Decisions regarding the rationing of chemotherapy are commonplace in many countries around the world—including those where patients must pay for chemotherapy out of pocket—and increasingly so in cancer settings that treat both well-off and socioeconomically disadvantaged patients. However, these limitations remain jarring to oncologists and patients with cancer in the United States.
Herewith, we describe some of the reasons for these drug shortages and why the situation is unlikely to change anytime soon. We also present a few stopgap methods for dealing with the problem and a more comprehensive proposal for the allocation of generic chemotherapy drugs in a time of shortage that may help preserve health equity in the United States.
Kevin B. Knopf, MD, MPH
Charles L. Bennett, MD, PhD, MPP
Generic Drugs and the Single Supply Chain
It is completely understandable why we have periodic cancer drug shortages in the United States and why it is always generic drugs that are in short supply. The U.S. health-care delivery system is based on market forces and Adam Smith’s “invisible hand”—a metaphor for how the system of interdependence in a free-market economy incentivizes self-interested individuals to produce what society needs. In this instance, there is such a small profit margin associated with the manufacture of generic drugs, particularly in comparison to branded, patented drugs, that the manufacturer acts in its own economic self-interest, which results in frequent drug shortages.
Moreover, at the initial production stage in the United States, a profit-centered branded pharmaceutical market is serviced by manufacturers who maintain dual supply chains for these profitable drugs. When a transition to generic-only drugs occurs, pharmaceutical manufacturers switch to a single supply chain for the production of those generic formulations. Single supply chains are prone to disruption, whereas supply chains that include redundancy are not. This explains in large part why we do not see such shortages in the supply of branded chemotherapy drugs.
Given this situation has existed for at least a decade in the United States, and the country continues to embrace even more market forces in cancer care delivery (eg, private equity firms buying up physician practices), it seems likely things will not improve over time. Rather, now that 60% of active pharmaceutical ingredients are sourced from China and 30% from India, an additional challenge in generic drug production is the rise in manufacturing perturbations in these areas. Indeed, the current generic chemotherapy shortage is due in part to a manufacturing problem that has developed at a large generic manufacturing plant in India.
Communicating Pending Shortages and Facilitating Solutions
One of us (KK) practices hematology/oncology in a safety net hospital that serves uninsured and underinsured patients primarily, but there has not yet been any limitation imposed on what chemotherapy we can prescribe. Like many other community-based centers in America, the Alameda Health System first tries to procure generic chemotherapy drugs in short supply through the “gray market”—small businesses that obtain drugs (frequently from pharmacies) that the nation’s largest authorized pharmaceutical wholesalers are unable to obtain from manufacturers. The gray market company sells these short-supply drugs directly to hospital pharmacies, typically at great cost and often with little oversight as to safety and quality. That said, the bargaining power of our facility is less than that of larger and better-financed centers in this market, so our shortages may be proportionally more pronounced than at other centers.
The Alameda Health System distributes a weekly e-mail to its physicians and pharmacists with estimates of the total weekly dosages available for cisplatin, carboplatin, and fluorouracil. The newsletter is followed by a list of patients who are receiving these drugs, by provider, during the coming week. Each oncologist reviews which patients are theirs and mentally notes what the goals of care are, which remain: (1) cure, when possible, (2) prolonged overall survival while maintaining or improving quality of life, and (3) palliation.
Our highest priority is placed on patients receiving potentially curative treatments. For some cancers, cisplatin is a necessary part of a curative regimen—for example, bleomycin, etoposide, and cisplatin for germ cell cancer; weekly cisplatin with concomitant radiation for head and neck or cervical cancer; and etoposide/cisplatin for limited-stage small cell lung or bladder cancer. These patients have the highest priority for our weekly allotment of cisplatin.
Many regimens use carboplatin in curative fashion (eg, as a single agent or with paclitaxel in ovarian cancer; in adjuvant regimens for lung or breast cancer; in chemoradiation for esophageal cancer), and we try to preserve carboplatin for these patients. If, in a given week, we have excess cisplatin and a shortage of carboplatin, we could offer these patients cisplatin for that week. Otherwise, these patients have the highest priority for the allotment of carboplatin dosages.
