This Week at FDA: FDA draws roadmap for pandemic era guidances

Welcome to another installment of This Week at FDA, your weekly source for updates – big and small – on FDA, drug and medical device regulation, and what we’re reading from around the web. This was a big news week for FDA watchers – we saw the release of the Biden administration’s FY 2024 budget request and FDA’s roadmap for how it will handle dozens of COVID-19 pandemic era guidances now that the COVID-19 public health emergency (PHE) is winding down.
 
In a Federal Register notice on Friday, FDA laid out its plans to sunset, phase out, or transition the 72 guidances it issued under the PHE declaration, which is set to expire on 11 May 2023. The guidances span all of FDA’s product centers, except for the Center for Tobacco Products, and cover topics including the agency’s watershed guidances on the development and licensure of COVID-19 vaccines, its expectations for emergency use authorization (EUA) submissions for said vaccines and guidance on remote interactive evaluations during the PHE.
 
The dozens of guidances also applied to various minutiae under FDA’s remit that were hit by pandemic-related disruptions, including enforcement policies for more than a dozen medical devices, tests and digital health products; temporary flexibilities for food and nutritional labeling; exceptions to risk evaluation and mitigation strategy (REMS) and Drug Supply Chain Security Act requirements; and recommendations on reporting changes to glass vials and stoppers due to shortages.
 
The notice contains four tables that list guidances that will be transitioned in different ways: Table 1 contains guidances that will be terminated when the PHE expires; Table 2 lists 22 guidances that FDA will revise to remain in effect for 180 days after the PHE ends; Table 3 includes 24 guidances that will remain in effect for 180 days after the PHE ends that FDA plans to further revise and potentially extend further; and Table 4 comprises the four guidances that will remain in effect indefinitely.
 
Notably, FDA’s EUAs themselves and its authority to issue new EUAs are not impacted by the end of the PHE, as they are covered under a separate declaration from the PHE declaration.
 
In another sign of the pandemic waning, FDA revised and reissued its umbrella EUA for disposable, single-use surgical masks for health care workers to no longer accept new masks under the EUA. Existing masks listed under Appendix A will remain authorized.
 
On Thursday, the Biden administration released its FY 2024 budget, in which FDA is seeking a 10% boost in budget authority over FY 2023, a $372 million increase. While the budget lays out the administration’s priorities and policy aspirations, it’s up to Congress to pass a budget.
 
This week, Covis Pharma announced it will voluntarily withdraw its preterm birth drug Makena, more than a decade after it was granted accelerated approval and more than two years after FDA formally proposed to withdraw the drug after a confirmatory trial failed to show that it worked. Covis has proposed to phase out the drug, allowing current patients to continue taking it until its inventory is exhausted; however, FDA has said it is inclined to remove the drug immediately. A final decision from the Office of the Commissioner is expected soon.
 
We also read this interview with FDA Commissioner Robert Califf in STAT that touches on FDA’s advisory committees, recruitment and other issues facing the agency.
 
Drugs & biologics
 
The US Government Accountability Office (GAO) on Friday released a report making recommendations for FDA to review its efforts to promote advanced manufacturing technologies.
 
Earlier this week, FDA tweeted about its effort to address a hospital shortage of the asthma drug albuterol after Akorn, the sole maker of a specific dosage form of the drug stopped producing it.
 
Endpoints reports that Teva Pharmaceuticals received a Form 483 for its Fairfield, NJ facility following an inspection in November 2022. The inspection report details multiple good manufacturing practice (GMP) issues, including inadequate cleaning of equipment and utensils. Investigators found pink and red residue on equipment used to make its cefadroxil 500 mg capsules, even though the drug does not contain any dyes or flavors. Another drug that was previously manufactured using the equipment does contain flavorings and red coloring. The firm also received 30 complaints for defective coatings for cephalexin.
 
FDA’s Office of Generic Drugs has updated its GDUFA III quarterly activities report to include metrics for January 2023. The office said it approved 56 abbreviated new drug applications (ANDAs) and tentatively approved another 20 applications.
 
FDA’s Antimicrobial Drugs Advisory Committee will meet on 17 April to review Entasis Therapeutics’ new drug application (NDA) for sulbactam-durlobactam to treat infections caused by Acinetobacter baumannii-calcoaceticus complex, including multidrug-resistant and carbapenem-resistant strains.
 
The agency’s Gastrointestinal Drugs Advisory Committee is scheduled to meet on 19 May to review Intercept Pharmaceuticals’ NDA for the accelerated approval of obeticholic acid (OCA) to treat pre-cirrhotic liver fibrosis caused by nonalcoholic steatohepatitis (NAHS).
 
FDA approved or expanded the use of several drugs within the past week, including approving Pfizer’s Zavzpret (zavegepant) nasal spray to relieve pain from migraines and Amphastar’s naloxone hydrochloride nasal spray for opioid overdoses, and expanding the use of Eli Lilly’s Verzenio (abemaciclib) in combination with endocrine therapy to treat certain patients with early breast cancer.
 
Reuters reports that Eli Lilly’s solanezumab failed to prevent Alzheimer’s disease in a large clinical trial. While the company stopped developing the drug in 2016, it funded the 1,100 person trial alongside the National Institutes of Aging, the Alzheimer’s Association and several other organizations.
 
