FDA warns researchers and drugmakers for clinical study, GMP violations
The US Food and Drug Administration (FDA) has issued warning letters to two researchers for failing to meet good clinical practice (GCP) requirements and for not complying with their own trial protocols. The agency also cited several drug manufacturers for failing to adhere to current good manufacturing practices (CGMP).
Sourav Mishra
Among the warning letters posted on 19 May, FDA cited Sourav Mishra, a clinical investigator at the All India Institute of Medical Sciences, for failing to ensure his clinical trial was conducted according to the investigational plan. The agency noted that it identified the shortcomings during inspections of the trial facilities in Odisha, India, as part of its Bioresearch Monitoring (BIMO) program.
"As a clinical investigator, you are required to ensure that your clinical investigations are conducted in accordance with the investigational plan," said FDA. "The investigational plan for Protocol 0270-222 required you to prohibit the use of cytochrome P450 CYP3A4 and CYP2D6 inhibitors to subjects during the entire study duration, and before baseline for at least five half-lives of the given drug, if given prior to the first dose of the study intervention.
"You failed to adhere to this requirement," the agency added. "Specifically, all three enrolled subjects were orally administered Aprecap (aprepitant), a moderate inhibitor of CYP3A4, during the study."
According to FDA, Mishra told inspectors that the oncology department's typical practice is to administer Aprecap 125/80 capsules before a patient receives chemotherapy and said he would pay closer attention to prohibited medication in the protocol going forward. The agency, however, said the response was inadequate because he didn't sufficiently detail what he would do to prevent similar violations.
"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 also raises concerns about the validity and integrity of the data collected at your site," said FDA. "Specifically, as stated in the protocol, Cytochrome P450 CYP3A4 and CYP2D6 inhibitors were prohibited during the study as they affect the pharmacokinetics of the study intervention, which is the primary objective of the clinical trial.
"In addition, the prohibited medication can interfere with the investigational product metabolism, which can increase the risk of side effects and reduce investigational product efficacy," the agency added. "As the clinical investigator, you are responsible for ensuring compliance with the protocol requirements for prohibited and concomitant medications."
FDA also raised concerns that Mishra had failed to properly obtain informed consent from trial subjects. The agency said the informed consent form (ICF) lacked the level of detail to ensure subjects were sufficiently informed about their participation in the trial and to minimize undue influence on their decision to participate. Furthermore, inspectors said that the lack of clarity and poor wording in the forms could lead participants to mistakenly conclude that the investigational drug had already been proven effective and to unduly influence their participation in the trial.
Naseem Jaffrani
Naseem Jaffrani, another clinical investigator and cardiologist based in Alexandria, LA, was also investigated under FDA's BIMO program and cited for failing to comply with an investigational plan. More specifically, the agency said he failed to follow protocol by not reporting serious adverse events (SAEs) to the clinical trial sponsor within 24 hours of learning of the event.
FDA noted that there was a subject who experienced three separate SAEs, including a non-ST elevation myocardial infarction (NSTEMI); a COVID-19 pneumonia, chronic obstructive pulmonary disease exacerbation, and hospitalization for congestive heart failure; and a pulmonary embolism and deep vein thrombosis post-COVID-19 pneumonia. However, the agency said that Jaffrani did not report the events to the sponsor for weeks or months after they occurred.
FDA further said that the investigational plan required all SAEs to be reported to Medpace Clinical Safety, a clinical research organization (CRO), within 24 hours of becoming aware of them. The agency also noted that the institutional review board (IRB) suspended enrollment and dosing for one of the protocols.
According to FDA, Jaffrani acknowledged that he failed to meet his clinical investigator responsibilities by relying on the clinical research coordinators and providing insufficient oversight of their work. As part of the corrective and preventive actions (CAPA), he said he would participate in the review of all his studies with the new site management and attend mandatory training sessions, including those on GCP. He also told investigators he would implement a system to determine whether an SAE has occurred at each visit for each trial participant and to notify the sponsor and IRB if one occurs within 12 hours.
"While we acknowledge the corrective and preventive actions that you have taken and plan to take, your response is inadequate because you have not provided sufficient details on how you, as a clinical investigator, will ensure adequate supervision and oversight of study personnel to whom you have delegated study procedures and tasks (for example, verifying that study activities performed by study personnel adhere to the protocol requirements), and how you plan to prevent similar violations from occurring in the future," said FDA. "You also did not provide sufficient details about how you will implement a system for reporting SAEs to ensure that the SAEs are reported in accordance with protocol requirements.
“Without these details, we are unable to determine whether your preventive action plan is adequate to prevent similar violations in the future," the agency added. "Your failure to conduct the clinical investigation in accordance with the investigational plan, and specifically, your failure to report all SAEs to the sponsor within 24 hours of your knowledge of their occurrence, raises significant concerns about your protection of the study subjects enrolled at your site, and raises concerns about the reliability of the data collected at your site."
CGMP violations
Hangzhou Yiqi Biotechnology and Harbin Jixianglong Biotech, active pharmaceutical ingredients (API) manufacturers based in China, and JW Nutritional, an over-the-counter (OTC) drug manufacturer in Texas, were all warned by FDA for CGMP violations.
Harbin Jixianglong and Hangzhou Yiqi were told they failed to demonstrate that their manufacturing processes can reproducibly manufacture APIs that meet predetermined quality attributes, while JW Nutritional failed to test samples of each component for conformity with all appropriate written specifications for purity, strength, and quality. Harbin Jixianglong was also cited for failing to ensure that its specifications and test procedures were scientifically sound and appropriate to ensure that its final products conform to established standards of quality and purity, while Hangzhou Yiqi was similarly cited for failing to validate and verify the suitability of its analytical methods.
Furthermore, FDA said Harbin Jixianglong's quality unit (QU) failed to do its job, ensuring that its APIs were CGMP-compliant and traceable during commercial distribution. The company was also cited for failing to ensure the water used in its manufacturing process for producing a sterile drug product was monitored and controlled for total microbial counts, objectionable organisms, and endotoxins.
"You manufacture GLP-1 APIs that were imported into the United States. These GLP-1 APIs are intended for use in sterile injectable drug products," said FDA. "Your firm failed to ensure that the [redacted] water you used in the [redacted] manufacturing steps of your APIs was suitable for its intended use.
"[Readacted] water must be suitable for its intended use and routinely tested to ensure ongoing conformance with appropriate chemical and microbiological attributes," the agency added. "Routine and representative monitoring of microbial counts and identification of contamination in the system and at the point of use are integral to maintaining a state of control and the suitability of water used in manufacturing operations."
Similarly, Hangzhou Yiqi was also cited for failing to ensure the water used in its manufacturing process was suitable for its intended use.
"Based on the records and information you provided, you failed to demonstrate that your [redacted] water system is adequately monitored to ensure that it consistently produces water suitable for use in the manufacture of APIs intended for further processing into sterile drug products," said FDA. "Your [redacted] water system must be adequately designed and properly maintained to minimize and control the potential for contamination.
"It must be suitable for its intended use and routinely tested at an adequate frequency to ensure ongoing conformance with appropriate chemical and microbiological attributes," the agency added.
Another notable issue raised by the FDA is that it emphasized to JW Nutritional that it is seen as an extension of the manufacturer, despite being an independent manufacturer, and must conform to all CGMP requirements, as any other manufacturer.
"You are responsible for the quality of drugs you produce as a contract facility regardless of agreements in place with product owners," said FDA. "You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act for safety, identity, strength, quality, and purity."
Harbin Jixianglong Biotech, Hangzhou Yiqi Biotechnology, JW Nutritional
