Dawn of a new (legal) drug crisis?
With little notice until recently, a shortage of medicine is starting to impair treatment at America’s hospitals. Common, cheap and necessary drugs needed to fight bacteria or cancer, to ease pain or to nourish premature infants are running out.
Many of these meds are injectables, which must be made under sterile conditions. All are generics, which sell for pennies compared to the buck-buster drugs that feed the bottom lines at the big-name drug companies.
Most shortages are unnanounced until a wholesaler’s shipment arrives lacking an ordered drug. “It’s unbelievable,” says Sara Shull, manager of the drug policy program at the University of Wisconsin Hospitals and Clinics in Madison. “Today I was trying figure out alternatives to papaverin,” an old drug used to prevent spasm in the many surgeries that involve grafting a blood vessel. “We have identified some alternatives, and I am now I working with the surgeon to figure out how to dose them, how to apply them. Is it bathed on? Sprayed on? He’s busy, we’re all busy, and sorting this all out takes a lot of time. The continual need to find replacements gives me a headache.”
Shortage-induced substitution played a role in Alabama, where nine hospital patients were killed by intravenous nutrients this summer, says Allen Vaida, executive vice president of the Institute for Safe Medication Practices, a non-profit that targets medicine hazards. “Because of a shortage, this compounding pharmacy was making a product from raw material, and it got a bacterial contamination.” (The maker of the nutrient solution, Meds IV pharmacy in Birmingham, Ala., is apparently out of business.)
Injectable nutrients are a shortage with broad implications, says Shull. “No matter what your disease process, you need normal calcium levels [and] normal potassium levels to maximize your therapy, and products needed to build total parenteral nutrition [for patients who can't take food by mouth] have been short for months. Patient care has been impacted.”
Last month, Richard D. Paoletti, a vice president of Lancaster General Health in Pennsylvania, told Congress that wholesalers had failed to supply one-fifth of the 4,344 individual drugs ordered during August 2011.
Running long on shortages
Pharmacists have always had to find substitute medicines, as patients keep coming through the door, but Vaida cites Food and Drug Administration numbers to argue that shortages are now at “crisis” proportions. “The FDA shows 70 shortages in 2006, 129 in 2007 and last year, there were 211. So far this year, we are already above 200 shortages, and the year isn’t done. Shortages have been around forever, but they have never reached this number.”
Some drugs can be substituted, says Vaida, but “especially with chemotherapy and nutritional products, it’s not like are three alternatives for some medications, as there are with blood-pressure drugs. Some chemotherapies are specific for certain cancers, and if they are not available, you may have no alternative or [you] may have to use a third-line alternative.”
The pharmaceutical situation has never been more complicated, with more than 45,000 prescription drug products on the market, from about 1,400 manufacturers. Although we could not easily find numbers, drug shortages are also rising in the United Kingdom, where the supply situation is complicated by the restriction on exports within the European Union.
Shortages have many possible causes, but because manufacturers tend to be closed-mouthed, it’s not clear which problems are most momentous or easiest to solve:
Quality control. Injectable and intravenous drugs must be made in sterile conditions, a complication that helps explain why they dominate shortage lists. Even common, low-tech items, needed for total parenteral nutrition, are running short, Vaida says. “We see shortages of injectable nutrients and electrolytes, potassium phosphate, sodium phosphate, even multivitamins in injectable form,” he says.
Profitability. The key benefit of generic drugs — a low price — ironically sets the stage for shortages, says Vaida. “Over the years, many of these generic prices have come down dramatically. With biological and immunological products, manufacturers can make lot more money,” he says. It sounds obvious and straightforward, but Vaida says “a lot of manufacturers may not own up” to withdrawing unprofitable drugs.
Consolidation. Mergers among manufacturers making the same products render future shortages more severe, Vaida says. “If three plants go down to one plant, and there is a quality issue at the plant, you can’t start producing somewhere else, unless those plants have been [FDA] inspected for that drug.”
