Last month President Obama signed into law the Food and Drug Administration Safety and Innovation Act of 2012—taking what oncologists deem are key steps in preventing ongoing and future drug shortages. The law includes the reauthorization of the Prescription Drug User Fee Act, updated (since PDUFA IV was passed in 2007) to require manufacturers to give FDA six months advance notice of anticipated drug shortages. PDUFA also includes generic drug user fees, predicted to yield $1.5 billion in additional resources for the FDA to review new drugs, which could reduce the FDA's time for reviewing new drug applications from 30 months to 10 months.
“The enactment of this law makes significant strides in addressing a crisis in public health,” Michael P. Link, MD, Immediate Past President of the American Society of Clinical Oncology, said in a public statement. “The generic user fee and additional provisions in the legislation will reduce the number of drug shortages, but our work is not done.”
He pointed to the advanced-notification requirement in the new law as a critical step to help prevent future shortages, but said ASCO is still calling on legislators to add an enforcement mechanism for the provision, such as fines or penalties, when drug manufacturers do not comply.
“PDUFA is certainly a good step forward,” agreed the Immediate Past Chair of ASCO's Government Relations Committee, Richard L. Schilsky, MD, Professor of Medicine and Section Chief of Hematology/Oncology at the University of Chicago, speaking in a telephone interview after the legislation had been approved by both houses of Congress. But, there are still several lingering questions to solve about what is at the root cause of the shortages.
“In general since late spring, things have been starting to settle down with these generic drug shortages. Last winter I was getting emails from our pharmacy every other week with a long list of drugs in short supply and from patients who were scheduled to be treated for whom we might not have enough drug,” he said. “This is beginning to improve. It's not totally resolved, and there is the concern it could worsen at any time, but it's going in the right direction right now.”
FDA Efforts Making a Difference
At the Annual Meeting in June, ASCO hosted a news briefing providing an update on the drug shortage crisis. Discussants, including Link, Schilsky, and the Deputy Director of the FDA's Office of New Drugs, RADM Sandra Kweder, MD, agreed that efforts like the President's Executive Order 13588, “Reducing Prescription Drug Shortages” (bit.ly/WhiteHouse-ExecOrder13588), effective last October, have lessened the number and frequency of generic prescription drug shortages—particularly of sterile injectables, including doxorubicin, leucovorin, cisplatin, paclitaxel, etoposide, dexamethasone, cytarabine, bleomycin, fluorouracil, vinblastine, and vincristine—standard to much of oncology care (OT, 8/10/11 issue).
Kweder noted that more than 150 shortages were prevented in 2011, and 50 shortages had been prevented in 2012 (as of early June), because of the order's voluntary call for—which the new PDUFA law now requires—manufacturers to provide earlier notice of production problems that could lead to shortages.
“Early notification by manufacturers of when they are having production difficulties makes a huge difference in our ability to prevent the public from bearing the burden of drug shortages,” she said. “FDA is committed to working with industry to quickly resolve any quality or manufacturing problems that arise to ensure continued patient access to vital safe and effective medicines.”
Earlier this year, the FDA helped avert a Doxil shortage by temporarily allowing the import of a foreign substitute, and the agency helped expedite review and approval of a new preservative-free form of methotrexate, when manufacturing concerns threatened adequate stores (OT, 3/25/12). The agency has also issued a draft guidance, outlining specifically to manufacturers how to report potential shortages or disruptions to production of needed drugs.
“The FDA's really been on the front lines in managing and trying to prevent and mediate the drug shortage, and they've been doing a great job using available resources and authorities,” Schilsky said.
Complex Problems in Generic Drug Manufacturing
But despite the strides made, Kweder and the ASCO representatives at the news briefing agreed, there are still complex problems to solve in the generic drug manufacturing space.
“Long-term availability of these vital medicines remains uncertain,” Link said. “We are seeking long-term solutions to make sure that the shortages are no longer a threat to patient care.”
One problem, Schilsky explained in the interview, is that a small number of generic drug manufacturers produce the majority of the generic drugs. The general feeling is that the business model for generic drugs and the reimbursement constraints imposed by law really don't allow the generic drug pricing to respond to laws of supply and demand in the predicted way.
“When they run into a problem and have to make a decision about making a big investment to solve the problem for generic oncology drugs—which is going to be a very small part overall of their market space—they have to make the decision: Is it worth it to make that investment, or should we just shut down the production of that drug and focus on the drugs that are easier to make and have a bigger market?
“Fundamentally, we need a better understanding of the business model of generic drug manufacturing, and then we need in some way to ensure that the generic drug manufacturers earn a sufficient profit to stay in the game,” he said.
Another problem: rapid growth in the generic manufacturing industry in the past 10 years. The American Society of Health-Systems Pharmacists reported to OT last year that the number of new generic drugs in 2006 (70) increased to 129 in 2007, to 149 in 2008, to 166 in 2009, and to 211 in 2010 (OT, 2/25/11). The growth of generic manufacturers to power the production of these in-demand drugs just cannot keep up.
