated that these additional treatments occurred because a physician subinvestigator misinterpreted the drug administration plan. You stated that the Institutional Review Board (IRB) was notified of this occurrence within the time frame specified by the IRB policy.
As part of your written response, you stated that the subject would be observed at each remaining study visit according to the protocol for any adverse events or toxicities related to the additional doses. You also stated that since the standard of care treatment of this disease is continuation of (b)(4) after Week 50, it is unlikely that the additional doses increased risk to the subject. However, as noted above, subjects (such as the pediatric subjects in this study) who are administered vincristine are exposed to a risk of serious toxicities, including but not limited to neurologic and hematologic toxicity. Since Subject (b)(6) received additional doses that were not required by the protocol, this subject was exposed to an increased risk of these toxicities.
As a part of your written response, you indicated that the following actions have been or will be taken:
- Study staff were re-educated on the importance of verifying correct dosing plans and the corrective and preventive actions.
- Study staff designated to prescribe study drug treatment will review the protocol drug treatment plan before creating orders or administering the drug treatment plan, and will verify drug orders with the study’s investigational pharmacist if there is any uncertainty about the correct orders.
- Randomization results received from the sponsor will be forwarded to subjects’ primary oncologist(s), the study’s principal investigator, and the pharmacist, and will be added to the weekly research meeting agendas.
- The investigational pharmacist will review study drug orders and ensure that they coincide with the subjects’ assigned randomization.
While we acknowledge the corrective and preventive actions that your site has taken and plans to take, your response is inadequate because you did not include sufficient details about your corrective action plan. For example, you did not provide sufficient details about the policies and procedures that you would institute at your site to ensure compliance with study protocols and to ensure that ongoing and future clinical investigations will be conducted in compliance with applicable FDA regulations. Additionally, given the significance of the protocol violation involving a pediatric subject, we request follow-up documentation regarding the policies and procedures being implemented at your site to ensure compliance with study protocols, including randomization assignments. Without this information, we are unable to determine if your corrective action plan is adequate to prevent similar violations in the future.
We emphasize that as the clinical investigator, it is your responsibility to ensure that studies are conducted in accordance with the investigational plan, to protect the rights, safety, and welfare of subjects and to ensure the integrity of study data. Your failure to conduct the clinical study in accordance with the protocol resulted in the unnecessary administration of additional doses of vincristine and dexamethasone to a pediatric subject. This conduct raises significant concerns about your protection of the study subjects enrolled at your site.
2. You failed to ensure that an IRB that complies with the requirements set forth in 21 CFR part 56 was responsible for the initial and continuing review and approval of the proposed clinical study [21 CFR 312.66].
As a clinical investigator, you are required to ensure that an IRB that complies with the requirements set forth in 21 CFR part 56 is responsible for the initial and continuing review and approval of a proposed clinical investigation. You failed to ensure that an IRB that complies with 21 CFR part 56 continued to review and approve your conduct of Protocol (b)(4).
Specifically, IRB approval for Protocol (b)(4) lapsed from January 14, 2022, to January 24, 2022.
During this lapsed period, the following study activities were performed:
- Study drug was dispensed to Subject (b)(6) on (b)(6), and (b)(6).
- Bone marrow and peripheral blood specimen samples were collected from Subject (b)(6) on (b)(6).
You stated that the lapses were attributable to a multitiered review of the continuing review, which delayed the continuing review from being addressed at a timely, regularly scheduled IRB meeting, as well as to staff turnover after submission of a continuing review. We note that as the clinical investigator, you are responsible for the oversight and conduct of the study at your clinical site, which includes ensuring the continuing IRB review and approval of the proposed clinical investigation. However, you continued to perform study activity even when IRB approval had lapsed.
As a part of your written response, you stated that the study, which had expired, has now been re-approved by the IRB for continuation of study activities. In addition, you stated that study staff who are delegated to submit continuing review to the IRB will be provided with email notifications at 90, 60, and 30 days before the date on which the study’s approval expires.
You stated that study staff will begin development of the continuing review process when the 90-day email is received, to enable a submission to the IRB before receipt of the 30-day notification. You also indicated that study staff involved in IRB submission have been re-educated about maintaining IRB approval and re-educated on the CAPA.
While we acknowledge the corrective and preventive actions that your site has taken and plans to take, your response is inadequate because you have not provided sufficient details about how you will ensure continuing IRB review for ongoing and future clinical studies. For example, you did not provide sufficient details about the policies and procedures you would institute at your site to ensure submission of IRB continuing review before study approval expiration dates, including procedures regarding email notifications at 90, 60, and 30 days before the date on which the study’s approval expires. Without this information, we are unable to determine if your corrective action plan is adequate to prevent similar violations in the future.
IRB review serves an important role in the protection of the rights and welfare of human research subjects. The purpose of IRB review is to ensure, both in advance and by periodic review, that appropriate steps are taken to protect the rights and welfare of humans participating as subjects in the research. Your failure to ensure continuing IRB review and approval of Protocol (b)(4) impeded the IRB’s ability to determine the adequacy of your application to conduct Protocol (b)(4), which raises significant concerns about the extent to which subjects’ rights and welfare were protected during the lapse in approval. We also note that we are particularly concerned about the potential impact on subjects’ rights, considering that the pediatric subjects enrolled in Protocol (b)(4) are a vulnerable population.
This letter is not intended to be an all-inclusive list of deficiencies with your clinical study of an investigational drug. It is your responsibility to ensure adherence to each requirement of the law and relevant FDA regulations. You should address any deficiencies and establish procedures to ensure that any ongoing or future studies comply with FDA regulations.
This letter notifies you of our findings and provides you with 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 you have taken to prevent similar violations in the future. Failure to address this matter adequately 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.
If you have any questions, please call Miah Jung, Pharm.D., M.S., at 240-402-3728. Alternatively, you may email FDA at CDER-OSI-Communications@fda.hhs.gov. Your 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 5219
10903 New Hampshire Avenue
Silver Spring, MD 20993
Sincerely yours,
{See appended electronic signature page}
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
--------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record.
--------------------------------------------------------------------------------------------
/s/
------------------------------------------------------------
DAVID C BURROW
12/19/2023 06:30:26 AM
____________________
1 Additional study drugs used in Protocol (b)(4) include: (b)(4).
