Article In Brief
The shortage of immunoglobulin products, announced earlier this summer, is impacting neurology patients in different parts of the country. Neurologists are addressing the shortage in different ways—from tiering and triaging the most urgent cases, to switching brands and dosing.
On September 25, Columbia University Irving Medical Center (CUIMC) director of neuromuscular clinical trials, Jinsy Andrews, MD, MSc, FAAN, received the notice she had been expecting from the CUIMC pharmacy: The institution's supplies of immunoglobulin (Ig) were limited.
“We had heard since the middle of the summer about shortages of Ig around the country, but we apply strict evidence-based measures, especially in neurology, to be selective about patients for Ig treatment, so up until now it hadn't impacted our practice,” said Dr. Andrews. “But the 25th was the first day here at CUIMC that we got the shortage notification so we will have to be far more serious about determining the use of Ig treatment. It hasn't come to the point yet where we have to create an internal task force to triage requests, and hopefully we can avoid that by being even more meticulous about cases we refer for Ig therapy and considering alternative treatments.”
Over the past several years, neurologists who prescribe Ig therapies for their patients have become accustomed to the fluctuating supplies of these products. No one has pinned a precise date on the beginning of this latest shortage, but most neurologists who spoke to Neurology Today, like Dr. Andrews, said that they began either experiencing or hearing about limited supplies of Ig around the middle of the summer.
In an update marked current as of August 12, 2019, the US Food and Drug Administration (FDA) noted: “There is an ongoing shortage of Immune Globulin (Intravenous) (IGIV) and Immune Globulin (Subcutaneous) (IGSC) products in the United States. This shortage could impact patient care. In the setting of the increased demand for IG, other factors that ordinarily might not impact availability may have a greater effect. These could include uneven product distribution across different localities, logistics of contractual obligations, production delays, and other factors.”
Because it is derived from human plasma, manufacturing and distribution of Ig is complicated and costly. Guidelines established by the International Union of Immunological Societies and the World Health Organization state that the source material should be plasma obtained from a pool of at least 1000 donors, and that final products should be free of any potentially harmful contaminants, which includes testing for HIV 1 and 2, hepatitis C virus antibodies, hepatitis B surface antigen, and high titers of ABO antibodies, to reduce the risk for hemolytic reactions.
“These are living products that are very difficult to manufacture,” said Patrick Schmidt, president and chief executive officer of Ig wholesale distributor FFF Enterprises, in an August webinar about the shortage hosted by the patient advocacy organization Myositis Support and Understanding. “From the time plasma is collected to the time when you might see it in an infusion setting is upwards of seven months.”
In addition to the complexities of the manufacturing process, Ig supplies have also been subject to strain recently by increased use of Ig products for both on- and off-label diagnoses. Between May 2018 and April 2019, according to Schmidt, 91.2 million grams of Ig were distributed in the US, or an average of 7.6 million grams per month—for a population of between 175,000 and 200,000 patients. “One month, there were nine million grams distributed; another month, there were six million grams,” Schmidt said. “It doesn't come out in a consistent supply, but the demand is constant.”
Ig is currently approved by the FDA for the treatment of primary immunodeficiencies, Kawasaki disease, preventative care after bone marrow transplants, multifocal motor neuropathy, and chronic inflammatory demyelinating polyneuropathy (CIDP). Other neurologic indications for which it is used off label include myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome, epilepsy, pediatric intractable Guillain-Barré syndrome, and multiple sclerosis. (There are multiple other off-label uses in specialties including hematology, rheumatology, pulmonology, and infectious disease.)
Tiering and Triage
“We have a lot of people on Ig, and the shortage has affected our area in Philadelphia fairly significantly,” said Sami L. Khella, MD, FAAN, professor of clinical neurology at the Perelman School of Medicine at the University of Pennsylvania, and a neuromuscular specialist who focuses on the treatment of patients with MG and acquired inflammatory neuropathies.
“We see patients from all over Pennsylvania, Delaware, and New Jersey, as well as from out of the region. Both the hospital and our outpatient infusion suites have not been able to get the supplies of Ig they were getting in the past. Different companies have different inventories of Ig products, so it has been very much dependent on which specialty pharmacy was giving what drug to what patient. Even the hospitals were telling us that we would have to prioritize only patients who needed it acutely for their survival. We had some patients who were in acute medical need—who couldn't walk if they didn't get this drug—but they weren't going to die immediately from its lack, and they had to go lower on the priority list.”
As an example, Dr. Khella described an elderly patient who requires Ig every three weeks for CIDP. “Without it, her legs become very weak she says. When there has been a delay in her therapy due to these shortages, she has fallen and fractured bones, requiring surgical repair. She has been refractory to all other drugs except intravenous immunoglobulin (IVIg). And she is far from my only patient in this situation.”
Neurologists at the University of Colorado's Anschutz Medical Campus in Aurora are also feeling the Ig shortage. “Our hospital has a process in place to triage the requests. When the pharmacy and therapeutics committee gets their allotment for the month, they divide it up based on who needs it the most. Inpatients get first priority, then the scheduled outpatients who are on a regular infusion schedule,” said Dianna Quan, MD, FAAN, professor of neurology and director of the neuromuscular fellowship. “Each doctor gets an email asking how bad their patient's situation is, and then they tier them as critical, emergent, non-emergent, or ‘can hold it.’”
