Drug shortages: The invisible epidemic

On Wednesday, September 20, 2017, Hurricane Maria made landfall in Puerto Rico and brought with it flash flooding so severe it eliminated the island’s power grid.¹ Causing devastating loss of life and more than $100 million in property damage, Hurricane Maria also affected the $40 billion pharmaceutical industry, which brought drug manufacturing to the island in the late 1970s for tax breaks and lower wages not available in the mainland U.S.^2,3 In the aftermath of this Federal Emergency Management Agency (FEMA)-declared major disaster, pharmaceutical factories, like other businesses in Puerto Rico, faced severe difficulty obtaining diesel fuel to power their plants.^4,5 With phone lines also down, companies like Boston Scientific ran ads on the radio requesting their employees to report on their status.⁶ Hurricane Maria also had a rippling effect on the mainland, specifically in hospitals where intravenous (IV) saline became in short supply in the months following the storm, affecting the ability of medical personnel to administer fluids and a range of IV medications. Pharmacy shipments of IV fluids from Puerto Rico to mainland hospitals became sporadic and often were delayed by weeks.^2,7

The drug shortages following Hurricane Maria received national attention, but, the fact is, these shortages have been a persistent problem for the last 15 years, with more than 100 vital medications affected annually.⁸ Although new shortages have generally decreased, the number of ongoing drug shortages remains high. Manufacturing problems contribute to nearly a quarter of these shortages; however, more than 50 percent are in short supply for unknown reasons.^9,10 This dilemma affects the quality of patient care and the health care market. Many of the antibiotics and critical care medications that surgeons and intensivists use daily are frequently unavailable due to shortages. A shortage may not necessarily change the treatment plan or outcome for a particular patient, but the consequences of this ongoing epidemic are noticeable in many health care settings.

Impact on patient care

Drug shortages touch patients in two major ways: relegating physicians to order alternative therapies that may be of inferior quality and effectiveness, and thereby increasing the risk of adverse effects and unforeseen complications. At present, data are limited to case reports, case series, and survey data.

In the wake of Hurricane Maria, the shortage of small-volume IV saline bags, particularly 50 mL and 100 mL sizes, has been notable. Inconspicuous at first glance, these bags are vital to the delivery of medications like antibiotics and electrolyte replacements such as potassium chloride.¹¹ Providers have needed to alter usual protocols to work around this shortage, by administering drugs via IV pushes or transitioning to 500 mL and 1000 mL bags. Administering doses via IV push requires staff to provide a slow push for up to five minutes rather than a longer drip. Individual nurses, pharmacists, and other health care professionals need to be educated on how to alter their usual medication delivery practices. An organization of hospital pharmacists—the American Society of Health-System Pharmacists (ASHP)—has taken the initiative to inform staff on recommended steps to follow due to the shortage of small-volume parenteral solutions. Together with efforts contributed by the University of Utah, Salt Lake City, these organizations have created a resource for providers and pharmacies seeking to adapt to this shortage.¹² The IV fluids shortage that occurred after Hurricane Maria also forced the federal government to change the way it regulates these products. For example, the U.S. Food and Drug Administration (FDA) organized importation of supplies from other countries and allowed extending expiration dates to compensate for the shortage.¹¹

Although no official reports of IV bag shortage-related patient complications have been issued, drug shortage-related adverse events have been reported. One recent example was associated with drug substitution. Injectable sodium bicarbonate is a vital and versatile drug used in critical scenarios such as cardiac arrest or in the management of acidosis. It also is used as a base for medication suspension. In one instance, injectable sodium bicarbonate was unavailable, and a pharmacist suspended the common antacid omeprazole using a powdered sodium bicarbonate alternative. Baclofen was mistaken for bicarbonate and resulted in a severe baclofen overdose in an infant, which led to seizures, respiratory distress, and flaccid paralysis.¹³

Sometimes, a drug in short supply is still available, though the dosage form may be limited. One example is when hydralazine was available only as a 10 mg tablet in 2010. This situation posed a significant challenge for patients who take up to 400 mg/day. Patients were forced to count out 40 tablets to get the correct dose. Though the tablet form of hydralazine is now readily available, the injection form that is needed for severe high blood pressure remains on the shortage list.¹⁴

Even before the IV fluid shortage, the drug shortage epidemic has altered the care of surgical patients in the operative and perioperative settings. When propofol availability became limited, methohexital was sometimes substituted, leading to increased postoperative nausea in patients who were undergoing elective operations at outpatient surgery centers.¹⁵ At one institution, a shortage of aminocaproic acid, a drug used to decrease bleeding during cardiac surgery, resulted in providers restricting its use to only the highest risk patients.¹⁶ Formulations of pain medications also are affected by drug shortages, which has led to overdoses of drugs like fentanyl and ketamine.¹⁷ Patient surveys on the topic of drug shortages show that most patients undergoing elective surgery would want to know if a drug they needed was in short supply, and would prefer to delay an operation if it would affect their care.¹⁸

Unfortunately, drugs used in surgical patient care are commonly in short supply, and many of them are used in critical settings. A recent study found that more than half of the listed medications on the shortages list were for acute care drugs, with 70 percent being injection drug products.¹⁹ The FDA and the ASHP both track drug shortages online, with 194 drugs in short supply listed on the ASHP website as of September 14, 2018 (see Table 1).^14,20

At the bedside, physicians often are frustrated by the restricted medication-prescribing ability created by drug shortages. Sharing this burden are hospital pharmacists, infectious disease specialists, and intensivists, who consequently must make complex prescribing decisions with limited information. Maintaining an adequate inventory in the middle of drug shortages is a difficult task, leading some providers and organizations to stock up in anticipation of a shortage, which increases costs and risks wasted inventory.

