National drug shortages worsen during COVID-19 crisis: Proposal for a comprehensive model to monitor and address critical drug shortages

The Food and Drug Administration (FDA) defines a drug shortage as an interruption in the total supply of all clinically interchangeable FDA-regulated medications where the supply is inadequate or expected to be insufficient to meet projected demand.1 The most common reasons for drug shortages include shifting of a company’s resources from manufacturing to research, shortage of raw materials, voluntary recalls, natural disasters, and supply issues resulting from demand exceeding production capacity.2 Despite the United States’ position as a global leader in pharmaceutical research and innovation, only 28% of manufacturing facilities making active pharmaceutical ingredients (APIs) to supply the US market were domestically based, with the remainder being based in China (13%), India (18%), and other countries.3 The strain on pharmaceutical manufacturing can be amplified in times of crisis, as rapid changes to either the supply of needed resources (labor and raw materials) or demand for pharmaceuticals may occur. The lack of a robust domestic manufacturing infrastructure in the United States has resulted in frequent drug shortages of essential medical items and medications during crises. For example Hurricane Maria affected Puerto Rico’s pharmaceutical manufacturing infrastructure and drastically impacted the supply of intravenous saline bags and parenteral amino acid preparations in 2017.4 In August 2018, China reported its first case of the African swine fever virus, which resulted in the culling of nearly 50% of pigs used in the production of heparin.5,6 The FDA Drug Shortages Task Force has identified lower-priced drugs and sterile injectables as being potential targets of drug shortages.7 Recommendations for addressing shortages have included taking steps to increase the understanding of reasons for shortages and contracting practices; developing a system for measuring and rating quality management of pharmaceuticals; and considering new contracting approaches to help ensure reliable supplies.7 Additional FDA recommendations to prevent or mitigate the impact of future drug shortages include extending expiration dates on certain products, expanding review of new drug applications, promoting generic manufacturing, and creating critical drug lists.8 FDA has also recommended action steps that other agencies could take to address drug shortages and quality issues, including providing manufacturing incentives; using FDA-provided data on manufacturing quality when making purchasing decisions; developing redundancy, capability, and capacity in manufacturing; and minimizing the import and sale of goods by unauthorized sources.9 However, despite these recommendations and actions, the first 3 to 4 months of the coronavirus disease 2019 (COVID-19) pandemic resulted in a greater number of shortages in US domestic medications supply than occurred in the previous 2 years. This brief report highlights drug shortages due to the COVID-19 crisis as of April 14, 2020, and provides recommendations for reducing future drug shortages in response to future threats. The COVID-19 pandemic has uncovered many issues with the drug supply chain in the United States. As the pandemic has progressed, air and ground traffic have been reduced, exports limited, and factories forced to close. In response to the growing risk of public health crises resulting from the COVID-19 outbreak, many countries around the world have attempted to secure adequate supplies of essential medications by limiting exports. India has restricted exportation of many of its API that are essential in making medications like metronidazole, clindamycin, and hydroxychloroquine.10 Finland subsequently restricted exports of hydroxychoroquine API.11 The European Union Commission has responded to member states holding exports of essential medicines and creating national stockpiles by asking all members to lift export bans.12 Also, the commission requested that member states increase drug manufacturing and monitor medication supply and demands.13 To ease the expected supply-side shortages, many API manufacturers have ramped up production. For example, Sanofi, who produces two-thirds of World Health Organization (WHO)–designated essential medicines, pledged that its manufacturing plants would operate 7 days a week to attempt to keep pace with increased demand.14 Also, in February 2020 Sanofi announced that it was moving its API manufacturing to Europe, by consolidating 6 manufacturing sites into a single spinoff company, with the goal of shortening the supply chain and enhancing the ability to increase production when needed.15 Because of COVID-19 infections and hospitalizations, demand for a number of medications has increased. Both FDA and the American Society for Health-System Pharmacists (ASHP) have reported that many antibiotics and antiviral medications are currently in short supply. Antibiotics such as vancomycin, cefazolin, and gentamicin and many other intravenous drugs are being used in patients who experience post-COVID-19 pneumonia.16 China supplies 80% of all antibiotics to the US market.17 Despite claims that manufacturing plants in China have been operating normally, the United States has experienced a significant shortage of several of these essential medicines.18 Albuterol (salbutamol) metered dose inhalers are being used to treat