WARNING LETTER
Smitha C. Reddy, M.D./ACRC Studies, LLC
MARCS-CMS 634702 —
May 27, 2022
Delivery Method:
VIA UNITED PARCEL SERVICE
Product:
Drugs
Recipient:
Recipient Name
Smitha C. Reddy, M.D.
Smitha C. Reddy, M.D./ACRC Studies, LLC
15725 Pomerado Road, Suite 103
Poway
,
CA
92064-2058
United States
Issuing Office:
Center for Drug Evaluation and Research | CDER
United States
WARNING LETTER
FDA Ref.: 22-HFD-45-05-01
Dear Dr. Reddy:
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 August 4 and August 20, 2021. Investigator Theressa B. Smith, representing FDA, reviewed your conduct of the following clinical investigations:
Protocol
(b)(4)
, “
(b)(4)
, performed for
(b)(4)
Protocol
(b)(4)
, “
(b)(4)
, performed for
(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, Investigator Smith presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your October 8, 2021, written response to the Form FDA 483.
From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your written response dated October 8, 2021, 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. We wish to emphasize the following:
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)
required you to ensure that subjects randomized to a specific intervention group received the assigned investigational drug for that intervention group. In addition, Protocols
(b)(4)
and
(b)(4)
required blinding of certain study staff to avoid bias. You failed to adhere to these requirements. Specifically:
a. The investigational plan for Protocol
(b)(4)
required you to randomize subjects to
(b)(4)
intervention arms: investigational drug
(b)(4)
weekly
(b)(4)
twice daily (BID)
(b)(4)
; or
(b)(4)
arms), respectively,
(b)(4)
until Week 12. At Week 12, those subjects randomized to
(b)(4)
would switch from
(b)(4)
(either
(b)(4)
weekly; or
(b)(4)
BID). You failed to adhere to this requirement.
Specifically, Subject
(b)(6)
was randomized to a
(b)(6)
arm from Study Visit Week 0 to Study Visit Week 12, switching to
(b)(6)
Study Visit Week 12. However, instead of
(b)(6)
, you incorrectly administered active investigational drug
(b)(4)
to this subject at Study Visit Weeks 2, 3, and 4.
We acknowledge that the finding discussed above for Week 4 was not included on the Form FDA 483 you received, and that therefore, your written response does not address this specific issue.
In your October 8, 2021, written response, you acknowledged the observation. You indicated that there is no explanation except that the unblinded pharmacist inadvertently administered investigational product not assigned to this subject at Weeks 2 and 3. You also noted that the unblinded pharmacist has been removed from the study and from the site, and that the unblinded study coordinator who completed the study forms is no longer working at your site. In addition, you indicated that your site staff have been retrained on study drug preparation, dispensation, and administration, as well as re-educated on the importance of documenting all activities related to study-specific visits.
The primary objective of Protocol
(b)(4)
was to compare the efficacy of investigational drug,
(b)(4)
versus
(b)(4)
. Your failure to properly randomize subjects to assigned treatment arms, as required by the protocol, raises concerns regarding the reliability of data collected at your site, and jeopardizes subject safety and welfare.
b. The investigational plan for Protocol
(b)(4)
required an independent
(b)(4)
assessor to perform all
(b)(4)
assessments (that is, the evaluation of
(b)(4)
for
(b)(4)
and
(b)(4)
) to reduce bias. Protocol
(b)(4)
also specified that the independent
(b)(4)
assessor would not be permitted to
(b)(4)
, or
(b)(4)
; that the assessor should not
(b)(4)
during the clinical study; that the assessor
(b)(4)
with them during the
(b)(4)
assessment, or
(b)(4)
; and that the assessor must not
(b)(4)
. You failed to adhere to these requirements.
Specifically, subinvestigator
(b)(4)
was designated as an independent
(b)(4)
assessor and performed
(b)(4)
assessments for Subject
(b)(6)
. However,
(b)(4)
also reviewed
(b)(4)
for this subject. For example,
(b)(4)
performed
(b)(4)
count assessments for Subject
(b)(6)
at Screening on
(b)(6)
, and at Baseline Day 1 on
(b)(6)
; however,
(b)(4)
also initialed and dated (or signed and dated) the following study records for this subject:
i.
(b)(6)
, Screening Visit physical exam study record
ii.
