WARNING LETTER
Namita A. Goyal, M.D.
MARCS-CMS 677324 —
October 10, 2024
Delivery Method:
UPS and Electronic Mail
Reference #:
CBER-24-677324
Product:
Biologics
Recipient:
Namita A. Goyal, M.D.
200 S. Manchester Ave, Suite 110
Orange
,
CA
92868-3214
United States
namitag@hs.uci.edu
Issuing Office:
Center for Biologics Evaluation and Research (CBER)
United States
WARNING LETTER
CBER-24-677324
October 10, 2024
Dear Dr. Goyal:
This Warning Letter informs you of objectionable conditions observed during a Food and Drug Administration (FDA) inspection conducted at your clinical study site between June 12, 2023 and June 23, 2023. The FDA investigator met with you during the inspection to review your conduct as a clinical investigator of a clinical study entitled:
(b)(4)
(hereinafter, the protocol).
FDA conducted this inspection under the Bioresearch Monitoring (BIMO) Program, which includes inspections designed to review the conduct of research involving Investigational Products (IP) and to ensure that the rights, safety, and welfare of human subjects have been protected. At the conclusion of the inspection, a Form FDA 483, Inspectional Observations, was issued and discussed with you.
Based on our review of the Establishment Inspection Report (EIR), documents accompanying that report, the Form FDA 483, and your written responses dated July 17, 2023 and August 9, 2023 to the Form FDA 483 (Response Letter), you violated regulations governing the proper conduct of clinical studies involving investigational products, including regulations published in Title 21 of the Code of Federal Regulations, parts 312 (21 CFR 312) and 50 (21 CFR 50) (available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRsearch.cfm?CFRPart=312). 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 an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations. [21 CFR § 312.60].
A. Subjects were consented and enrolled in the study despite failing to meet required eligibility criteria outlined in the protocol.
i. Subject
(b)(6)
participated in the study despite meeting exclusion criterion #13 for participation in another clinical trial within 30 days prior to their screening visit.
A letter addressed to you dated January 19, 2018, from Cedars-Sinai informed you that this subject completed all study activities in another ALS study on January 15, 2018. However, this document was not located in the subject file, and you did not acknowledge the letter until brought to your attention by the FDA investigator. This subject was screened on January 10, 2018, five days prior to completion of the other ALS study; was subsequently randomized on March 28, 2018; and was administered the first dose of the investigative product (IP) on
(b)(6)
.
ii. Subject
(b)(6)
was randomized on April 30, 2019 and received the first dose of the IP on
(b)(6)
, despite the following:
a. The subject failed to meet inclusion criterion #10 for geographic accessibility to the study site. The subject did not reside in the United States prior to and during participation in the study.
b. The subject failed to meet inclusion criterion #5, which states that study participants were required to have an
(b)(4)
. The subject was consented and subsequently failed screening on February 26, 2019 due to a
(b)(4)
SVC. The Medical Monitor granted permission for Subject
(b)(6)
to proceed with the study if the subject was otherwise qualified. Site staff was later notified that the SVC at screening was actually
(b)(4)
and that the report received from their spirometer was inaccurate, however the subject was not otherwise qualified and should have been previously excluded due to inclusion criterion #10.
c. In a Note to File dated September 25, 2020, you acknowledged that the
(b)(4)
calibrations were not performed on the spirometer (used for SVC) from April 2020 through September 2020, in order to reduce the risk of exposure to COVID-19. In addition, during your inspection it was discovered that
(b)(4)
spirometer calibrations were also missing for December 2018 through June 2019, therefore the initial and corrected SVC at screening for this subject are unreliable. (
See Additional Concerns section for additional details
)
In your response dated July 17, 2023, you state that you were missing documentation to confirm that subject
(b)(6)
was not participating in other ALS trials at the time of screening and stated that you did not have access to the Cedars-Sinai letter informing you of the subject’s exact study dates prior to the inspection. You also explained that a Note to File from the Sponsor stated that the sponsor “interpreted exclusion criterion #2 as a study participant who was still participating in the active phase of the trial and receiving study medication.” We acknowledge your response and corrective and preventative actions; however, exclusion criterion #13 (any participation in a clinical trial within 30 days prior to screening) is not addressed in your response.
