ASHP Guidelines on Managing Drug Product Shortages in Hospitals and Health Systems

Abstract

Drug product shortages can adversely affect drug therapy, compromise or delay medical procedures, and result in medication errors.1,2 Health care professionals are increasingly concerned about the clinical effect that shortages have on patients and the tremendous resources required to address shortages.3,–5 Adverse patient outcomes related to drug product shortages1,2,6,–9 have prompted aggressive management strategies by health care providers and gained the attention of the Joint Commission,10 the government,11,12 and the media.13,14 Drug product shortages adversely affect health-system finances by increasing the cost of delivering patient care, largely through higher drug acquisition and personnel costs.6 In addition, shortages create a high level of frustration for everyone involved, including purchasing agents, pharmacists, nurses, physicians, and patients.7 Managing drug product shortages is particularly complex for practitioners in hospitals and health systems (hereinafter, “health systems”), because these facilities routinely treat patients with acute or emergent conditions, use a significant number of medically necessary or single-source products, and use high-cost new drug technologies. These health care providers are challenged during drug product shortages to ensure the provision of seamless, safe, and therapeutically equivalent drug therapy, preferably at comparable costs. The pharmacy department must take a leadership role in efforts to develop and implement appropriate strategies and processes for informing practitioners of shortages and ensuring the safe and effective use of therapeutic alternatives. Strategic planning is required for managing drug product shortages, just as it is for disasters such as major weather events and mass-casualty incidents. Because a thorough understanding of why drug product shortages occur is essential for their successful management, these guidelines begin with a description of factors that contribute to or exacerbate shortages. The guidelines then describe a three-phase approach to contingency planning for management of drug product shortages and include strategies for prevention. Given the differences and complexities in health-system organizational arrangements and practice settings, some aspects of these guidelines may not be applicable in all settings. Pharmacy managers should use their professional judgment in assessing and adapting these guidelines to meet their needs. For the purpose of these guidelines, a drug product shortage is defined as a supply issue that affects how the pharmacy prepares or dispenses a drug product or influences patient care when prescribers must use an alternative agent. Shortages can be the result of one or a combination of factors throughout the supply chain. The supply chain includes sources of raw materials, manufacturers, regulators, wholesalers or distributors, prime vendors, group purchasing organizations, and end-user health care systems. The factors that follow contribute to disruptions in the availability of drug products. Disruptions in the supply of raw or bulk materials are especially problematic when the primary or sole source experiences production difficulties or discontinues production, affecting multiple manufacturers. An estimated 80% of the raw materials used in pharmaceuticals comes from outside the United States.4 Availability problems can arise when armed conflict or political upheaval disrupts trade, animal diseases contaminate tissue from which raw materials are extracted, climatic and other environmental conditions depress the growth of plants used to produce raw materials, or raw materials are degraded or contaminated during harvesting, storage, or transport. Drug product shortages can also occur when the primary or sole manufacturer of a drug product halts or delays production in response to a Food and Drug Administration (FDA) enforcement action concerning noncompliance with current good manufacturing practices (cGMPs). Contributing factors may include antiquated manufacturing equipment, a shift of resources from maintenance of equipment and facilities to research and development, loss of manufacturer personnel experienced in production and compliance issues as a result of company mergers or retirements, cGMP-related problems with subcontractors who supply products to multiple pharmaceutical manufacturers, and limited FDA resources for timely inspections of manufacturing sites.4 Resolution of these issues is often a lengthy process and may include inspections to ascertain cGMP compliance, issuance of an injunction against the manufacturer, or seizure of products. In some instances, a manufacturer’s decision to close a specific manufacturing facility results in unintended drug product shortages. Such was the case when the sole source for hyaluronidase production closed, leaving no supplier.5 FDA enforcement actions are intended to protect the public from potentially unsafe drug products. These actions are evaluated by FDA’s Center for Drug Evaluation and Research (CDER) drug shortage coordinator to determine if the action might create a shortage of a medically necessary drug product.12 (FDA’s definition of a medically necessary product is discussed in the “Government intervention” section below.) In the event that a significant corrective action involves a medically necessary product, FDA will help the manufacturer return to compliance, consider qualifying additional manufacturing sites, or, in extreme circumstances, permit importation of the product from a foreign manufacturing source once the required quality controls are met. Voluntary recalls, generally related to manufacturing problems, can cause shortages, especially when a sole manufacturer’s drug product dominates the market supply. Voluntary recalls are generally temporary and occur as a result of a minor lapse in manufacturing procedures that would not be subject to FDA legal action. Recalls usually affect specific lots and are conducted either because of a lack of assurance that the recalled product is safe or for reasons not related to safety, such as technical deficiencies in the drug’s labeling. An ethical dilemma could arise when it is predictable that complying with the voluntary recall may cause a drug product shortage in a given health system. Changes in a product’s formulation or manufacturer may also delay product availability. One example is the transition from albuterol metered-dose inhalers (MDIs) containing chlorofluorocarbons to MDIs containing hydro-fluoroalkanes in 2006. Manufacturers’ business decisions are