Chemotherapy Shortages: When is Enough, Enough?

Shortages of life-saving chemotherapy agents and supportive care drugs have presented physicians treating children with cancer with difficult decisions regarding drug allocation and prioritization. Guidelines released by the Children’s Oncology Group Allocation Task Force aim to support health care providers in mitigating factors that contribute to drug shortages and in determining how to ethically allocate scarce drugs to their patients.

Over the past several years, children with cancer and those who care for them have faced a seemingly unimaginable scenario: shortages of life-saving chemotherapy agents and supportive care drugs.^1-3 Many of the drugs in short supply comprise the backbone of proven regimens needed to treat and to cure children, and adults, with cancer. With few, if any, effective alternatives, shortages present both practical and ethical problems. Surprisingly, this largely American problem has failed to garner more attention.

Shortages of medications and other essential resources have a long-standing history. One of the first large-scale drug shortages was in the early 1920s and involved insulin.⁴ This was followed by shortages of penicillin in the 1940s, which affected a far greater number of patients.⁵ However, over the past 10-plus years, the number of drug shortages—including shortages of chemotherapeutics—has skyrocketed, reaching an all-time high of 320 drugs in short supply in September 2014.⁶ As Michael Link, past president of the American Society of Clinical Oncology, has reported, more drugs are in short supply than ever before, and shortages are lasting longer.⁷ Chemotherapy agents are particularly prone to scarcity and are consistently ranked among the top five drug classes in short supply. Over the past 10 years, 8 of the 10 drugs commonly used in the treatment of acute lymphoblastic leukemia—the most common childhood cancer, which affects thousands of children each year in the United States and has a survival rate approximating 90%⁸—have temporarily been unavailable. The estimated annual cost associated with managing these drug shortages is $416 million.⁹

The factors contributing to drug shortages are complex and are especially common in the United States;^10-15 they include economies of scale, limited profit margins, quality failures, consolidation in the marketplace, a lack of manufacturing redundancy, inadequate market competition to drive down prices, regulatory considerations, and the federal government’s inability to negotiate drug prices.

ETHICAL AND POLICY IMPLICATIONS OF DRUG SHORTAGES

The consequences of drug shortages are far-reaching. Beyond the economic costs, drug shortages directly impact patients’ lives; this is especially true for children with cancer. Drug shortages in general, and shortages of chemotherapeutics and supportive care agents in particular, are linked to delayed administration of life-saving therapies, increased medication errors, inferior outcomes, and patient deaths.^16-21 Ultimately, drug shortages prevent clinicians from providing standard of care therapies, and they hinder critical clinical research that is essential in order to guarantee ongoing advances in understanding disease processes and improving outcomes.

Additionally, chemotherapy shortages result in substantial and unwarranted anguish and distress for patients and their families, while clinicians are confronted with the untenable and, at times, tragic choice of deciding which patients under their care will not receive a life-saving medication.

In an effort to address these and other difficult issues, in January 2013, a multidisciplinary, transnational Working Group was formed to examine the ethical and policy implications of chemotherapy shortages in childhood cancer.

Our efforts resulted in a Consensus Statement²² that, rather than focusing on prioritization, was designed to prevent and to mitigate lack of access to essential drugs for children with cancer. Our group endorsed two core ethical values: (1) maximizing the potential benefits of highly effective (life-saving) drugs; and (2) ensuring equitable access among patient groups. From these, we developed 6 recommendations. Each recommendation includes an ethical rationale, action items, and barriers that must be overcome.

As the Working Group reported, and as appreciated by others, solving the drug shortage problem will ultimately require a major policy shift that is grounded in coordination and cooperation, including broad stakeholder engagement with representatives from government, industry, professional organizations, and patient advocacy groups. Implementing a policy change of this magnitude requires both the motivation and the time to engage in a thoughtful and deliberative process; it is not amenable to a quick fix. Given the ongoing shortage of medications (at the time of this writing, nearly 200 drugs), until such a change is in place, we must be prepared as a society to make difficult decisions about allocating scarce life-saving chemotherapy among equally deserving children.

