Adarsh Daswani, M.D.

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 October 18 and October 29, 2021. Investigators Dustin R. Abaonza and Yuanyuan Li, representing FDA, reviewed your conduct of a clinical investigation [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, Investigators Abaonza and Li presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your November 18, 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 November 18, 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 and the protection of human subjects. We wish to emphasize the following:

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 randomized treatment was administered, randomized treatment dose adjustments were made by the Interactive Response Technology (IRT) system, and protocol-specified procedures were followed when hemoglobin concentration (Hgb) measured by HemoCue was ≥12 g/dL. You failed to adhere to these requirements. Examples of this failure include, but are not limited to, the following:

a. From Study Day 1 until end of treatment, the protocol required subjects randomized (b)(4).

You failed to adhere to these requirements. Specifically, (b)(4) doses were not administered to the following subjects randomized to receive (b)(4) and on (b)(4):

i. For Subject (b)(6), thirty-four (b)(4) doses were not administered, including fourteen consecutive doses.

ii. For Subject (b)(6), forty-three (b)(4) doses were not administered, including twelve consecutive doses from (b)(6). On (b)(6), this subject had severe (b)(4) and was hospitalized to receive 1 unit of packed red blood cells.

iii. For Subject (b)(6), fifteen (b)(4) doses were not administered.

b. The protocol required randomized treatment dose adjustments to be made programmatically by the IRT system, based on the HemoCue Hgb value measured at least every 12 weeks from Week 52 through end of treatment.

You failed to adhere to this requirement. Specifically, IRT transactions were not conducted to obtain the randomized treatment dose for the following subjects:

i. Subject (b)(6) did not have IRT transactions performed at Week 76 ((b)(6)), Week 88 ((b)(6)), or Week 124 ((b)(6)). Of note, Week 76 and Week 88 were consecutive protocol-required study visits. ii. Subject (b)(6) did not have IRT transactions performed at Week 88 ((b)(6)), Week 100 ((b)(6)), Week 112 ((b)(6)), or Week 124 ((b)(6)). Of note, Week 88, Week 100, Week 112, and Week 124 were consecutive protocol-required study visits.

iii. Subject (b)(6) did not have IRT transactions performed at Week 64 ((b)(6)).

c. The protocol required that, if HemoCue Hgb was ≥12 g/dL at a study visit, HemoCue Hgb was to be repeated at the same study visit and the values were to be averaged. If HemoCue Hgb was repeated and confirmed to be ≥12 g/dL, randomized treatment dose was to be temporarily held. HemoCue Hgb was to be checked at a study visit 4 weeks later. If HemoCue Hgb was <11.5 g/dL, provided it had been at least 2 weeks since the previous study visit, randomized treatment was to be restarted at one dose step lower.

You failed to adhere to these requirements. Specifically, Subject (b)(6), randomized to (b)(4), had a HemoCue Hgb of 12.6 g/dL, which was repeated and confirmed to be ≥12 g/dL (12.6 g/dL) on (b)(6). However, randomized treatment dose was not held, and (b)(4) was administered on (b)(6).

Subsequently, on (b)(6), HemoCue Hgb was 12.7 g/dL, which was repeated and confirmed to be ≥12 g/dL (12.7 g/dL), and (b)(4) was held. However, on (b)(6), (b)(4) was administered, rather than reducing or holding the (b)(4) dose as required by the protocol.

On (b)(6), HemoCue Hgb was <11.5 g/dL (10.9 g/dL). However, (b)(4) was not administered as required by the protocol, even though it had been at least 2 weeks since the previous study visit. Subsequently, on (b)(6), (b)(4) was administered without reducing the dose of (b)(4) by one dose step.

You stated during the inspection that nurses would periodically tell you, “We are supposed to have a dose and don’t have a dose,” and you would then text the study coordinator. You also stated that you first became aware that the study coordinators were ordering replacement kits to resupply the inventory rather than using the IRT system to generate randomized treatment doses, when the monitor emailed you in January 2020, which we note is over a year after multiple subjects missed multiple doses, as described above.

In your November 18, 2021, written response to the violations listed above, you confirmed what you had stated during the inspection. You reiterated that, among other things, your lack of awareness of study staff’s not performing IRT transactions as required by the protocol, leading to missed and incorrect doses of randomized treatment for an extended period of time, suggests inadequate oversight. You also stated that your lack of awareness that a particular individual was performing the task of study coordinator suggests inadequate oversight.

We emphasize that your failure to conduct the clinical study in accordance with the protocol raises significant concerns about your protection of the study subjects enrolled at your site, and also raises concerns about the validity and integrity of the data collected at your site. Specifically, your failure to administer doses, make protocol-required dose adjustments, and perform IRT transactions to appropriately generate randomized treatment doses as required by the protocol, jeopardizes subject safety and welfare and raises significant concerns about the validity and integrity of the data collected at your site. As the clinical investigator, you are responsible for ensuring compliance with the protocol-required IRT transaction and dosing requirements.

In addition, you stated in your written response the corrective and preventive actions you have taken or plan to take, including the development of a new oversight standard operating procedure (SOP) to improve protocol compliance and communication and awareness of issues between you and your study staff, and to ensure that all staff involved in conducting and managing a research study are qualified and trained to undertake their delegated duties. You also stated that you are retaking a good clinical practice course and a course on oversight and responsibilities in clinical research; that you are requiring the site management organization to notify you whenever a study coordinator is departing or being assigned to the study; and that you are assigning a backup study coordinator to each of your studies.

While we acknowledge the actions that you and your site have taken or plan to take, we request that you specify the corrective actions that you, as a clinical investigator, have taken or plan to take to prevent similar violations in the future. For example, the SOP does not include sufficient details about the policies being instituted to ensure compliance with the protocol, particularly with respect to ensuring that similar violations having to do with IRT transactions and treatment requirements are prevented. Without these details, we are unable to determine whether your corrective actions appear adequate to help prevent similar violations in the future.

We emphasize that as the clinical investigator, you were ultimately responsible to ensure that your clinical 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. 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 integrity 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 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 that 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 or e-mail her 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