We acknowledge that Observation 1. A. ii. above was not included on the Form FDA 483 you received, and that therefore, your written response does not address this finding.
B. Subject
(b)(6)
was administered the IP prior to it being released for infusion, which failed to comply with the investigational plan. The IP was infused to Subject
(b)(6)
at 12:28 pm on
(b)(6)
; however, according to the Disposition of IP form IDF-2217, the product was not released for infusion by the Quality Assurance (QA) Manager at the manufacturing facility until at least 1:37pm that same day,
(b)(6)
.
In your response dated July 17, 2023, you stated that IP was administered to the subject after it was “internally released at the manufacturing site, following the signing of the CoA” [certificate of analysis], which was sent instead of the required Final Disposition Form. However, your response fails to explain how your site concluded that the product was internally released without proper documentation and fails to address the potential unblinding of study personnel from IP details listed on the CoA.
C. According to the Final Product Transport Record IDF-2216,
(b)(6)
inspected IP for Subject
(b)(6)
on
(b)(6)
at 12:40 pm prior to infusion.
However, the Site Signature and Responsibilities Log lists
(b)(6)
start date at the site as January 23, 2019, and she was not authorized to perform study tasks until March 5, 2019 in accordance with the investigational plan.
In addition, it appeared that
(b)(6)
signed a Protocol training log dated October 10, 2018, which was three months prior to
(b)(6)
start date. It is therefore unclear when
(b)(6)
actually started and whether or when
(b)(6)
was actually trained on the protocol and associated duties. (
See Additional Concerns section for additional details
)
In your response dated July 17, 2023, you stated that verification of IP is not a delegated task and is instead a standard of practice. We disagree that verification of the IP is a standard practice that does not require delegation. When you signed the Form FDA 1572, you agreed to ensure that all employees are informed about their obligations, including delegation of responsibilities as outlined in the investigational plan. We acknowledge that
(b)(6)
signature on a training form predating her employment was not included on the Form FDA 483 you received, and therefore was not addressed in your response. However, it is evident that your site’s Protocol training log is inaccurate.
D. On January 31, 2020, the Institutional Review Board (IRB) approved a modification to the study protocol to allow informed consent (IC) for subjects who have completed the study to be done by telephone because an in-person visit was not necessary. The IC would then be mailed to the subject, signed, and returned to the PI in accordance with the investigational plan.
Progress notes for Subject
(b)(6)
note that the subject was reconsented by phone on May 28, 2020, however no IC dated May 28, 2020 was located at the study site.
Progress notes from May 6, 2020 for Subject
(b)(6)
note that the subject was reconsented by phone. Progress notes from August 3, 2020 note that the phone consent was done June 6, 2020, not May 6, 2020. No ICs dated May or June 2020 were located.
2. Failure to obtain legally effective informed consent prior to involving a human being as a subject in research … under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence. [21 CFR § 50.20].
A. According to the IRB protocol application, written consent would only be obtained from study subjects. There were several instances when someone other than the subject signed the IC form and two instances where witnesses were present without explanation of their impartiality, as outlined in the IC.
B. Subject
(b)(6)
signed the IC for subjects who have completed the study on March 20, 2020. Page two of this consent asks the subject to sign to agree to genetic testing. This area of the IC was not signed, however the subject’s records contained genetic results from a buccal sample submitted March 31, 2020.
In your response dated July 17, 2023, you acknowledged that an impartial third party should have been utilized for the consent process if subjects were physically unable to sign their name due to muscle weakness secondary to ALS, as opposed to a family member. We reviewed your responses and your corrective and preventative actions on the consent process for these observations. The corrective and preventative actions you propose are acceptable, if successfully implemented.
3. Failure to assure that an IRB that complies with the requirements set forth in 21 CFR part 56 is responsible for initial and continuing review and approval of the proposed clinical study and failure to obtain IRB approval prior to changes in research activity. [21 CFR § 312.66].
A. You failed to ensure that study personnel who were also IRB members did not participate in IRB reviews that may present conflicting interests, as required by 21 CFR § 56.107(e).
