Headlines from the June meeting of the American Society of Clinical Oncology (ASCO) in Chicago announced to the general public what oncologists and hematologists have known for more than two years: sporadic shortages of cancer drugs are forcing suboptimal treatment plans for patients, and government efforts have not filled the void.
Two months after three surveys were presented at ASCO’s 49th Annual Meeting, our editors asked both the FDA and Keerthi Gogineni, MD, MSHP, who presented one of the studies in Chicago, to offer updates on cancer drug shortages.
Gogineni, a medical oncologist in the Abramson Cancer Center and the Perelman School of Medicine in Philadelphia, was a co-author of the study conducted at the University of Pennsylvania.
While the FDA’s Lisa Kubaska, PharmD, reports that the 2012 Food and Drug Administration Safety and Innovation Act (FDASIA) is helping the agency identify shortages and find temporary solutions, such as importations of drugs, Gogineni states that some shortages remain, even though the FDA is “doing what it can.”“There are factors that contribute to drug shortages that the agency has limited control over,” Gogineni said.
Kubaska and Gogineni agree that the majority of shortages are due to quality control problems at several large drug manufacturing plants. Kubaska said preventing shortages is a “top priority,” and that passage of FDASIA has enhanced the agency’s ability to anticipate pending problems through an early notification system. However, the FDA and physicians like Gogineni on the front lines view things differently.
Said Kubaska, “There has been one new shortage in 2013, lomustine tablets, which was resolved through import of a drug with unapproved packaging until the approved package could be made available.”Gogineni said that her own hospital “has had considerable difficulty acquiring this drug to treat patients with brain tumors. There is an ongoing attempt to obtain this drug by enabling NextSource Biotech to import the product but under a different trade name.
Theoretically this should have made emergency supplies of the drug easier to obtain by July 2013, but practically speaking, this has not been the case.” What the Surveys Found In the Penn study,1 94% of 214 oncologists and hematologists said their patients’ treatment had been affected by drug shortages between March and September of 2012. Of those doctors reporting shortages, 83% said they had been unable to provide standard chemotherapy at some point during that time period, and 13% reported that patient enrollment or continuing participation in clinical trials had been compromised due to drug unavailability.
Two-thirds of the respondents work in community oncology settings.A separate pair of surveys conducted by ASCO reported that members of the organization noticed only a slight easing of drug shortages between October 2012 and April 2013, but during the same period became increasingly concerned about the limited availability of treatments critical to supportive cancer care, such as antiemetics, pain medications, and basic IV fluids and electrolytes.
In the University of Pennsylvania survey, respondents said that the drugs most commonly in shortage were leucovorin, liposomal doxorubicin, 5-fluorouracil, bleomycin, and cytarabine. (According to Kubaska, the FDA arranged to have the first two temporarily imported to address the shortage.) These drugs are commonly used in the treatment of various forms of cancer, including gastrointestinal, blood, breast, ovarian, and testicular cancers. Cytarabine is particularly critical for curing certain forms of acute leukemia, ASCO stated.
Researchers noted that doctors adapted to such shortages in different ways, including switching treatment regimens (78% of doctors), substituting alternate drugs partway through therapy (77%), delaying treatment (43%), choosing among patients to determine which should receive the available supply of the chemotherapeutic agent (37%), omitting doses (29%), reducing doses (20%), and referring patients to another practice where drugs in shortage were available (17%). Most providers (70%) said they had no institutional guideline or committee to help make the difficult treatment modification decisions.“We were surprised by the large number of cancer doctors that had to make changes in the way they care for patients due to drug shortages,” Gogineni said in Chicago.
“Unfortunately, cancer drug shortages will likely be a persistent issue. Doctors are adapting to this new reality as best they can, but more uniform guidance is needed to ensure that modifications are made in the most educated and ethical way.”The research was supported, in part, by a Pfizer Medical and Academic Partnership Research Fellowship in Bioethics.ASCO’s 2012 and 2013 surveys of its members asked whether, in the previous six months, legislative and regulatory efforts to address drug shortages had been effective. A total of 390 and 462 doctors, respectively, responded.
Although the results from the second survey suggested that chemotherapy drug shortages may have eased very slightly, the changes were small, and practices were still faced with the need for drug substitutions.
Moreover, respondents expressed growing concern over the shortage of supportive care drugs.In the more recent survey, 59% of responding physicians were aware of ongoing drug shortages in their own or colleagues’ practices, versus 70% in the earlier survey.
