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Drug shortages pose challenges, spark open communication in US health care

The past several years have witnessed a significant number of drug shortages affecting various aspects of medical care, including treatment of various infectious diseases. To some extent, the reasons for the development of these drug shortages can be simplified, although the processes surrounding drug manufacturing and drug distribution are more complex.

Although what constitutes a drug shortage may seem intuitive, the FDA defines a “drug shortage” as a situation in which the total supply of all clinically interchangeable versions of an FDA-regulated drug is inadequate to meet the current or projected demand at the user level. Drugs that are currently considered to be in a shortage are tracked primarily by two organizations, and are listed on their websites: the FDA and the American Society of Health-Systems Pharmacists.

The FDA lists 65 specific drugs as “currently in shortage”; of these, 14 are categorized as anti-infective agents, while 36 are categorized as pediatric use agents (all therapeutic categories). Several examples of antibiotics commonly prescribed to pediatric patients in short supply include cefazolin, cefepime and meropenem. In contrast, ASHP lists 157 drugs in short supply.

Edward A. Bell

Differences in defining what a “drug shortage” is explains why the reported shortage numbers from the FDA and ASHP are not similar. Shortages of vaccine products are not listed on the FDA Drug Shortages Web page, but are listed and described by the CDC Web page, Current Vaccine Shortages and Delays, as well as listed on the ASHP Drug Shortages Web page. Both the FDA and ASHP websites provide valuable information, but information listed on the ASHP website is generally more descriptive and lengthy, including listing of manufacturers with continued supply and those without available supply.

Causes of drug shortages

Although the causes of drug shortages are multifactorial, the most common reason relates to drug manufacturing problems, specifically production difficulties affecting the quality of the product. Other causes include a reduction or limited supply of raw materials, delays in shipping of products, increased product demand, product discontinuation or loss of a manufacturing site (eg, loss from fire or natural disaster).

The typical drug in shortage is a generic injectable product. Overall, generic drug products are more susceptible to shortages as these products are typically manufactured by just a few companies. Several of the large pharmaceutical manufacturers of generic injectable products have recently developed manufacturing difficulties, and this has affected the supply of many specific products, resulting in shortages. Only a small number of manufacturers produce the majority of generic injectable products, which exposes drug production to shortages when manufacturing problems or difficulties occur. As one may imagine, the drug manufacturing process is complex and highly regulated by the FDA to ensure adequate drug product purity and safety. Injectable drug products can be more difficult to produce in large quantities, as they must be manufactured in sterile conditions.

Characteristics of the drug supply and inventory processes also contribute to difficulties with drug shortages. Most drug products are supplied to health care institutions and medical offices through wholesalers, and supplies of drug products are commonly described as having “just-in-time” inventory, implying that inventories are typically maintained low to reduce inventory costs. When a delay or problem in the manufacturing process of a specific drug product occurs, a clinically impactful shortage may quickly result. When a limited supply of a drug product is initially reported, other drug products within the same, or similar, drug class may then be increasingly prescribed, resulting in shortages of these products as well.

Some institutions also may purchase more of the product than is usual, in hopes of minimizing clinical problems due to the drug shortage. Other problems often follow, such as the appearance of “gray” markets (when a drug product is obtained outside of normal supply methods, even though storage and handling of the products may be unreliable), rising costs of the products in short supply, and potential, significant clinical ramifications. These include concerns about the availability of other safe and effective drugs for specific uses and indications, and who should receive limited drug supplies.

Clinical consequences

Most recently, drug classes largely affected by drug shortages include oncology agents, anti-infectives, anesthetics, and nutritional and electrolyte products. As described above, many of these products are injectable dosage forms. While several different drug classes and specific agents may be used for the pharmacotherapy of many conditions, the available options with evidence for efficacy and safety can be more limited in the pediatric population, especially with oncologics, anesthetics and anti-infectives.

