As the blog’s resident pharmacist I’ve taken on the topic of drug shortages a few times over the past several years, an issue that may sometimes be invisible to patients but something that most pharmacists grapple with every day of their working lives. Prescription drugs routinely go into shortage situations, and all evidence suggests that the problem has been worsening, not improving, over the past several years. Even before the COVID-19 pandemic emerged, the FDA listed hundreds of drugs currently in shortage, a situation also observed in countries like Canada and also the United Kingdom. Many countries maintain standing lists of drugs that are in short supply. In general, most of these shortages have traditionally been generic drugs, not brand-name products. All health systems rely heavily on lower-priced generics to help offset the cost of new, patented, high-cost drugs. There are substantial barriers for manufacturers to enter the generic drug manufacturing market, and there is significant competition that drives prices down low. The result has been the gradual outsourcing and consolidation of manufacturing, with supply chains that may stretch across continents. There are far fewer shortages of brand name drugs but they can occur when manufacturers experience problems with manufacturing or changes in demand.
I first blogged about drug shortages back in 2011 and the post could have been written yesterday, with perhaps even more urgency, as the problems seems to be getting worse, not better, despite efforts to reduce them. In 2018, FDA Commissioner Scott Gottlieb established the Agency Drug Shortages Task Force to determine the root causes of drug shortages, and propose recommendations to address them. And that was pre-COVID. While access to personal protective equipment, intensive care units and ventilators have grabbed headlines, there is increasing concern about access to prescription drugs – not just to treat COVID patients, but longer-term effects on access to many prescription drugs.
Initial worries
The first concerns about COVID-related drug shortages emerged shortly after Wuhan, China was locked down in early January. As China is a major supplier of active pharmaceutical ingredients (APIs) to the rest of the world, there were concerns that the lockdown would threaten shipments of APIs out of Wuhan to the rest of the world, disrupting the manufacture of drugs worldwide. The table below (from the FDA’s Task Force on shortages) shows the distribution of manufacturing of APIs and finished products (e.g., tablets/capsules/vials) in 2019: largely done outside North America. Just 12% of APIs used in American drugs were manufactured in the USA, and only 37% of finished products were actually manufactured domestically:
As you can see, 14% of APIs come to the US from China and, the first COVID-related drug shortage was reported by the FDA on February 27. The drug and manufacturer were not named. At that time, the FDA noted:
Also, as part of our efforts, the FDA has identified about 20 other drugs, which solely source their active pharmaceutical ingredients or finished drug products from China. We have been in contact with those firms to assess whether they face any drug shortage risks due to the outbreak. None of these firms have reported any shortage to date. Also, these drugs are considered non-critical drugs.
The second wave of shortages
This attention to APIs coming out of China was the focus of regulators and the broader health care market for several weeks. In mid-February, the scrutiny remained on China. Even as late as mid-March, European regulators seemingly were focusing on supply chains and travel restrictions. It was only after the COVID started to spread outside China, and case numbers exploded in Europe did broader recognition start of what I’ll call the second wave of drug shortages – the treatments essential to keep patients intubated, ventilated, and alive in intensive care units. By late March and early April, it was apparent that existing supplies of these medications were insufficient to treat the thousands of new patients that required hospitalization. On April 6, the European Union noted:
Some EU Member States have indicated that they are starting to see shortages of certain medicines used for patients with COVID-19 or are expecting such shortages to occur very soon. These include medicines used in intensive care units such as certain anaesthetics, antibiotics and muscle relaxants as well as medicines used off-label for COVID-19. EU authorities are therefore putting in place additional measures to mitigate the impact of the pandemic on the supply chain of medicines in a coordinated manner.
It’s worth reiterating that drug “shortage” is just an imbalance between supply and demand. These can be local, regional, national, and international. While primary concerns were about supplies of drugs, from China, treating COVID patients was causing shortages through surges of demand. And as the pandemic has taken hold in United States, the same surges in demand occurred. By late March, demand was surging and outstripping supply:
Demand for drugs given to patients on ventilators is outstripping supply, according to Vizient Inc., a pharmaceutical-purchasing group that works with more than half of U.S. hospitals and health systems. Hospital orders for sedatives, analgesics and neuromuscular blockers increased 58% overall in March compared with January, Vizient said. Those medicines are used to prevent movement, manage pain and soothe patients who can’t breathe without the assistance of a machine.
On April 2, The New York Times reported:
Across the country, as hospitals confront a harrowing surge in coronavirus cases, they are also beginning to report shortages of critical medications — especially those desperately needed to ease the disease’s assault on patients’ respiratory systems.