based on a variety of factors, including availability of generic products, market size, patent expiration, drug-approval status, regulatory compliance requirements, and anticipated clinical demand. Occasionally, manufacturers temporarily or permanently reduce production quantities of certain drug products as they shift production efforts or reallocate resources to other products. A manufacturer’s reasoned, sound business decision to discontinue production of a drug product because of insufficient financial return or a high cost to correct manufacturing issues can cause an unanticipated, serious shortage, especially in the instance of a sole-source or medically necessary product.15 For example, a shortage of diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed was precipitated when one of the manufacturers, claiming low revenues, discontinued its product in 2000.5 Manufacturers are not required to notify FDA of a drug discontinuation unless the product is a sole-source or medically necessary product.16 For medically necessary drugs, FDA can encourage other manufacturers to produce the product or request that the manufacturer not suspend production until an alternative source is available. However, FDA does not have the authority to require a company to make any product, even if it is medically necessary. Even with advance notice, some agents, such as vaccines or antibiotics, are complex to manufacture, and shortages may result even if other manufacturers are willing and able to produce the product. Similarly, business decisions on the part of wholesale distributors and end-user health systems may contribute to drug product shortages. Manufacturer mergers often result in decisions to narrow the focus of product lines or move a production line to a new facility, resulting in the discontinuation or delayed availability of drug products. Mergers between two companies that manufacture similar product lines typically result in single-source products. As the number of manufacturers of a product decreases, resiliency in the supply chain also decreases, making product supplies more vulnerable. Many vaccines in the United States are single-source products, in part because of discontinuations and consolidations. Most hospitals and health systems obtain the majority of their drug products through wholesale distributors. Restricted distribution methods that bypass the normal supply chain can also create shortages. As the result of either market approval requirements or postmarketing surveillance, manufacturers limit the availability of specific drug products. Only selected suppliers and end users who comply with manufacturer agreements can obtain the product. A manufacturer can also place restrictions on available limited supplies, requiring health systems to order directly from the manufacturer or through a specialty distributor to receive an allocation. Communication and transportation efficiencies throughout the supply chain have allowed inventory reductions at all levels. Most manufacturers, distribution centers, and health systems use “just-in-time” inventory management to reduce the cost of inventory on hand and optimize cash flow. This strategy is recognized as sound business management for all stakeholders, but an unexpected shortage at any point in the supply chain can significantly affect the end user and patient. Some manufacturers and distributors use inventory management strategies that minimize end-of-quarter or end-of-year product inventories or limit shipments based on yearly quotas. Poor ordering practices, stockpiling before price increases, hoarding caused by rumors of an impending shortage, and unexpected delivery delays may affect inventory levels in individual health systems. Hospitals in rural areas face additional inventory challenges caused by distant distribution centers and the inability to easily borrow an item from a nearby hospital. Drug product shortages may also occur when all hospitals in an area disproportionately use the same wholesaler. Some shortages are wholesaler dependent, as shortages of drugs can occur when contracts with suppliers are delayed. Occasionally, the demand for a drug product unexpectedly increases or exceeds production capacity. This may occur when a new indication is approved for an existing drug product, when usage patterns change in response to new therapeutic guidelines, when a substantial disease outbreak occurs, or when unpredictable factors influence demand. Shortages may be prolonged when the raw materials are limited or manufacturing processes are complex or dependent on a long lead time. For example, when the Centers for Disease Control and Prevention (CDC) recommended annual influenza vaccination for children age 6–59 months in 2006, only one product had FDA-approved labeling for use in children 6–23 months old.17,18 The increased frequency of drug product shortages has precipitated the development of nontraditional distributors, also known as open-market, gray-market, or alternative distributors. These specialty, licensed distributors or brokers obtain products in short supply for the purpose of reselling them to end users who are unable to obtain them through their normal suppliers. These distributors aggressively market the availability of these products to hospitals, specialty health systems, home care agencies, and physician practices, generally at substantially higher prices. Typically, these distributors have a limited quantity of product, often only enough for one or two patients. Many do not offer a return or refund on a product if it expires or is not used. Especially worrisome is the inability to ascertain the product’s pedigree or ensure the reliability of the product’s source, which could be outside the United States, and proper handling and storage throughout the chain of custody. The extent to which the activities of such nontraditional distributors contribute to drug product shortages is unknown. Compounding pharmacies have also pursued the production of drugs that are in short supply. Caution is warranted because preparations from these pharmacies may not meet applicable state or federal standards (e.g., United States Pharmacopeia chapter 797 or FDA labeling requirements). The sources of raw materials used by compounding pharmacies have been questioned, and apparent lapses in quality control have resulted in serious patient injury, including death.13 Natural disasters can have a profound effect on the availability of drug products. Damage to manufacturing facilities, particularly those that are the sole source of a drug product or category of products, is likely to cause long-term shortages. Damage to manufacturing