(b)(6)
, Baseline Day 1 physical exam study record
In your October 8, 2021, written response, you acknowledged the observation and indicated that the unblinding of one of your subinvestigators, who was assigned to perform independent
(b)(4)
assessment, occurred inadvertently. You also noted that your investigation of the observation determined the following causes:
Source documents were not specific about the staff member who was responsible for the specific assessments.
You and your subinvestigators need more training on roles in the study and on compliance with the delegated tasks.
Your written procedures may not adequately ensure compliance with protocol-delegated tasks.
You noted that your site,
(b)(4)
, has taken or plans to take the following corrective and preventive actions:
Retraining the study coordinator on the importance of maintaining the tasks for all study staff, according to the delegation of responsibilities
Ensuring that the study coordinator has access to the site’s delegation log for each protocol
Retraining you and your subinvestigators on the importance of maintaining their roles, as stated in the delegation of authority log
Review of standard operating procedures (SOPs) by you and
(b)(4)
upper management to ensure adequate procedures regarding study-related task delegation
In Protocol 201791, an independent
(b)(4)
assessor was required to perform
(b)(4)
assessments to reduce bias. Unblinding of the protocol-required, independent
(b)(4)
assessor raises significant concerns about the integrity of the data collected at your site.
c. Protocol
(b)(4)
required the assessment of qualitative endpoints (that is,
(b)(4)
and
(b)(4)
assessments) to be conducted by a blinded assessor. You failed to adhere to these requirements.
Specifically, you were not permitted by the protocol to conduct the qualitative endpoint assessments because you were not a blinded
(b)(4)
assessor and were performing unblinded tasks for the study; however, you performed the following blinded tasks:
i. For Subject #
(b)(6)
, treatment period 4 Day 0 (TP4 D0)
(b)(4)
assessment
ii. For Subject #
(b)(6)
, corrections to TP4 D0
(b)(4)
evaluation
In your October 8, 2021, written response, you acknowledged this observation. You stated that your study coordinator made an “honest mistake” and inadvertently offered the
(b)(4)
assessment record to you, although you were not delegated to complete this task. You also noted the following causes:
Site staff, including you, subinvestigators, and study coordinators, failed to know and understand their delegated roles in the study.
Source documents were not created to highlight which study staff were responsible to performed delegated tasks.
You noted that your site,
(b)(4)
, has taken or plans to take the following corrective and preventive actions:
Retraining your site staff, based on an SOP on delegation of study-related tasks
Training your site staff on proper documentation according to the ALCOAC (that is, Attributable, Legible, Contemporaneous, Original, Accurate, and Complete) guidelines
Review of your site SOP on “Delegation of Study-Related Tasks” by the end of 2021.
Protocol
(b)(4)
required assessments of qualitative endpoints to be conducted by a blinded assessor. Additionally, the protocol notes that study personnel will endeavor to safeguard the integrity of the qualitative endpoint blind to minimize bias in the study. Failure to ensure that only designated staff perform delegated study-related tasks, such as protocol-required blinded assessments, raises significant concerns about the reliability of data from your site.
While we acknowledge the actions your site has taken to prevent recurrence of the observations noted in this letter, including the hiring of a quality assurance specialist, development of new SOPs, and site staff training, we request that you specify the corrective actions that you, as a clinical investigator, have taken to prevent similar violations in the future. For example, regarding incorrect drug administration, you indicated that all other site staff will be retrained on study drug preparation, dispensation, and administration; however, you did not indicate whether you have been or will be trained or retrained on study drug procedures to prevent similar violations. Without this information, we are unable to determine if your corrective action plans are adequate to prevent similar violations in the future, because they do not provide sufficient details about these SOPs and training.
We emphasize that as the clinical investigator, it was ultimately your responsibility to ensure that this study was conducted properly and in compliance with FDA regulations, both to protect the rights, safety, and welfare of study subjects and to ensure the integrity of study data. Failure to perform study procedures as required by the protocol, including (1) procedures to ensure that subjects randomized to a specific intervention group received the assigned investigational drug for that intervention group, and (2) procedures for the blinding of certain study staff, raises significant concerns about the safety of subjects enrolled in this study and the reliability of data from your site.
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 an opportunity to address the deficiencies specified above. 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 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.
If you have any questions, please call Miah Jung, Pharm.D., M.S., at 240-402-3728. Alternatively, you may e-mail 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 5352
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
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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.
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/s/
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DAVID C BURROW
05/27/2022 09:28:36 AM
Content current as of:
06/14/2022
Regulated Product(s)
Drugs