A Call to Action for Children With Cancer
Need for a Sustainable Response to Shortages of Treatments for Children with Cancer
Finding treatments that prevent or cure disease and safe lives is the brass ring of drug development. Developing these drugs, particularly those that treat serious childhood illness, is a complex and challenging process. One of the great historical milestones in pediatric cancer was the development of treatment for Acute Lymphoblastic Leukemia, or ALL, the most common cancer in young children. Today, by using a combination of drugs, children with ALL have a more than 80 percent cure rate—a remarkable achievement.
Chemotherapy for pediatric ALL is life saving, it has stood the test of time, and the evidence of its efficacy is unequivocal. Initial management of ALL uses “tried and true” drugs and can achieve an early complete remission in more than 98 percent of cases. After remission, the drugs are important in achieving a longstanding cure. Methotrexate, for example, is periodically injected into the spinal fluid to manage risk of central nervous system disease. Many of the drugs used to treat ALL are now generic and low cost and thus represent model drugs in our current health care environment—effective, life saving, and cheap.
But there is a problem. Like several hundred other drugs, some of those needed to treat children with ALL are in short supply and may run out within a few weeks. In the case of methotrexate, particularly the preservative-free injectable version, the supply has been tenuous for some time but now it is an acute matter of life and death for children with ALL. Recent quality control problems at a U.S.-based methotrexate manufacturer have tipped the balance. In December 2011 Ben Venue Laboratories, Inc., of Bedford, Massachusetts, extended their voluntarily suspended methotrexate production of the drug in compliance with the inspection findings of Federal Drug Administration, European Medicines Agency, and other global regulatory authorities. While the basis for drug shortages is multifactorial, the root cause of the methotrexate crisis (and the shortages of other low cost drugs) is economic.
Despite the desire for low-cost therapeutics, when drugs become commodities, the profit margin is small and sustainability is based on minimizing the cost of production and some assurance of adequate demand. It is not surprising (and in fact expected) that “commodity drugs” run into problems over time, given that investment in them is logically a lower priority, compared to other newer products where the demand and profit margins are more favorable. The ecosystem that supports availability of low-cost generic drugs is thus fragile and highly susceptible to manufacturing and quality problems.
The number of companies making any given “commodity drug” is typically small and thus temporary interruptions at one company put substantial stress on the overall market for that drug. While manufacturing processes for older drugs may be well established, they also become routine, leaving little incentive for manufacturers to invest in them or innovate. Quality control processes and manufacturing facilities are expensive to maintain. When there is little return on that investment, cost containment necessitates operating in a streamlined manner that is less tolerant to the variances (like equipment malfunctions, operator errors, inadvertent contamination, etc.) that are inevitable, even under optimal circumstances. If a problem occurs, such as at the methotrexate plant, it has ripples throughout the supply and distribution process.
In the case of methotrexate, oncologists have pointed out that the acute situation is “a perfect storm.” As it turns out, these storms are not that uncommon. The flu shot has been around for decades and it is highly effective in preventing incidences of serious flu, cost effective, safe, and recommended by the Centers for Disease Control and Prevention. Until recently, however, the U.S. manufacturing capacity for influenza vaccine production had shrunken to minimal levels.
The flu shot was also a “commodity.” Manufacturing costs were low, but so were margins, with prices driven by government contracting as well as other factors. Not only was U.S. manufacturing capacity limited, but the manufacturing processes for the influenza vaccine were also antiquated, with little or no investment or innovation. Because of a short production timeline (given the seasonal changes that occur in the virus) and outdated facilities/processes, the influenza vaccine was periodically in short supply and triage was required, leaving many unprotected against the illness. In 2004 contamination problems in a single U.K. manufacturing facility resulted in a severe shortage of vaccine supply for the United States, forcing authorities to prioritize the vaccine to only those with the highest risk and leaving many others unprotected.
Despite the public health need for a reliable supply of the seasonal influenza vaccine, we were only moved to real action when the urgency was heightened by fear of bird and swine flu and the realization that influenza could be a threat to national security. We were woefully unprepared as a nation. Public health and homeland security response resulted in the investment of hundreds of millions of dollars to incentivize process improvements and the development of U.S. manufacturing capacity to address the situation. Collaborative efforts among the Biomedical Advanced Research and Development Authority, the FDA, CDC, and NIAID were directed at funding development of new more efficient methods for production of flu vaccine and stimulating facilities and process improvements. By 2009 the number of U.S. manufacturers of flu vaccine doubled. We are all better off as a result, not just by being better prepared for a bioterrorist threat, but also by advancing our ability to provide routine flu vaccination to those who need it.
The headlines in the past several weeks have been replete with awareness of the problem of drug shortages in oncology. The real and present risk to the lives of children with ALL must have us act with urgency to assure that we do everything possible in the short term to address impending shortages. Time is running out before this threat becomes a life-threatening reality for ALL patients, and it is our duty to act in their interest. The FDA is addressing the acute crisis and now has approved additional manufacturers to increase supply. It is yet not clear if we will escape the methotrexate crisis without significant human costs, but even if we do, a longer-term solution for sustainable availability of critical drugs is needed. There are more “perfect storms” on the horizon.
Legislative initiatives, such as the Preserving Access to Life-Saving Medications Act, are making their way through congressional committees that increase FDA authority to require notification of events that will affect supply of critical drugs. In October 2011 President Obama issued an executive order directing the FDA to take action to prevent prescription drug shortages and protect consumers. These are needed steps but are not sufficient, given the fundamental economic root cause of the problem. The president, Congress, FDA, manufacturers, and media have their eye on the issue of drug shortages. In many cases the issue is not the medical science; these drugs have been proven to be safe, effective and, in cases like methotrexate, life saving. But they are not as scientifically “sexy” as new innovative drugs and so get less attention. Because they form the bedrock of our medical armamentarium, we need to find the right balance of cost and predictability.
Edward Connor, M.D., is Director of Innovation Development and Investigational Therapeutics at the Clinical and Translational Science Institute at Children’s National Medical Center, and a Professor of Pediatrics at the George Washington School of Medicine and Health Sciences. Photo credit: AP Photo/Stew Milne.
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