In a show of support for measures to incentivize the development of new antifungal and antibacterial products, more than 230 organizations wrote to Senate Health, Education, Labor and Pensions Chair Bernie Sanders (I-VT) and Ranking Member Bill Cassidy (R-LA) calling on the lawmakers to include the PASTEUR Act “in any moving legislative vehicle this year, including the reauthorization of the Pandemic and All Hazards Preparedness Act.”
 
FDA this week issued final guidance on when evaluations of gastric pH-dependent drug interactions with acid-reducing agents (ARAs) are needed. The guidance updates the 2020 draft version by adding footnotes to update the framework to evaluate the pH-dependent drug-drug interaction (DDI) liability of an investigational drug based on solubility and dissolution and provides additional literature and FDA guidance references for clarity, as well as modified examples of proton pump inhibitors (PPIs) and their doses for clinical DDI studies.
 
FDA is expected to issue new draft guidance on clinical trial considerations to support oncology accelerated approvals and recommendations for decentralized clinical trials for drugs, biologics and devices. Both guidances reached the Office of Management and Budget this week.
 
Patrizia Cavazzoni, director of FDA’s Center for Drug Evaluation and Research, last Friday said there is “no indication” that contaminated cough syrups found in several countries have entered the US drug supply chain. Initial reports found these cough syrups had unacceptable levels of diethylene glycol (DEG) and ethylene glycol (EG). Since then, the drugs have been found in at least seven countries and have caused more than 300 deaths, with most of these deaths occurring in children under the age of five. Cavazzoni called the outbreak “one of the largest epidemics of DEG poisoning in history.”
 
Bloomberg reported this week that House Appropriations ranking Democrat Rosa DeLauro (D-CT) is demanding that FDA hold UK drugmaker GSK accountable for having minimized the cancer risk posed by its heartburn drug Zantac. FDA requested Zantac and its generics to be removed from the market in 2020 after it was found that the active ingredient in the drug ranitidine could degrade to form a probable carcinogen. A year before Zantac’s approval in 1983, GSK research found the drug could form nitrosamines in certain situations, but these findings were not shared with senior managers in the US, or with FDA, according to the news outlet.
 
In related news, USP announced the release of the Nitrosamines Analytical Hub, a tool to address nitrosamine impurities. The hub is a public, web-based repository of downloadable analytical procedures to test pharmaceuticals for nitrosamine impurities. In addition, USP has published a general chapter in USP-NF, General Chapter <1469> on nitrosamine impurities and has eight USP nitrosamine reference standards to help regulators, manufacturers and other stakeholders better understand nitrosamine impurities. USP said the procedures published in the hub are meant to complement these reference standards.
 
Medtech
 
Both STAT and Endpoints reported on the unusual move by FDA to comment on its review of Lucira’s EUA for its combination COVID-19 and influenza test. FDA rarely makes such comments but felt the need to after the company cited its “protracted” review in its bankruptcy filings days before the EUA was issued. In a statement, Center for Devices and Radiological Health (CDRH) Director Jeff Shuren said the company needed to redesign its test after it was first submitted to remove a toxic substance and that the EUA request contained fewer positive influenza A samples than the agency had requested in its EUA template.
 
This week, FDA authorized the Sofia 2 SARS Antigen+ FIA, Sofia SARS Antigen FIA Control Swab Set. The kit is the first antigen test authorized by the agency as a prescription use-only test to detect the SARS-CoV-2 virus within six days of symptoms and meant to be used at point-of-care settings. Alongside the de novo authorization, the agency said it is classifying such tests as Class II devices and establishing special controls for simple devices to directly detect SARS-CoV-2 viral targets from clinical specimens at point-of-care settings or at home use.
 
FDA updated a safety communication about the risk of rare cancers such as squamous cell carcinomas (SCC) and various lymphomas linked to certain breast implants. The agency noted there have been 19 cases of SCC to date in the literature, and in most cases, people were diagnosed years after the initial implantation. It also noted that there have been three reported deaths from the disease.
 
The agency also sent a letter to healthcare providers on the potential risk of exposure to toxic compounds when using dialysis systems. The letter follows an earlier one the agency issued last year warning providers about potential risk of exposure to non-dioxin-like (NDL) polychlorinated biphenyl acids (PCBAs) and NDL polychlorinated biphenyls (PCBs) when using certain hemodialysis systems manufactured by Fresenius Medical Care. FDA said it knows other manufacturers use the same materials and are working with them to address potential safety concerns.
 
FDA’s Orthopedic and Rehabilitation Devices Advisory Committee is set to convene on 20 April to review Active Implants' de novo application for its NUsurface Meniscus Implant. According to the agency, it is a polymeric disc-shaped device implanted in the medial compartment of the knee to distribute the load between the distal femur and proximal tibia and is intended to improve pain and function in the medial compartment of a knee in which the medial meniscus has been resected.
 
In other device news, Laura Perryman, the former CEO of Florida-based company Stimwave, has been charged by the Department of Justice with scheming to sell a fake implantable chronic pain device and make millions over the span of several years by defrauding Medicare. Federal authorities said the company knowingly sold a piece of plastic that had "no medical efficacy at all."