FDA compliance chiefs detail FY2023 trends, plans for FY2024

Washington — Top US Food and Drug Administration (FDA) officials from the drug, biologics and medtech inspection offices said failure to maintain good manufacturing practices (GMPs) and marketing unapproved products are still the main reasons for issuing warning letters.

FDA officials offered insight into their work over the past year and emerging trends at the 2023 enforcement conference hosted by the Food and Drug Law Institute (FDLI). They also discussed plans for the upcoming fiscal year, including cracking down on sponsors who fail to update data on ClinicalTrials.gov, as well as policing manufacturers of counterfeit and contaminated products.

Medtech

Keisha Thomas, associate director for compliance and quality at the Office of Product Evaluation and Quality (OPEQ) at the Center for Devices and Radiological Health (CDRH), spoke about what her office has been up to the past year and where medtech inspection trends are headed. She noted that in FY 2023 OPEQ conducted 89 official action indicated (OAI) inspections.

“Corrective and Preventive Actions (CAPAs) always remain at the top in the device space [for OAI inspections]. Complaint handling is number two, medical device reporting is third, process validation is fourth, and rounding that out is design changes,” Thomas said. “There is a large percentage of OAIs that also include unapproved device charges.”

The agency issued 28 device warning letters in FY 2023, of which about 70% were due to unapproved use of the device in question. Additionally, the agency announced 790 device recalls.

On top of focusing on its traditional enforcement and quality compliance duties, Thomas said OPEQ will prioritize going after repeat inspection violators over the next fiscal year.

“We’re developing strategies for addressing companies that are in and out of compliance within a short period of time,” she said. “This is fundamentally firms who have gotten warning letters or some type of compliance action, have corrected it and mediated it, and then very shortly behind that they are seeing repeat violations in those spaces.”

Thomas also said OPEQ is focusing on stopping counterfeit devices, ensuring manufacturers comply with the agency’s unique device identifier (UDI) requirements, going after manufacturers who are delinquent in conducting their post-approval studies and providing data, balancing the use of traditional enforcement tools with new quality tools, and addressing premarket application data integrity and fraud issues.

“This may be surprising to some people, but we actually are finding and detecting a lot of premarket submissions that are coming in that have data integrity [issues] and potentially fraudulent data that is being used to support the applications for marketing,” Thomas said. “I don’t think I need to tell anyone here that if you’re getting a product approved or cleared based on fraudulent data, how dangerous that can be.”

Thomas reiterated that FDA is still expecting to finalize a rule updating its Quality Management System Regulation, which aims to harmonize 21 CFR 820 to the ISO 13485 standard. While she emphasized that the matter is out of their hands since they submitted the proposed rule to the Office of Management and Budget (OMB), she told Focus that officials are “crossing our fingers” that they will be able to finalize the much-anticipated rule very soon (Related: Combination products: Non-harmonized regulations are hurting manufacturers, Regulatory Focus 29 November 2023).

Biologics

Melissa Mendoza, director at the Office of Compliance and Biologics Quality (OCBQ) in the Center for Biologics Evaluation and Research (CBER), noted that her office has received a number of complaints related to amniotic fluid eye drops being marketed for dry eye disease and other dry eye conditions.

Mendoza highlighted a number of important cases, including issuing warning letters to human cells, tissues, or cellular or tissue-based products (HCT/Ps) manufacturers for failing to maintain GMPs.

“We’re seeing a lot of umbilical cord products and also products derived from skin, amniotic membrane and amniotic fluid; although that is not HCT/P,” she said. “We’ve also issued a number of untitled letters in this space, while they did not include GMP violations as they didn’t follow an inspection, they’re consistent in some respects to some of these letters.”

Mendoza updated attendees about FDA’s ongoing litigation against the stem cell producer, Cell Surgical Network, which was handed a permanent injunction from FDA in 2018 for GMP violations. She noted that the case is now on appeal before the Ninth Circuit Court, with arguments scheduled to begin in February 2024.

Mendoza also noted that FDA has been issuing pre-notices to researchers for potential non-compliance with ClinicalTrials.gov. She added that CBER has been identifying clinical trials that are not complying and stakeholders should expect to see more action on the issue from the center.

Ensuring researchers publish their study findings on ClinicalTrials.gov is a priority for FDA Commissioner Robert Califf. In early December, he published a blog post on the importance of ensuring that researchers are transparent with the agency by providing and updating clinical data on the site.

As stated in the FDA’s unified agenda a few months ago, CBER will propose amending HCT/P regulations under 21 CFR part 1271, Mendoza said.

“These proposed changes would establish requirements for the submission of records or other information to FDA upon request in advance or in lieu of an inspection,” Mendoza said. “The changes would also require the participation in a remote interactive evaluation of such establishments upon FDA’s request.”

Another top priority for Califf over the past year has been to reorganize the Office of Regulatory Affairs (ORA). Mendoza noted that the plan would affect her office as it would merge current compliance functions within ORA into existing compliance offices at the various products centers in order to streamline their operations and expedite decision-making. (Related: Califf: FDA will be a ‘more activist’ agency, Regulatory Focus 24 August 2023)

Drugs

Jill Furman, director of the Office of Compliance (OC) at the Center for Drug Evaluation and Research (CDER), highlighted two areas that her office has had to address in FY 2023, including contaminated ophthalmic products and diethylene glycol (DEG) contamination in medical products.

Earlier this year, the World Health Organization (WHO) issued a safety alert after hundreds of children died from DEG contamination traced to children's cough syrup and FDA has stepped up to ensure such products aren’t for sale in the US.

“Although we did not find any contaminated product in the United States, the outbreak did span at least seven countries and was associated with at least 300 fatalities, sadly mostly in young children under the age of five,” Furman said. “This has been one of the largest epidemics of DEG poisoning in history and a similar contamination back in 1937 led to the modern Food, Drug and Cosmetics (FD&C) Act.”

Furman told the attendees that in FY 2023, CDER inactivated more than 19,000 drug listings from FDA’s drug registration and listings system, and classified 264 recall events involving more than 1,100 products. Additionally, CDER issued 115 warning letters across its compliance programs and another 65 drug-related warning letters in partnership with ORA.

Furman noted that about 46% of the warning letters were for current good manufacturing practice (CGMP) violations.

“About 45% of those CGMP warning letters were issued after reinspection of a firm, and it’s fair to say that we generally consider repeat observations when we evaluate our cases,” she said. “About 28% of our CGMP warning letters were based on evidence that we collected from records requests, and this is a significant increase based on the previous year and can be explained by some of our work safeguarding the public from DEG contamination.”

A total of 27% of warning letters handed out in FY2023 were for marketing an unapproved new drug or misbranding, 6% were for clinical trial oversight, 6% were for compounding facility violations and 5% were for refusal to provide access to and copying of records violations, according to Furman.

“It's critical that we focus our regulatory actions on matters that will have the greatest impact on public health, and our compliance and risk management processes are evolving so that we can set our priorities while also remaining nimble so that we are able to respond to emergencies rapidly and effectively,” she said.

FDLI

FDA compliance chiefs detail FY2023 trends, plans for FY2024

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