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Problems continue despite actions by regulators to better prevent and address drug shortages.
FDA recently took the unusual step of approving the import of a widely used cancer drug from a Chinese manufacturer in the face of an outcry from physicians and patients over short supplies of vital oncology therapies. Although the regulators have revved up efforts in recent years to better prevent and address drug shortages, serious problems continue to plague drug production and distribution, particularly for a number of generic injectables.
National drug shortages rose in the first quarter of this year, according to the University of Utah Drug Information Service for the American Society of Health-System Pharmacists (ASHP) (1). Most of the serious shortages involve sterile injectables that are difficult to obtain quickly from alternative sources. FDA officials indicated they were looking for additional temporary suppliers of cisplatin, carboplatin, and methotrexate, all in short supply at cancer centers. FDA posted information on temporary importation of unapproved cisplatin from Chinese manufacturer Qilu Pharmaceuticals, to be distributed in the United States by Canadian-based Apotex Corp., on its drug shortages page on June 6, 2023 (2). FDA Commissioner Robert Califf noted in a social media message that the drug will come from registered facilities and will undergo careful assessment to ensure that the imported injectable chemotherapy is safe for patients.
Another example of FDA exercising regulatory flexibility is its decision to permit India manufacturer Intas Pharmaceuticals to export cisplatin and several other medically necessary injectable medications in short supply in the US, despite citation for multiple manufacturing deficiencies found during recent site inspections (3). FDA has required the company to provide third-party certification to confirm that products meet quality attributes and are not involved in data integrity violations. With the resumption of FDA plant inspections delayed by the COVID-19 pandemic, particularly with foreign facilities, the agency has uncovered more data and production quality issues that have led to import restrictions which have limited supplies.
Manufacturers are required to notify FDA in advance of anticipated production and supply problems, and the agency encourages industry to establish redundant production operations. But plant closures and problems in obtaining needed ingredients and supplies often cause supply reductions that can hit patients hard. Although FDA gained added authority during the COVID-19 pandemic to expand manufacturer notification of supply difficulties, notably for medical devices, some of these authorities are expiring. Legislation to strengthen reporting requirements for drug and medical devices makers have been proposed for inclusion in a measure to reauthorize the Pandemic and All-Hazards Preparedness Act, but dissension has delayed such efforts. Some legislators also want to revise the Controlled Substances Act to ensure patient access to ADHD treatment Adderall by better control of supply and preventing diversion.
FDA also would like to be able to require industry reports on rising demand for certain drugs, as occurred during the recent surge in respiratory infections. The agency currently lacks authority to collect this information and cannot compel any firm to produce more of a certain product. Brand manufacturers of new treatments, such as Novo Nordisk’s new weight-loss drug Wegovy, can better manage supply by taking steps to lessen demand, such as reducing supplies of a lower starting dose to discourage new patient treatment. Ideally, firms could respond to supply problems by shifting production lines to increase production of a needed medicine, but often are hampered by limited staff, resources, and ingredients. FDA recommends that manufacturers stockpile backup supplies of critical medicines, but, again, cannot require such action.
The broader problem is that shortages of cancer drugs and many widely used sterile injectables are produced by generic-drug manufacturers with limited redundancy in production due to very tight margins, as health plans and pharmacy managers push down prices. If a facility inspection uncovers serious quality issues or a company experiences increased costs for materials and operations, that may compel a plant shutdown that can impact the broader supply chain. In remarks at the annual meeting of the Biotechnology Information Organization (BIO) in June 2023, Commissioner Califf ascribed most drug shortages to generic-drug companies going out of business, either because they fail to invest in quality operations or because they can’t make a profit, as hospitals and pharmacies seek lower prices.
Such concerns were cited in a discussion of supply chain resilience at the Food and Drug Law Institute (FDLI) annual conference in May 2023, where a generic-drug maker warned against imposing added costs and burdens on industry, such as requiring production of extra supplies or stockpiles, due to unpredictable revenues from their commodity-like products. He advised against FDA’s proposed quality metrics requirements, which assume that purchasers will pay more for medicines from facilities that earn high quality ratings, a scenario that generics firms consider unlikely.
FDA described the challenges in coping with these issues in its latest report to Congress on drug shortages for 2022 (4). This annual update required by Congress since 2012 cites a decline in new drug shortages last year, but acknowledges still high ongoing shortage situations, as seen in the recent ASHP report. The agency continues to press for early notification of anticipated shortage situations to provide time to work with manufacturers to identify treatment options and to provide regulatory flexibility where appropriate. The report also describes increased collaboration with foreign regulatory authorities to identify supply chain disruptions involving overseas suppliers. FDA would like more information from manufacturers on supply chain components, such as inventory levels, and proposes to expedite the review and approval of generic-drug applications and supplements to address short supplies.
Jill Wechsler is Washington reporter for Pharmaceutical Technology.
Vol. 47, 7
When referring to this article, please cite it as Wechsler, J. Drug Shortages Continue to Plague FDA and Manufacturers. Pharmaceutical Technology 2023 47 (7).