CONSIDERATIONS FOR DRUG ALLOCATION DECISIONS

Surprisingly, little formal guidance exists to help oncologists make these tragic prioritization choices. Seventy percent of medical oncologists reported that their hospital or practice lacked formal guidance in this regard.²⁰ Although a greater percentage of pediatric oncologists reported center-level guidance coping with drug shortages,²¹ the guidance provided was neither uniform nor was it necessarily grounded upon a particular ethical framework or construct.

Understandably, oncologists struggle when confronted with having to prioritize life-saving chemotherapeutics. A major point of consideration is the specific allocation criteria that should be used. For example, should priority access to scarce drugs be granted to patients with better prognoses or to those with the worst prognoses? Should drugs be allocated via lottery or on a first-come-first-serve basis? Should children receive preference over adults? Should patients enrolled in a clinical trial receive preferential access to a scarce drug over those who opt not to participate in these trials? Do hospitals have a responsibility to share scarce drugs with one another? Who should make allocation decisions: the physician at the bedside or an independent neutral panel?

The aforementioned insulin and penicillin shortages are instructive and provide a historical perspective when considering the methods by which each of these essential medications was ultimately allocated. Like many current drug scarcities, both insulin and penicillin shortages were the result of an inability to manufacture adequate supply. Dr Frederick Banting, one of the discoverers of insulin, was responsible for its prioritization. Banting’s allocation decisions were often biased and arbitrary and were influenced by “emotional, political, and personal appeals,” such that acquaintances and the politically well-connected persons received priority over others.⁴ 

The decision to preferentially allocate penicillin to US soldiers and not civilians during the penicillin shortages at the height of World War II was made by the Committee on Chemotherapeutic and Other Agents.⁵ This decision was made without public comment and caused quite an outcry among the larger public who disagreed with the decision-making rationing process and with the failure to disclose the criteria for patient selection. Each of these examples sheds light on the limitations associated with individual and committee-based allocation of life-saving medications and emphasizes the importance of a transparent and public prioritization process.

Although patients and physicians in many other countries are more accustomed to health care rationing and prioritization, rationing of medical care has largely failed to gain support in the United States, despite calls for such a practice by a diverse group of scholars and policy makers. Yet, health care rationing still occurs in the United States. For example, insurance company decisions regarding medication formularies and reimbursement for diagnostic interventions or treatments represent a form of rationing referred to as implicit rationing. Another form of implicit rationing is a patient’s ability to pay. Examples of explicit rationing include priority access to vaccines, allocation of organs for transplantation, and hemodialysis.

RECOMMENDATIONS OF THE ALLOCATION TASK FORCE

In the absence of a coordinated response to solving drug shortages, and recognizing the need to provide clinicians with ethical guidance, a 7-member Allocation Task Force was formed following a charge from the Chair of the Children’s Oncology Group. The interdisciplinary and multi-institutional Allocation Task Force possesses a range of both clinical and ethical expertise and includes a parent advocate.

The Allocation Task Force developed an ethical framework for allocating scarce chemotherapy and supportive care agents with the aim of providing concrete recommendations and reasoning for explicit decision-making when clinicians are confronted with an actual drug shortage. The preliminary framework was revised following review by an independent panel of peer consultants with expertise in pediatric oncology, law, regulatory affairs, pharmacology, bioethics, and advocacy. The final report²³ was endorsed by the leadership of the Children’s Oncology Group and the American Society for Pediatric Hematology/Oncology.

Given the problematic nature of bedside allocation decision-making, which is often inefficient, uncomfortable, prone to subjective preferences, and reliant upon clinicians’ primary obligation of beneficence, prioritization decisions should be made by a multidisciplinary institutional Drug Shortage Committee or similarly appointed body (eg, Pharmacy and Therapeutics Committee, Ethics Committee), with appropriate stakeholder representation.

Functioning as a hypothetical drug shortage committee, the Allocation Task Force reached consensus on an ethical framework, which delineates a process for actual rationing of life-saving chemotherapy and supportive care agents. In establishing its framework, the Allocation Task Force considered existing allocation schema and emphasized a consistent approach grounded upon ethical, legal, and sociocultural considerations.

