Over the last few years, the number of drugs on shortage has remained the same. It may even have gone up. Hospitals continue to confront the issues and devise responses.
Drug shortages continue to occur in the United States. The number of drugs in short supply or completely unavailable may have gone down, but that number is still high. Worse, the types of products in short supply are as important as drugs used to fight cancer or as ubiquitous as normal saline for IV injection.
In 2011, FDA received reports of 251 drug shortages, of which 183 were sterile injectable drugs. In 2012, 117 new drug shortages arose, 84 of which were sterile injectable drugs - but this number does not reflect the number of drug shortages that originated earlier and were continuing.
“The number of new shortages has gone down in the last few years, but the total number of drugs on shortage has remained the same, if not gone up a little,” said Allen Vaida, PharmD, executive vice president with the Institute for Safe Medication Practices in Horsham, Penn.
Erin FoxThe shortages affect hospitals and health systems nationwide. A national survey of 358 directors of pharmacy conducted in 2013 found that 99% (211 out of 214) reported that they had experienced a shortage of an injectable oncology drug in the previous year. And 64% said that they had completely run out of at least one injectable oncology drug.1
“It is unbelievable that in the United States we have this level of drug shortage,” said Erin R. Fox, PharmD, director of the Drug Information Service at University of Utah Health Care in Salt Lake City. “A manufacturing failure on this scale in any other industry would get so much attention.”
Most shortages are due to manufacturing problems, Fox said. Some manufacturing facilities are not in good shape. If a production line that makes several drugs goes off-line for any reason-contamination problems, machinery breakdown, a natural disaster, a shortage of ingredients - many different products are affected, she said.
David GaughMany manufacturers have not retooled their facilities in years, while the number of companies that make a given product may have dropped from three or four to only one, Vaida said. If a sole manufacturer decides to shut down a plant for several months or a year in order to upgrade, or any problems occur, there is a dramatic effect on supplies.
“Shortages are complex and multifaceted, and each shortage situation requires specific evaluation and resolution,” said David Gaugh, RPh, senior vice president, sciences and regulatory affairs, with the Generic Pharmaceutical Association in Washington, DC. “Some products in shortage are only made by one or two manufacturers, while other situations require coping with unplanned disruptions in manufacturing for any variety of reasons. There is no single cause and no single solution.”
Some of the inflexibility in drug manufacturing is due to changing business practices. Manufacturing procedures have been tightened over the last few decades, and both companies and healthcare facilities keep much smaller inventories than they once did, Vaida said, adding, “There is no redundancy in the marketplace.” Even if another manufacturer wants to take up the slack when a shortage occurs, the process takes time, he said.
Changes in how drugs and products are ordered also have an effect. Hospitals now order more frequently and keep less inventory in stock, Vaida said. Twenty years ago a hospital might receive a wholesale delivery three times a week; now some get deliveries twice a day. One consequence is that low or no inventory means less leeway when a shortage occurs.
Even when the manufacturer comes back up to speed with production, shortage continues for a while. A product may officially be in production, “but no one can buy it for a couple of months because it needs to fill the pipeline back up,” Vaida said.
Salvatore GiorgianniThe cost of regulations for sterile solutions has not dropped, but the profit margin has, said Salvatore J. Giorgianni Jr., PharmD, CMHE, a consultant pharmacist with Griffon Consulting Group Inc., in Fort Myers, Fla., and chair of the American Public Health Association Men's Health Caucus. Giorgianni is also a member of the Drug Topics editorial advisory board.
“I look at this from the perspective of a business person,” Giorgianni said. “How many runs of a product that I lost money on do I continue to do when the cost of regulation is continuing to increase?’ The same market forces may eventually extend shortages to products such as oral medications, he warned.
The leanness in the industry may need some correction, said ISMP’s Vaida. There should be some redundancy built into the making of certain critical products, with a manufacturer having the ready capability to produce a critical drug or a product at another plant.
“Is there a cost to doing that? Yes, there may be,” Vaida said. “But we have learned in the last five or six years that there is a bigger cost with all these shortages.”
Valerie Jensen“Anything related to shortages is getting the utmost priority,” said Capt. Valerie Jensen, RPh, U.S. Public Health Service, and associate director of the Drug Shortages Program in FDA’s Center for Drug Evaluation and Research. The FDA is working with manufacturers to increase manufacturing capacity and speed any regulatory approval.
During shortages, the agency also is allowing the use of products on a contingency basis that it would not permit otherwise, Jensen said. For example, use of an injectable in which particulates are found is permitted if it is used with a filter, she said.
The FDA Safety and Innovation Act (FDASIA) of 2012 gave the agency new authority to deal with drug shortages, which is helping the situation now. In 2011, FDA was able to prevent 195 drug shortages; in 2012, 282.2 FDASIA also expanded to 11 the number of FDA staffers dealing with shortage problems, Jensen said.
FDASIA is helping, said GPhA’s Gaugh. The act, which includes the Generic Drug User Fee Act, gives FDA authority to collect user fees, which GPhA supports, he noted. Both acts expedite approvals and reduce the backlog of abbreviated new drug applications (ANDAs).