hospitalized patients with respiratory problems.19 Although albuterol is manufactured in several countries, including the United States, China, Spain, Mexico, India, and the United Kingdom, the unexpected increased demand has led to shortages.20 Hydroxychloroquine and chloroquine, antimalaria drugs that are also used for lupus and rheumatoid arthritis, showed potentially promising results in treating COVID-19 symptoms in early trials. Despite the lack of high-quality, controlled clinical trials assessing the efficacy of these treatments, WHO identified hydroxychloroquine and chloroquine as promising treatment modalities. FDA approved them for emergency use on March 28, 2020.21 Promotion of these drugs as potential cures subsequently led to individuals stockpiling these medications, to the detriment of those who depend on the drugs for management of chronic immunological conditions. Adding to the stress on medication supplies, the Indian government blocked the export of hydroxychloroquine and its formulations on April 4, 2020.22 In March 2020, the French health minister announced that ibuprofen may worsen outcomes in patients with COVID-19.23 The resulting increased demand for acetaminophen, coupled with restricted exportation from India, left US pharmacies experiencing intermittent acetaminophen shortages.24 Furthermore, ASHP reported shortages of metronidazole and clindamycin within weeks of India’s export restrictions.16 Even though limitations on these medications were removed by the Indian government on April 6, 2020, these drugs remained on the ASHP shortage list through April 14, 2020.16,25 This correlation between restricted exports from other countries and shortages in the United States illustrates how foreign manufacturing of pharmaceuticals and related policies can rapidly affect domestic supplies. As the pandemic progressed, increased demand and supply chain disruptions resulted in shortages of crucial sedative, anesthetic, and analgesic medications commonly used in mechanical ventilation for COVID-19 pulmonary complications. Examples of critical medications in shortage were dexmedetomidine, etomidate, fentanyl, hydromorphone, ketamine, lorazepam, midazolam, morphine, and propofol.1,16 In March 2020, there was a 51% increase in demand for sedatives and anesthetics and a 67% increase in analgesic medication demand.26 Compounding the problem of increased demand, supply chains have also been impacted by manufacturing issues and shipping delays.27,28 WHO maintains a list of medications considered essential medicines that satisfy the priority healthcare needs of the global population.28 These medications are those that WHO suggests should be in adequate quantities within a functioning health system at all times. Both FDA and ASHP maintain lists of medications in short supply. Between March 2018 and December 2019 (a 22-month period), ASHP reported 200 new drug shortages, whereas between January 2020 and mid-April 2020 (a 3.5-month period), 199 new drug shortages were reported. Among those medications on the ASHP drug shortage list, the 199 new drug shortages reported represented 175 unique drugs. Of these 175 drugs, 46.3% were on the WHO essential medicines list.29 As a result of these shortages, clinicians may be forced to use suboptimal or more expensive medicines to treat common and/or serious conditions. A number of new proposals, rules, laws, and recommendations have been announced by US government agencies to address drug shortages, including some measures to address shortages due to the COVID-19 pandemic. As of April 7, 2020, FDA had approved an abbreviated new drug application for hydroxychloroquine sulfate, an action that supports increased production of hydroxychloroquine and chloroquine in response to supply chain disruptions and increased demands.30,31 FDA also granted hydroxychloroquine and chloroquine emergency use authorization, restricting access to specific FDA-approved indications and COVID-19 treatment.32 Furthermore, hydroxychloroquine has been listed as a national emergency stockpile medication, leading Sandoz and Bayer Pharmaceuticals to donate supplies of these medications to a national stockpile. Also on April 7, 2020, the Drug Enforcement Administration (DEA) allowed 2020 aggregate production quotas to be increased by 15%.33 These quotas affect production of controlled substances in high demand during the COVID-19 pandemic and intermediates used in their production, such as hydromorphone, ephedrine, and fentanyl. Also, DEA approved increased imports of medications used to support mechanical ventilation, including ketamine and midazolam, and issued temporary exceptions to its regulations limiting manufacturer inventories of Schedule II controlled substances. On April 16, 2020, FDA released a temporary policy allowing the compounding of 13 injectable drugs for hospitalized patients, including medications used for pain and sedation and maintaining blood pressure, as well as an antibiotic to mitigate drug shortages caused by supply chain disruptions.34 Sterile compounding outsourcing facilities must be registered with FDA under section 503B of the Food, Drug, and Cosmetic (FD&C) Act. The policy relaxes manufacturing rules and expands the list of medications and facilities permitted to manufacture these medications. On March 27, 2020, FDA published an update regarding permanent discontinuance or interruptions in manufacturing under section 506C of the FD&C Act. The guideline addresses