Fluorouracil is used in many curative regimens, and its shortage presents a problem. Capecitabine can sometimes be substituted, although there is an ongoing shortage of this medication as well. EPIC’s widely used electronic health record oncology module, Beacon, has hardwired the use of a bolus dose of fluorouracil with FOLFIRI (leucovorin, fluorouracil, irinotecan) and FOLFOX (leucovorin, fluorouracil, oxaliplatin) regimens—despite protests by oncologists. This bolus adds no benefit for the patient, only toxicity, and in times of chemotherapy scarcity, I have had better luck convincing my oncology and pharmaceutical colleagues to omit it.1
We have not been able to afford infusion pumps for outpatient FOLFIRI/FOLFOX and instead use FLOX- and FLIRI-based regimens in the outpatient settings. (FLOX and FLIRI entail a single push of fluorouracil rather than repeated doses of the drug by infusion pump over multiple days, and thus, much less fluorouracil in total.) If our patient needs infusional fluorouracil, to date, they have had to be admitted to the hospital.
At Alameda Health System, the inpatient pharmacy has a separate supply from the outpatient pharmacy, and the two physical locations have not been able to share. When some chemotherapy is available only for inpatients, we need to admit the patient for that chemotherapy to be given on an inpatient basis. Thus, some patients receiving FLOX or FLIRI may switch to FOLFOX or FOLFIRI if we need to arbitrage this situation.
In some cases, particularly for patients who are being treated with a goal of overall survival and are responding to treatment, doing well, and currently stable, we will opt to delay treatment by a week in the hope the following week will bring more carboplatin, cisplatin, or fluorouracil. To that end, in addition to the weekly e-mail, there is constant texting and messaging between oncologists and pharmacy regarding any need for chemotherapy drug tradeoffs to accommodate our shortages.
Public Health Emergencies and Strategic Stockpiling
If this situation is unlikely to improve on its own, we must embrace a comprehensive approach in a time of scarcity to preserve health equity as best we can. A novel policy-based approach proposed by one of us (CLB) and collaborators at the Arnold Ventures Drug Access and Affordability Program of the Johns Hopkins Bloomberg School of Public Health is to consider the shortage of generic chemotherapy agents used in life-saving treatment of patients with cancer as a national public health emergency.2
Since 9/11, the United States has developed a well-organized and extensive strategic stockpile system that includes 14 stockpiles housing pharmaceuticals, ventilators, masks, and other medical supplies that are needed if a national public health emergency occurs.3 These 14 stockpiles are all located within 5 hours from any person in the country. If an anthrax outbreak occurs, there are nine U.S. Food and Drug Administration (FDA)-approved drugs or biologics that are stockpiled and can be transported quickly to any part of the United States.
The Director of the Strategic National Stockpile could authorize purchases of chemotherapy drugs deemed to be essential for patients with cancer, paralleling the World Health Organization’s List of Essential Medicines. These drugs could be stored in the stockpiles, released to the market, and replenished with replacement drugs over time as the initial supplies approach expiration dates for use.
If the Centers for Disease Control and Prevention would declare oncology chemotherapy drugs as a public health emergency, then the stockpiles could be used to store national supplies of these drugs and would relieve the public health emergency. Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence, recently proposed a reserve should be created for these drugs, and this is addressed with these stockpiles. The think tank and advocacy organization Friends of Cancer Research has also supported this concept. No new stockpiles are needed. Other solutions such as increasing domestic supplies of generic oncology drugs are longer-term solutions.
In sum, public health emergencies arise when patients with cancer do not have access to essential generic chemotherapy agents. Local and national actions, such as those outlined here, could go a long way to saving the lives of thousands of children and adults with cancer.
DISCLOSURE: Dr. Knopf is a paid consultant and a shareholder at VIVIO Health and a shareholder at Cadex Genomics. Dr. Bennett reported no conflicts of interest.
REFERENCES
1. Bellamy L, Purcell WT: One institution’s experience with implementation of EPIC/Beacon: Lessons learned. Oncology (Williston Park). 28:105-106, 108, 2014.
2. Yang YT, Socal M, Bennett CL: Addressing the drug-shortage crisis in oncology. JAMA Oncol. January 4, 2024 (early release online).
3. Bennett CL, Georgantopoulos P, Gale RP, et al: United States’ regulatory approved pharmacotherapies for nuclear reactor explosions and anthrax-associated bioterrorism. Expert Opin Drug Saf 18:1-6, 2023.
Dr. Knopf is a medical oncologist and Division Chief, Hematology/Oncology, Highland Hospital, Alameda Health System, Oakland, California, Assistant Clinical Professor of Medicine at University of California, and a member of the Institute for Health Policy Studies, San Francisco. Dr. Bennett is the Frank P. and Jose M. Fletcher Chair of Medication Safety and Efficacy; Director, SmartState Center for Medication Safety and Efficacy, The University of South Carolina College of Pharmacy, Columbia, South Carolina; and Affiliated Investigator, Arnold Ventures Program on Drug Access and Affordability at The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO or The ASCO Post.
