WARNING LETTER

Mobeen Mazhar, M.D. MARCS-CMS 660335 — May 31, 2023

Delivery Method:: VIA UNITED PARCEL SERVICE AND VIA E-MAIL
Reference #:: 23-HFD-45-05-01
Product:: Drugs

Recipient:: Recipient Name

Mobeen Mazhar, M.D.; Mobeen Mazhar, M.D.; 10425 Huffmeister Road, Suite 330
Houston, TX 77065
United States

Issuing Office:: Center for Drug Evaluation and Research | CDER; United States

WARNING LETTER

FDA Ref. No.: 23-HFD-45-05-01

Dear Dr. Mazhar:

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 March 22 and April 28, 2022. Investigator Andrea A. Branche, representing FDA, reviewed your conduct of the following clinical investigations:

Protocol (b)(4), “(b)(4),” of the investigational drug (b)(4), performed for (b)(4).
Protocol (b)(4), “(b)(4),” of the investigational drug (b)(4), performed for (b)(4)
Protocol (b)(4), “(b)(4),” of the investigational product (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 Branche presented and discussed with you the Form FDA 483, Inspectional Observations.

From our review of the FDA Establishment Inspection Report and the documents submitted with that report, 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) and part 50 (21 CFR 50) 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) required you to ensure that subjects met prescreening laboratory criteria to be eligible for study screening. The protocol also required you to ensure that subjects met all eligibility requirements before enrollment and beginning the single-blind, two-week, placebo run-in portion of the study, and before randomization to receive study drug or placebo during the double-blind treatment portion of the study. Additionally, the protocol required you to report adverse events of special interest (AESI) to the sponsor no more than 24 hours after learning of the event. You failed to adhere to these requirements. Examples of these failures include but are not limited to the following:

a. The investigational plan for Protocol (b)(4) required you to exclude subjects with an office diastolic blood pressure (DBP) equal to or exceeding 100 mm Hg (the average of the last two of five unattended measurements using an automated oscillometric sphygmomanometer device after approximately five minutes of rest in the seated position). You failed to adhere to this requirement. Specifically:

i. Subject (b)(6)’s average of the last two of five unattended measurements of DBP at Screening (Visit 2) was 110.5 mm Hg. However, this subject was randomized and started the double-blind treatment portion of the study on (b)(6) (Visit 7), and study drug was dispensed to the subject through (b)(6).

ii. Subject (b)(6)’s average of the last two of five unattended measurements of DBP at Randomization/Baseline (Visit 6) was 100 mm Hg. However, this subject was randomized to the double-blind treatment portion of the study on (b)(6) (Visit 6), and study drug was dispensed to the subject through (b)(6).

b. The investigational plan for Protocol (b)(4) required you to ensure that subjects had a plasma renin activity (PRA) value that was equal to or less than 0.6 ng/mL and a serum aldosterone value that was equal to or greater than 6 ng/dL to enter the study screening process. You failed to adhere to this requirement. Specifically:

i. Subject (b)(6)’s serum aldosterone value at Prescreening (Visit 1) was less than 1 ng/dL. However, this subject signed the IRB-approved screening/main study informed consent form and underwent screening tests and procedures, including physical examination, the automated office blood pressure measurements, 12-lead electrocardiogram, and laboratory assessments, on (b)(6).

ii. Subject (b)(6)’s serum aldosterone value at Prescreening (Visit 1) was 3 ng/dL. However, this subject received study drug during the double-blind treatment portion of the study. Study drug was dispensed to the subject through (b)(6).

