Drug shortages in the United States are becoming increasingly common and, unfortunately, can lead to compromises or delays in treatments or procedures, result in medication errors, and have an unknown clinical impact on affected patients.1,2 In a recent survey conducted by the Institute for Safe Medication Practices (ISMP), more than 1,800 health care professionals expressed that drug shortages have negatively impacted public health, and even considered it a national health care crisis.1 The drug-shortage crisis has been unavoidable in most areas of practice, and one of the most significantly impacted specialty areas is oncology. Approximately 20 chemotherapeutic agents, most of which are widely used generics that are a staple in many cancer-treatment regimens, are currently at shortage levels.3 Drug shortages are frustrating and make caring for our oncology patients difficult at times, and the problem is complex and multifaceted with no easy answers in sight. Nurses should understand what causes a drug shortage and how it impacts health care institutions before addressing the impact on oncology practice.
CAUSES OF A SHORTAGE
The cause of a drug shortage is most often multifactorial, but almost always starts with the pharmaceutical manufacturers. Complicating the matter is that pharmaceutical industries are recommended to contact the Food and Drug Administration when a drug shortage or limitation in supply is anticipated. Despite the FDA urging to forewarn of a drug shortage, however, pharmaceutical manufacturers are not required to provide such warning, and often do not.4,5 The result is a sudden and unanticipated discontinuation of a medication’s supply chain that leaves clinicians with the daunting and cumbersome task of allocating available stock to those patients with the greatest need and finding alternative therapies for the others.4 Although there is proposed legislation requiring drug manufacturers to provide 6 to 12 months’ advanced notice of market withdrawals, issues in supply chain or raw materials, or any foreseeable hurdles to the drug manufacturing process to the FDA and health care providers,6 the industry does not always have the ability or time to give advance notice of erratic influences on production such as voluntary recalls, lack of raw materials, and natural disasters.
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A substantial concern is the industry’s lack of adherence to Good Manufacturing Practices (GMPs), which the FDA administers and enforces in the United States. GMPs include manufacturing policies and procedures for developing high-quality medications, dietary supplements, medical devices, diagnostic chemicals, and food products.7 Most countries have a standard set of GMPs for their pharmaceutical industry; however, the FDA standards are notoriously stricter than GMPs in other countries and are dependably enforced, resulting in higher expectations for compliance in the United States. The intent of the high level of FDA enforcement is to ensure superior quality products are produced and to protect the health and safety of the American public, but this can unintentionally result in an unexpected freeze of the drug supply. When the FDA determines that production of a particular drug does not meet its GMPs, it has the ability to cease further production but not the legal authority to require the manufacturer to comply within a specific time frame or to continue manufacturing the drug in question at all. For generic drugs, compliance with GMPs may cost the manufacturer more money than it would lose by discontinuing production of the drug; therefore, the manufacturer may not pursue manufacturing generic drugs. Such was the case with hyaluronidase, a commonly used antidote for chemotherapy-induced extravasations, leaving no such supplier to date.8 Depending on the medication in question, the FDA can conduct a medical necessity evaluation and petition another manufacturer to continue or start production of a drug,5 or allow the drug to be imported from a foreign country until GMP standards are met.5 In the interim, however, a drug shortage may result.
Athough difficulties with regulatory issues and manufacturing obstacles appear to be a big piece of the drug-shortage issue, there are other contributing factors. Disruptions in the flow or supply of raw materials used in the pharmaceutical manufacturing process may further exacerbate or cause a drug shortage. Up to an estimated 80% of raw materials used in pharmaceutical manufacturing are obtained from outside the United States.7 Political instability, climatic change or natural disaster, or issues with contamination of either plants or animals can abruptly and uncontrollably interfere with the importation of raw and bulk materials. This is especially problematic when the sole supplier is from one particular region. Other examples can be voluntary recalls, often relating to minor manufacturing issues outside of FDA regulatory control; changes in product formulation (eg, the chemical propellants in albuterol metered-dose inhalers were changed in 2006); or simply the business decision of the manufacturer to halt production due to low revenue or decreased demand.2 In addition, mergers and acquisitions among pharmaceutical companies are becoming increasingly common, and their efforts to streamline the manufacturing process may also cause delays or shortages in a drug’s availability.
IMPACTS ON THE HEALTH CARE SYSTEM
The immediate effects of a drug shortage are easily comprehensible: patients may or may not get a medication that they require to treat their medical illness or may be treated with an alternative or second-line agent. Further consideration reveals additional problems involving stockpiling and distribution. Unlike other issues between the FDA and pharmaceutical manufacturers, these concerns are directly tied to health care institutions and their actions in response to a drug shortage. Although the intent is to provide the utmost quality of care to patients, their actions may inadvertently worsen or prolong a drug shortage.5
One such action is stockpiling drugs. Stockpiling is defined as buying a larger-than-needed supply of medications either in response to or in anticipation of a drug shortage. This can directly create or prolong a drug shortage by reducing the amount of drug available to other health care institutions.8,9 Another common practice is to stockpile the second-line or alternative agent in anticipation of need secondary to a drug shortage (eg, stockpiling epirubicin [Ellence, generics] during the doxorubicin [Adriamycin, Doxil, Rubex, generics] shortage in 2010). This is risky for an institution; if the drug shortage is anticipated and never occurs, the institution is financially responsible for a bulk supply of a drug that may never get used.9 Most manufacturers typically respond to a drug shortage by allocating a supply of the drug based on previous sales. The bulk purchase of a drug in anticipation of a shortage rarely, if ever, effects this allocation. Furthermore, a given drug may have a lengthly lead time, meaning the time from raw materials to patient use is comparatively prolonged. The manufacturer may have ample time to correct the issue before the shortage ever affects the end-user. Therefore, most professional organizations, including the American Society of Health-System Pharmacists (ASHP) and the National Comprehensive Cancer Network (NCCN), strongly advise against health care institutions stockpiling or hoarding any medications in anticipation of or in the event of a drug shortage.10,11
Drug shortages can also lead to the use of nontraditional wholesalers and suppliers, frequently termed as the grey market.2,4 Typically, grey market wholesalers obtain a small supply of a medication either immediately before or after a drug shortage is announced, then offer the drug to health care institutions, physician practices, nursing homes, et cetera, at an inflated price. As the origin of grey market drugs is either unknown or derived from foreign markets, there is no guarantee of the drug’s pedigree or assurance that the drug was stored and transported appropriately through chains of custody. Similarly, compounding pharmacies have attempted to make drugs on short supply; however, compounded medications are not always subject to the same federal regulations as commercially prepared drugs. Significant concerns exist about the quality of the raw materials used in compounded drugs and the overall product dispensed by these pharmacies.
