After receiving intravenous immunoglobulin (IVIg) to treat chronic inflammatory demyelinating polyneuropathy (CIDP) for nearly 20 years, Christina Caron heard about a recent immunoglobulin shortage via social media. Then, an outpatient center could not guarantee that the medication would be available on the day of a scheduled infusion. “You feel your body declining. Meanwhile, you’re just hopeful” that the product will be there, she said.
She received the immunoglobulin infusion as scheduled, which was a relief. People in her social media groups, however, had their infusions canceled.
CIDP can feel “like pulled muscles all through my body,” Ms. Caron said. “It’s scary when you know what you need to be better, and it’s possible that it’s not going to be available for you.”
During a shortage, patients may go without treatment, have treatment delays, or have dose reductions. “Those are all things that we know are happening anecdotally, but we do not have a way to quantify it,” said Erin Fox, PharmD, senior director of drug information and support services at the University of Utah, Salt Lake City. A 2019 report by a Food and Drug Administration drug-shortage task force highlighted a need to quantify how drug shortages harm patients, Dr. Fox said.
The Drug Information Service of the University of Utah maintains a database of drug shortages based on communications with drug companies. The service began noticing immunoglobulin product shortages in November 2018, Dr. Fox said. In August 2019, the FDA announced that there was a shortage of immunoglobulin products that “could impact patient care.” The agency cited “uneven product distribution across different localities,” “logistics of contractual obligations,” and “production delays” as factors that might have limited availability “in the setting of increased demand for [immunoglobulin].”
According to a trade group, issues accessing immunoglobulin products were most acute during the summer of 2019. Access seems to have improved since then, said Dr. Fox.
Two immunoglobulin products were on the FDA’s list of current shortages of regulated biologic products as of January 2020. The Drug Information Service’s list of affected immunoglobulin products, updated on February 3, 2020, includes additional products. The service’s Drug Shortage Bulletins are distributed by the American Society of Hospital Pharmacists.
Dr. Erin Fox
Product switches may be unavoidable
“[Immunoglobulin] products are lifesaving and critical products for a number of acute and chronic conditions including, but not limited to: B-cell chronic lymphocytic leukemia, chronic inflammatory demyelinating polyneuropathy, idiopathic thrombocytopenic purpura, Kawasaki disease, and primary immunodeficiency diseases,” according to the bulletin about the immunoglobulin shortage. “Product switches may be inevitable during times of shortage. Make every attempt to maintain consistent therapy when possible.”
There are more than a dozen intravenous and subcutaneous immunoglobulin products. Certain immunoglobulin products are FDA approved for particular indications, although physicians sometimes use them off label. Privigen, Hizentra, Gamunex-C, and Gammaked are indicated for CIDP. Products may vary in terms of infusion times and sugar content, which can affect tolerability and kidney function, Dr. Fox said.
Shortages could prompt clinicians to ensure they are using immunoglobulin for appropriate indications at appropriate doses and to try other medications first, Dr. Fox suggested.
“When [immunoglobulin] supplies are limited, health care providers, hospitals, and medical systems may be required to decide which patients will receive priority treatment,” the FDA announcement said. The agency encouraged “an evidence‑based approach to such decisions” and suggested that “medical systems with only one [immunoglobulin] product contract may wish to consider a second [immunoglobulin] product contract to improve resilience during and after this time of shortage.”
Ms. Caron, who lives in Bangor, Maine, first received a diagnosis of Guillain-Barré syndrome, then CIDP. She established a treatment regimen of immunoglobulin infusions every several weeks. Recently, she tried a formulation of immunoglobulin that is administered subcutaneously at home.
“By the time it’s time for my next infusion, I’m typically having difficulty with my walking, my balance,” she said. “It is incredibly frustrating to have my body holding me back when I know there is something that can help me.”
A friend who has Lambert-Eaton myasthenic syndrome wrote a column for Lambert-Eaton News in July 2019 about the immunoglobulin shortage. The friend, Dawn DeBois, had symptoms flare when her immunoglobulin treatment was delayed by the shortage. She mentioned in her column that Ms. Caron had posted on social media about the shortage and about the importance of plasma donations, which are used to manufacture immunoglobulin products. Ms. Caron said she posted about the shortage to inform friends around the country about how donating plasma could help patients like her.
Ms. Caron works full time, is married, and has two kids. When CIDP affects patients’ ability to function, “there are a lot of other people who are impacted by it other than just the patients,” she said.
“In neurology, this medication is used to improve paralysis,” said Sami Khella, MD, chief of the department of neurology at Penn Presbyterian Medical Center in Philadelphia. “Patients are very often dependent on the drug to maintain their muscle strength. And you can imagine: If you lose muscle strength, your ability to function is severely impaired.”
Shortages are “quite an ordeal for the physician and patient,” he said. Physicians have to scramble to find an available immunoglobulin product and to see whether the patient’s insurance provider will accept it.