Faced with a drug shortage, the Allocation Task Force recommends a 2-step process. Step 1 includes strategies to mitigate an existing shortage based upon maximizing efficiency and minimizing waste. Select examples of mitigation strategies include the following:

1. Drug shortages should be viewed as a public health crisis. Not only will this result in greater public awareness, it also provides a mechanism for potential remediation. A recent example of such remediation includes the November 2013 joint CDC and FDA initiative allowing importation of a Swiss vaccine to curtail an outbreak of  bacterial meningitis strain B at two US universities.²⁴ 
2. Hospitals should not order more of a drug than is typically required in a given period. 
3. Hospitals that lack a drug required by a patient should attempt to secure a supply for that patient from another institution or refer the patient to another institution able to provide the necessary care. 
4. Patients receiving similar therapies should be “cohorted” to share vials that are otherwise meant for single-use.
5. If appropriate, an alternate dosing approach (eg, lower dosage or less frequent dose) should be administered.
6. If scarcity is expected to be short-lived, administer the scarce drug out of sequence.
7. If feasible, compound drug on own or acquire from a commercial compounding pharmacy.
8. If stability and sterility profile supports doing so, consider extending drug usage beyond typical and accepted practice (ie, administer an expired drug).

Step 2 elucidates the actual prioritization decision-making process, across and within diseases, based upon a modified utilitarian model that maximizes benefit according to the total number of lives saved or the number of life-years saved. Faced with prioritization, allocation decisions must be reasoned, explicit, transparent and public. Such accountability is more likely to gain the public’s trust that institutions are acting in a legitimate and fair manner and that limit setting is based upon values and principles. 

Select examples of specific considerations for allocation include:

1. Consider “curability” and/or prognosis, including the threshold of curability.
2. Base allocation decisions on the strength of the data.
3. Consider a drug’s importance or need to a given patient’s prognosis.
4. Consider the critical role that certain drugs have in the management of cancers with poorer outcomes.
5. Consider the total amount of the scarce drug required.
6. Consider the phase of therapy. 
7. Do not use clinical trial participation as a factor for prioritization.
8. Engage patients and families affected by drug shortages and appropriately apprise them of decisions about their treatments.

CONCLUSION

Children with cancer are among the most vulnerable of patients and deserve access to life-saving chemotherapeutics. Shortages of life-saving medications represent nothing short of a public health crisis and should be viewed as such. They are akin to a national emergency or a national disaster.

Physicians and administrators faced with having to decide which of two children with cancer receives a scarce life-saving treatment need guidance and should not feel that they are on their own without a roadmap. The context of allocation is always complex, but it is unethical to leave these challenges unaddressed. It is our hope that our framework will be helpful and spur further substantive action on this crucial issue.

Although necessary, our guidance will not resolve the drug shortage problem. Ultimately, what is needed is a nimble health care system that is able and committed to instituting change to prevent these shortages from ever occurring. Such a system must readily engage with stakeholders who may not share the same set of priorities. The fact that children with cancer cannot obtain the life-saving drugs needed to cure their diseases is a national disgrace. As a society, we must take the necessary steps to put an end to this wrong. 

For another perspective on this issue, read the Counterpoint, "Keeping Cures on the Shelf," by George Dahlman.

References

1.    Goldsack JC, Reilly C, Bush C, et al. Impact of shortages of injectable oncology drugs on patient care. Am J Health Syst Pharm. 2014;71(7):571-578.

2.    Goldberg P. Drug shortages reach all-time high–Ben Venue exit will make matters worse. The Cancer Letter. 2013;39(38):1-5.

3.    Fox ER, Sweet BV, Jensen V. Drug shortages: a complex health care crisis. Mayo Clin Proc. 2014;89(3):361-373.

4.    McGough LJ, Reynolds SJ, Quinn TC, Zenilman JM. Which patients first? Setting priorities for antiretroviral therapy where resources are limited. Am J Public Health. 2005;95(7):1173-1180.