Dr. Quan noted that this prioritization has led to fluctuations in patients' stability. “We've had situations with patients who are doing well and so they are classified as stable, and you hold therapy. But then when you do that, they get worse with more weakness and disability, so the next go-round you have to classify them as emergent.”
In addition to tiering patients based on severity of need, many neurologists are being stricter about which diagnoses receive Ig. “Here at a tertiary institution, I may receive a patient from an outside neurologist who might not be a neuromuscular specialist who had prescribed Ig as ‘something to try,’ even if the evidence is not strong for this particular diagnosis,” said Dr. Andrews. “It's difficult to take people off a therapy, even if the evidence doesn't strongly support [it], particularly if they believe they are receiving some benefit. We want people to really be cognizant of the shortage when they're prescribing. When it was more widely available, maybe you could prescribe Ig for a patient you weren't sure really needed it, but now that we have a limited supply, my message to the community is to be certain that this is a patient who really needs the medication.”
At Stanford University, a committee has been formed to regulate IVIg usage in the infusion center. “Requests for indications not well supported by evidence are reviewed by the committee. At this moment, less than 10 percent are denied, though that may change depending on availability,” said Yuen T. So, MD, PhD, FAAN, professor of neurology and president-elect of the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM). “The committee occasionally also asks for a reduction in dosage or frequency of administration, if they seem excessive. Prescribing physicians may take their denied requests to another infusion center or home infusion agency.”
Switching Sources, Brands, and Dosing
In many cases, specialty pharmacies with a national reach are better able to access supplies of Ig than are individual hospitals and health systems. “Once our monthly allotment is gone, it's hard to negotiate any more supply,” said Dr. Quan. “So especially for new starts, we are trying to find ways to move them into the community to receive home infusion via one of the vendors who is able to source it more broadly.”
Columbia has been doing the same for some of its patients, said Thomas H. Brannagan, MD, FAAN, director of the Peripheral Neuropathy Center. “The majority of the major specialty home infusion pharmacies have Ig product. For example, I have two patients with CIDP who were getting IVIg in our hospital's outpatient unit, and we found specialty pharmacies that both of these patients were able to move to. But some patients don't want to do that. I had a patient with multifocal motor neuropathy who was receiving IVIg at one of the University of Pennsylvania hospitals, and they ran out there. We tried to see about getting home care, but he preferred to go to the infusion center; by the time they had supplies back, he was about a week late in getting his dosage.”
Patients are also being asked to switch from one Ig product to another, depending on availability. There are currently more than a dozen branded IVIg products, and eight Ig products for subcutaneous administration, according to the FDA.
“Personally, I'm most familiar with Gammunex, and that was my typical practice pattern, but there is no definitive data as far as one product being better than another,” says Dr. Quan. “So now we are providing whatever is available.”
That's fine for most patients, says Bennett H. Myers, MD, an attending neurologist and co-director of the Neuromuscular Disorders Center at the Dent Neurologic Institute in western New York. “We've been lucky that we've been able to maintain supplies of Gammunex, but we currently don't have access to any other brands. We do have some patients who have had allergic reactions to Gammunex in the past; we were successfully treating them with Gammagard, but now we can't get that.”
He's been able to switch some patients to Gammunex accompanied by large doses of IV steroids, but others have had to stop Ig treatment altogether and use alternative therapies such as plasmapheresis, mycophenolate mofetil, azathioprine or methotrexate. “I have one patient with MG who did well with Gammagard, but had an immune reaction to Gammunex that nearly led to respiratory failure, so we've had to treat that patient with plasmapheresis instead. We just do the best we can do.”
At the Mayo Clinic, many patients have had to change brands because of supply issues, and others have had their tapering schedules accelerated. “So far, no one that I am aware of has had any gaps in therapy,” says Eric J. Sorenson, MD, FAAN, vice chair of the department of neurology at the Mayo Clinic in Rochester, MN and past president of the AANEM. “We have had a couple of close calls; two patients on chronic therapy whom we manage long distance were scrambling to get a source in their local communities, but both ultimately did. One patient with multifocal motor neuropathy had to drive several hours to come here to get two doses while he was trying to get it locally, however.”
Many institutions are being stricter about Ig dosing as well. “Ig dosing is based on body weight, and the data are suggestive that it should be based on ideal body weight rather than actual,” Dr. Sorenson said. “In the past, we have dosed following actual body weight, but our institution has now been insisting on using ideal weight, so some patients have been getting lower doses of Ig than before. So far, I can't think of anyone who has had any clinical problems as a result.”
Dr. Sorenson believes that this shortage will run its course as past shortages have. “This is about the third one I've gone through in my career, and eventually the supply catches up again,” he said.
In the meantime, Dr. Andrews advises cautious prescribing. “At this moment in time, I don't feel we will have to deny Ig to the patients who truly fit the criteria. But be thoughtful and make sure the evidence supports Ig use in each patient you prescribe it to. We want that message to get out throughout neurology so that the day doesn't come when we have to be limited in prescribing a lifesaving therapy to a patient who clearly needs it.”
Dr. Andrews has received compensation as a consultant for Cytokinetics, Biohaven, and Avexis, and has research grants from Roche, Biogen, and Orion Pharma. She has not received any compensation as a consultant for immunoglobulin-related products and has not received research grants from commercial interests manufacturing immunoglobulin products. Drs. Quan, Sorenson, had no disclosures.