As drug shortages occur and result in an increase in the use of pharmacotherapeutic agents not typically used for specific treatments, medication-related errors may be more likely to occur, and have been reported. Products from different manufacturers (with different appearances, strengths or concentrations) are purchased to replace drug products that are in short supply. These product differences have led to confusion, including prescribing and administration errors. Examples reported include inappropriate administration of injectable solutions of phenytoin, hydromorphone, or 5% sodium bicarbonate when shortages occurred with fosphenytoin, morphine or 5% dextrose, respectively. Some of these reported errors have resulted in fatal outcomes.

Pharmacotherapeutic agents used in the treatment of oncologic disorders may be especially prone to significant clinical ramifications, as treatment regimen indications and uses are often based upon systematic clinical trials. The AAP has recognized this concern, with publication of recommendations from the Working Group on Chemotherapy Drug in Pediatric Oncology (2014); these recommendations include, among others, giving equal priority to evidence-based uses of drugs whether they occur within or outside of clinical trials.

Similarly, the Infectious Diseases Society of America and the Pediatric Infectious Diseases Society have jointly published recommendations to minimize the clinical impact of drug shortages when treating infectious diseases, including: enhanced application of the term “medically necessary” drug products as defined and applied by the FDA, improved communication among health care professionals and governmental agencies, and consideration for increased importation of some drug products from outside the United States.

Recently implemented federal regulation has lessened the overall impact of drug shortages to some extent. In 2012 the FDA Safety and Innovation Act required pharmaceutical manufacturers to notify the FDA at least 6 months in advance of drug product manufacturing difficulties or discontinuations. While this legislation is helpful, manufacturers may not always be able to identify impending shortages.

Enhanced communication among the FDA and other federal health agencies, pharmaceutical manufacturers, and professional medical organizations also has been helpful. Experts have called for further communication and sharing of relevant information on drug shortage and availability. Drug shortages, however, are likely to continue into the near future. Some health care institutions have published descriptions and recommendations for managing drug shortages, such as institutional recommendations for drug therapy regimens that can replace specific drug shortages. As drug shortages may also pose potential ethical dilemmas (eg, who should receive the limited drug supply?), institutions may additionally benefit from discussions on strategies to manage them.

Disclosure: Bell reports no relevant financial disclosures.

The past several years have witnessed a significant number of drug shortages affecting various aspects of medical care, including treatment of various infectious diseases. To some extent, the reasons for the development of these drug shortages can be simplified, although the processes surrounding drug manufacturing and drug distribution are more complex.

Although what constitutes a drug shortage may seem intuitive, the FDA defines a “drug shortage” as a situation in which the total supply of all clinically interchangeable versions of an FDA-regulated drug is inadequate to meet the current or projected demand at the user level. Drugs that are currently considered to be in a shortage are tracked primarily by two organizations, and are listed on their websites: the FDA and the American Society of Health-Systems Pharmacists.

The FDA lists 65 specific drugs as “currently in shortage”; of these, 14 are categorized as anti-infective agents, while 36 are categorized as pediatric use agents (all therapeutic categories). Several examples of antibiotics commonly prescribed to pediatric patients in short supply include cefazolin, cefepime and meropenem. In contrast, ASHP lists 157 drugs in short supply.

Edward A. Bell

Differences in defining what a “drug shortage” is explains why the reported shortage numbers from the FDA and ASHP are not similar. Shortages of vaccine products are not listed on the FDA Drug Shortages Web page, but are listed and described by the CDC Web page, Current Vaccine Shortages and Delays, as well as listed on the ASHP Drug Shortages Web page. Both the FDA and ASHP websites provide valuable information, but information listed on the ASHP website is generally more descriptive and lengthy, including listing of manufacturers with continued supply and those without available supply.

Causes of drug shortages

Although the causes of drug shortages are multifactorial, the most common reason relates to drug manufacturing problems, specifically production difficulties affecting the quality of the product. Other causes include a reduction or limited supply of raw materials, delays in shipping of products, increased product demand, product discontinuation or loss of a manufacturing site (eg, loss from fire or natural disaster).