Failure to communicate. Companies are not required to notify the FDA — or anybody else — when they stop producing a drug, either deliberately or due to a manufacturing problem. No matter the human costs, a decision to quit manufacturing is considered a normal business decision not subject to agency review or influence.
How short is short?
A drug is considered “short” if a specific dosage and formulation is unavailable, and in some cases, a similar item can be substituted. But Shull says that’s still a problem in a big hospital. If a product that is normally purchased in a pre-loaded syringe is only available in a vial, University of Wisconsin Hospitals and Clinics can no longer send a “unit of dose” to the nurse, and “that’s what the nurses are expecting,” Shull says.
Changing procedures complicate care and raise costs, Shull adds. “All our people are working in a complex system, with lives on the line. These shortages can be a recipe for increased errors.” Her hospital must dedicate one staffer to securing supplies of the common blood-thinner heparin, she says. Searching for alternate sources is less rewarding than studying the efficacy of various medication treatments, she adds. “It’s not what I was taught in pharmacy school, but when your back is up against the wall, you have no other options.”
Beyond impairing patient care, shortages have also become a major burden in medical research. Tests of new medicines, often set up to run at several hospitals nationwide, must give standardized meds to the treatment and control groups, and chaos can result when the drugs become unavailable. “These shortages are now affecting clinical trial options for patients with cancer,” Robert DiPaola, director of the Cancer Institute of New Jersey, told the House Energy and Commerce Subcommittee on Health on Sept. 23. “Due to the uncertainty of being able to obtain many of these drugs, enrollment of patients on clinical trials has been delayed or stopped in several of our trials.”
Howard Koh, assistant secretary of health and human services, reinforced that message to the committee: “Many of the cancer drugs in short supply … are mainstays of the anti-cancer arsenal, and were largely developed through federally funded research begun 20, 30, even 40 years ago. They are still essential to treatment and research,” he said. The National Cancer Institute is currently sponsoring 349 clinical trials that require these drugs, Koh added. “Taken together, these studies represent thousands of patients, as well as a significant federal investment in clinical trials research.”
At the same hearing, Mike Alkire, chief operating officer of Premier healthcare alliance, told Congress how widespread the shortages have become. In a recent Premier survey, 53 percent of hospital pharmacists said they had faced at least six shortages “that had the potential to cause a medication safety issue or an error in patient care.” And 34 percent of respondents said at least six shortages had “resulted in a delay or cancellation of a patient-care intervention.”
Premier estimates that the 2,500-plus non-profit U.S. hospitals in its membership pay an extra $66 million per year due to these shortages — which translates to $415 million at all U.S. hospitals.
Market going gray?
When the usual sources run dry, hospital pharmacists often get emails, faxes and phone calls from the “gray market,” sources outside the usual supply chain. In the summer of 2011, the Institute for Safe Medication Practices surveyed 549 hospitals and found that:
56 percent were getting solicitations “daily” from as many as 10 gray marketeers;
One-third to one-half of hospitals reported that gray market prices were 10 times above their usual sources;
Only 23 percent of gray-market purchases were “authenticated” to verify drug source, purity and dosage; and
12 percent of the respondents knew of a problem related to purity, dose or storage, or sale of recalled, counterfeit or stolen products.
Gray market prices for medications: Nice work if you can get it?
Alkire, of the Premier alliance, told Congress that the gray market is “appalling,” with an average markup of 650 percent. Forty-five percent of the offers were marked up at least 1,000 percent above normal price, and drugs for leukemia and non-Hodgkin’s lymphoma were marked up 4,000 percent. “We saw similar markups for medicines for sedation during surgeries; to dilate veins and prevent brain or heart spasms; and to prevent damage during a heart attack,” Alkire said.
For these reasons, University Hospital at UW-Madison does not buy gray, says Shull, although it does buy from a wholesaler that seems to have supplies of drugs when nobody else does.
The gray market arouses suspicion: How do some firms know about shortages before anybody else? How do they obtain drugs when normal sources are short?