The most commonly reported shortages include drugs that are used to keep patients’ airways open, antibiotics, antivirals and sedatives. They are all part of a standard cocktail of medications that help patients on mechanical ventilators, control secondary lung infections, reduce fevers, manage pain and resuscitate those who go into cardiac arrest.
Demand for these drugs significantly increased in March as the pandemic took hold in the United States. Orders for antibiotics like azithromycin and antiviral medicines like ribavirin nearly tripled. Medicines used for sedation and pain management, including fentanyl, midazolam and propofol, increased by 100 percent, 70 percent and 60 percent respectively.
Demand for albuterol, a common asthma inhaler medication, has also risen significantly, given its importance in easing the breathing of patients with severe infection.
While not all of these drugs are currently in a shortage situation, their rising use are raising concerns that shortages are far more likely. This is being observed across North America. From a Canadian hospital:
Even though ICUs have yet to be overrun with a feared surge of coronavirus cases, the drugs are being administered at a far higher rate than usual, say doctors and pharmacists. “Some hospitals have reported they’re essentially using a 30-day supply of certain medications in just one day,” said Dr. Michael Warner, ICU head at Toronto’s Michael Garron Hospital. “Overall, our consumption of these drugs could increase by an order of magnitude.”
Importantly, none of these drugs can be easily manufactured. Most of them are sterile injectable drugs, which are more difficult and complex to manufacture, compared to oral products like liquids, tablets, and capsules. In the case of brand-name drugs, there may be only a small number of manufacturing sites worldwide. It’s not known if supplies and reserves exist for these drugs, or how quickly manufacturers can ramp up manufacturing to cope with worldwide surges in demand. Wholesalers in the U.S. reported difficulties meeting orders, particularly in New York, at the end of March:
Using its comprehensive data on purchasing patterns and current fill rates, Premier found that these products experienced the greatest spikes in demand during the month of March but were also unable to be supplied in the requested quantities – two early warning signals for shortages. Drugs include antimalarials and antivirals that may be an effective COVID-19 treatment, as well as antibiotics used to cure infections. Other products at risk of shortages include bronchodilators for keeping airways open, as well as sedatives and neuromuscular blockers used to intubate patients. Demand for these products was even higher in COVID-19 hotspots like New York, suggesting that products could move from regional shortages into national shortages as the disease spreads to additional communities.
Drugs have now moved into true shortage situations.
In the past few days (April 13), the FDA has continued to report new shortages of drugs for patients that require ventilation and intensive care:
Increasing demand for sedatives used to help put COVID-19 patients onto ventilators means the US Food and Drug Administration (FDA) added two more – this time the injectables propofol and dexmedetomidine – to its list of drug shortages.
The propofol shortage was also previously listed by the American Society for Health-System Pharmacists (ASHP) earlier this month, with manufacturers noting increased demand. Michael Ganio, senior director of pharmacy practice and quality at ASHP, previously told Focus via email: “We have multiple reports of increases in purchases and utilization of sedatives like midazolam, fentanyl, and propofol to treat COVID-19 patients who require mechanical ventilation.”
And:
A Pfizer spokesperson told Focus via email: “As of today, Pfizer’s manufacturing and distribution network continues to operate at high performance with no operational disruptions due to COVID-19. Historically, Pfizer has had a market share of approximately 15% for Propofol. We recently have observed an unprecedented surge in demand for Propofol beyond Pfizer’s historical demand which is limiting our ability to fully satisfy customer orders in the short-term. We are making every effort to advance the ordering of additional materials, increase our production, reduce lead times and expedite orders to customers, especially those in high-impact areas.”
As we see the pandemic spread across countries and around the world, time will tell if we have “flattened the curve” enough for manufacturing and supplies to match the needs of hospitalized patients who needs these drugs to stay alive.
Treating COVID: The third wave of shortages
I don’t want to spend time in this post talking about possible COVID treatments, as the data are evolving quickly. Earlier this week David Gorski discussed the weak evidence to support the use of hydroxychloroquine and azithromycin to treat COVID-19. While current treatment guidelines (as of April 14) do not recommend the use of either product outside of a clinical trial, the hype around these products has caused surges in demand that have led to concerns of shortages for non-COVID patients that rely on these medications to treat their illness. From April 10, in The Journal of the American Medical Association:
Hydroxychloroquine is recommended for all patients with lupus, especially those with no contraindication such as pregnancy. It relieves constitutional, musculoskeletal, and mucocutaneous manifestations and decreases thrombotic events, organ damage, and mortality. Hydroxychloroquine helps maintain disease remission and prevent flares. Among patients with lupus that is not organ threatening, 80% achieve remission with hydroxychloroquine and may sustain it with this therapy for long periods.2
Although there is no rigorous scientific evidence supporting the use of hydroxychloroquine in COVID-19 as of early April 2020, consumers are stockpiling the drug not only for treatment but also prophylaxis prompted by media reports of possible efficacy. A rationale for hydroxychloroquine use in COVID-19 is based on in vitro studies showing that chloroquine inhibits virus replication.3 Because hydroxychloroquine and chloroquine may have in vivo antiviral and anti-inflammatory effects, they offer a potential means to mitigate COVID-19.
