Injectable dexamethasone is more difficult to manufacture than tablets, because production needs to take place under sterile conditions. SOUMYABRATA ROY/NURPHOTO VIA AP
By Eli Cahan Jun. 21, 2020
Science’s COVID-19 reporting is supported by the Pulitzer Center.
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.#
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.
Related
FDA just gave a thumbs down to Trump’s favorite COVID-19 drugs
Could a global ‘observatory’ of blood help stop the next pandemic?
See all of our coverage of the coronavirus outbreak
But that doesn’t mean there won’t be shortages, says Stephen Schondelmeyer, director of the Pharmaceutical Research in Management and Economics Institute at the University of Minnesota, Twin Cities. “Even though this is an old drug that’s been around a long time, I think people saying that it’s commonly available … spoke too soon, without looking at the data,” he says. Since the trial findings came out, there has been “a degree of irrational exuberance,” about dexamethasone, Schondelmeyer says. “We are already seeing hoarding behaviors and lack of availability of the product because of it,” he adds.
“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 in trouble with the U.S. Food and Drug Administration (FDA) for serious problems in its production process. According to a letter from the agency, the company said in October 2019 that it would stop producing injectable drugs for the United States.
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 University of Pennsylvania’s Perelman School of Medicine 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 U.K. 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 SCCM 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 one-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 United States before the Recovery results came out, according to an independent shortage tracking tool run by the American Society of Health-System Pharmacists. FDA lists the drug as “in shortage” as well. Dexamethasone is not in the U.S. Strategic National Stockpile.
Hoarding and speculative procurement appear to have already started.Emer Cooke, World Health Organization
The question is whether production of the intravenous form of dexamethasone can be ramped up quickly. Whereas 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 more than 100 people.)
Issues with quality control up the supply chain
Most of the drug is produced by two Indian companies, Wockhardt and Cadila Healthcare. Wockhardt has a “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 Advanced Research and Development Authority and the Department of Homeland Security to enhance the resilience of the United States’s pharmaceutical supply chain, is skeptical. “There aren’t a lot of [unused] plants that can make sterile injectables of anything, let alone dexamethasone, so I’m not sure how much capacity they really have,” he says. Ramping up supply “takes a lot of time, even if the world was normal and sane, let alone during COVID.”
FDA has turned away Cadila’s products at the U.S. border 83 times since 2004 because of quality concerns. Since 2015, the agency has sent the company three warning letters related to its production process. FDA inspectors found myriad inadequacies at Cadila’s facilities, including noncompliance 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 the most recent of the three letters, dated 29 October 2019, FDA writes that Cadila Healthcare has informed the agency that it will “permanently cease production of injectable drug products for the United States.” This history “makes me very nervous, as to whether they can ramp up in the first place, and if they can, if that’s a product anyone should use,” Schondelmeyer says. (The company did not respond to requests for comment.)
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 and no disruptions related to stockpiling … I think this is a manageable development,” he says. Based on the study, the drug should only be used in severe cases, a small subset of the total number of COVID-19 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. 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, it’s difficult to be rational,” Deutschman says. “There’s always a temptation to take the results of a trial and overextend them.”
*Correction, 22 June, 3:15 p.m.: An error in the description of FDA’s October 2019 warning letter to Cadila Healthcare has been corrected.
*Correction, 24 June, 8:05 a.m.: An incorrect statement about back orders of injectable dexamethasone at U.S. drug suppliers has been removed from this story.
Posted in:
Health
Coronavirus
doi:10.1126/science.abd4447
Eli Cahan
Eli is an intern on the News staff of Science. He is pursuing a master’s degree in health policy as a Knight-Hennessy Scholar at the Stanford School of Medicine and his MD at the New York University (NYU) School of Medicine. Twitter
A cheap steroid is the first drug shown to reduce death in COVID-19 patients
The steroid dexamethasone may quickly be added to the global standard of care for severe COVID-19 patients. REUTERS/YVES HERMAN
By Kai Kupferschmidt Jun. 16, 2020
Science’s COVID-19 reporting is supported by the Pulitzer Center.
After months of dire news about the spread of the novel coronavirus and a mounting global death toll, a glimmer of hope arrived today: Researchers announced that dexamethasone, a cheap, widely available corticosteroid, significantly reduced deaths of severely sick COVID-19 patients in a major clinical trial. Although full trial data have not yet been released, several outside commentators hailed the result as a “breakthrough.”
“These are really surprising, but really very convincing results,” says Martin Landray of the University of Oxford, one of the principal investigators of the Recovery trial in the United Kingdom that evaluated the steroid. If they hold up, adds Devi Sridhar, an expert on global public health at the University of Edinburgh, they could be a game-changer for critical patients, as the drugs are accessible even in lower-income countries.
Related
‘We’ve got to be able to move more quickly.’ The pandemic reality of COVID-19 clinical trials
HIV and TB increase death risk from COVID-19, study finds—but not by much
FDA just gave a thumbs down to Trump’s favorite COVID-19 drugs
See all of our coverage of the coronavirus outbreak
The Recovery trial, one of the biggest efforts to evaluate whether existing drugs can treat COVID-19, included 2104 patients given a relatively low dose of 6 milligrams of dexamethasone for 10 days. When their outcomes were compared with those of 4321 patients receiving standard care, the steroid reduced deaths by one-third in patients already on ventilators and by one-fifth in patients receiving supplemental oxygen in other ways, Recovery researchers announced in a press release. They did not find any benefit in patients not receiving respiratory support.
