During the first week of November 2011, President Obama signed an Executive Order directing the FDA to take steps to help resolve the drug shortages that were affecting patient care across the country. The oncology community was hit especially hard; many of the drug shortfalls were generic chemotherapy injectables such as vincristine, methotrexate, leucovorin, cytarabine, doxorubicin, and paclitaxel.
Fundamental Questions
Despite the Executive Order and widespread press coverage, drug shortages still exist, challenging the oncology community’s ability to deliver quality care to all our patients. A session at this year’s ASCO Annual Meeting attempted to answer two fundamental questions: Why is this happening, and how can we treat our patients?
Session Chair Hagop M. Kantarjian, MD, of The University of Texas MD Anderson Cancer Center, said that during the Q&A following a lecture he gave in 2010 at Rush University Medical Center, a doctor asked what he could give his patient with newly diagnosed acute myeloid leukemia (AML) in light of the cytarabine shortages.
“His question shocked me, especially when one considers that using cytarabine in combination provides a 40% cure rate in AML, a disease that prior to the advent of this drug had a 0% cure rate,” said Dr. Kantarjian. He put the cytarabine shortage in human terms, mentioning that there are approximately 12,000 new AML cases per year, and that depriving those patients of this lifesaving drug would result in about 5,000 preventable deaths. “The answer to this doctor’s question is sobering: There is no alternative to cytarabine in the clinical scenario he presented,” added Dr. Kantarjian.
Root Causes
Although the drug shortfall is still a major problem, since the President’s Executive Order, which energized the initiative to address the issue, the shortages have been substantially reduced.1 “However, it is important to examine and identify the root causes of these disturbing shortages in order to stave off future problems,” said Dr. Kantarjian.
Dr. Kantarjian commented that the rise in drug shortages had a temporal correlation with the payment shift under the Medicare Modernization Act (MMA), moving from the average wholesale price (AWP) to the average sale price (ASP) plus 6%; the Medicare ASP reimbursement is substantially lower, especially among generic drugs.
“Although this is a complex issue, the data show that as the profit margin on generic injectable sterile drugs decreased, many of the companies producing these agents left the market. This created consolidation, and now only four drug companies account for 70% of the generic market, which poses a potential drug shortage problem if a manufacturing problem should occur in just one of the limited number of producers,” said Dr. Kantarjian.
There are numerous, well-documented reasons for U.S. drug shortages, such as contamination or lack of raw materials, quality control issues that force FDA shutdowns, regulatory complexities, and overburdensome recertification requirements to clear the manufacture of generics.2 However, Dr. Kantarjian stressed that a growing number of experts blame the economic factor, which has limited the financial incentives to produce generics, as a leading cause of drug shortages.
“I believe that economics are a root cause for our drug shortage problem. Along with the regulatory and manufacturing issues I mentioned, the decrease in financial incentives has led to a diversion of generics to foreign markets,” said Dr. Kantarjian. An inescapable narrative in the economic theory, one that has been editorialized in the mainstream press, is that because of the unique payment structure in medical oncology, community doctors often choose brand drugs over generics, further exacerbating the shrinking generic market.
“The argument is that faced with two choices of equally effective drugs, a low-cost generic or a higher-priced brand drug, oncologists may choose the latter to increase profit margin. I find this reasoning to be based on cynicism, not fact, because the data show that most shortages in generics occur when there is no alternative drug,” said Dr. Kantarjian.
Possible Solutions
In the face of mounting calls for changes to the oncology payment structure—ostensibly to remove perverse incentives to prescribe higher-priced drugs—Dr. Kantarjian takes a different view on the issue. “Despite certain problems, we should keep the current payment system in community oncology. To remove it, as some advocate, would in essence result in large hospital-based oncology conglomerates, mostly in urban rather that rural areas, which would compromise the quality and quantity of patient care for many U.S. populations,” stressed Dr. Kantarjian.
Instead of putting the onus on oncologists, he offered possible solutions to stave off future drug shortages, such as mandating confidential reporting of drug shortages anticipated within 6 months and improving the FDA’s ability to locate and facilitate alternative solutions within 3 to 6 months of notification. “But I think the most important solution is to start a dialogue about establishing a pricing floor for generics, which would never fall below a level that allows physicians or the generic drug manufacturing company to turn a reasonable profit,” Dr. Kantarjian said.
ASCO Recommendations
Past ASCO President Richard L. Schilsky, MD, asserted that ASCO continues to be at the forefront of the drug shortage problem, using its lobbying and educational skills on the Hill, testifying in various subcommittee meetings and workshops, even having one-on-one meetings with Department of Health and Human Services Secretary Kathleen Sebelius.
“The organization has been particularly visible in the media in order to raise awareness in the general public about the impact that drug shortages have on American cancer patients,” said Dr. Schilsky, pointing out that Charles Penley, MD, testified at the House Energy and Commerce hearing and Past ASCO President Michael Link, MD, briefed Congressional staff on how the drug shortage problem affected patients with cancer.
Among the recommendations that ASCO put forth to lawmakers, Dr. Schilsky singled out the recommendation on user fees. “We feel that Congress should establish generic user fees to ensure that FDA has the resources to review new and supplemental generic drug applications quickly and provide flexibility to allow the Agency to use fees as economic incentives for manufacturers,” he said.
Dr. Schilsky explained the various aspects of new iterations of the Prescription Drug User Fee Act (PDUFA), one of which—the FDA Safety and Innovation Act (S3187)—introduces user fees for review of generic drugs and requires manufacturers to provide early notification of impending drug shortages. “While legislation is a good step, current FDA authorities in many ways enable only stopgap measures, and permanent solutions will require enhancing the business model of generic drug manufacturing,” concluded Dr. Schilsky. ■
Disclosure: Drs. Kantarjian and Schilsky reported no potential conflicts of interest.
References
1. Hamburg M: Six month check-up: FDA’s work on drug shortages. Posted May 3, 2012. Available at blogs.fda.gov. Accessed September 24, 2012.
2. Link MP, Hagerty K, Kantarjian HM: Chemotherapy drug shortages in the United States: Genesis and potential solutions. J Clin Oncol 30:692-694, 2012.