(b)(6), (b)(4)
was a sub investigator for your study from October 27, 2017 to November 19, 2020.
(b)(6), (b)(4)
was also a member of the overseeing IRB, UCI Human Research Protections, from October 24, 2019 through at least June 1, 2020. There was no IRB recusal documentation found for
(b)(6), (b)(4)
, although IRB recusals were available for two other sub investigators who were also IRB members
(b)(6), (b)(4)
.
B. You failed to obtain IRB approval for the study interest questionnaire and script used to screen potential participants for study
(b)(4)
. This document (undated) was completed for Subject
(b)(6)
We acknowledge that Observation 3.A. above was not included on the Form FDA 483 you received, and that therefore, your written response does not address this finding. In your response dated July 17, 2023, you acknowledge that your unapproved questionnaire should not have been in use and confirmed that the questionnaire was only used once. You stated that internal processes for study-specific phone screening are being implemented and staff will be retrained on phone scripts and recruitment. Your response to Observation 3.B. above is acceptable. In your response to this letter, please address
(b)(6), (b)(4)
membership on the IRB roster and the lack of recusal documentation.
4. Failure to prepare and maintain adequate and accurate case histories [21 CFR § 312.62(b)].
A. You failed to record all adverse events (AEs) pertinent to the investigation for the following:
i. Subject
(b)(6)
reported vomiting during a visit on
(b)(6)
and called to report significant pain after a gastrostomy procedure on
(b)(6)
. Neither AE was reported on the subject’s AE log.
ii. Subject
(b)(6)
reported swelling on the ball of foot and cheek on January 14, 2019 that occurred the previous day. It was noted that this was not an AE, but the events were not added to the medical history.
iii. For Subject
(b)(6)
, back pain from November 5, 2019 as not transcribed into the Progress Notes.
In your response dated July 17, 2023, you acknowledge that the AEs for subjects
(b)(6)
and
(b)(6)
were missed, and in your response dated August 9, 2023, you acknowledge that back pain for subject
(b)(6)
was missed. You stated that you re-reviewed subject records and AE reporting requirements and will develop an SOP to ensure study teams are proactively documenting and communicating source documentation within the medical record system. The corrective and preventative actions you propose are acceptable, if successfully implemented.
B. You failed to maintain a copy of the original bone marrow aspiration (BMA) record within subject records. Multiple discrepancies were observed between the sponsor forms, progress notes, and electronic data capture (EDC) regarding the time at which these activities were performed for at least nine subjects.
C. There is no evidence medical records were requested and/or reviewed for the hospitalization reported by Subject
(b)(6)
for pneumonia (SAE) occurring
(b)(6)
through
(b)(6)
to assure all adverse events and concomitant medications were reported.
D. Protocol section 1.7.1. states that all medications taken prior to the first transplantation will be recorded as prior medications. Lactated Ringer’s solution was sometimes infused during BMA procedures; however, they were not always recorded and reported to the sponsor.
Lactated Ringer’s solution was infused on Visit 5 during bone marrow aspiration for subjects
(b)(6)
and
(b)(6)
; however, they were not recorded and reported to the sponsor as other BMA medications were.
E. Duplicate electrocardiogram (ECG) assessments were performed for Subject
(b)(6)
on
(b)(6)
at 10:20 and 10:21.
There is no justification recorded as to why duplicate assessments were conducted, which assessment would be documented within the EDC and an incorrect RR interval was recorded.
In your response dated July 17, 2023, you acknowledge the discrepancies in the BMA times, as described in 5.B. above. You also re-reviewed records for subject
(b)(6)
, from observation 5.C. above and discovered a HIPAA authorization to obtain medical records for the hospitalization from
(b)(6)
through
(b)(6)
, along with hospital records and an imaging report. In this response you also acknowledged the duplicate ECG assessments for subject
(b)(6)
described in 5.E. above and stated that the ECG was repeated to confirm abnormal left ventricular hypertrophy. You ensured that future repeated measurements would be adequately documented with the reason for repeat recorded. Your response is acceptable.
