Pratik Doshi, M.D. / Alembic Pharmaceuticals Ltd.

This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection conducted at Alembic Research Centre in Vadodara, Gujarat, India, between March 3 and 7, 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 Form FDA 483, Inspectional Observations. We acknowledge receipt of your March 26, 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 March 26, 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, parts 312 (21 CFR 312) and 50 (21 CFR 50) governing the conduct of clinical investigations and the protection of human subjects.1 We wish to emphasize the following:

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 50.22, 50.23, and 50.24,2 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. Under 21 CFR 50.20, “an investigator shall seek … [informed] consent only 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.”

You failed to seek informed consent for the above-referenced clinical investigation under circumstances that provided the prospective subject or representative with sufficient opportunity or information to consider whether to participate and that minimized the possibility of undue influence. Specifically, the ‘Nature and Purpose of this Study’ section of the informed consent form (ICF) stated, “This study is a clinical research project, but no part of it is of an experimental nature.” Stating that no part of the study is experimental may lead individuals to mistaken conclusions about whether the study is a “clinical investigation” as defined in 21 CFR 50.33 and 21 CFR 312.34. The lack of clarity on this point may lead individuals to mistaken conclusions about whether any such procedures are experimental – information that is required to be provided to subjects in accordance with the basic elements of informed consent found at 21 CFR 50.25(a)(1). Statements that do not clearly describe the experimental nature of a study may unduly influence individuals to agree to participate when they might not do so otherwise.

In your March 26, 2025, written response to the Form FDA 483, you acknowledged the observation regarding the ICF statement and stated that the rationale for having the statement in the ICF was based on your firm’s understanding of, among other things, the nature and purpose of bioequivalence studies. However, you acknowledged that bioequivalence studies are considered experiments, in accordance with 21 CFR parts 312 and 50. You further stated that all information pertaining to the conduct of the study and the investigational products were adequately described in the ICF; that the Ethics Committee approved the ICF; and that the information was sufficient to avoid the possibility of coercion or undue influence on the subject’s decision to participate in the study.

While we acknowledge that other information pertaining to the conduct of the study and the investigational product were described in the ICF, stating that “no part of it is of an experimental nature” created inconsistencies within the ICF, and these inconsistencies may lead individuals to mistaken conclusions about the type of study and its purpose. As a result, these inconsistences resulted in subjects’ not having sufficient opportunity to decide whether to participate in the study and may have unduly influenced the subjects’ decision to participate. As a result, you failed to obtain informed consent.

In addition, in your written response, you stated that your site has taken the following corrective and preventive actions: (1) You revised the “Preparation of Informed Consent Form” Standard Operating Procedure (SOP) to include the definitions of a “clinical investigation” under 21 CFR 50.3 and 312.3; (2) you updated the “Informed Consent Form” template to remove the phrase “but no part of it is of an experimental nature”; (3) you trained clinical personnel on the revised SOP; and (4) you initiated an amendment, with Ethics Committee approval, to all ICFs of ongoing and planned studies to ensure compliance with the revised SOP.

While we acknowledge the corrective and preventive actions that your site has taken, your written response is inadequate because you did not provide sufficient details about how you, as the clinical investigator, will ensure adequate compliance with the informed consent regulations at 21 CFR part 50. For example, while we acknowledge that you participated in training on the revised SOP, you did not participate in any training on FDA regulations governing the conduct of clinical research or the protection of human subjects. Additionally, although you stated that you initiated an amendment to all ICFs of ongoing and planned studies to ensure compliance with the revised SOP, your written response did not include the revised ICFs with Ethics Committee approval for all ongoing and planned studies. Without this information, we are unable to determine whether your corrective actions appear adequate to prevent similar violations in future clinical investigations.

We emphasize that as the 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, including obtaining legal effective informed consent from subjects before their enrollment. Your failure to obtain informed consent in accordance with 21 CFR part 50 before involving subjects in research jeopardizes the rights, safety, and welfare of subjects and raises concerns about whether subjects had an adequate opportunity to fully assess the risks and benefits of their participation in the clinical investigation.

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 without further notice to you. 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.

Your written response, and any questions or concerns about this letter or the inspection, should be sent via email to the FDA at CDER-OSI-Communications@fda.hhs.gov.