Table 1. Partial list of drug shortages as of September 2018

Source: American Society of Health System Pharmacists

Forces driving drug shortages

Ensuring quality can sometimes be costly. Drugs commonly used for decades became unavailable as a consequence of the FDA’s 2006 Unapproved Drugs Initiative (UDI). The objective of the UDI was to target older drugs that were in use before FDA approval in an effort to certify that these medications fulfilled present-day standards. Though the goal of the UDI was to promote safety, it unintentionally increased drug prices and shortages. Under this initiative, companies could get approval for common, previously generic drugs and obtain temporary exclusivity. In 2012, Par Pharmaceuticals used existing literature to obtain FDA approval for vasopressin, a drug that had been in use for almost a century. The average wholesale price increased from $4.27 to $138.40 in November 2016, leading some hospitals to limit their stock of vasopressin.²¹ Similarly, 90 percent of the drugs newly approved since the UDI were approved not on the basis of new clinical data, but on existing literature. Following the UDI, drug shortages increased, and the length of shortage also significantly rose to 217 days two years after implementation, from 31 days prior to the UDI.²²

In addition, increased regulations have resulted in the unexpected closure of production facilities. For example in 2012, Sandoz, a Canadian division of Novartis, suspended production of several sterile injectable drugs after an FDA inspection. The FDA raised concerns about drug sterility and purity, which reduced the availability of several generic drugs, many of which had no available alternatives.²³

Furthermore, poor quality control measures and failed inspections have led to mass recalls. Hospira, a leading producer of sterile injectable drugs, was purchased by Pfizer Inc. in September 2015, and its plants have been plagued with quality issues. In particular, the McPherson plant in Kansas received a warning letter from the FDA in February 2017 highlighting several issues, including cardboard contamination of vancomycin and several instances of poor aseptic technique.²⁴

Additionally, raw material supply can pose a complicated problem. Heparin, a drug commonly used in surgical patients, is derived from pig intestine that mainly comes from China. Efforts to reduce production costs led to contamination of the drug and several deaths, culminating in a massive heparin recall in 2008.²⁵

Manufacturing issues are just one cause of drug shortages. The system that hospitals use to purchase drugs also contributes to the shortage problem. Manufacturers research, design, and produce prescription medications under the oversight of many federal regulations in the U.S. and abroad.

However, pharmacies rarely purchase these goods directly from the manufacturer. Pharmacies employ group purchasing organizations (GPOs) to ensure greater negotiating power and leverage in contracts with distributors, also known as wholesalers, who purchase the medications from the manufacturer.

The supply bottleneck often occurs at the wholesaler, regardless of whether the nation is experiencing a drug shortage. One wholesaler may have a back order for a certain medication, while another does not. Wholesalers also may hold drugs in reserve for preferred GPOs, which results in certain pharmacies experiencing a shortage while others do not.

A further wrinkle in the supply chain is the transportation of medications from manufacturers. If a certain medication is only manufactured in one region of the country, then that medication is likely to be in shortest supply at the pharmacy that is farthest from the manufacturer or port of entry (see Table 2 for an overview of the causes of drug shortages).²⁶

Table 2. Causes of drug shortages

Source: U.S. Food and Drug Administration

Current efforts

The FDA established the Drug Shortages Program in an effort to mitigate the effects of these shortages. In 2012, the Food and Drug Administration Safety and Innovation Act (FDASIA) outlined the role of the FDA in overseeing drug shortages. Because of FDASIA, the FDA receives earlier notification about potential production delays, providing the agency with more time to avert a shortage. The FDA prevents 100–200 drug shortages annually. Some measures that the FDA takes to reduce shortages include expediting the inspection process, working with the Drug Enforcement Administration to regulate controlled substances, and improving communication and tracking through the Drug Shortage Data System.²⁰ Additionally, up-to-date information can be provided via a smartphone application and blog to connect with the public.²⁷

The 2014 Drug Shortages Summit in Washington, DC, brought together leaders of professional organizations, manufacturers, hospital associations, and government entities to discuss “efforts to address the quality, regulatory, and economic issues that may underlie drug shortages and also identified new potential solutions that merit further consideration.”²⁸ Similar efforts need to be put in place to identify the causes of drug shortages and prevent them from occurring. The FDA also should weigh the benefits of importing critical medications during times of severe shortages.

Conclusion

Drug shortages pose a significant problem for all patients. Although the IV fluid shortages in U.S. hospitals in the aftermath of Hurricane Maria have brought this epidemic the attention it deserves, drug shortages have been a long-standing problem and are an ongoing issue. Continued efforts and support at the federal level, as well as from manufacturers and GPOs, are needed to prevent shortages of vital medications. Additionally, increasing education and awareness for the prescriber, pharmacist, and nurse may help prevent adverse events related to substitutions.

References

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