The Drug Isn't Available, So What Now?

Health-System Edition, January 2020, Volume 9, Issue 1

Ramifications of shortages can be severe, but the FDA and ASHP have suggested solutions.

The United States currently faces about 200 drug shortages.

A drug shortage—a supply issue that affects how a pharmacy prepares or dispenses a medication—has an impact on patient care when clinicians must use alternative agents, according to the American Society of Health-System Pharmacists (ASHP).1

The crisis pervades all health care aspects and specialties. Although drug shortages historically involved mostly chemotherapeutic agents, the crisis has expanded to areas such as anesthesiology, critical care medicine, infectious disease, neurology, and nutrition.2

In October 2019, the FDA issued a report, “Drug Shortages: Root Causes and Potential Solutions,” to identify the etiologies of shortages and provide recommendations to address them long term.3 The crisis is multifactorial and complex in nature but attributable to the lack of incentives to produce medications that are less profitable, the lack of a system to reward manufacturers that make high quality products, and regulatory challenges that hinder recovery and growth.

Most drug shortages affect generic injectable formulations because of their minimal profit margin to make such basic medications.1,4 Of note, 90% of a given drug’s total supply comes from just 1 manufacturer, and 3 manufacturers supply 71% of the market.5,6 If 1 facility runs out of raw materials or has problems with its production line or the quality of products, that single company’s issues will drastically affect the entire supply chain.

Because of the complexity of manufacturing and the high cost of production, seldom are there new suppliers to replenish the necessary drugs in a reasonable amount of time. For example, one of the longest and worst drug shortages involves intravenous fluids (IVFs), such as normal saline 0.9% and dextrose 5%.7 IVFs are used for hydration therapy in all areas of hospitals and in the most basic form of drug reconstitution and preparation by pharmacy technicians. In a given month, a community hospital may need 20,000 bags of normal saline for its daily operation.

Impact of a Natural Disaster

Consider the September 2017 case of Hurricane Maria’s devastation of Puerto Rico, where the majority of the US drug facilities were located. With the bulk of the supply chain wiped out by an unforeseeable natural disaster, drug shortages worsened because existing facilities could not increase production to meet the demands. Hurricane Maria highlighted the need for “contingency plans and enhanced redundancies in production and distribution” recommended by ASHP in its drug shortage roundtable held in November 2017. 8

Quality issues were also identified as a root cause of the drug shortage crisis. The FDA issues Form 483 to facilities at which problems are uncovered during site visits. Some of these problems include adulterated ingredients, microbial contamination of raw materials, and particulates in final products. Because the margins for error are slim, some manufacturers claim that they cannot afford to invest more resources to meet quality standards, remodel old buildings, and replace outdated machinery.

Similar quality issues have been found in facilities located in other countries that export medications to the United States. In February 2014, a New York Times article highlighted the safety of medications made in manufacturing plants in India. The country is the second-largest exporter of medications to the United States, and its facilities have been implicated in falsifying data and selling counterfeit medications, among numerous other quality-related problems.9

Another root cause of drug shortages involves “logistical and regulatory challenges” that make it difficult for the market to recover after a disruption, according to the FDA analysis of the crisis. It described the supply chain as becoming “more complex and fragmented,” stating that even the seemingly simple task of increasing production may need approval from numerous regulatory agencies.

Consequently, at the end of the round-table with health care professional organizations and policy makers, ASHP urged greater transparency regarding the causes of shortages and their expected durations, as reported by the manufacturers. The ASHP report also recommended legislation that would establish incentives to encourage manufacturers to produce drugs in shortage, rewarding those that develop contingency plans to maintain a supply in the event of a manufacturing disruption.

One such drug manufacturer, Civica Rx, aims for transparency in its contracts, location, operation, pricing, and production practices. As stated on its website, the company’s goal is to “be a model generic drug company by providing high-quality FDA approved products at affordable prices” to “ensure that essential generic drugs are available and affordable

to everyone.”10

Effect on Day-to-Day Operations

As a clinical pharmacist specializing in pediatric emergency medicine, I am affected by drug shortages on a daily basis. Besides managing my regular duties of attending codes, educating the health care team and patients, optimizing medication regimens, providing therapeutic recommendations, and working with a multidisciplinary team in the emergency department (ED), I also have to respond to drug shortages, which have become the norm of hospital pharmacy operations. Because this task involves discussion with multiple key drivers, including management, nurses, patients and their family members, pharmacy buyers, and prescribers, the process is cumbersome and time-consuming, diverting valuable attention and time from meaningful patient care activities.

Furthermore, dealing with a drug shortage may delay treatment and increase medication errors, because the staff is unfamiliar with alternative products that have different concentrations, labeling, and packaging. Medication errors can happen in the process of prescribing, verification, compounding, dispensing, and administration. Uncertainty about and unfamiliarity with new products may affect medication safety and, ultimately, patient care. In the worst-case scenario, these alternatives may be less effective or more costly; lead to disease progression, relapse, or treatment failure; or produce more toxic adverse drug reactions.

