Albuterol, bupivacaine, hydrocortisone, and dopamine – these are only four of the approximately 260 drugs that have experienced national shortages over the past 12 months (asamonitor.pub/41eZ3Hx; asamonitor.pub/40TNKVa). These scarcities have led to treatment delays, rationing, and, in some cases, changes to therapeutic plans (asamonitor.pub/3mxTgh5). Substitutes and alternative therapies have led to medication errors and patient harm (asamonitor.pub/3UCjdZy). In addition to these direct patient costs, there is a significant financial loss associated with addressing the ongoing shortages. Nationally, hospitals incurred an additional $229.7 million per year in costs between 2011 and 2013 because of more expensive generic replacements for shortage drugs. This figure does not include indirect costs of off-contract purchases, therapeutic alternatives, or additional labor requirements (asamonitor.pub/43wqhuP). This danger to public health and safety is particularly pertinent for anesthesiologists because the growing list of critical, lifesaving medications in short supply is disproportionate in this field (asamonitor.pub/3zXuAli). The causes for these rolling medication shortages are complex and require a comprehensive approach in order to mitigate the effects on patient care.
Addressing drug shortages has been a top priority for the federal government, policymakers, manufacturers, and other health care stakeholders for over a decade. As such, legislative action was taken in 2012 with the passage of the Food and Drug Administration Safety and Innovation Act (FDASIA). This law requires manufacturers to notify the FDA of interruptions in prescription medication production, provides the FDA with far-reaching tools and authority to try to prevent shortages, and requires the FDA to provide an annual report to Congress on the state of prescription medication shortages. Despite these safety measures, prescription drug shortages continue to persist, with medications remaining scarce for longer periods of time, in some cases for more than eight years (asamonitor.pub/3mxTgh5).
In 2018, a bipartisan group of U.S. senators and representatives requested the FDA to convene an interagency federal task force to analyze the causes for prescription medication shortages and to provide potential solutions. The FDA’s Drug Shortages: Root Causes and Potential Solutions report of 2019 outlines the top reasons why the free market principles of supply and demand have failed to correct the drug availability problem. The report found that current market conditions limit manufacturers’ profitability. As a result, it reduces their willingness to maintain a presence, or enter the market for older, typically generic, prescription drugs. The market is stuck in a “race to the bottom” pricing model. For similar reasons, manufacturers are less likely to invest in practices that can minimize production disruption.
Over the years, there have been significant consolidations in the health care industry to improve efficiency and increase negotiating power with manufacturers. As cited in the FDA report, in 2018 the four largest group purchasing organizations accounted for 90% of the market for medical supplies (JAMA 2018;320:1859-60). Due to this unbalanced dynamic, suppliers in many cases are selling drugs at, or below, the cost of production. At the same time, there is very little incentive for purchasers to account for manufacturers’ reliability and quality management when determining a price point (asamonitor.pub/3mxTgh5; asamonitor.pub/3zXuAli).
On the other hand, expanding or modernizing manufacturing facilities and processes to decrease the chance of supply disruption is a costly and time-consuming investment. This capital expenditure can often exceed $100 million, which is in addition to the already inflated cost of maintaining sterility in injectable medications (A comparison of capital and operating costs for aseptic manufacturing facilities. 2010). The disincentive for mature quality management systems is exacerbated by the fact that purchasers receive very limited information linking the drug product with the facilities where they were produced. With this opacity in place, manufacturers are more likely to keep costs low and minimize investments in manufacturing quality beyond the minimum required by the FDA (asamonitor.pub/3mxTgh5; asamonitor.pub/41a5z2). Furthermore, both multinational manufacturers and large-volume drug buyers bear only a small cost due to a specific medication shortage, whereas patients, health care providers, and third-party payers bear a much larger financial, and clinical, burden (asamonitor.pub/3mxTgh5). Due to relatively low ramifications, high production costs, and competitive pricing of prescription drugs, production of more profitable medications makes more economic sense for suppliers. The median quarterly sales revenue for a generic medication in 2016 was $300,000, whereas brand name medications have revenues in the millions (NBER 2017:w23640). These contributing factors are the reason drugs facing national shortage are typically old, cheap, generic, and injectable (asamonitor.pub/3mxTgh5).
