The drug shortage in the United States seems to be improving, but it’s unlikely to disappear any time soon. For the past few years, critical shortages of drugs—primarily generic sterile injectables used in anesthesiology and for the treatment of infections and cancer—have forced US physicians to use alternatives that are less effective, more costly, or associated with more adverse events. And in some cases, no alternatives have been available.
In 2010, 178 drug shortages were reported to the Food and Drug Administration. In 2011 that number grew to 251, of which 183 were sterile injectables. Currently, the website of the American Society of Health-System Pharmacists lists 226 ongoing shortages (www.ashp.org/drugshortages/current).
In a survey of members conducted by the American Society of Anesthesiologists in March 2012, 98% of 3063 respondents reported current shortages of at least one anesthetic. Of those, 96% reported having to use an alternative drug, 50% had to change an anesthetic procedure in some way because of a shortage, 7% had to postpone cases, and 4% had to cancel cases.1
Efforts by the FDA, specialty societies, patient advocacy groups, and other stakeholders have raised awareness of the situation, and steps have been initiated to mitigate the problem. The passage of the Food and Drug Administration Safety and Innovation Act (FDASIA) in July is viewed as a possible turning point. Among other measures, it requires all manufacturers—not just sole manufacturers, as in the previous law—to inform the FDA of impending shortages so that action can be taken to prevent them, such as identifying additional sources of the product or allowing for temporary foreign import.
But, the recent fungal meningitis outbreak crisis involving contaminated products from the New England Compounding Center and subsequent shutdown of its parent company, Ameridose, highlights the ongoing vulnerability of the entire drug manufacturing system.
Increasing reliance on compounding pharmacies has been blamed on the shortages, and now Ameridose’s voluntary shutdown is worsening the problem, since the company was a major supplier of six products that were already in short supply.2
Whether manufacturers can be held liable for damage resulting from a shortage of their product may soon be addressed in a court case. A federal appeals court has allowed a lawsuit against drug manufacturer Hospira by a woman with a vitamin A deficiency who is now blind in one eye after she was unable to obtain the company’s injectable Aquasol A because manufacturing problems resulted in a shortage.3
There have been reports of patient deaths and of “gray market” price gouging as a result of the shortages. And recently, members of Congress have called for an investigation into the possible role of the pricing structure of hospital Group Purchasing Organizations in contributing to the problem.4
Several forces combined to create the shortages, including manufacturing problems, difficulties in obtaining raw materials, and economic considerations. The older, generic sterile injectable drugs are typically made by just one or two manufacturers, they are more costly and labour intensive to make than oral drugs, and their profit margin is relatively low.
Over 70% of shortages in recent years have involved quality or manufacturing problems and delays, FDA spokeswoman, Lisa Kubaska, told the BMJ.
Tennessee oncologist W Charles Penley, chair of the government relations committee at the American Society of Clinical Oncology, says that some of the shortages have been of “very basic” intravenous drugs, including narcotics, calcium, magnesium, and sodium bicarbonate, as well as, in his specialty, older drugs such as the adjuvant leucovorin and the chemotherapeutic agent doxorubicin liposomal.
“These are all drugs that are relatively inexpensive, but they’re drugs for which we don’t have great substitutes.” Penley says.
In infectious diseases, antimicrobial resistance plays a major role in the shortage problem, according to Edward Septimus, professor of internal medicine at Texas A&M Health Science Center, Houston, and a member of the antimicrobial resistance committee of the Infectious Diseases Society of America.
“We’re having significant increase in antimicrobial resistance, especially with the gram negative organisms. We often use a single anti-infective empirically. If you don’t have some of those agents, you might not be able to find a therapeutic alternative for some patients,” he says.
“Many of these low volume, low profit drugs are made by just one manufacturer at a single site,” he said. “So, if there are manufacturing problems at that one site, there’s no backup, there’s no redundancy in the system.”
And in recent years, pharmaceutical companies have stopped developing new antimicrobials, opting instead for drugs for chronic disease that patients need to take for a lifetime rather than just a single bout of illness.
