The reasons forshortages of expensive infused drugs are particularly complicated,involving complex manufacturing processes, scientific uncertaintyand financial motivations.(Photo: Shutterstock)

Medical treatment has knocked down tumors in 6-year-old EastonDaniels' brain, but the drug used also wiped out his immunesystem.

To bolster his immune function and help keep him healthy, he hasvisited a hospital for intravenous infusions of immune globulinabout every month for the past year and a half.

But in early July, his family was stunned by a letter fromCincinnati Children's Hospital: "All of Easton's appointmentscanceled until further notice," said his dad, Jeremy Daniels, whoworks in custodial services for a school.

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Like Cincinnati Children's, hospitals and clinics nationwidereport a shortage of the medication, whose long manufacturingprocess starts with donated blood plasma. Often referred to asIVIG, intravenous immune globulin is used for a wide variety ofmedical conditions, beyond those for which it was first targeted —some treatments proven effective and some not. It is rich inantibodies, which are proteins that help fight off infection.

With IVIG in short supply, hospitals are left to make toughchoices about who receives it, setting up a type of triage, likethat faced by Easton's family, who find themselves caught in a grayarea over which conditions qualify.

"IVIG can be a useful treatment for evidence-based purposes, butit's also often used as a last-chance, nothing-is-working Hail Marykind of approach for myriad conditions even when there is not clearevidence that it helps the patient," wrote Dr. Jerry Avorn, aprofessor of medicine at Harvard Medical School, in an email. Hewas speaking in general, not about any specific patient.

Nationwide, drug shortages of all kinds — from antibiotics to heart drugsto saline solution — are increasing and having a high impact onpublic health, the Food and Drug Administration said in a Novemberpublic meeting. They often result from manufacturing problems —such as when a factory shuts down or too few suppliers exist tomeet demand.

But the reasons for shortages of expensive infused drugs areparticularly complicated, involving complex manufacturingprocesses, scientific uncertainty and financial motivations.

In the case of IVIG, the expensive treatment may be a victim ofits own widening use.

Dating to the 1950s, immune globulin is often the only therapyfor certain genetic, life-threatening conditions that disable thebody's infection-fighting function. Its intravenous form isFDA-licensed for six conditions,including primary immunodeficiencies; Kawasaki disease, whichcauses inflammation in the blood vessels; preventive care afterbone marrow transplants; and a neurological condition calledchronic inflammatory demyelinating polyneuropathy.

Today, it is prescribed for patients whose immune systems havebeen compromised by viruses or treatments for cancer, so-calledsecondary immunodeficiency, although there may be other medicinesfor reinvigorating the immune system in those cases.

Prescribing a medicine for a purpose not approved by the FDA —known as off-label use — is legal and common. It sometimes leads tonew and effective uses of a drug.

Some evidence shows that expanding the use of immune globulin topatients with a wider variety of illnesses, including types ofcancers or recurrent infections, is helpful. But it is also beingtried for conditions "where it is ineffectual and may actuallyincrease the risks to patients," the American Academy of Allergy,Asthma and Immunology warned in a March 2017 journal articlethat weighs the clinical rationale for various uses of thetherapy.

In part as a result of this expanding off-label use, theindustry's trade group shows a 66%increase in distribution of the treatment from 2012 to 2018across North America and Europe.

And Avorn said a portion of these uses may be encouraged byfinancial motivations. Cincinnati Children's, for example, charges$6,800 to $10,000 for every 10-gram dose, according to thehospital's list prices, which are generally higher than insurerspay. Adults often get more than 10 grams per infusion.

"And anytime an extremely costly infusion medicine is used inany setting, it's worth looking at who benefits economically fromits use, especially for conditions in which data on effectivenessis limited or absent," Avorn said.

Nonetheless, increasing demand helped create the shortages, saypharmacists and others who study shortfalls. Immune globulin takesup to a year to produce, which includes plasma collection fromhealthy donors, processing, packaging and shipping — often atoverseas manufacturing centers.

There are several manufacturers, with combined global sales of about $22.6 billion.

Aside from trying to boost plasma collection to deal with ashortfall, "the other piece is stewardship [of the supply], andthat really is up to the hospitals, by and large," said John Boyle,CEO of the Immune Deficiency Foundation, a group that advocates onbehalf of people with genetic defects of the immune system."Hospitals use an enormous portion of the plasma products outthere."

Many are scrambling to come up with ways to stretch theirsupplies.

Some, like Cincinnati Children's, give top priority to patientswith no other alternatives, often those with primary immune deficiencies, and those for whom not getting thetreatment would be life-threatening.

Others, whose indications "were not as clear-cut or it was notnecessarily dangerous to them to forgo it were placed on the bottomof the list," said Dr. Derek Wheeler, chief of staff at CincinnatiChildren's.

Shortages are not affecting every hospital or clinic. Thatvariation occurs because facilities have contracts with specificdistributors or manufacturers, each of which can have a differentsupply line.

Dr. Cristina Porch-Curren, an immunologist in Camarillo, Calif.,said her patients have not run into problems getting the treatment,although one had to change brands.

She is concerned about the increasing use of immune globulin for"off-label" conditions.

"Off-label doesn't always mean bad. If you have someone who isreally sick, with some terrible infection, on occasion that may beOK," she said. But with limited supplies, she worries about growinginterest by researchers and some physicians in using immuneglobulin for more widespread or ongoing conditions, such asdementia.

"That's concerning, especially for patients with primary immunedeficiencies [who have no other alternatives]," she said.

Back in Cincinnati, a temporary solution has been found forEaston.

FFS Enterprises offered to supply his family with a differenttype of immune globulin after Easton's father reached out to thecompany, which is one of the largest distributors of the therapy.Instead of an intravenous dose, it has given Easton a subcutaneousform, injected as a shot at home. His doctor approved the switch,said Daniels, and the drug distributor said it would pick up thecost if his insurer, the state's Medicaid program, balks.

Kaiser Health News isa nonprofit news service covering health issues. It is aneditorially independent program of the Kaiser Family Foundation,which is not affiliated with Kaiser Permanente.

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