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WARNING LETTER

FDA Ref. No.: 25-HFD-45-12-03

Dear Dr. Damodara Kumaran:

This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection conducted at Senthil Specialty Hospital in Pondicherry, Puducherry, India, between January 20 and 24, 2025. The investigator representing FDA reviewed your conduct of a clinical in vivo bioequivalence study (Protocol (b)(4), “(b)(4)”) of the investigational drug (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, the FDA investigator presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your February 14, 2025, 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 February 14, 2025, 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.¹ 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 investigations are conducted in accordance with the investigational plan. The investigational plan for Protocol (b)(4) required you to collect safety assessments, including hematology and pulmonary function tests, every week after the first dose of investigational drug in Period I (during the study washout period) and for six weeks after dosing in Period II (that is, on Day 8, Day 15, Day 22, Day 29, Day 35, and Day 42 of each dosing period).

You failed to adhere to these requirements. Specifically, for Subjects (b)(6), and (b)(6), hematology and pulmonary function safety assessments were not completed after investigational drug dosing on Day 8, Day 22, and Day 35 during both Period I and Period II, as required by the protocol. As a result, half of the protocol-required safety assessments for these subjects were not completed during the study.

In your February 14, 2025, written response to the Form FDA 483, you stated that you modified the study visit schedule for pragmatic reasons, including subjects’ needs, their travel commitments, and their ongoing treatment plans. You stated that the deviation considered the established late onset of myelosuppression, and that the selection of subjects was based on their historical tolerability of (b)(4). You also stated that you employed regular follow-ups, including telephone consultations, to identify and promptly address any adverse events. Furthermore, you stated that this monitoring strategy was tailored to ensure maximum oversight of subject safety, which was discussed and planned during the study initiation visit, and that the sponsor and ethics committee remained aware of these protocol deviations.

While we acknowledge your statement that you purposely deviated from the investigational plan to limit protocol-required study visits for pragmatic reasons, and that the sponsor remained aware of these protocol deviations, you did not provide evidence to demonstrate that the sponsor approved of such actions before you deviated from the investigational plan. You also did not provide evidence of the telephone consultations you stated that you employed in regular follow-ups of subjects, to identify and address adverse events.

Furthermore, your written response is inadequate because you did not provide information about any completed or proposed corrective actions that would prevent similar violations in the future. For example, you did not provide details about how you will ensure that ongoing and future clinical investigations at your clinical research site will be conducted in compliance with the investigational plan and applicable FDA regulations. Without this information, we are unable to undertake an informed evaluation of your response.

We emphasize that, as the clinical investigator, it is your responsibility to ensure that studies are conducted in accordance with the investigational plan, both to protect the rights, safety, and welfare of subjects and to ensure the integrity of study data. The investigational drug, (b)(4), may cause subjects to experience certain adverse events, such as myelosuppression, which can lead to fatal infections and bleeding. (b)(4) may also cause subjects to experience pulmonary toxicity (lung damage), characterized as lung infiltrates and/or fibrosis. To minimize these risks, the protocol required hematology and pulmonary function tests to assess subjects’ bone marrow and lung functions at baseline and at weekly safety monitoring visits after the receipt of the investigational drug. Your failure to conduct the study in accordance with the investigational plan – and specifically, your failure to ensure that Subjects (b)(6)’s bone marrow and lung functions were monitored at the study-required intervals after receiving the investigational drug – raises concerns about your protection of the study subjects enrolled 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 with an opportunity to address the deficiencies noted 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 address this matter adequately may lead to regulatory action. If you believe that you have complied with the FD&C Act and relevant regulations, please include your reasoning and any supporting information for our consideration.

Should you have any questions or concerns about this letter or the inspection, please email FDA at CDER-OSI-Communications@fda.hhs.gov. Your written response and any pertinent documentation should be addressed to:

Brittany L. Garr, MPH
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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1 In accordance with 21 CFR 320.31(c), the provisions of 21 CFR part 312 are applicable to this bioequivalence study because Protocol (b)(4) was conducted under an Investigational New Drug application (IND).

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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
12/22/2025 12:05:47 PM