“If you look at return on investment and think of how expensive it is to bring drugs to the market place, there’s a financial disincentive for Big Pharma to invest in anti-infectives . . . Until five or 10 years ago, there was always a drug in the pipeline to hopefully bail us out when there was a multidrug resistant organism. We don’t have that luxury anymore.”
Despite the immensity of the problem, at least some of the factors that have contributed to the shortages are now being addressed, and the situation isn’t as bad today as it was a year ago. Professional societies have been talking to the FDA and lobbying Congress in efforts to enable fixes.
For example, when the American Society of Anesthesiologists first learnt of the impending shortage of propofol, it held informational calls with the FDA encouraging it to authorize importation of a foreign formulation of the sedative (Propoven).
Currently, both US manufacturers of propofol are releasing product and the FDA will continue to monitor the situation and authorize the importation of Propoven until demand can be fully met through domestic sources, the society’s vice president for scientific affairs, Arnold J Berry, told the BMJ.
The federal government has taken significant steps to deal with the shortages over the past 14 months. In October 2011, President Obama issued an executive order directing the FDA to take further action to stem the shortages.5
In December 2011, a report from the US Government Accountability Office documented a 200% increase in drug shortages from 2006 through 2010 and cited constraints on the FDA’s lack of authority over drug makers’ actions.6
The subsequent July 2012 passage of the FDA Safety and Innovation Act eased many of those constraints. The law requires the FDA to issue a warning letter to manufacturers that don’t notify it of impending shortages and to make the letter and the company’s response available to the public.
Since the law was passed, the FDA has received daily calls and emails from manufacturers about potential problems, with the number of monthly notifications more than doubling, Kubaska says.
Other provisions in the act might also help. The law allows the FDA to collect user fees from industry to fund reviews and encourage development of new drugs and devices. And the Generating Antibiotics Incentives Now (GAIN) Act, included within the safety and innovation act, gives five additional years of market exclusivity to pharmaceutical companies as an incentive to develop new antimicrobials to treat resistant infections.
Penley said that the act contained many, but not all, of the provisions that the American Society of Clinical Oncology had lobbied for. What’s missing, he said, was the ability to force manufacturers to comply. “There weren’t penalties. If a [company] didn’t perform . . . the worst that could happen was to have their name published on an FDA website. There weren’t many teeth in the bill.”
The society, among others, had suggested fines for non-compliance. Instead, the FDA will monitor the impact of the law over time to see if the shortages begin to abate. “The hope would be that if people and manufacturing firms do the right thing that [penalties] won’t be necessary…We’ll just have to wait and see,” Penley said.
The generic industry is pledging to act. Earlier this year, the Generic Pharmaceutical Association, which represents the manufacturers and distributors of generic medicines, proposed an “unprecedented multi-stakeholder tool” called the Accelerated Recovery Initiative to alleviate supply problems of critical drugs through voluntary collaboration.7 The idea is that a third party, IMS Health, would collect, analyze, and report information on supply problems to the FDA in real time. The association is currently in talks with the FDA regarding implementation, a spokesman said.
How much difference will recent changes make? Overall, says Penley, “I’m feeling better than I felt two years ago about the problem. We’ve begun to identify the individual problems that lead to shortages. The problem is in full view now. Awareness has been raised . . . But it’s something we will need to continue to be vigilant about and to monitor.”
And as the Ameridose situation shows, “There will always be things we can’t foresee . . . When we identify problems, we need to continue to work with the FDA.”
In Berry’s view, “The [act] was a step in the right direction to resolve drug shortages, but unfortunately, we expect shortages of anesthetic drugs to continue.”
Septimus is also circumspect, “I’m cautiously optimistic people will come up with solutions . . . Right now I consider this an urgent and important issue. I do not consider it to be an emergency, but I do not want it to get to that point.”
Cite this as: BMJ 2012;345:e8551
Competing interests: The author has completed the ICMJE unified disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declares no support from any organisation for the submitted work; no financial relationships with any organisation that might have an interest in the submitted work in the previous three years; and no other relationships or activities that could appear to have influenced the submitted work.
Provenance and peer review: Commissioned; not externally peer reviewed.