There are logistical problems, often a result of the challenging financial dynamics already discussed, which lead to generic medication scarcities. Over the past two decades, in order to manage cost and improve profits, medication manufacturers have increasingly moved production of generic medications overseas and are relying more on contract regional manufacturers (asamonitor.pub/41vehrw). As of 2019, 73% of active pharmaceutical ingredients (APIs) were produced in foreign countries and regions like China, India, and the European Union (asamonitor.pub/41vehrw; asamonitor.pub/3zXk5i3). Production of finished dosage forms, which is the term for the finalized pharmaceutical product, has moved outside the country for 85% of generic medications (Ann Pharmacother 2022;56:1106-12). With such a complex, fragmented supply chain, ensuring the ongoing production of a product is a logistical challenge at baseline. Making modifications or improvements poses many challenges and can lead to supply disruption due to even the smallest error (asamonitor.pub/3mxTgh5).
Regulations to ensure safety can also serve as a roadblock to a quick recovery from a national shortage. The majority of generic medications only have two manufacturers producing that medicine in the entire world (Am J Health Syst Pharm 2018;75:1742-50). Additionally, most manufacturing facilities are typically working at or above 80% capacity (asamonitor.pub/3mxTgh5). A disruption in production by even one supplier can lead to a drastic international shortage, and there is no inbuilt capacity from the other suppliers to ramp up production substantially (asamonitor.pub/3zXk5i3; asamonitor.pub/3H7NqKH). Even if manufacturers plan to increase production, finding other sources for materials, such as the API, requires approval by the FDA as well as every other country’s regulatory body in which the medication is present. This can mean seeking approval from hundreds of countries. While this is only one example, such regulatory hurdles make the rapid accommodation for interruptions difficult.
There is no simple solution for the fundamental problems facing the pharmaceutical manufacturing industry. As clinicians who deal with most aspects of medical therapy, from therapeutic planning to administration, anesthesiologists are particularly well equipped to partner with pharmacy colleagues to develop and implement strategies, ensuring the least amount of patient harm from medication shortages and therapeutic alternatives. The American Society of Health-System Pharmacists (ASHP) is a leading resource in managing this persistent problem. Per ASHP guidelines, any mitigation plan should include the tenets of the following phases: assessment, analysis, communication, and implementation. As a part of the assessment, the pharmacy must validate the details of the shortage, such as estimated duration, stock on hand, and potential supply of alternative therapies. At the same time, clinicians should identify the patient population affected, any need for patient prioritization of the limited medication, and therapeutic alternatives. This interprofessional team would develop an impact analysis focusing on therapeutic differences between the shortage medication and the alternatives, administrative and logistical changes required, and financial ramifications. Using the information on hand, the interdisciplinary group should formalize a comprehensive action plan and communicate with all affected clinicians on the degree of the shortage, recommended alternatives, and temporary guidelines and procedures. Lastly, the mitigation plan should be implemented, knowing that changes may be required as new information surfaces (Am J Health Syst Pharm 2018;75:1742-50).
Although crisis situations are not ideal for innovation, lack of resources can be an impetus for change. Across the country, due to medication limitations, anesthesiologists have utilized the opportunity to trial novel protocols. For example, in 2017 and 2018 there was a national parenteral opioid shortage. In order to continue providing good care to patients, departments accelerated their use of regional anesthesia and multimodal analgesia (Reg Anesth Pain Med 2018;43:453-5). In many cases, the results were beneficial, and practices have been adopted even after opioids returned to the market. For instance, the ambulatory surgical center for Seattle Children’s Hospital experimented with a dexmedetomidine and ketorolac combination for tonsillectomy and adenoidectomy surgeries during the opioid shortage (Pediatr Anesth 2019;29:682-9). Results were beneficial to the point where the surgical center has been able to eliminate the need for perioperative opioids in its patients (asamonitor.pub/3mAHsuA.
The unending shortage of generic pharmaceutical medications is a byproduct of an imbalanced market without incentives to create supply chains resilient against product disruption. Current legislation has been unable to make a significant impact, as evidenced by the worsening problem. The competitive price points negotiated by purchasers and the inability of manufacturers to factor supply chain reliability into pricing, as well as the high investment costs for production modernization, all contribute to the “race to the bottom” pricing model. With a multinational, complex supply chain providing medications to all parts of the world, there are logistical and regulatory hurdles that make quick changes and flexibility difficult. Effectively navigating this ongoing difficulty requires planning. Clinicians must build an infrastructure and management strategy to deal with the various shortages of different drug classes lasting for different durations. Although not ideal, with effective information gathering, cooperation in assessing alternative therapies, and transparent communication, there is a chance at minimizing the impact on patient care. Clinicians must continue utilizing their ingenuity to advance care, but a long-term solution is necessary and will need to incorporate the requirements of all stakeholders. A rethinking of the pharmaceutical marketplace is sorely needed so that it is both sustainable and keeps patient care at the forefront. Until a solution is discovered, medication shortages will continue, and patient care will suffer.