facilities in Puerto Rico in 1998 from hurricane George caused shortages of several drug products. Fires, hurricanes, tornadoes, and floods are examples of natural disasters that may temporarily compromise drug product supplies. In some instances, these shortages may be exacerbated by an escalated need for certain classes of drug products to care for victims of the disaster. In 2005, areas affected by and affected by an increased need for and the inability to obtain The of a shortage a of events drug and therapeutic Drug include the shortage and its anticipated the availability of supplies from alternative and alternative supplies the of compounding the product, and and about alternative and the cost of all The of process may an of the effect on patient care and development of a strategy for the to all professionals and to affected patients when In an would be a for providers in advance of impending drug product would them to address and all aspects and of the In of pharmacists, when with the of a drug product, on which to decisions about patient for the product. of the supply especially manufacturers and distributors, have been in and to health systems. The in is exacerbated by the and in the supply chain. The pharmacy department must take a leadership role in managing shortages by and appropriate strategies and processes for the safe and effective use of therapeutic alternatives. Health systems should develop a contingency planning strategy to for the of a prolonged drug product it often is not to when shortages will the process for with them can be defined in The health should a point to implement and process and an organizational approach to and The should determine and for during of the process (e.g., pharmacy and medical can be and and a of the current and the effect of the shortage on the health system. An effective the for the shortage and an end and supply are The of all activities that can be before the of the shortage are on the health when a order or other is is often before patients on the drug product and alternative should be drug products have limited therapeutic can have significant patient care and cost Health systems need to the effect of those on their should also include the development of methods for and The contingency involves and for which is limited because of financial or the health For example, products are available only in and at a high cost when no therapeutic are available or when shortages are control availability is not health systems must for a product’s The purchasing is often the who a shortage and may be the for managing drug product shortages. This must be of in the health supply chain that may a shortage (e.g., one to manufacturers have no more the purchasing is not a or must with a a shortage is the point or or should an to its A the and an of the current inventory and usage patterns can be used to determine the of the can product manufacturers, distributors, and other sources to determine the for the shortage and its This may be available on the Drug Center to the can a shortage of when the product will be available help determine the health to the shortage and its and long-term management the end result is the the to and the of effect to the for the shortage and in the supply chain problems raw materials to manufacturer, manufacturer to or wholesaler to health system. A lack of raw materials may affect several manufacturers of the drug product. A manufacturer’s problems may affect only its product. on distributors are dependent on their inventory levels. a shortage is the pharmacy should the inventory on hand and the it will inventory includes all supplies of the drug product the health including the care medication storage and distribution and on available quantities and the pharmacy should how long the health can a can be from and issue by distributors, the purchasing and the pharmacy and medication storage and can in usage the system. of all alternative drug products should be to of current use and are should be when assessing how long the available inventory of the shortage drug product and alternative products will A all factors to the shortage (e.g., current medical alternative sources or to determine the effect on patient care and costs. Shortages affect safe medication practices throughout the medication distribution and process a health system. alternative or must consider in their procedures for and distribution and the effect on compliance, and product The extent to which a health will be affected by a given shortage on the health and level of and its an shortage is the health should take to for known and problems in patient care and costs. The in the is to therapeutic to the drug product. A process for and therapeutic for the health should be The health should make decisions about alternative in with and pharmacy and obtain approval of the appropriate medical should be to ensure supplies to meet new demand. In supplies of the alternative may be affected by the current about the drug product shortage, alternative temporary therapeutic guidelines, and should be to clinical by the effective available the health system. Communication of is essential for ensuring patient and medication caused by differences between drug and other systems and systems must be with Pharmacy department for prescribers with medication and with should be about the alternative decisions and is necessary to and pharmacy or The when the of arrangements with other a or system. supplies of a potentially product and about alternative should be the This is limited for rural hospitals and for area hospitals by a wholesaler. a limited supply of a drug available and for specific patient are a health may the drug for specific patient (e.g., medical may on patient on and if available for the drug in may be in to appropriate drug Such are particularly in with long-term shortages such as with limit product use for patients or in the health should be by a Communication is essential to ensure that supplies are available to of guidelines for must be to in the of medication with management and or may be when supplies are For example, during the influenza vaccine shortage of health systems not have product to follow recommended guidelines and use of the product to specific patient management is a during a to do stockpiling in advance of a shortage can can exacerbate the shortage and supplies from other health systems with patients in Health systems should from which two can cause shortages when health systems the supply chain and manufacturing and inventory is and may not be by normal usage if shortages do not occur as pur

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