In your response dated August 9, 2023, you acknowledge that Lactated Ringer’s was not documented as a concomitant medication for subjects
(b)(6)
and
(b)(6)
as described in observation 5.D. above. Subjects
(b)(6)
and
(b)(6)
were not included on the Form FDA 483 you received, and therefore, your written response does not address this finding. You stated that you have re-reviewed protocol section 1.7 Prior and Concomitant Therapy as well as completed training on 21 CFR § 312.62 and ICH GCP. The corrective and preventative actions you propose are acceptable, if successfully implemented.
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 maintain accurate subject case histories, failure to conduct the clinical study in accordance with the protocols, and failure to provide accurate and reliable data raises significant concerns about the validity and integrity of all the data collected at your site.
Additional Concerns
In addition to the violations described above, we offer the following comments:
As stated in 1.A.ii.b.,
(b)(4)
calibrations were not performed on the spirometer used to measure subjects’ SVC from December 2018 to June 20, 2019. It also appears that spirometer calibration failed for
(b)(4)
July in 2019. In total your site failed to perform spirometer calibrations for at least 12 months during the study and failed to recognize a
(b)(4)
of failed calibration.
(b)(4)
efficacy endpoint criteria in this study. During this period, your site performed approximately 150 SVCs (three per subject, per visit, one selected). In total 50 SVCs were affected and possibly inaccurate for 32 subjects, with 15 screening visits involved.
As stated in 1.C., training dates for study personnel did not always correlate with actual employment dates at the site. A Note to File from the PI stated it was discovered February 4, 2018 that protocol training that took place on November 3, 2017 was not documented for all site personnel, excluding the PI.
(b)(6)
all signed the training log for the November 3, 2017 training. However according to the Delegation Log, start dates for all 4 personnel occurred after the training date – November 8, 2017, February 21, 2018, April 19, 2018, and April 20, 2018, respectively.
We acknowledge that these two discussion items were not presented to you during your inspection; therefore, your written responses do not address these findings. As a clinical investigator, it is your responsibility to ensure that data collected from study subjects are accurate and contemporaneous and can be relied upon in evaluating eligibility and in all analyses of the study endpoints. As 50 SVCs were possibly affected by the uncalibrated spirometer, the reliability and validity of the associated SVC data is compromised.
When you signed the Form FDA 1572, you agreed to maintain adequate and accurate records and to ensure that all study staff participating in the conduct of the study are informed about their obligations. Your own records state that there was no documentation of protocol training from November 3, 2018. It is apparent that your protocol training log was not created concurrently with the training. It is also apparent that attendance indicated by staff signatures was inaccurate since staff signatures on the log pre-date their actual employment at the site by as much as five months.
Conclusion
Neither this letter nor the observations noted on the Form FDA 483, which were discussed with you at the conclusion of the inspection, are intended to be an all-inclusive list of deficiencies that may exist in connection with your clinical study of investigational new drugs. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations. It is your responsibility to ensure full compliance with all applicable requirements in the FD&C Act, and all applicable regulations.
This letter notifies you of our concerns and provides you an opportunity to address them. Failure to adequately address these matters 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.
We request that you respond in writing within fifteen (15) working days from your receipt of this letter, outlining the specific steps you have taken or plan to take to address any violations and prevent their recurrence. Include any documentation necessary to show that the matters have been addressed. If you cannot address these matters within fifteen (15) working days, please explain the reason for your delay and the timeframe for completion. If you believe that you have complied with the FD&C Act, and applicable regulations, include your reasoning and any supporting information for our consideration.
Your response should be sent via email to CBERBIMONotification@fda.hhs.gov and cc ORABIMOWCorrespondence@fda.hhs.gov. We prefer an email response, but a written response can also be sent to: U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, Document Control Center, 10903 New Hampshire Avenue, WO-71-G112, Silver Spring, MD 20993-0002. If you have any questions regarding this letter, please contact the Division of Inspections and Surveillance, CBER at 240-402-8979.
Sincerely,
/S/
Melissa J. Mendoza
Director, Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
cc:
Eric Pittman, Director
FDA ORA-BIMO West
550 West Jackson Blvd, Suite 1500
Chicago, IL 60661-5716
Content current as of:
10/22/2024
Regulated Product(s)
Biologics