One of Dr. Khella’s patients with CIDP had his treatment delayed by about 2 months during the shortage. The delay significantly affected the patient “to the point that he started to fall,” Dr. Khella said. “I think it’s harrowing for some patients when they cannot get drug that they expect and depend on.”
In a shortage, second-line therapies, such as glucocorticoids or other immunosuppressant drugs, may be an option, he said.
By February 2020, the shortages that had affected his patients had resolved.
Dr. Sami Khella
‘An exquisite ecosystem’
The Drug Information Service’s list of affected drugs does not necessarily match the FDA’s list of drug shortages. A company might tell the Drug Information Service that pharmacists are not able to order their usual amount of a product, the company is allocating product to specific customers, or the drug is in shortage because of increased demand. Drug manufacturers might disagree that such rationing indicates a shortage.
The service approaches the issue from the perspective of what clinicians need to know to take care of patients today, Dr. Fox said. “Receiving less really does trickle down and affect patient care,” and many organizations have had to deny the treatment or implement restrictions.
The FDA’s announcement about the immunoglobulin shortage directed health care providers to phone numbers compiled by the Plasma Protein Therapeutics Association (PPTA) for information about acquiring products.
Amy Efantis is president and CEO of PPTA, a trade association that represents most of the global manufacturers of immunoglobulin products. Three months after the FDA receives plasma collection and distribution data from manufacturers, PPTA receives an aggregated version of the data, known as “grams collected” and “grams out the door.” “The collection in the U.S. has had a very nice increase. Grams out the door has increased steadily,” she said.
It has been frustrating to hear about patients having significant issues with access, she said. When the shortage became “more acute” over the summer, PPTA provided the phone numbers to facilitate accessing products. Factors contributing to increased demand for immunoglobulin may include patients living longer and physicians more readily diagnosing conditions that can be treated with immunoglobulin. Europe has lagged North America in collecting plasma, she noted.
Immunoglobulin products come from “an exquisite ecosystem where people are donating plasma to save the life of patients,” Ms. Efantis said. “Our companies can’t ramp up and respond [to a shortage] in a 3-month period.” It takes 7-12 months for a plasma donation to become a therapy for a patient – from vein to vein – and “the raw material is coming from individual people,” she said. Patient groups, companies, and regulators have “a shared goal of ensuring patients have access to the treatments that they need,” Ms. Efantis added.
Sharing shortage experience on social media
Dania Palanker, JD, received a diagnosis of CIDP in February 2017. Ms. Palanker is an assistant research professor at the Center on Health Insurance Reforms at Georgetown University’s Health Policy Institute, Washington. Online, people talked about their immunoglobulin infusions being canceled or delayed. It caused fear. Some felt their symptoms worsen. Newspapers described centers triaging which patients would receive the drug.
Ms. Palanker commented about the shortage on Twitter in September 2019. “As someone with CIDP, I would happily give my medicine over to some with a primary immunodeficiency if it would save their life even if it meant more pain and fatigue for me,” she wrote. “The problem is the drug shortage. And that shortages keep happening.”
Her physician’s office had difficulty finding a new pharmacy for her after another pharmacy closed. The pharmacies that the office usually worked with were not taking new patients because of the shortage, which ended up delaying her IVIg treatment by a few months.
In December 2019, Ms. Palanker commented about the shortage again and noted the therapy’s cost: “We are recovering from an immunoglobulin shortage in the U.S., which is made from human plasma and retails for upwards of $9,000 for a treatment.”
“We often rely on small groups of manufacturers. If there’s a problem in one, it can have a huge effect,” she said in an interview. “IVIg is not new. The use of drugs changes over time. If it is used for more conditions, we need to make sure our manufacturing can keep up with that. … They should be able to see the trend, especially for a drug that makes them lots of money.”
Investing in infrastructure
Manufacturers said they are investing to increase manufacturing efficiency and plasma collection.
“Regarding CSL Behring, the company has not and is not experiencing manufacturing issues or supply disruptions related to our [immunoglobulin] products, Hizentra or Privigen,” said Dana B. Lynch, a spokesperson for the company. “The FDA has not listed a shortage for our [immunoglobulin] products. CSL Behring has consistently supplied our products at rates well ahead of the market volume growth to help meet growing demand; however, we cannot fill the entire gap created by shortages of other manufacturers’ products. The company continues to put every effort into manufacturing more product with ongoing investment in state-of-the-art facilities around the world to increase manufacturing efficiency.”
A spokesperson for Grifols, which manufactures Gamunex-C, said the company “is providing more [immunoglobulin] to patients than it has at any time in our history” and that it plans to increase the size of its plasma donation center network in the United States, which includes 250 centers. In addition, Grifols is building a fractionation plant in Clayton, N.C. “When it’s operational next year, it will have the world’s largest plasma fractionation site, with a plasma fractionation capacity in the United States of 14 million liters, an increase of more than 35%, compared with today,” the company said.
Dania Palanker, JD