'Cascade of Impact': COVID-19 surge again threatens patient access to maintenance drugs
In a disturbing repeat of last year’s run on hydroxychloroquine, U.S. health care systems are scrambling to maintain tocilizumab access for rheumatology patients following the drug’s emergency use authorization for COVID-19 and the surge in delta variant cases.
Between June 24 and August 13, demand for tocilizumab (Actemra, Genentech) in the COVID-19 setting drove a 279% increase in requests for the IV formulation of the drug, according to data from Vizient, a member-driven health care performance improvement company. Further data showed a simultaneous reduction in fill rates of IV tocilizumab prescriptions by hospitals from 99% to 45%.
The impact of this trend on the rheumatology community could be severe. Patients with conditions ranging from rheumatoid arthritis and giant cell arteritis to polyarticular and systemic juvenile idiopathic arthritis, along with cytokine release syndrome, all benefit from tocilizumab.
According to a statement from manufacturer Genentech, the issue is ongoing beyond the dates of the Vizient study. “This new wave of the pandemic has led to Genentech experiencing an unprecedented demand for Actemra IV — well over 400% of pre-COVID levels over the last 2 weeks alone and it continues to increase,” the company noted.
All of this comes on the heels of a number of shortages related to the pandemic, from personal protective equipment and ventilators at the outset to hydroxychloroquine through the heart of 2020, according to Steven Lucio, PharmD, vice president of pharmacy solutions at Vizient. “This has been part of the collateral damage of COVID,” he told Healio Rheumatology. “Now we are starting to feel the same pressure with tocilizumab, with the supply not being able to keep up with the demand. It is a challenge for rheumatologists.”
The hope is that the players in this scenario — rheumatologists, pharmacists and hospital administrators among them — have learned from past mistakes and are equipped to manage drug inventories moving more successfully forward. But understanding the scope and nature of the shortages, and how to best mitigate them, is critical.
If tocilizumab was the only drug impacted, it would be one issue; but the problem is bigger than that. Findings from Vizient showed that demand for the tocilizumab alternative baricitinib (Olumiant, Eli Lilly & Co.) has increased 1,421% over the same time period, leading to a drop in fill rates from 99% to 89%.
Also, as might be expected, demand for remdesivir (Veklury, Gilead Sciences) increased 632% and dexamethasone demand increased 47.5% over the period between June and August studied by the Vizient group.
“The NIH said recently that it is not possible to get Actemra or Olumiant,” Lucio said. “This is all part of the hardship that the rheumatology community has had to endure. It really highlights the tangential effects a pandemic or natural disaster can have on vulnerable populations.”
While Lucio believes that shortages of all the aforementioned drugs are unlikely to be widespread enough to leave most or all rheumatology patients without their medications, he urged ongoing vigilance. “We tend to see this in extreme critical care situations,” he said. “The loss of one product leads to the next one going short, a cascade of impact. I am not saying that that is going happen, but if you have even one patient who has difficulty getting treatment, it is a problem.”
However, there is hope in the current go-round of drug shortages. A Genentech spokesperson told Healio Rheumatology that manufacturers are well aware of the situation. “We have begun receiving scheduled replenishments of Actemra in the U.S. and anticipate additional replenishments of all SKUs of Actemra IV and subcutaneous formulations,” the statement read.
However, given that the use of the drug in COVID-19 is unpredictable and based on the changing course of the pandemic, the company stressed that availability may vary. “Patients interested in subcutaneous Actemra should speak with their doctor,” the statement noted, and then offered some practical advice for practitioners. “For the most up-to-date information on product availability for Actemra IV and/or subcutaneous formulations, hospitals and practices should contact their authorized distributors.”
While the natural inclination may be to look to the hydroxychloroquine debacle for clues as to how the tocilizumab shortage will unfold, Lucio suggested that comparing these “apples to oranges” may not be so helpful. “We certainly hope that what we learned in the earlier part of the pandemic will help us with what is happening with tocilizumab,” he said. “Many organizations had to deal with these supply challenges, and we have certainly become very astute at trying to closely manage inventories, largely by closely managing the patients who need those drugs.”
However, the future of tocilizumab availability for rheumatology patients depends on a few key factors. “One depends on if we are able to change trend lines for vaccinations,” Lucio said. “Or, failing that, if we can somehow bring about a diminishing amount of COVID cases altogether.”
That, obviously, is a big if. With that in mind, experts like those at Vizient and manufacturers like Genentech are focused on avoiding shortages for demanding populations, like patients with RA.
But the way of avoiding these shortages — along with the attendant interruptions or delays in treatment that could lead to worsening disease outcomes — is imperfect, according to Lucio. “We are hearing from more and more of our members that patients with RA who get the IV product are moving to the subcutaneous formulation of tocilizumab,” he said. “This, obviously, is not ideal.”