Mazer-Amirshahi et al looked at the effect of these drug shortages specifically in the ED setting.11 The article noted common ED classes of medications in critical shortage, such as analgesics, antiemetics, antimicrobials, benzodiazepines, and electrolyte solutions. Two examples that may pose a threat to public health are influenza and oseltamivir shortages. The authors discussed several cases of compounding errors and compromised sterility, as well as increased costs and resource use.

Pediatric patients are particularly vulnerable. For example, the zinc shortage resulted in more dermatitis cases at Children’s National Hospital, and the shortage of cefotaxime to treat neonatal fever/sepsis led to greater use of aminoglycosides, which carry the risks of nephrotoxicity and ototoxicity, as well as additional laboratory draws and increased cost, labor, and pain to monitor the drug’s pharmacokinetics.12 Moreover, because of the lack of available dosage forms, pediatric patients need individualized dosing that requires calculations and extemporaneous compounding. The drug shortage crisis poses an even higher risk of medication errors and adverse events for these patients because there are more challenges with delivery systems and administration.

Because market forces do drive production as it pertains to drug shortages, the ASHP roundtable report encouraged the Federal Trade Commission to scrutinize mergers and their impact on drug production and shortages as they ultimately affect patient care. For example, when Pfizer acquired Hospira, the merger spawned questions about future production and continuation of certain products. Specifically, Hospira was 1 of the few manufacturers left to produce lifesaving medications, such as epinephrine, sodium bicarbonate, and dextrose 50% vials and carpujects, critical medications used in resuscitation efforts and other medical emergencies. Any delay in receiving these agents because of drug shortages and time to gather therapeutic alternatives can lead to a delay in correcting life-threatening electrolyte imbalances, reversing multiorgan damage and cardiac perfusion.

Finally, consider this: If we can pass legislation to ban something as simple as plastic straws in restaurants and plastic bags in grocery stores to reduce plastic use, can’t we resolve shortages of lifesaving medications for our sickest, most vulnerable patients?

I would like to thank Victoria Adams Serrano, PharmD, FASHP, for her guidance and help with this article.

REFERENCES

  • ASHP Expert Panel on Drug Product Shortages, Fox ER, Birt A, et al. ASHP guidelines on managing drug product shortages in hospitals and health systems. Am J Health Syst Pharm. 2009;66(15):1399-1406. doi: 10.2146/ajhp090026.
  • Drug shortages continue to compromise patient care. Institute for Safe Medication Practices website. ismp.org/resources/drug-shortages-continue-compromise-patient-care. Published January 11, 2018. Accessed November 1, 2019.
  • Report | drug shortages: root causes and potential solutions. FDA website. www.fda.gov/drugs/drug-shortages/report-drug-shortages-root-causes-andpotential-solutions. Updated October 29, 2019. Accessed November 10, 2019.
  • Ventola CL. The drug shortage crisis in the United States: causes, impact, and management strategies. P T. 2011;36(11):740-757.
  • Agency Drug Shortages Task Force. FDA website. www.fda.gov/drugs/drug-shortages/agency-drug-shortages-task-force. Updated October 30, 2019. Accessed January 1, 2020.
  • Fox ER, Sweet BV, Jensen V. Drug shortages: a complex health care crisis. Mayo Clin Proc. 2014;89(3):361-373. doi: 10.1016/j.mayocp.2013.11.014.
  • Drug shortages roundtable: minimizing the impact on patient care. Am J Health Syst Pharm. 2018;75(11):816-820. doi: 10.2146/ajhp180048.
  • ASHP drug shortages roundtable report. American Society of Health-System Pharmacists website. ashp.org/Drug-Shortages/Shortage-Resources/Roundtable-Report. Accessed January 2, 2020.
  • Harris G. Medicines made in India set off safety worries. The New York Times. February 14, 2014. nytimes.com/2014/02/15/world/asia/medicines-made-in-indiaset-off-safety-worries.html. Accessed January 1, 2020.
  • Civica Rx. civicarx.org/. Accessed November 10, 2019.
  • Mazer-Amirshahi M, Pourmand A, Singer S, Pines JM, van den Anker J. Critical drug shortages: implications for emergency medicine. Acad Emerg Med. 2014;21:704-711. doi: 10.1111/acem.12389.
  • Ruktanonchai D, Lowe M, Norton SA, et al; Centers for Disease Control and Prevention (CDC). Zinc deficiency-associated dermatitis in infants during a nationwide shortage of injectable zinc [erratum in MMWR Morb Mortal Wkly Rep. 2014;63(4):82]. MMWR Morb Mortal Wkly Rep. 2014;63(2):35-37.