A recent small (n = 36), open-label nonrandomized trial in France suggested that therapy with hydroxychloroquine and azithromycin decreased viral load and replication,4 garnering significant media attention. However, randomized clinical trials are required to assess the efficacy and safety of hydroxychloroquine as prophylaxis or treatment for COVID-19. The FDA has authorized its use for treatment of patients hospitalized with COVID-19 but not for prophylaxis. President Trump has touted hydroxychloroquine therapy, despite very limited evidence of efficacy.5,6
Since being prominently featured in the press and on social media as a potential COVID-19 therapy, demand for hydroxychloroquine has exploded and a shortage has ensued. Some physicians are prescribing it for prophylaxis as well as outpatient treatment of COVID-19, often along with azithromycin. Some health care workers are taking it as prophylaxis without any evidence to support this use.
Azithromycin is a common treatment used for adult and pediatric infections, including pneumonia. A shortage of azithromycin may mean selecting inferior products or challenges in treating these infections. Given these are both oral drugs, it’s hoped that shortages will be short-lived without causing harm to patients that need them.
Hydroxychloroquine and azithromycin are the most well-known products that are being used to treat COVID-19. There are a number of products being utilized and/or investigated in clinical trials, with new drugs likely to be added over the coming weeks and months. From the British Columbia Centre for Disease Control is a list of “unproven” products as of April 12:
- lopinavir/ritonavir (Kaletra®)
- remdesivir
- oseltamivir
- ribavirin and interferon
- colchicine
- tocilizumab/sarilumab
- corticosteroids
- antibiotics
As “old” drugs are repurposed and investigated, it is possible that we will see unpredictable surges in demand for products, raising the risk of additional shortages, with effects beyond COVID. Like patients with lupus are already experiencing, a drug can move from stable into shortage in a matter of a few weeks, and manufacturing supply chains may struggle to adapt. What we have now in the USA and other countries is a growing list of drug shortages – the number of drugs that are short in the USA due to COVID now numbers 23 at my last count.
A fourth wave of shortages?
I’ve described these shortages as waves and I’m not sure if that’s the right analogy, as the different drivers of shortages are going to have overlapping effects for some time. The fourth category or wave of shortage that I want to discuss is the manifestation and exacerbation of what we have been experiencing for years, in a new world where supply chains may be more tentative. As I have noted in past posts, problems in manufacturing and distribution of prescription drugs can emerge throughout the supply chain. In some cases, it is regulatory agencies like the FDA that identify quality or safety issues, interrupting production. In other cases it may be difficult to obtain or process raw materials that meet FDA quality standards. When these problems emerge, manufacturers may decide that supporting production for low-profit or low-volume products doesn’t make economic sense, leading to discontinuation, and yes, more shortages. While this is outside my area of expertise, I am skeptical that shifting manufacturing of APIs from China or India is something that can occur quickly, or can be done without additional supply chain interruptions. My sense is that manufacturing hundreds of different drug products to high standards may be more difficult that manufacturing PPE. It is unlikely that manufacturers who may derive little profit from these products will be willing (or able) to do this. Consequently, massive changes cannot (or will not) occur without significant intervention and direction from governments and regulators. Price hikes for low cost generics may be inevitable, as more countries insist on domestic manufacturing. Whether or not this shift in manufacturing can (or should) occur is something that we will observe over the coming months and years as we find out what the new normal looks like.
The COVID-19 pandemic has exacerbated and made apparent the long-standing challenges with pharmaceutical drug manufacturing and supply. It’s possible this could lead to the changes that are essential to address long-standing problems that have become worse over the past decade. The supply chain has been brittle and vastly too opaque for years. Some countries, like New Zealand, mandate a level of manufacturing transparency that is unavailable in other countries. Group purchasing organizations, wholesalers, manufacturers, regulators, health systems, and insurers need to find new ways to collaborate and share information in order to fix these fragile supply chains and to reduce the impact of shortages on patients. More transparency will help. Leadership is essential. I’ve noted before that no single organization “owns” drug shortages. Health systems need to act now, decisively, to fix these problems.
Photos from the US Navy and Marco Verch used under a CC Licence.