“There is speculation going on,” says Vaida. “Some secondary wholesalers may try to buy up some available drugs and sell them for higher prices. Often times, they are looking for people who need the product, and try to obtain it from whatever sources. Some are playing it almost like Wall Street, anticipating what may go on shortage — if two manufacturers have just consolidated, and there’s a generic product that is only going to be made by one of them.”
Cures for missing meds
Many measures have been proposed to ease the medication shortage:
Ease the imports: If drugs sold in other countries were exported from the United States, or made in foreign factories with reliable inspection, why not allow accelerated importation? Although re-importation from Europe is now permissible, it takes a long time to get FDA approval, says Vaida, but the shortage is forcing that process to be accelerated. “If the product is available in Europe, the FDA is moving quicker to evaluate and approve it,” he says.
FDA funding and flexibility. Although the FDA has bragged that it has averted 99 medicine shortages so far this year, many observers say the agency needs more money to do the kind of policing and coordination that would eliminate more shortages. “We need to make sure the FDA has the resources necessary to carry out its mission, and we need communication within the FDA, so offices are on same page as headquarters,” says Joseph Hill, director of federal legislative affairs at the American Society of Health-System Pharmacists. “There are situations, for example, where the bar code on a product is damaged, and technically they maybe can’t offer the product for sale, but if it’s in short supply, and obviously is still safe, we believe there ought to be exceptions.”
Stockpiling: Some advocate amassing reserves of medically necessary drugs that seem particularly vulnerable to shortage, due to a history of poor supply, manufacturer consolidation or a difficult manufacturing process. This logical solution, however, is costly: drugs are varied, expensive and subject to decay in storage.
Let’s talk: The cardinal countermeasure concerns communications. Under a bill now before Congress, manufacturers would be required to notify the FDA before discontinuing a drug. Currently, says Vaida, “The biggest frustration is that hospitals find out there is a shortage when a drug does not come in with their order. That’s all the notice they are getting, and all of a sudden they have to switch, they have two hours to let everybody know in a 700-bed hospital, ‘Here’s the new drug: it may have to be dosed differently, administered differently and prepared differently.’”
The FDA seems to be getting the message. In testimony to the subcommittee on Sept. 23, Koh claimed that the agency had already headed off 99 looming shortages in 2011, compared to 38 for all of 2010. But Koh added that today’s shortages “include standard therapies for the treatment of lung, breast, ovarian, testicular and colorectal cancers, as well as several types of lymphomas and leukemias.”
Sometimes, Koh said, common-sense, proven measures can sidestep shortages. “… the FDA was able to mitigate a shortage by allowing the use of a filter to safely remove foreign particles contained within vials of injectable drugs, averting the obvious risk to patients of having metal shavings or other particulate matter injected into their veins.”
A pessimist, of course, could say the higher number of averted shortages simply reflects the greater number of shortages overall.
At any rate, organizations concerned with shortages say they are in a vise. “From our members’ perspective, it’s become [a] crisis,” says Hill. “We are seeing shortages nationwide. We have been tracking this for about 10 years, but in the last few years, we’ve seen a spike in the numbers.”
Given the problem’s multiple and sometimes obscure, roots, Hill sees “no single solution, and that’s the troublesome part. Unfortunately we will be dealing with this for a while. But there are some things we can do. We’d like to establish a mandatory early-warning system, so a manufacturer that has a problem has to notify the FDA. The FDA says it has avoided 99 shortages in the past year when it had that information. When there are multiple sources, the FDA can reach out to other manufacturers and urge them to ramp up production.”
David J. Tenenbaum
- FDA shortages info. ↩
- FDA: drug shortages list. ↩
- Another listof drug shortages. ↩
- Podcast: managing drug shortages. ↩
- Deaths due to shortages. ↩
- Social media account of drug shortage workshop. ↩
- Another workshop account: the cancer impact. ↩
- Drug rationing. ↩
- Effect of shortages on cancer research. ↩
- Forced into the Gray Market. ↩
- ISMP: gray market, black heart. ↩
- The big shortage. ↩