5.    Adams DP. Wartime bureaucracy and penicillin allocation: the Committee on Chemotherapeutic and Other Agents, 1942-44. J Hist Med Allied Sci. 1989;44(2):196-217.

6.    ASHP. Drug Shortages: Current Drugs. Current Drug Shortage Bulletins. https://www.ashp.org/DrugShortages/Current/. Accessed February 8, 2016.

7.    Park A. Inside America’s Drug Shortage. Time. https://healthland.time.com/2012/03/19/where-have-all-our-drugs-gone/. Published March 19, 2012. Accessed February 8, 2016.

8.    Hunger SP, Lu X, Devidas M, et al. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children’s oncology group. J
Clin Oncol. 2012;30(14):1663-1669.

9.    Kaakeh R, Sweet BV, Reilly C, et al. Impact of drug shortages on U.S. health systems. Am J Health Syst Pharm. 2011;68(19):1811-1819.

10.    Office of the Assistant Secretary for Planning and Evaluation. ASPE Issue Brief: Economic analysis of the causes of drug shortages. aspe.hhs.gov. https://aspe.hhs.gov/sites/default/files/pdf/108986/ib.pdf. Accessed February 8, 2016.

11.    Dill S, Ahn M. Overview of U.S. drug shortages. fda.gov. fda.gov/downloads/Drugs/UCM327108.pdf. Published November 6, 2012. Accessed February 8, 2016.

12.    Woodcock J, Wosinska J. Economic and technological drivers of generic sterile injectable drug shortages. Clin Pharmacol Ther. 2013 Feb;93(2):170-176.

13.    US Food and Drug Administration. Frequently Asked Questions About Drug Shortages. fda.gov. https://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm050796.htm#q10. Accessed February 8, 2016.

14.    Lipworth W, Kerridge I. Why drug shortages are an ethical issue. Australas Med J. 2013;6(11):556-559.

15.    Parsons HM, Schmidt S, Karnad AB, et al. ReCAP: association between the number of suppliers for critical antineoplastics and drug shortages: implications for future drug shortages and treatment. J Oncol Pract. 12(3):249-250.

16.    Institute for Safe Medication Practices. Drug shortages: national survey reveals high level of frustration, low level of safety. ISMP Medication Safety Alert! 2010;15(19):1-6.

17.    Institute for Safe Medication Practices. A shortage of everything except errors: harm associated with drug shortages. ISMP Medication Safety Alert! 2012;17(8):1-4.

18.    Metzger ML, Billett A, Link MP. The impact of drug shortages on children with cancer – the example of mechlorethamine. N Engl J Med. 2012;367(26):2461-2463.

19.    McBride A, Holle LM, Westendorf C, et al. National survey on the effect of oncology drug shortages on cancer care. Am J Health Syst Pharm. 2013;70(7):609-617.

20.    Gogineni K, Shuman KL, Emanuel E. Survey of oncologists about shortages of cancer drugs. N Engl J Med. 2013;369(25):2463-2464.

21.    Salazar EG, Bernhardt BM, Li Y, Aplenc R, Adamson PC. The impact of chemotherapy shortages on COG and local clinical trials: a report from the Children’s Oncology Group. Pediatr Blood
Cancer. 2015;62(6):940-944. 

22.    DeCamp M, Joffe S, Fernandez CV, Faden R, Unguru Y; Working Group on Chemotherapy Drug Shortages in Pediatric Oncology. Chemotherapy drug shortages in pediatric oncology: a consensus statement. Pediatrics. 2014;133(3):e716-e724.

23.    Unguru Y, Fernandez CV, Bernhardt B, et al. An ethical framework for allocating scarce life-saving chemotherapy and supportive care drugs for childhood cancer [published online ahead of print January 29, 2016]. J Natl Cancer Inst. doi: 10.1093/jnci/djv392.

24.    The New York Times Editorial Board. Responding to a meningitis outbreak. The New York Times. https://www.nytimes.com/2013/11/23/opinion/responding-to-a-meningitis-outbreak.html. Published November 22, 2013. Accessed February 25, 2016.