Dexamethasone’s effect is seemingly much stronger than that of remdesivir, the only other drug so far shown to help COVID-19 patients in a randomized clinical trial. That antiviral reduced the number of days critical patients were hospitalized, but it did not clearly reduce deaths.
Tedros Adhanom Ghebreyesus, director-general of the World Health Organization (WHO), hailed the dexamethasone results as “great news” given it’s the first COVID-19 drug that has clearly proved to reduce mortality. “The results are pretty remarkable for severely ill patients,” adds Nahid Bhadelia, a physician at Boston Medical Center. “I can see ICU [intensive care unit] physicians being more likely to provide steroids in the critically ill who are mechanically ventilated and who are not improving from other interventions based on these results.”
But she and others expressed disappointment that the Recovery team did not release additional information. “More detailed data would help us identify which subset of COVID-19 patients would benefit from steroids,” Bhadelia says.
Landray acknowledges the criticism. “I fully understand why scientists want to see the details. I’m a scientist, I want to see the details.” But with thousands of people dying of COVID-19 every day, it was important to get the basic message out first, he says. “There is this tension between having the final details and the final decimal points nailed down, and having what is actually a clear-cut and practical message in the public domain.”
Recovery is evaluating several experimental COVID-19 therapies, including the HIV drug combination Kaletra, convalescent plasma, and the controversial antimalarial drug hydroxychloroquine. When researchers found 2 weeks ago that hydroxychloroquine did not improve patient outcomes, they stopped that arm of the trial. In the other arms, Landray says, they stuck to their plan to wait until 2000 patients had received a treatment and 4000 patients had enrolled in a control arm, because that would provide a 90% chance of picking up a reduction in deaths of about 18%. Dexamethasone was the first drug to reach the milestone, so the researchers stopped its arm on 8 June and began to look at the data.
“The decimal points might change a bit when we tidy things up, but we’ve got to a point where the message will not change,” Landray says, adding that Recovery hopes to make public the full data within about 10 days. If the findings hold up under scrutiny, it would mean that treating eight ventilated patients with dexamethasone would save one life. “That is a big effect,” says Ashish Jha, a global health expert at Harvard University’s T.H. Chan School of Public Health who is eager to see the data.
The United Kingdom’s National Health Service has already announced its standard care for COVID-19 patients will now include dexamethasone. “It’s very, very rare that you announce results at lunchtime, and it becomes policy and practice by tea time, and probably starts to save lives by the weekend,” Landray says.
Although much of the early hope for COVID-19 treatment focused on drugs that might directly attack the virus (like remdesivir and hydroxychloroquine), there has also been considerable debate about medicines that dampen the immune system, like dexamethasone. In its fight against the virus, the body’s defenses can overreact, eventually breaking down the thin barrier between the insides of the lungs and the surrounding tissue. That causes the lungs to fill up with liquid and triggers acute respiratory distress syndrome (ARDS) in which patients can end up essentially drowning in their own liquid.
But reducing the immune response through steroids could also hobble the body’s fight against the new coronavirus or secondary infections, Bhadelia says. For this reason, the guidelines of WHO and the U.S. National Institutes of Health have so far recommended against using steroids in COVID-19 patients, she points out.
Doctors have used steroids to treat viral pneumonias in the past, including those caused by the severe acute respiratory syndrome virus or H1N1 influenza, says Wei Shen Lim, a respiratory physician at Nottingham University Hospital. But there were no randomized clinical trials with those viruses and available data were hard to interpret.
A Cochrane review looking at the data from H1N1 patients, co-written by Lim, found that patients treated with corticosteroids had a higher risk of dying. But that might be explained by the fact that sicker patients were more likely to receive steroids, Lim says. “Before the Recovery trial, I was neither an advocate for or an opponent of steroids,” he says. “You couldn’t be sure.” To get a clearer answer, Lim designed a trial to evaluate steroids in viral pneumonias in the case of another pandemic. When COVID-19 emerged, that was integrated into the Recovery trial as one arm, using dexamethasone.
In places like Spain, dexamethasone has already been widely used against COVID-19. Carlos Ferrando, an anesthesiologist at the Hospital Clinic of Barcelona, was one of the authors on a paper published in Lancet Respiratory Medicine on 7 February that showed the steroid reduced mortality in non–COVID-19 patients with ARDS. When COVID-19 patients started to show up in Spanish hospitals, Ferrando started a randomized clinical trial to test dexamethasone, but recruitment into the placebo group was slow because most patients were given the steroid, he says. Ferrando is now analyzing data from thousands of patients in Spanish ICUs, about 80% of whom received steroids, he says. “It seems like we have a signal that those corticoids decrease mortality, but we need to finalize the analysis.”
Sridhar says the positive result of the Recovery trial also holds an important lesson for the debate about how best to initially respond to a pandemic like this: that delaying the spread of a pathogen, through temporary stay at home orders or other measures, can give people infected later in a pandemic a better chance of surviving. “It shows the value of buying time for science to deliver, and indicates that with time, more and more findings will come to light that help doctors manage COVID-19 patients with better clinical outcomes.”
But even if steroids reduce mortality, they do not solve the problem of COVID-19 patients potentially overwhelming a health care system, Sridhar cautions. That’s because the drug can help treat patients who are already sick, but not prevent the illness in the first place. “The real game-changer will be a drug that prevents people going from mild symptoms to a severe state, and a vaccine.”
Posted in:
Health
Coronavirus
doi:10.1126/science.abd3683
Kai Kupferschmidt
Kai is a contributing correspondent for Science magazine based in Berlin, Germany. He is the author of a book about the color blue, published in 2019.Twitter
No comments:
Post a Comment