Also in the 2013 survey, more than 40% of doctors said that drug shortages had not been resolved. Seventeen percent said the shortages were worse than in the fall of 2012, 16% responded that they were the same, and 9% said that some shortages had improved while others had worsened.
“Quality cancer care also means providing patients with the right treatments at the right times, and we’re learning today that cancer drug shortages are still interfering with that mission,” said ASCO spokesperson Andrew D. Seidman, MD, an oncologist at Memorial Sloan-Kettering Cancer Center in New York City. “This ongoing crisis must not be forgotten—it demands urgent solutions from regulators, policy makers, and manufacturers today.”
According to ASCO, generic drugs, especially common chemotherapies, have been most affected by shortages. In oncology, there are often no replacements for the standard agents that have been shown to improve survival, the organization reported, and when there are substitutes available, they are sometimes brand name drugs, which can be several-hundredfold more expensive. This cost burden is shared by patients and institutions, as brand name drugs typically have higher copayments and out-of-pocket costs, ASCO stated.
In many cases, ASCO said, there is also a lack of clinical trial evidence to determine the appropriate dosage for the substitute drug. In addition, according to a survey taken by the Institute for Safe Medication Practices,2 mistakes are sometimes made in the formulations or strengths of drugs given as alternatives for medications in short supply.
Drug shortages have also spawned borrowing and hoarding among medical institutions, the sale of counterfeit drugs, and a gray market for medications in limited supply, experts have said.“ASCO believes that there are likely numerous causes of drug shortages and will continue to call on Congress to convene a blue ribbon panel that includes providers, manufacturers, suppliers, FDA, and patients to develop comprehensive legislation to resolve these critical shortages,” said ASCO Chief Medical Officer Richard L. Schilsky, MD. “The Government Accountability Office is also conducting a comprehensive investigation of the causes of the shortages, and we will be eager to learn its assessment when the report is published early next year.” Many Factors Behind Shortages At last year’s annual meeting of ASCO, Rear Admiral Sandra L. Kweder, MD, deputy director of the FDA’s Office of New Drugs, blamed the shortages on manufacturing and quality problems and the plant closures that often result. Most shortages have involved sterile injectable drugs, she said, and as of last June, more than half of those were “due to product quality issues such as particulates, microbial contamination, impurities, and stability changes resulting in crystallization.
”Shortages may also occur due to industry consolidation, increases in demand, and a lack of access to pharmaceutical ingredients, she said.Why does one plant shutdown prove so disruptive? In late July, Gogineni told our editors that there are a combination of underlying reasons. “There is little redundancy in the system,” she said, and there is “a marked increase in new sterile injectable product applications without a concomitant increase in manufacturing capacity [which] has led firms to divert production to more expensive, branded agents.”The FDA, Gogineni explained, is authorized to address quality issues, but its ability to boost manufacturing capacity is quite limited—it can expedite reviews of “new” manufacturers. “It can take years for a manufacturer to increase capacity. There are few penalties for failing to supply critical drugs, and no incentive for companies to invest in ‘excess’ capacity. This is not something the FDA would have control over,” she said.
Alongside the financial incentives to produce new drugs, Hagop M. Kantarjian, MD, a professor and chair of the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, has blamed the shortages on the extremely low price of generics, which he said can’t be raised to meet demand due to a Medicare physician reimbursement formula.Under the recent government sequestration that slashed the budgets of many federal agencies, including the FDA, that formula became even more likely to hold down the prices of generic drugs, a dynamic that could further contribute to drug shortages, Schilsky said at the June 3rd press briefing.
The FDASIA, which became effective in October 2012, requires drug manufacturers to alert the FDA six months in advance about anticipated market withdrawals or drug-supply interruptions. The aim is to give the FDA time to step in with tactics such as helping to arrange for other companies to pick up the slack.
In the six months that followed the passage of the FDASIA, there was a six-fold increase in early notifications from manufacturers, Commissioner Margaret Hamburg, MD, wrote on the FDA’s website. In that six months, the FDA prevented 128 drug shortages and saw fewer occur—42 reported between January and May 2012, compared with 90 new shortages reported during that period in 2011, she stated.
“This data is a testament to how the FDA exercises flexibility and discretion in much of our work on drug shortages and the importance of strong collaboration and constant communication with industry, health professionals, and patients,” Hamburg wrote.
Schilsky added that he is hopeful about another tenet of the FDASIA, which requires generic drug makers to contribute money intended to bolster the FDA’s resources, so it can review generic drug applications more quickly and conduct swifter inspections of generic drug manufacturing facilities when questions about safety come up.Based on anecdotal evidence, Schilsky said, he believes that similar shortages are ongoing in many European countries.