FDA warns Indian drugmaker over quality lapses, clinical researcher for enrollment issues

The US Food and Drug Administration (FDA) on Tuesday published a warning letter to Indian drugmaker Hikal Limited for supplier evaluation and its handling of complaint investigations. The agency also warned an oncologist for failing to follow clinical trial enrollment protocols and for failing to obtain informed consent from a trial participant.

Hikal Limited

FDA warned Hikal Limited for failing to meet current good manufacturing practices. The agency said the company's quality unit (QU) failed to ensure quality-related complaints were investigated and resolved in several instances. More specifically, it said the QU failed to adequately determine the root cause of metal contaminations in its active pharmaceutical ingredients (API) in 22 complaints since 2020. The company said the metal particles may have happened during equipment cleaning and may be technically unavoidable, but the agency was not satisfied with the answer.

"You referenced an industry standard on technically unavoidable particles in excipients as applicable," said FDA. "According to this guideline, technically unavoidable particles are inherent to the product and are not foreign contamination introduced by incomplete cleaning.

"Not only is this standard not applicable to your active ingredient manufacturing process, it also specifies that appropriate evaluation of materials of construction and particle mitigation strategies are required," the agency added. "Based on your investigation indicating a cleaning deficiency as a likely root cause, you do not have evidence to support that the metallic particles present are inherent to the manufacturing process."

Hikal was also told it had an ineffective corrective actions and preventive actions (CAPA) plan. The company said it initiated CAPAs after receiving complaints about foreign materials in APIs, but it continued to find contamination after it completed the CAPA investigations.

FDA also cited Hikal for failing to have a system to evaluate critical materials suppliers. While the company had procedures to evaluate a supplier if they exceed a specific rejection rate, it did not have a process to re-evaluate the supplier after initial qualification.

"This deficiency in your supplier qualification procedure allowed you to continue using materials from qualified suppliers after you determined their materials were found defective," said FDA. "For example, your firm received repeated customer complaints about particles in your APIs that you concluded most likely originated from your supplier of [redacted] drums and lids.

"Despite notifying the supplier of these quality issues and continuing to receive customer complaints, your firm failed to implement timely corrective actions, such as qualifying alternate suppliers, enhancing supplier oversight, or discontinuing use of defective materials from this supplier," the agency added.

Shirish Gadgeel, MD

FDA also sent a warning letter to Shirish Gadgeel, a cancer researcher at the Henry Ford Hospital in Michigan, for good clinical practice (GCP) violations. FDA said its investigator found that Gadgeel did not follow the investigational plan for at least one study. The agency noted that Gadgeel failed to ensure trial participants met all eligibility criteria before they were enrolled, and that participants who met specific protocol-defined criteria should have been removed from the trial.

"Despite not meeting this inclusion criterion, Subject [redacted] was enrolled and started study drug on August 3, 2021," the agency added. "This subject continued to receive study drug through November 16, 2021, thus receiving up to at least Cycle 6 of study drug."

Gadgeel was also cited for failing to obtain informed consent from a trial participant properly. FDA notes that the trial protocol required researchers to obtain separate special consent forms for inherited genetic analysis from participants, which they didn't do in at least one instance.

The researcher told FDA that it was an oversight related to using an unscheduled test kit and that the researchers had taken several corrective actions to mitigate the matter. However, the agency said the response was insufficient because he did not provide enough details about the mitigating steps.

"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, both to protect the rights, safety, and welfare of subjects and to ensure the integrity of study data," said FDA. "Your failure to conduct the clinical studies in accordance with the protocol, and your failure to obtain legally effective informed consent before involving subjects in research, raise significant concerns about your protection of the study subjects enrolled at your site and raise concerns about the validity and integrity of the data collected at your site."

Hikal Limited, Shirish Gadgeel, MD

FDA warns Indian drugmaker over quality lapses, clinical researcher for enrollment issues

Related topics

Recommended content

Welcome to the new RAPS Digital Experience