Medical
treatment has knocked down tumors in 6-year-old Easton Daniels’ brain, but the
drug used also wiped out his immune system.
To
bolster his immune function and help keep him healthy, he has visited a
hospital for intravenous infusions of immune globulin about every month for the
past year and a half.
But in
early July, his family was stunned by a letter from Cincinnati Children’s
Hospital: “All of Easton’s appointments canceled until further notice,” said
his dad, Jeremy Daniels, who works in custodial services for a school.
Like
Cincinnati Children’s, hospitals and clinics nationwide report a shortage of
the medication, whose long manufacturing process starts with donated blood
plasma. Often referred to as IVIG, intravenous immune globulin is used for a
wide variety of medical conditions, beyond those for which it was first
targeted — some treatments proven effective and some not. It is rich in
antibodies, which are proteins that help fight off infection.
With
IVIG in short supply, hospitals are left to make tough choices about who
receives it, setting up a type of triage, like that faced by Easton’s family,
who find themselves caught in a gray area over which conditions qualify.
“IVIG
can be a useful treatment for evidence-based purposes, but it’s also often used
as a last-chance, nothing-is-working Hail Mary kind of approach for myriad
conditions even when there is not clear evidence that it helps the patient,”
wrote Dr. Jerry Avorn, a professor of medicine at Harvard Medical School, in an
email. He was speaking in general, not about any specific patient.
Nationwide,
drug shortages of all
kinds — from antibiotics to heart drugs to saline solution — are increasing and
having a high impact on public health, the Food and Drug Administration said in
a November public meeting. They often result from manufacturing problems — such
as when a factory shuts down or too few suppliers exist to meet demand.
But the
reasons for shortages of expensive infused drugs are particularly complicated,
involving complex manufacturing processes, scientific uncertainty and financial
motivations.
In the case
of IVIG, the expensive treatment may be a victim of its own widening use.
Dating
to the 1950s, immune globulin is often the only therapy for certain genetic,
life-threatening conditions that disable the body’s infection-fighting
function. Its intravenous form is FDA-licensed for six conditions, including primary
immunodeficiencies; Kawasaki disease, which causes inflammation in the blood
vessels; preventive care after bone marrow transplants; and a neurological
condition called chronic inflammatory demyelinating polyneuropathy.
Today,
it is prescribed for patients whose immune systems have been compromised by
viruses or treatments for cancer, so-called secondary immunodeficiency,
although there may be other medicines for 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 to new and effective uses of a drug.
Some
evidence shows that expanding the use of immune globulin to patients with a
wider variety of illnesses, including types of cancers or recurrent infections,
is helpful. But it is also being tried for conditions “where it is ineffectual
and may actually increase the risks to patients,” the American Academy of
Allergy, Asthma and Immunology warned in a March 2017 journal article that weighs the clinical
rationale for various uses of the therapy.
In part
as a result of this expanding off-label use, the industry’s trade group shows a
66% increase in distribution of the treatment
from 2012 to 2018 across North America and Europe.
And
Avorn said a portion of these uses may be encouraged by financial motivations.
Cincinnati Children’s, for example, charges $6,800 to $10,000 for every 10-gram
dose, according to the hospital’s list prices, which are generally higher than
insurers pay. Adults often get more than 10 grams per infusion.
“And
anytime an extremely costly infusion medicine is used in any setting, it’s
worth looking at who benefits economically from its use, especially for
conditions in which data on effectiveness is limited or absent,” Avorn said.
Nonetheless,
increasing demand helped create the shortages, say pharmacists and others who
study shortfalls. Immune globulin takes up to a year to produce, which includes
plasma collection from healthy donors, processing, packaging and shipping —
often at overseas 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 a shortfall, “the other
piece is stewardship [of the supply], and that really is up to the hospitals,
by and large,” said John Boyle, CEO of the Immune Deficiency Foundation, a
group that advocates on behalf of people with genetic defects of the immune
system. “Hospitals use an enormous portion of the plasma products out there.”
Many
are scrambling to come up with ways to stretch their supplies.
Some,
like Cincinnati Children’s, give top priority to patients with no other
alternatives, often those with primary immune deficiencies,
and those for whom not getting the treatment would be life-threatening.
Others,
whose indications “were not as clear-cut or it was not necessarily dangerous to
them to forgo it were placed on the bottom of the list,” said Dr. Derek
Wheeler, chief of staff at Cincinnati Children’s.
Shortages
are not affecting every hospital or clinic. That variation occurs because
facilities have contracts with specific distributors or manufacturers, each of
which can have a different supply 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 is really sick, with some
terrible infection, on occasion that may be OK,” she said. But with limited
supplies, she worries about growing interest by researchers and some physicians
in using immune globulin for more widespread or ongoing conditions, such as
dementia.
“That’s
concerning, especially for patients with primary immune deficiencies [who have
no other alternatives],” she said.
Back in
Cincinnati, a temporary solution has been found for Easton.
FFF
Enterprises offered to supply his family with a different type of immune globulin
after Easton’s father reached out to the company, which is one of the largest
distributors of the therapy. Instead of an intravenous dose, it has given
Easton a subcutaneous form, injected as a shot at home. His doctor approved the
switch, said Daniels, and the drug distributor said it would pick up the cost
if his insurer, the state’s Medicaid program, balks.
[Correction:
This story was updated at 3:15 p.m. ET to correct the name of the company
supplying the Daniels family with an injectable form of immune globulin.]
Julie
Appleby: jappleby@kff.org,
@Julie_Appleby
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