“These aren't kits you build,” Kweder said. “Every piece of equipment in these firms is custom-made—it takes two to five years to build [one plant].”
Rushed growth makes it difficult to meet the quality standards needed for sterile injectable drug production. “When quality standards are not met at a manufacturing facility, the entire facility is shut down. . . . Several of the drugs that I mentioned that were in shortage were due to a single facility closing—leading to dozens of shortages at the same time.”
Medical Organzations Call for Action
Key medical groups have applauded the most recent legislation, but like ASCO, agree more work is needed.
“On the whole, the measures in this law are an important first step toward ensuring the highest quality of care for cancer patients,” American Association for Cancer Research CEO Margaret Foti, PhD, noted via email. “This issue is complex and is also influenced by factors outside of government control, but the law does acknowledge the need to further examine these complexities through the creation of a task force and the authorization of a GAO [U.S. Government Accountability Office] study.”
In a statement earlier this year when he was ASCO President, Link outlined three legislative priorities to augment the PDUFA legislation that the society deemed “essential” to avoiding future shortages:
1. requiring advance notification of potential shortages,
2. providing economic incentives to ensure continued availability, and
3. establishing FDA user fees for generic drugs.
His statement also called for a Congressional bipartisan, bicameral working group to accomplish these goals.
In June, the American Society of Hematology released a statement in which they, along with the European Hematology Association and the European Cancer Patient Coalition, issuing a common call to action for an increased national and international effort to avert shortages (especially of hematologic drugs), aiming to raise awareness of how sterile injectable shortages critically impact care of patients with blood disorders. The groups urge more efforts by medical groups to collect data on the shortages and report it to their respective governments, as ASH has done for the past 18 months on its Drug Shortages Portal (bit.ly/ASHDrugShortagesPortal).
And, the American Medical Association adopted a policy in June supporting the creation of a task force to enhance the U.S. Department of Health and Human Services Secretary's response to preventing and mitigating shortages and to create a strategic plan to address ongoing aspects of drug shortages.
“There are likely numerous causes for drug shortages,” Schilsky summed up, “and the only way to get to the root of the problem is to bring providers, manufacturers, suppliers, FDA, and patients together to examine all causes and possible solutions.”
Controversial Report Faults FDA
A House Committee on Oversight and Government Reform report, released June 15, argued that the drug scarcities (cited to have begun in 2010) were the result of excessive regulatory actions taken by FDA Commissioner Margaret Hamburg, MD, that led to unnecessary manufacturing shutdowns (http://1.usa.gov/NuOlE4, opens as pdf).
“This shortage appears to be a direct result of over aggressive and excessive regulatory action. Addressing this shortage requires a common sense regulatory approach that considers market conditions and the overall impact,” the Chairman of the Oversight Committee, Representative Darrell Issa (R-CA), said in a news release. “These drugs can save lives and keep people who need them living healthy lives. The FDA is failing to ensure the availability of quality products.”
Section IV of the report states:
* “One obvious question that FDA should answer is why nearly all of America's major producers of generic injectable medications were essentially required to remediate facilities at the same time.”
* “In a common sense regulatory approach, there would not be a simultaneous remediation effort at four of the five largest American producers of generic injectable products creating significant shortages. Tragically, the cost of shutting down production lines seems to have vastly exceeded the corresponding benefits.”
* “The Committee could not find any evidence that any products produced—many of which have been produced for decades—at the facilities undergoing remediation had harmed anyone beyond typical side effects associated with any type of medication.”
Asked to respond to the allegations in the report, FDA spokesperson Sarah Clark-Lynn said via email that quality standard breaches led to every manufacturing facility shutdown: “In every instance cited in the Committee's report, the companies were all having serious quality problems that could put patients at risk.”
In several cases, the presence of particulate matter (such as glass shards, metal, or fiber) had been found in injectable vials, she said, a point also emphasized at the ASCO news briefing by the FDA's Sandra Kweder, MD. In a recent case, Clark-Lynn said, inspectors found glass particles in vials of potassium phosphate, an injectable drug needed for intravenous nutrition in critically ill patients, manufactured by American Regent.
“FDA has done everything possible to mitigate these shortages,” she said, “including allowing special mitigation steps to keep product available—such as including filters to strain out particles.”
OT contacted Congressman Issa's press office for comment from the representative or a spokesperson, but was told there was nothing they would add beyond the report itself and the news release.
Congressman DARRELL ISSA (R-CA) Chairman of the U.S. House of Representatives Committee on Oversight and Government Reform
PODCAST: In an interview on the iPad edition of this issue, Richard L. Schilsky, MD, who has led ASCO's charge in urging Congress to take notice of the increasing scarcities of needed cancer drugs, shares with OT three major ways in which the shortages have had an impact on the cancer care community. He is Professor of Medicine and Section Chief of Hematology/Oncology at the University of Chicago Medicine, specializing in the treatment of GI cancers and the development of new cancer treatments.
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Access the hyperlinks (shown in grey) in this article and throughout the issue by reading it on OT's free iPad app: http://bit.ly/OT-iPadApp© 2012 Lippincott Williams & Wilkins, Inc.
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