The reason for this is that if a patient is well-maintained on any therapy, shifting gears can be problematic, even if that shift is merely in the delivery of the drug. “There are considerable efforts being made with inventory to make sure things don’t fall off the cliff,” Lucio said.
Lucio offered some hardboiled advice to rheumatologists to ensure their patients can get their tocilizumab and other prescriptions filled. “You need to have your pharmacy on speed dial,” he said. “You need to understand what strategies have been put in place to manage that inventory.”
A “bidirectional dialogue” between physician and health system about patient load and the inventory of drugs is also necessary. “Your pharmacy can work with wholesalers, they can work directly with the drug company itself to bring inventory together,” he said. “But none of this will help patients if you don’t know about these avenues and protocols.”
The benefits of a knowledgeable and proactive rheumatologist can be felt by patients. “Of course, if you can keep them on the formulation that is working for them, that will be beneficial,” Lucio said. “But changes in therapy can also include changes in copays or out-of-pocket expenses. Patients know that their provider is working the pharmacy or other players to avoid disruptions in their care.”
In short, every rheumatologist should have a roadmap in place for keeping their patients on their treatment. “If their care is, in fact, disrupted, you need to know the next step in the plan,” he said, and stressed one other consideration. “The protocols are different from health system to health system, so you should make sure to understand the protocols where you are practicing.”
Tocilizumab Utility in COVID-19
If there is an elephant in the room, it is the extent to which tocilizumab, baricitinib or other drugs in the rheumatology armamentarium can have efficacy in COVID-19. This unknown factor could have a huge impact on the extent and nature of shortages going forward.
“The emergency use authorization was based on four randomized, controlled studies that investigated the safety and efficacy of Actemra in more than 5,500 hospitalized patients with COVID-19,” according to the Genentech statement.
The RECOVERY study, published in the Lancet, was led by researchers in the United Kingdom and included more than 4,000 hospitalized COVID-19 patients with hypoxia and systemic inflammation. Results showed that tocilizumab improved survival and other clinical outcomes and did not depend on the amount of respiratory support. Moreover, tocilizumab may increase the clinical benefit of systemic corticosteroids in these patients.
Salama and colleagues published findings from the EMPACTA study in the New England Journal of Medicine. “In hospitalized patients with COVID-19 pneumonia who were not receiving mechanical ventilation, tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or death, but it did not improve survival,” the researchers concluded. “No new safety signals were identified.”
Rosas and colleagues published findings for the COVACTA trial in the New England Journal of Medicine. They found that among hospitalized patients with severe COVID-19 pneumonia, tocilizumab failed to significantly improve clinical status or lower mortality over placebo at 28 days.
While results of the REMDACTA study have not yet been published in a peer-reviewed journal, early data indicated that a combination of tocilizumab and remdesivir may not shorten hospital stay length.
“The results of these studies suggest that Actemra may improve outcomes in patients receiving corticosteroids and requiring supplemental oxygen or breathing support,” the Genentech spokesperson told Healio Rheumatology. “There have been no new safety signals identified for Actemra in any of these studies.”
These early findings suggest that there may be “more real clinical hope” for tocilizumab than there ever was for hydroxychloroquine, according to Lucio. “There does seem to be a consistency of this medication helping people who are critically ill,” he said.
However, further studies are necessary to elucidate the extent to which tocilizumab can lower mortality or reduce the length of hospital stay.
Regarding the utility of baricitinib in COVID-19, Lucio was similarly cautious. “It seems like a drug that hopefully helps beyond just wishful thinking,” he said. “But we do not know for sure.”
In the meantime, Lucio urged rheumatologists to pay attention to the FDA, CDC and the American College of Rheumatology for guidance on all things pertaining to patient management, including trends in drug shortages.
“Given all that we have been through, these organizations have become more adept at updating guidelines and developing best practices more rapidly,” Lucio said. “There is a general feeling that we know better how to disseminate information to help clinicians. There is also not as much of a spiral of uncertainty as there was.”
While rheumatologists and their patients can take comfort in this, if there is a question that remains, it is the extent to which delta, mu and other COVID-19 variants will impact drug shortages. Unfortunately, even experts like Lucio, who have been studying the trends and publishing data, are unable to predict the future. The only real way to prevent shortages is to produce more of the drugs in question.
“Genentech and Roche are working as quickly as possible to expedite replenishments and increase manufacturing capacity and supply, including through active collaboration with external partners,” the Genentech statement read. “Genentech has implemented new distribution strategies for hospital and clinic customers to enable access for the greatest number of patients, as supply permits.”
Lucio underscored this point. “People who manage supply chain are spending days and nights to prevent and mitigate as much of the patient component as possible,” he said.
- Recovery Collaborative Group. Lancet. 2021;doi:10.1016/S0140-6736(21)00676-0.
- Salama C, et al. NEJM. 2021;doi:10.1056/NEJMoa2030340.
- Rosas IO, et al. NEJM. 2021;doi:10.1056/NEJMoa2028700.