We acknowledge that this finding was not included on the Form FDA 483 you received.

c. The investigational plan for Protocol (b)(4) required you to report AESIs to the sponsor immediately (that is, no more than 24 hours after learning of the event), regardless of their causality to the study drug treatment. You failed to adhere to this requirement. The protocol specified events that would be considered AESIs for all study drugs ((b)(4) and placebo), including hyperkalemia, defined as having serum potassium values greater than 5.2 mEq/L. Subject (b)(6)’s serum potassium values were elevated at the following visits during the double-blind treatment portion of the study: Visit 11 on (b)(6) (5.5 mEq/L); Visit 12 on (b)(6) (5.6 mEq/L); and Visit 13 on (b)(6) (5.6mEq/L). You did not complete and sign the Safety Event Report Form that was used to report the hyperkalemia AESIs to the sponsor until December 2, 2021.

We emphasize that failure to conduct the clinical investigation in accordance with the protocol raises significant concerns about your protection of the study subjects enrolled at your site, and raises concerns about the validity and integrity of the data collected at your site. Specifically, the enrollment of subjects who do not meet eligibility criteria and the failure to report AESIs within the time frame specified in the protocol jeopardize subject safety and welfare. Additionally, your failure to properly prescreen and screen subjects to ensure that they met all protocol-required eligibility criteria raises concerns about the reliability of the data collected at your site. Three of the six subjects who were randomized and treated with investigational product at your site were ineligible for enrollment in the study, failed to meet the requirements for screening, or both. As the clinical investigator, you are responsible for ensuring compliance with the protocol required eligibility criteria and with the AESI reporting requirements.

2. You failed to obtain informed consent in accordance with the provisions of 21 CFR part 50 [21 CFR 312.60 and 21 CFR 50.20].

As a clinical investigator, you are required to obtain informed consent in accordance with 21 CFR part 50. FDA’s regulations at 21 CFR 50.20 state that, except as provided in 21 CFR 50.23 and 21 CFR 50.24, no investigator may involve a human being as a subject in research covered by the regulations unless the investigator has obtained the legally effective informed consent of the subject or the subject’s legally authorized representative.

You failed to obtain legally effective informed consent for Subject (b)(6), who was enrolled in Protocol (b)(4). Specifically, study-related screening procedures and the start of the placebo run-in period were performed before you obtained this subject’s written informed consent on the screening/main study informed consent form.

Subject (b)(6) signed the IRB-approved screening/main study informed consent form on (b)(6). However, study-related screening tests and procedures, including physical examination, the automated office blood pressure measurements, 12-lead electrocardiogram, laboratory assessments, and placebo run-in administration, were performed for this subject on (b)(6), approximately 14 days before the date on which you obtained the subject’s informed consent.

We emphasize that your failure to obtain informed consent before involving subjects in research jeopardizes the safety and welfare of subjects by denying them an opportunity to assess the risks and benefits of their participation in the clinical investigation. As a clinical investigator, you are responsible for ensuring that informed consent is obtained from subjects in accordance with 21 CFR part 50.

During the inspection, you stated that you were involved in the subjects’ clinical care, but you were unaware of the requirements needed to properly conduct a clinical study and were not able to devote the time necessary to conduct the study. Additionally, you stated that many of the deficiencies in the conduct of the study were caused by the actions of a site management organization. You further stated that you closed all studies at your site following a sponsor’s site-quality audit in late November 2021, and that should you conduct clinical research in the future, you would notify FDA in writing of plans for Good Clinical Practice training.

While we acknowledge that you closed all clinical studies at your site, you have not provided details about how you plan to prevent similar violations from occurring if you decide to participate as a clinical investigator in a future clinical investigation. Your explanation, when taken into consideration with the violations described above, suggests systemic failures in your conduct of this clinical investigation.

Furthermore, we emphasize that as a clinical investigator, you are ultimately responsible for compliance with all applicable FDA regulations governing the conduct of clinical investigations and the protection of human subjects, which include adhering to the investigational plan and obtaining legally effective informed consent from subjects. Your failure to perform the above-mentioned study procedures as required by the protocol and your lack of oversight and supervision of the clinical study raise significant concerns about the safety of study subjects enrolled at your site and the reliability of the data generated at 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 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 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
05/31/2023 07:41:56 AM