The typical drug in shortage is a generic injectable product. Overall, generic drug products are more susceptible to shortages as these products are typically manufactured by just a few companies. Several of the large pharmaceutical manufacturers of generic injectable products have recently developed manufacturing difficulties, and this has affected the supply of many specific products, resulting in shortages. Only a small number of manufacturers produce the majority of generic injectable products, which exposes drug production to shortages when manufacturing problems or difficulties occur. As one may imagine, the drug manufacturing process is complex and highly regulated by the FDA to ensure adequate drug product purity and safety. Injectable drug products can be more difficult to produce in large quantities, as they must be manufactured in sterile conditions.

Characteristics of the drug supply and inventory processes also contribute to difficulties with drug shortages. Most drug products are supplied to health care institutions and medical offices through wholesalers, and supplies of drug products are commonly described as having “just-in-time” inventory, implying that inventories are typically maintained low to reduce inventory costs. When a delay or problem in the manufacturing process of a specific drug product occurs, a clinically impactful shortage may quickly result. When a limited supply of a drug product is initially reported, other drug products within the same, or similar, drug class may then be increasingly prescribed, resulting in shortages of these products as well.

Some institutions also may purchase more of the product than is usual, in hopes of minimizing clinical problems due to the drug shortage. Other problems often follow, such as the appearance of “gray” markets (when a drug product is obtained outside of normal supply methods, even though storage and handling of the products may be unreliable), rising costs of the products in short supply, and potential, significant clinical ramifications. These include concerns about the availability of other safe and effective drugs for specific uses and indications, and who should receive limited drug supplies.

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Clinical consequences

Most recently, drug classes largely affected by drug shortages include oncology agents, anti-infectives, anesthetics, and nutritional and electrolyte products. As described above, many of these products are injectable dosage forms. While several different drug classes and specific agents may be used for the pharmacotherapy of many conditions, the available options with evidence for efficacy and safety can be more limited in the pediatric population, especially with oncologics, anesthetics and anti-infectives.

As drug shortages occur and result in an increase in the use of pharmacotherapeutic agents not typically used for specific treatments, medication-related errors may be more likely to occur, and have been reported. Products from different manufacturers (with different appearances, strengths or concentrations) are purchased to replace drug products that are in short supply. These product differences have led to confusion, including prescribing and administration errors. Examples reported include inappropriate administration of injectable solutions of phenytoin, hydromorphone, or 5% sodium bicarbonate when shortages occurred with fosphenytoin, morphine or 5% dextrose, respectively. Some of these reported errors have resulted in fatal outcomes.

Pharmacotherapeutic agents used in the treatment of oncologic disorders may be especially prone to significant clinical ramifications, as treatment regimen indications and uses are often based upon systematic clinical trials. The AAP has recognized this concern, with publication of recommendations from the Working Group on Chemotherapy Drug in Pediatric Oncology (2014); these recommendations include, among others, giving equal priority to evidence-based uses of drugs whether they occur within or outside of clinical trials.

Similarly, the Infectious Diseases Society of America and the Pediatric Infectious Diseases Society have jointly published recommendations to minimize the clinical impact of drug shortages when treating infectious diseases, including: enhanced application of the term “medically necessary” drug products as defined and applied by the FDA, improved communication among health care professionals and governmental agencies, and consideration for increased importation of some drug products from outside the United States.

Recently implemented federal regulation has lessened the overall impact of drug shortages to some extent. In 2012 the FDA Safety and Innovation Act required pharmaceutical manufacturers to notify the FDA at least 6 months in advance of drug product manufacturing difficulties or discontinuations. While this legislation is helpful, manufacturers may not always be able to identify impending shortages.

Enhanced communication among the FDA and other federal health agencies, pharmaceutical manufacturers, and professional medical organizations also has been helpful. Experts have called for further communication and sharing of relevant information on drug shortage and availability. Drug shortages, however, are likely to continue into the near future. Some health care institutions have published descriptions and recommendations for managing drug shortages, such as institutional recommendations for drug therapy regimens that can replace specific drug shortages. As drug shortages may also pose potential ethical dilemmas (eg, who should receive the limited drug supply?), institutions may additionally benefit from discussions on strategies to manage them.

Disclosure: Bell reports no relevant financial disclosures.