As the demand increases for ventilators to treat Americans with severe symptoms of COVID-19, another shortage is being exacerbated – a shortage of the drugs needed to treat patients on ventilators.

Pharmacists in New York are already out of some drugs used to keep patient airways open, manage pain and control secondary infections in patients on ventilators, according to the American Society of Health-System Pharmacists (ASHP). “Even if hospitals had all of the ventilators needed to keep patients alive, this critical shortage of medications could make it impossible to maintain COVID-19 patients on those ventilators,” ASHP CEO Paul Abramowitz said.

Wayne Russell, vice president of pharmacy at Premier Inc, agreed. “Many hospitals in New York are in dire need of drugs required to intubate patients, such as neuromuscular blockers and sedatives,” he told BioWorld.

The demand for such drugs, many of which were already in short supply, spiked last month, especially in New York, which was the U.S. city hardest hit by the pandemic. For instance, a 4,100% increase in the demand for midazolam at hospitals in New York drove a 70% nationwide spike in demand for the sedative. Although the generic drug is produced by a number of companies, only 79% of the orders could be filled. The FDA added midazolam to its shortage list April 2.

Midazolam is just one example of drugs that are getting harder to come by because of the virus. According to a recent survey of Premier’s hospital members, antimalarial drugs used off-label to treat coronavirus infections were the most commonly reported shortage, with 70% of hospital respondents reporting a shortage. That was followed by 65% reporting shortages of bronchodilators, 40% reporting antibiotic shortages, 38% indicating antiviral shortages and 35% noting a shortage of sedatives.

Some of the drugs being used to treat patients with the virus have been in shortage for a few years, often because a generic manufacturer decided to discontinue production for commercial reasons, according to the FDA’s shortage list. Subsequently, the surge in demand for those drugs is exacerbating an existing supply problem. Other drugs, like midazolam and the antimalarials chloroquine and hydroxychloroquine, are new to the list.

As more hot spots pop up across the U.S., the shortages will be more broadly felt. “There is concern that if solutions to help increase the availability of these drugs are not implemented immediately, that the availability of these drugs will become the rate-limiting step to providing intubation – not the availability of supplies such as ventilators,” Russell said.

More than a ramp-up needed

Addressing the shortages is not just a matter of ramping up production to meet the demand. There are regulatory hurdles to overcome, as well as global logistics gnarled with manufacturing slowdowns, port closures and transportation delays.

“For commodity products, we can tap adjacent industries to begin production. But drug manufacturing is highly regulated, and it typically takes years and substantial investment to build additional capacity and gain … FDA approval,” Premier President Michael Alkire said. “Even if the FDA expedited approvals, inspections and other actions, drug manufacturing cannot be stood up overnight. Moreover, there are also secondary concerns about where replacement ingredients will be sourced, as many of these drugs rely on active pharmaceutical ingredients (API) from overseas.”

For some of the drugs facing shortages and a surge in demand, the FDA isn’t the only regulatory hurdle. Production of controlled substances such as fentanyl is limited by quotas set by the Drug Enforcement Administration (DEA). Before companies can increase production of a controlled substances, the DEA has to allocate additional quota.

ASHP, along with the American Hospital Association, the American Medical Association and other groups, have asked the DEA to immediately increase its allocation of annual production quotas for supportive opioids to drug manufacturers and outsourcing facilities, Abramowitz said in a letter last week to Vice President Mike Pence.

In its most recent statement on its response to COVID-19, the DEA said it was working with federal partners, DEA registrants and industry associations to ensure an adequate supply of controlled substances and medications during the pandemic. “DEA is in constant communication with controlled substance manufacturers, distributors and importers, and is unaware of any drug shortages at this time,” the agency said in the March 20 statement.

Abramowitz told Pence, “We are aware that the Department of Health & Human Services released a request for information regarding manufacturing capacity and other groups have written to the DEA for critical drugs, but we were dismayed to see that the medications necessary for ventilating patients were designated Tier 2. Failure to treat these drugs as anything other than absolutely essential will render ventilators worthless and exact a heavy patient toll.”

A temporary increase in the DEA quotas is just one action that’s needed to ensure an adequate supply of necessary drugs during the pandemic, according to Premier. It also is calling for:

  • creating a national dynamic allocation process that accounts for surge demand and prioritizes the needs of acute care providers, rather than capping orders at historic purchasing levels;
  • creating a streamlined and efficient process for accessing drugs from the Strategic National Stockpile;
  • leveraging air transport to expedite the transportation of necessary products such as APIs;
  • allowing health systems to temporarily transfer drugs freely between hospitals or other pharmacies without having to obtain licensure to distribute products;
  • creating a centralized FDA data repository quantifying inventory levels for critical drugs;
  • using the Defense Production Act to enable the FDA to leverage line and tech transfers to expeditiously increase domestic manufacturing of critical drugs;
  • creating incentives, such as committed volume or co-investment, to encourage manufacturers to enter the marketplace to resolve drug shortages;
  • providing 0% interest loans to manufacturers and distributors to increase inventory levels.

In addition, Premier said the FDA should immediately begin using its new authority under the CARES Act to require API manufacturers to begin reporting supply disruptions and to require manufacturers to disclose their exact API sources and locations of finished dosage drugs.

Logistics tangles

Then there are the global logistics issues that must be resolved. This is a new challenge. “I cannot recall when either domestic or international transportation exacerbated previous product shortages,” Russell said. “As opposed to a regional disaster, in a global situation, the cooperation of governments to allow open commerce and ensure customs releases from port to port are key to keeping the supply chain flowing.”

While delivering drugs and devices to U.S. hospitals hasn’t been a problem, importing products can be a complex challenge when they’re made in countries such as India that have imposed nationwide lockdowns, Russell said. Manufacturers in those countries may be cutting back on production because they can’t get staff to their manufacturing sites or to load or unload planes and ships, he added.

“We’re seeing entire ports shut down, such as Mumbai’s, which leads suppliers to move products to other ports, adding potential delays for air or sea transport of products into the U.S. … While sea shipments have been less affected than air transportation, many suppliers use the port of New York, which could be the next bottleneck in the chain,” Russell said.

No Comments