Injectable dexamethasone is more difficult to manufacture than tablets, because production needs to take place under sterile conditions.
Soumyabrata Roy/NurPhoto via AP
This week’s report that dexamethasone, a commonly used corticosteroid, reduces death rates of COVID-19 by up to one-third was greeted with enthusiasm around the globe.
But it also raised a question: Will there be enough of the medication? So far, doctors are not reporting problems getting dexamethasone for their patients. And as many news stories have pointed out, dexamethasone is off-patent, cheap, and relatively abundant.
But that doesn’t mean there won’t be shortages, says Steven Schondelmeyer, Director of the Pharmaceutical Research in Management and Economics Institute at the University of Minnesota. “Even though this is an old drug that’s been around a long time,” he says, “I think people saying that it’s commonly available… spoke too soon, without looking at the data.” Since the trial findings came out, there has been “a degree of irrational exuberance,” about dexamethasone, Schondelmeyer says. “We are already seeing hoarding behaviors,” he adds, “and lack of availability of the product because of it.”
“Hoarding and speculative procurement appear to have already started,” confirms Emer Cooke, Head of Regulation of Medicines and other Health Technologies at the World Health Organization (WHO). But she says it’s “probably too early to say if there will be a global shortage.”
The situation could become especially dire for the injectable version of the drug, which some physicians say is the preferred formulation and is more complicated to produce than oral dexamethasone. One major Indian manufacturer of intravenous dexamethasone, Cadila Healthcare, has repeatedly gotten into trouble with the U.S. Food and Drug Administration (FDA) for serious problems in its production process and told the agency it would cease all shipments of all injectable medications to the United States in October 2019.
The trial that identified dexamethasone’s potential benefit, named RECOVERY, included more than 6400 patients in the United Kingdom, 2104 of whom received the medication. Its outcome “offers miraculous hope that a dose of a commonplace medication might do what we all want it to do: help people survive,” says Lewis Kaplan, a surgeon at the Perelman School of Medicine at the University of Pennsylvania and president of the Society of Critical Care Medicine (SCCM). WHO director-general Tedros Adhanom Ghebreyesus praised the findings as a “lifesaving scientific breakthrough.” The United Kingdom’s National Health Service has already incorporated the drug into its standard of care for COVID-19 and the country issued restrictions on exports of dexamethasone. Demand appears to be surging worldwide.
How the drug is given makes a difference
But dexamethasone can be administered in several ways. According to the trial’s protocol, patients received the medication either orally or by intravenous injection. In many cases, the distinction may be trivial. But for the sickest patients, administering oral medications is “rolling the dice to some degree,” says Clifford Deutschman, an intensivist at the Feinstein Institutes for Medical Research and former SCCN president. Gastrointestinal problems in these patients can cause “inconsistencies in uptake of the medication,” leading to blood levels that are too low or too high, Deutschman says. And for patients on ventilators, administering the medication orally means grinding the pills up by hand and delivering them through fluids or a feeding tube. Both for safety and effectiveness, “hands down, if you’ve got the intravenous stuff, you give the intravenous stuff,” he says.
The sickest patients are the ones most likely to benefit from the drug. In the study, dexamethasone reduced the death risk for patients on a ventilator by a third, and for those requiring oxygen by one fifth. Patients with milder disease did not benefit.
Intravenous dexamethasone was already in short supply in the U.S. before the RECOVERY results came out, according to an independent shortage tracking tool run by the American Society of Hospital Pharmacists. The FDA lists the drug as “in shortage”as well. The drug is on backorder at two of the largest medicine distributors in the country, McKesson and Cardinal Health, says Deepak Sisodiya, Administrative Director of Pharmacy Services at Stanford Healthcare. (A spokesperson from Cardinal Health confirmed that the company has begun limiting allocations of the drug.) Dexamethasone is not in the U.S. Strategic National Stockpile.
Hoarding and speculative procurement appear to have already started.
The question is whether production of the intravenous form of dexamethasone can be ramped up quickly. While oral dexamethasone is “relatively straightforward to make,” the intravenous form is harder to manufacture, says former FDA Commissioner Mark McClellan, because it needs to be done under sterile conditions to prevent microbes from reducing efficacy or sickening patients. (In 2012, a fungal meningitis outbreak linked to contaminated steroid injectables killed over 100 patients.)
Issues with quality control up the supply chain
Most of the drug is produced by two Indian companies, Wockhardt and Cadila Healthcare. Wockhardt has “very limited” supply presently available for export, but has “enormous capacity” to produce both oral and intravenous dexamethasone and is able to ramp up further, its CEO said in a 17 June news report.
But Schondelmeyer, whose center recently launched a partnership with the U.S. Biomedical Advance Research and Development Authority and the Department of Homeland Security to enhance the resilience of America’s pharmaceutical supply chain, is skeptical. “There aren’t a lot of [unused] plants that can make sterile injectables of anything, let alone dexamethasone,” he says, “so I’m not sure how much capacity they really have.” Ramping up supply “takes a lot of time, even if the world was normal and sane, let alone during COVID” he adds.
FDA has turned away Cadila’s products at the U.S. border 83 times since 2004 due to quality concerns. Since 2015, the agency has sent the company 3 warning letters related to its production process. FDA inspectors found myriad inadequacies at Cadila’s facilities, including non-compliance with sterile procedures, evidence of Pseudomonas bacteria in the water system, and “several plastic bags filled with paperwork in the scrapyard“ including “a torn notebook of deficiencies.”
In its response to FDA’s most recent letter, the company said it would stop producing injectable drug products for the U.S. market. This history “makes me very nervous,” says Schondelmeyer, “as to whether they can ramp up in the first place, and if they can, if that’s a product anyone should use.”
WHO’s Cooke stresses the importance of buying dexamethasone from quality-assured suppliers. There’s a “high risk that rogue manufacturers will offer substandard or falsified options,” she says. Trusted producers should be able to meet the rising demand, Cooke adds, but if hoarding and speculative procurement continue, “it will create chaotic demand signals and put scale up plans at risk. This is especially true for injectable products,” whose production is harder to scale up.
Potential for shortages at the bedside
McClellan does not see major problems ahead. “If there’s a reasonable response to this news, with clinicians using the drug appropriately,” he says, “and no disruptions related to stockpiling…I think this is a manageable development.” Based on the study, the drug should only be used in severe cases, a small subset of the total number of patients. And physicians could use other corticosteroids—such as methylprednisolone, hydrocortisone, or prednisone—that may work as well.
Kaplan isn’t so sure: Dexamethasone has “unique properties” in the ways it interacts with the cells and proteins that produce the body’s immune response, he says. And demand may increase because doctors will prescribe the drug for less severe cases as well, Deutschman says, adding that he is “worried” this might accelerate shortages.
“When you’re standing at the bedside watching somebody die as the family stands outside, asking yourself, is there anything else I could have done,” Deutschman says, “it’s difficult to be rational…there’s always a temptation to take the results of a trial and overextend them.”