But is it the manufacturers’ fault?
A 2012 report by the House Committee on Oversight and Government Reform places much of the blame on the FDA. The report says that because the agency ramped up inspections and sent a flurry of warning letters, “four of America’s five largest manufacturers of generic injectable products” simultaneously shut down 30 percent of their manufacturing capacity.
FDA officials have responded that the increase of warning letters was only a “modest fluctuation” that didn’t correlate with the dramatic increase in shortages.
But records show that the number of warning letters related to drugs and biologics nearly doubled between 2009 and 2010, from 34 to 60, before falling to 48 the next year. The recent surge in shortages began in 2010.
Manufacturers are reluctant to talk. APP Pharmaceuticals, which produces calcium gluconate, sodium phosphate, and magnesium sulfate, and American Regent, which makes several IV nutrients currently in shortage, both declined to comment for this article.
“There’s no upside to our guys talking about that,” says a spokesperson for a manufacturers’ association. “Even if the FDA’s doing something terrible, we can’t criticize them. They regulate us. There’s not one cause of drug shortages. But if you call the FDA, they’ll say it’s our fault.”
Indeed, in a July 2012 letter to Congressman Elijah Cummings, a ranking member of the Oversight and Government Reform Committee, FDA assistant commissioner Jeanne Ireland passed the buck. “The root causes of drug shortages . . . lie largely outside of FDA’s purview,” she wrote. “During 2011 nearly 70 percent of all drug shortages were related to manufacturing production problems, including quality-related issues and delays. . . . In 2012, quality-related problems and delays have continued to account for the majority of shortages, especially those involving sterile injectable drugs.”
Valerie Jensen, associate director of the drug-shortage staff at the FDA’s Center for Drug Evaluation and Research, says the main cause of the current nutrient shortages has been the shutdown of American Regent. The company had recalls of IV calcium gluconate, dexamethasone sodium phosphate, and potassium phosphate, among other injectables, because of visible particulates (such as glass or silicone) in the products, which could disrupt blood flow. In 2011, the FDA sent the company a warning letter. At the end of 2012, Jensen says, the company chose to shut down to address its problems. Instead of reopening after 30 days as planned, as of press time it was still not fully operational.
Hospira cites “the difficulty of ramping up production to cover for the unanticipated loss of production from that manufacturer” as another factor contributing to the shortages, a company spokesman says in an e-mail. Hospira makes several injectable nutrients—plus lipids and injectable vitamin A—that are in shortage.
American Regent has begun to release small quantities of calcium gluconate and sodium phosphate, but there are still particles inside that pharmacists must filter out. The FDA wouldn’t normally allow these vials into the market.
“It is a risk, but the risk of not having the drugs is greater,” Jensen says. “Because we know the filter renders the drug safe for use, we felt this was the way to get that drug available for patients.”
• • •
The House committee report doesn’t mention the reasons the FDA cautioned the manufacturers. At some facilities, the agency found mold on the walls, open containers of urine, and metal chips in vials—serious problems, to be sure. An examination of FDA inspection letters reveals dozens of additional infractions. But the report notes that a review of the violations “did not find any instances where the shutdown was associated with reports of drugs harming customers.”
A March 2013 committee follow-up letter—which was obtained for this article but has not been made public—directs the FDA to turn over documents and appear for a briefing “in order for the Committee to understand how FDA is managing the drug shortage crisis.”
The rationing pits patient against patient, forcing health-care practitioners to decide who gets a critical nutrient and who has to go without.
“It appears that FDA failed to properly balance regulatory benefits and regulatory costs when the agency took actions that effectively shut down a significant amount of manufacturing capacity at most of America’s major producers of generic injectable drugs,” the congressional letter states.
The letter echoes an accusation in the original report that the FDA knew as early as mid-2011 that its enforcement measures might lead to shortages. That’s when FDA warning letters began to mention shortages, instructing manufacturers to contact the agency before making a decision that would result in a drop-off in production.
Jensen says the FDA changed the language after the drug manufacturer Teva closed down in 2010, triggering shortages of cancer drugs. “If FDA sends a warning letter, it just tells the company what they need to correct,” Jensen says. “If they decide they need to shut down, that’s a decision they make, but it’s something we try to avoid.”
The committee letter also accuses the FDA—based on January briefings with industry representatives—of taking too long to provide feedback on manufacturers’ plans to fix problems the FDA asked them to correct.
“FDA has been very slow to react and to do anything,” says Blair Childs, senior vice president for public affairs at Premier Healthcare Alliance, a large group-purchasing organization (GPO). “There’s a ‘we’re not the cause of the problem’ mentality.”
The manufacturers’ spokesperson says the FDA is constrained by “an enormous mandate without enough resources. They don’t have enough trained people; they don’t have enough money. The FDA’s always getting negative feedback for what they do wrong, and nobody’s standing up and saying the FDA could do a better job—here’s some more money.”
Jensen disagrees: “We feel like we are adequately resourced. Our drug-shortage program has greatly expanded. FDA has devoted great resources to this and will continue to do so.”
• • •
Other experts blame the shortages on GPOs. Hospitals typically don’t purchase drugs directly from manufacturers. Instead, hundreds of hospitals band together and work with a GPO, which bids manufacturers down to the lowest price possible. Because these consortiums have driven the prices of generic injectables so low, some say, manufacturing them isn’t profitable.
In November, six members of Congress, led by Ed Markey, asked the Government Accountability Office to investigate whether GPO contracting practices have contributed to the drug shortages.
“They drove prices so far down that [when there’s a production problem] manufacturers say, ‘We’ll look at it in another month or so,’ and then ‘another month or so,’ then the line goes down and shortages occur because revenue isn’t enough for them to keep up with their productions,” says Ohio State University’s Mirtallo.
But Childs disputes the idea that GPOs have the power to suppress prices to the point where production is no longer viable—or that they would want to. “It’s a nutty accusation,” he says. “We are going to do everything we can to drive market competition, but ultimately we want a healthy market.”
Distributors, manufacturers, and government officials say that to solve the shortage crisis, the stakeholders must collaborate, but it’s unclear how deep these commitments go. “Unfortunately, the companies consider it to be a trade secret of exactly which drugs are manufactured on what lines,” Fox says. “We’ve tried to have FDA public summits to get stakeholders in a room. When we ask places like Hospira, Bedford, Teva, and APP what would fix the problem and we say, ‘Do you need more money?,’ they don’t give a straight answer.”