the importance of early notifications in drug supply disruptions that can negatively affect the US market in the face of a global pandemic. The document outlines when parties are responsible for sending notification to FDA, what should be included in the notification, and the consequences of failing to notify FDA about any supply disruptions. These regulations allow FDA to effectively overlook the US drug market, respond to increased demands for certain drugs, identify possible supply chain disruptions, and cooperate with manufacturers within and outside the United States to maintain adequate supply.31 The Affordable Drug Manufacturing Act of 2020 (S 3162),35 proposed in the US Senate on January 8, 2020, included establishing an Office of Drug Manufacturing within the Department of Health & Human Services (HHS), with the purpose of identifying and regulating the rising cost of medications. Through oversight of drug manufacturing and supply, this office would be tasked with identifying and acquiring manufacturing rights for drugs whose APIs were not readily available from existing suppliers, when manufacturing specific APIs would improve other entities’ ability to manufacture a generic medication, or manufacturing the ingredient were necessary for the office to fulfill its duties. This office would also have the ability to prioritize manufacturing of drugs with the greatest impact on increasing competition, lowering drug prices, addressing drug shortages, and reducing prescription costs to federal and state health programs. Within the first year of this bill’s enactment, the new office would begin the public manufacturing of insulin, naloxone, and at least 3 specific antibiotics. Passage of this bill and creation of a new Office of Drug Manufacturing could reduce the costs of specific API, thereby potentially lowering costs for manufacturers and potentially improving competition and lowering prices for insurers and consumers. While funding would be required for this office at the taxpayers’ expense, it is likely that the benefits to taxpayers of establishing the office would outweigh the costs, provided some of the reduced prices were passed on to consumers. The Securing America’s Medicine Act of 2020 (S 3432),36 introduced in the Senate on March 10, 2020, proposed federal support for the development of advanced pharmaceutical manufacturing technologies and the establishment of a program to develop National Centers of Excellence in Advanced Pharmaceutical Manufacturing. Through the proposed Advanced Manufacturing Technologies Program, FDA would be allowed to support new drug manufacturing technologies that prevent or resolve a drug shortage, maintain an adequate supply of critical medications for national emergencies, and promote innovation in drug product design and manufacturing. If the legislation were passed, FDA would be tasked with expediting the development and implementation of the manufacturing technology. Institutions with the National Centers of Excellence in Advanced Pharmaceutical Manufacturing designation would help to develop and research advanced pharmaceutical manufacturing, train a workforce specialized in drug manufacturing, and support federal agencies in creating a secure national pharmaceutical stockpile that could rapidly address drug shortages. Proposed appropriations for this act were $100 million over a 5-year period. The Commission on America’s Medical Security Act (S 3478),37 introduced in the Senate on March 12, 2020, mandated a report that assesses, evaluates, and addresses the United States’ dependence on critical drugs and devices that are sourced from international suppliers. This report, to be produced in collaboration with the National Academies of Sciences, Engineering, and Medicine, would evaluate the supply chain of critical drugs and devices, determine potential public health or national security risks associated with overreliance on imports, review the potential economic impact of increased domestic manufacturing, and address any supply vulnerabilities through supply chain redundancy and improved domestic manufacturing. The results of this report would address medical supply chain vulnerabilities or potential disruptions. On May 19, 2020, in an initiative aimed at reducing US dependence on foreign manufacturing, it was announced that HHS, through an executive order from President Trump, had awarded a contract to a new US company to manufacture API and drugs for COVID-19 treatment.38 Under the $354 million (up to a maximum of $812 million) contract, privately held Phlow Corp, in collaboration with Civica Rx, Virginia Commonwealth University, and Ampac Fine Chemicals, would make more than a dozen generic drugs and their ingredients, including medicines for pain management, sedatives for ventilator support, medicines for maintaining blood pressure, and antibiotics.38,39 Collectively, these bills and executive orders how drug shortages and on foreign drug manufacturing have the of the federal the proposed bills a response to the chronic issues of drug shortages to and during the COVID-19 pandemic. While and for the establishment of a new Office of Drug Manufacturing and National Centers of Excellence to identify and address many of the issues resulting from the foreign manufacture of drugs, the bills to have a for for and for to with as of the of these to or some should there a critical for a more to addressing drug shortages. 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