However, FDA can neither manufacture a drug nor force a company to continue making something that it chooses to discontinue, Jensen said. If a company wants to discontinue a product, there is nothing the agency can do.
“The only way to mitigate current shortages and prevent future shortages from occurring is a collaborative effort with all stakeholders across the supply chain,” said Gaugh. “This means more communication between regulators and manufacturers, enhancing the ANDA review and approval process, and making sure that generic manufacturers continue to be part of the solution to this complex issue.”
To cope with shortages, many health systems turned to compounding pharmacies for products that could not be obtained otherwise.
“Traditional pharmacy compounding has, throughout history, served an important public health role in circumstances where patients cannot be treated with FDA-approved products,” said Sarah Sellers PharmD, MPH, president of q-Vigilance, a consulting firm in Barrington, Ill., and a former FDA official.
However, compounding introduces some risk. “Prescribers are generally unaware of risks that may be unintentionally introduced through compounding,” Sellers said. “Lacking this information, prescribers cannot fulfill the role of a learned intermediary when making benefit-risk decisions on behalf of their patients.”
But missteps at compounding pharmacies have drawn regulatory attention, Giorgianni added. The federal government passed the Drug Quality and Security Act as a response to last year’s outbreak of fungal meningitis linked to the New England Compounding Center.
And sometimes, when compounding pharmacies are asked to pick up the slack during a shortage, they may overextend themselves and problems can result.
Another issue compounders face involves FDA regulation. If the agency imposes on providers such as compounding pharmacies the same sorts of standards and inspections it applies to manufacturers, then those providers will be hit with additional production costs, Giorgianni said. “My worry is that while compounding pharmacies have been able to some extent to pick up the slack, that may not be the case in five years.”
Cancer treatment has been hit hard by shortages of injectable oncology drugs.
Richard Schilsky“In some cases there is no substitute for the drug in short supply,” said Richard L. Schilsky, MD, chief medical officer of the American Society of Clinical Oncology in Alexandria, Va. “In other cases, there may be a substitute, but is almost always a brand name, and that increases the cost and out-of-pocket co-pay.”
Shortages of drugs to treat pediatric cancers are especially worrisome, he added. “You are talking about potentially curative therapy, and you don’t want to jeopardize that.”
Switching drugs can cause other problems. Substituting one drug for another may call for dosing based on body surface area rather than body weight, a change that can give rise to dosing errors, and the new drug may have a different set of side effects that require different supportive drugs, Schilsky said.
Substitution may mean employing a drug that has not been completely tested for the type of cancer it will now be used to treat, Fox said. Clinical trials in chemotherapy are conducted with very specific combinations of drugs. “You need to know what to use instead, and nine times out of ten, we don’t know,” she added.
There have been calls for national guidelines on how to cope with oncology drug shortages. Guidelines are needed not only to determine the best substitutions, but also to govern allocation of drugs when they are in short supply.1
ASCO does not keep a list of suitable drug substitutions, Schilsky said. Such a list would be difficult to create, because drug substitutions often depend on the clinical context for a specific patient, he said. However, oncologists know what the potential substitutions would be for a given drug, he added.
Asking doctors to choose which patient will receive a drug in short supply puts them in a very difficult position, Schilsky said. He noted that when he was in practice at the University of Chicago the situation never came to that. “The pharmacist solved the problem in the nick of time, but that puts pressure on the pharmacists and takes more time on their part.”
There should be a list of critical drugs and products, said ISMP’s Vaida. “You should never be able to be out of normal saline or some of the electrolytes.” But such a list, he said, raises the question of who will have the authority to decide which drugs and products to include.
The creation of a critical drug list - or at least discussion of its creation - is a subject of communications between ISMP and ASCO and other medical groups, Vaida said. One element under consideration is an offer of incentives to manufacturers of products included on such a list, to ensure that they have a contingency plan in place in the event of a shortage, he added.
Because shortages keep recurring, the pharmacy community has learned how to cope. Hospitals have added personnel to monitor the marketplace so that they can react quickly to a shortage when it occurs. Some of the shortages have repeated themselves, Vaida said; in those instances, pharmacists know what they did the last time to solve the problem.
In the face of drug shortages, pharmacists have scrambled to find scarce supplies of a given product and worked hard to find substitutions or modifications to a drug regimen. “As healthcare providers, we must take care of the patient. We go to huge lengths with a shortage and do whatever we can,” Fox said. “In some cases, we make this problem invisible.”
1. Goldsack JC, Reilly C, Bush C, et al: Impact of shortages of injectable oncology drugs on patient care. Am J Health-Syst Pharm. DOI 10.2146/ajhp130569
2. Food and Drug Administration. http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm050796.htm (accessed 6/21/2014)
Valerie DeBenedetteis a medical news writer in Putnam County, N.Y.
FDA’s Strategic Plan for Preventing and Mitigating Drug Shortages (October 2013) http://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM372566.pdf
Drug Shortage Databases
ASHP Drug Shortage Resource Center
Current and Resolved Drug Shortages and Discontinuations Reported to FDA