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Volume 29, Issue 8
Regulators and manufacturers address economic and ethical issues for scarce medicines.
Drug shortages have lessened in the past two years, but remain sufficiently prevalent to raise serious concerns about ensuring patient access to crucial therapies. Ongoing shortages dropped from nearly 100 at the end of 2013 to approximately 60 a year ago, according to FDA’s Center for Drug Evaluation and Research (CDER). The American Society of Health-System Pharmacists (ASHP), which compiles data from the University of Utah Drug Information Service, similarly reports a notable decline in new shortages over the past five years (1). A main turning point was the enactment of legislation in 2012 that requires manufacturers to notify FDA in advance of likely supply problems for critical medicines. The legislation has helped the agency prevent and resolve such issues. The drug shortage situation “now is in a better place,” commented CDER deputy director Douglas Throckmorton at the ISPE/FDA/PQRI quality manufacturing conference in June 2016. He credited expanded international cooperation and aggressive action by FDA’s Drug Shortages Staff (DSS) in identifying alternative sources for scarce critical drugs. But supply problems still are “way too many,” he said, noting that quality manufacturing failings remain the lead cause of supply disruptions, particularly with sterile injectables.
Shortages arise largely in markets where a small number of manufacturers-mostly generic-drug firms-serve the market, allowing little redundant capacity. To keep prices low, companies use common manufacturing lines for multiple products, and with 24/7 production schedules, there often is no time cushion for managing problems. At the same time, sterile products involve complex manufacturing processes, making it difficult to deal quickly with failures that can affect multiple products. And low profit margins on these operations discourage industry investment in updating or establishing new facilities. As a result, clinicians and patients still struggle to cope with limited supplies of basic therapies, including cardiovascular drugs, electrolytes, and injectables used in emergency rooms and intensive care units. Vaccine shortages emerge regularly, the latest involving limited supplies of yellow fever vaccine in the face of a spreading epidemic in Africa. The World Health Organization (WHO) has recommended diluting doses to provide short-term but adequate protection to larger populations. Shortages of drugs needed for acute care in emergency rooms and intensive care units are particularly serious, according to a study published in the May 2016 issue of Health Affairs. It found that more than half of nearly 2000 drug shortages reported between 2001 and 2014 to the University of Utah data system were for acute-care drugs where shortages pose a high risk of patient harm (1). The authors, from the Yale School of Medicine, report particular difficulties in finding alternative medications for scarce antibiotics, painkillers, sedatives, and saline intravenous solutions used daily in critical care. Substitutes, moreover, often are less effective, less safe, and more prone to medication errors during emergency care. The analysts want FDA to do more to identify generic injectables produced by a single source and thus at risk of supply problems. They also support the use of tax credits, rebates, or temporary market exclusivity to encourage added generic-drug firms to produce needed injectables. Similarly, the WHO executive board released a
in January 2016 on global shortages of critical medicines for children, with a focus on business and competitive factors that reduce access to low-cost injectables (2). WHO suggested that setting minimum prices or establishing multi-year global advance purchase commitments could help keep vital medicines on the market. Broader interest in the economic drivers behind drug shortages has prompted the Pew Charitable Trusts and the International Society for Pharmaceutical Engineering (ISPE) to examine market issues affecting business continuity and supply-chain management decisions and investments related to drug shortages. More import of APIs and other components means that 68% of drugs in the United States contain ingredients from India and other counties, explained Frances Zipp, president of Lachmann Consultants, at the ISPE June conference. The project is interviewing key industry stakeholders on how factors such as market concentration, low margins, and product withdrawals affect shortage situations with an eye to presenting findings at the ISPE annual meeting in September. Continued shortages of medically necessary medicines, particularly those used in emergency care and for treating cancer, also raise important ethical questions about allotting scarce supplies. This is particularly difficult in treating children with cancer, where care largely involves older generic injectables, explained Yoram Unguru, pediatric oncologist at Sinai Hospital in Baltimore, at the ISPE conference. A Working Group on Chemotherapy Drug Shortages in Pediatric Oncology issued recommendations for an ethical framework for allocating scarce life-saving drugs for treating childhood cancer in the February 2014 issue of the journal
and examined the issue further in an article published online January 28, 2016 by the
Journal of the National Cancer Institute
(3, 4). Somewhat controversial is the group’s advocacy for sharing drugs among institutions and its decision against favoring patients who participate in clinical trials. Unguru urged pharma companies to do more to prevent shortages in the first place, and for all parties to adopt ethical allocation policies to maximize the benefit of scarce therapies. Oncologists and anesthesiologists are pressing for greater variety in vial sizes to reduce costs and help avoid drug waste when a full vial is not needed by a patient, a situation common in pediatric care.
Despite such ongoing drug supply issues, FDA’s advance notification program appears to help prevent and mitigate shortage situations. Throckmorton reported that manufacturers are submitting approximately 200-300 reports of potential supply issues annually, which helped FDA avert 150 drug shortages in 2015. This strong response means that FDA has had to issue only two non-compliance letters so far to firms for failure to provide adequate warning. After a manufacturer informs FDA of a likely shortage, CDER’s DSS assesses the risk of disruption and helps devise mitigation strategies, working with CDER approval and quality offices and with the Center for Biologics Evaluation and Research (CBER) and FDA’s Office of Regulatory Affairs (ORA). The analysts first determine if the product is medically necessary and checks for any applications under review that could help fill a gap or whether other manufacturers of the product can increase output. CDER’s Office of Process & Facilities (OPF) in the Office of Product Quality (OPQ) consults with DSS to assess alternative sources of supply and whether a facility with potential to provide a needed drug meets quality standards or requires a new inspection. Efforts by a manufacturer to increase production at an existing or new plant or to transfer technology to a new contract manufacturer may warrant accelerated review of microbiology, processes, and facilities, explained OPF acting director David Doleski at the ISPE conference. OPF may meet with firms at risk of shortage situations to discuss preventive strategies, coordinate a pre-approval inspection with ORA, and help resolve manufacturing issues. FDA officials also can exercise enforcement discretion to facilitate access to new sources of crucial drugs. Import alerts may exempt medically necessary drugs and short supply situations. ISPE is developing a “gap tool” to help manufacturers assess how well they can avoid shortages by anticipating potential supply chain risks, forecast product demand, and provide redundancy in production operations. And industry commitment to quality manufacturing, said Throckmorton, is key to long-term prevention of drug shortages.
1. S.I. Chen, et al.
, 35 (5) 798-804 (2016). 2. WHO Secretariat,
Addressing the global shortages of medicines, and the safety and accessibility of children’s medication
, WHO Executive Board, Dec. 18, 2015, 3. M. DeCamp et al.,
, DOI 10.1542/peds.2013-2946 (American Academy of Pediatrics, Published online February 02, 2014), 4. Y Unguru et al.,
JNCI J Natl Cancer Inst
108 (6) (January 29, 2016).
Vol. 29, No. 8
When referring to this article, please cite as J. Wechsler, "Quality Manufacturing Key to Stemming Drug Shortages," BioPharm International 29 (8) 2016.