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For Charles Penley, MD, a partner at Tennessee Oncology, in Nashville, the drug shortage hit home in the spring and summer of last year. What had been a concern for years suddenly bubbled over when supplies of some of the most commonly used cancer drugs evaporated without warning. Staffers scrambled to track down suppliers while physicians occasionally made do with alternative treatments.
“We had to change some things for our practice to stay on top of it,” says Penley, who chairs the Government Relations Committee of the American Society of Clinical Oncology (ASCO). “We assigned a staff member the responsibility of making sure the anticipated needs of each clinic could be met.”
It wasn’t easy. The practice includes more than 50 physicians at multiple sites. “We have places where patients and drugs must come together in a timely manner,” says Penley. The practice’s formulary committee worked out substitution policies where appropriate. When leucovorin and fluorouracil (sold under brand names like Adrucil and Carac) were in shortage, for example, doctors would occasionally substitute capecitabine (Xeloda).
“Xeloda is not a general substitute for leucovorin,” cautions Penley. “Leucovorin and 5-FU [fluorouracil] are often given in combination, and 5-FU was also in short supply. Xeloda was substituted for our colon cancer patients. We also used levoleucovorin [Fusilev], a stereoisomer of leucovorin, which is used primarily in pediatric patients but rarely in adults.” And since levoleucovorin dosing differs from leucovorin dosing, the former could not be substituted in a one-to-one ratio for the latter.
“The dosage calculations for our chemotherapy regimens had to be changed to reflect the different dosing when levoleucovorin was used,” says Penley. “This caused headaches for our IT department, given that all our chemotherapy regimens are in our electronic health records.”
For practices like Penley’s, drug shortages have become a constant thorn. And while shortages have eased in recent months, Tennessee Oncology still keeps a wary eye on the fragile stockpile of medications.
Under the new U.S. Food and Drug Administration Safety and Innovation Act, the FDA will come up with its own early-warning system designed to flag shortages. Drug manufacturers are required to give the feds six-month advance notice when they know one of their drugs will be in short supply. And the agency can use that time to prevent a problem — or at least notify providers that a problem is developing.
Faced with widespread complaints about shortages, the FDA is already ironing out kinks in the supply chain. Armed with an order from the president, the agency has claimed some success. And regulators say they can build on that.
“FDA will still be able to use all of the tools we have to prevent and address shortages,” an agency spokesperson said in an e-mail response to a Biotechnology Healthcare query. “However, under the legislation, since companies are now required to notify FDA six months before any discontinuance or interruption of supply of critical medications, we believe we will receive an increased number of notifications of potential shortages from manufacturers. The sooner we receive notices from the manufacturers, the more we are able to do early on, using the tools we have available, to work with the companies to prevent or address the shortage.
“The new legislation will not prevent all shortages,” the FDA spokesperson continued. “Some issues that can lead to shortages may take firms significant time to address, such as sterility problems and other severe problems that have developed during manufacturing.”
Penley and other top officials at ASCO doubt that a notification mandate without penalties for violators will accomplish more than what the FDA has been able to achieve on a voluntary basis over the past year.
“It might as well be voluntary,” says Richard L. Schilsky, MD, chief of the hematology/oncology section at the University of Chicago and Penley’s predecessor as chair of the ASCO Government Relations Committee.
At worst, manufacturers whose drugs are in short supply are likely to find their names on the FDA’s Web site, as the new legislation directs. That won’t help a company’s reputation, but it also won’t spur regulatory sensitivity among manufacturers. “For any legislation like this to be effective, there needs to be some sort of enforcement or enticement,” Schilsky adds. As it is, “There’s no carrot or stick.”
It’s not only practicing oncologists who have been forced to adapt. Researchers have had to do the same.
“It’s a huge issue for clinical trials,” says Schilsky. “I used to lead one of the National Cancer Institute-sponsored clinical trial cooperative groups. Over the last two years, that group has issued eight drug shortage notices to participating sites regarding 23 protocols. If you don’t have these drugs, you need to either stop enrolling patients or borrow the drug from someone who does have it. In a couple of cases, the group recommended substitutions.”
The drug shortage issue is far from resolved.
“We get e-mails weekly from pharmacy departments at all the major hospitals in Nashville talking about shortages of one sort or another,” says Penley. “So it’s still a problem.” These days, intravenous narcotics — the kind that are often self-delivered with the push of a button, like hydromorphone (Dilaudid) — are in short supply.
“The big problem is that it’s unpredictable,” says Schilsky. “There’s been no advance warning — that’s really the challenge. Any given week, you never know.” And that leaves an oncologist with three choices: “Omit the drug, delay treatment, or find a different source of the drug.”
“There are still some drugs that we can’t get,” notes Penley. “Doxil [doxorubicin HCl liposome injection], a form of Adriamycin, encapsulated, is still difficult to find. Leucovorin is still in modestly short supply — we’re able to keep a few days’ supply on hand and haven’t had any interruptions for a few months.”
Based on the FDA’s new authority and some actions that he’s seen outside of the FDA, Penley holds out hope that things will get better.
But don’t look for any consensus on this topic in Congress.
As far as Republicans on the House Committee on Oversight and Government Reform are concerned, the FDA is the problem, not the solution. In June, they blasted FDA commissioner Margaret Hamburg for taking what they believe is an over-the-top regulatory stance that interferes with the nation’s drug supply.
Jeanne Ireland, the FDA’s assistant commissioner for legislation, fired right back, saying that regulatory flexibility — working with manufacturers to speed reviews and recertify plants — helped to prevent 195 shortages last year. When serious safety issues occur at a manufacturer, she noted, the drug maker has to stop production and fix the problem. But shortages have risen steadily over the last few years, she added, even as the flow of FDA warning letters has continued.
Finding appropriate substitutes for oncologics in short supply has been a challenge. Current remedies for the shortage may not do enough.
At ASCO, no one in charge is taking sides.
“It’s hard to know what led to the improvement,” says Schilsky. “Perhaps the [president’s] order helped spur manufacturers to do better.
“The FDA has given many examples of where its been able to ameliorate drug shortages,” he adds. “There is a variety of things the FDA can do — it depends on what the problem is. If a manufacturing facility is offline and needs to come back online, the FDA can expedite the process to recertify the facility. If raw materials are in short supply, it [FDA] can help manufacturers find new supplies of raw materials. If another manufacturer can produce the product but is waiting to get a generic drug application reviewed, the FDA can expedite the review.”
Penley has heard all the hypotheses, such as the one that says low prices of some generic oncologics have caused manufacturers to walk away from production. Some experts have discounted that argument, he points out. On the other hand, Penley adds, some economic incentives might spur manufacturers to make sure supplies aren’t interrupted.
“There isn’t a comprehensive analysis of the business plan for the production and marketing of generic drugs,” says Schilsky. “There’s a widespread belief that there are few incentives for companies to stay in the game if they encounter significant problems in manufacturing. We have to come up with a business plan for these drug manufacturers that allows them to make enough money to invest in their facilities.”
“I think that will likely improve over time,” adds Schilsky, noting that the Prescription Drug User Fee Act establishes user fees for generic drugs — which will bring in about $1.5 billion that could be used to clear out the backlog of generic-drug applications.