A life-saving adjustment in IV nutrition cleared by the FDA

Fourteen years after Charles Rolfe received an experimental IV fish-oil solution, Omegaven has been approved by the FDA. (PHOTOS: WEBB CHAPPELL/ROLFE FAMILY)

In 2004, a surgeon and a hospital pharmacist went against the prevailing dogma. They began revising the IV nutrition formula being given to children unable to take food by mouth. In doing so, they saved many lives. Yet, it wasn’t until last month that their intervention, a new fat emulsion called Omegaven, gained formal approval from the Food and Drug Administration.

Children with intestinal failure due to gastroschisis, necrotizing enterocolitis or other diseases are typically placed on parenteral nutrition, an intravenous method of feeding. Without it, they would die. But prolonged use of IV nutrition — using the traditional formula — had a massive side effect: injury to the liver. The majority of children either died from liver failure or required a liver transplant.

By 2001, surgeon Mark Puder, MD, at Boston Children’s Hospital was tired of watching babies slowly die from liver disease that should be preventable. He suspected something needed to be adjusted in the IV nutrition formula — particularly the fat component, derived from soybean oil and known as Intralipid.

But the prevailing view was that parenteral-nutrition-associated liver disease was a result of other components of the IV formula, not the lipid portion, since liver damage occurred even when the lipid was omitted from the formula.

Puder and surgical resident Jenna Garza, MD, decided to tease apart the biology. Kathleen Gura, PharmD, a clinical pharmacist specializing in nutrition, also joined the project. Doing multiple studies in mice, they tested various formulations, combinations and administration routes.

Omegaven: Patient zero

In the midst of this, Gura was trying to help a patient who needed treatment for an essential fatty acid deficiency, but had a soy allergy and couldn’t receive Intralipid. Gura successfully treated hi with a fish-oil based formula — Omegaven — from a European company, Fresenius Kabi. Some formula was left over, so she and Puder decided to try it in the mice.

Puder and Gura (PHOTOS: KATHERINE COHEN/BOSTON CHILDREN’S HOSPITAL)

Results were dramatic: the liver disease the mice had developed with Intralipid disappeared.

“I presented the laboratory data at Grand Rounds,” says Puder. “One of my surgical colleagues, Rusty Jennings, had a patient with rapidly progressing liver disease, and asked, ‘Can you try Omegaven in my patient?’”

Puder and Gura got approvals from the FDA and Boston Children’s Institutional Review Board to try it on a compassionate-use basis. On September 26, 2004, Charles Rolfe became the first baby in the world to receive Omegaven as the sole lipid in his IV nutrition solution.

Born with gastroschisis, a birth defect in which the intestines develop outside the body, Charles spent the first eight months of his life at Boston Children’s, receiving IV nutrition and tube feedings. With the standard lipid emulsion, his liver had deteriorated to the point that he would soon die without a transplant. His parents were willing to give Omegaven a try, even though it had been studied only in mice.

“It was risky and I was very hesitant,” says Puder. “But Charles had run out of options and was running out of time.”

With Omegaven, Charles quickly began to recover. Labs showed his liver was functioning perfectly. Just over a month after his first dose of Omegaven, he was taken off the transplant waiting list.

“He went home within a few weeks after getting it,” says his mother, Alyson.

Overcoming skepticism

We received a lot of support from the nurses,” notes Gura. “Back in the day, a lot of nurses transferred to other units because it was so hard to see children die slowly of liver disease.”

Even with this success, not all of Puder’s and Gura’s colleagues were convinced that the standard IV nutrition formula should be changed. Clinical nutritionists dismissed Omegaven, saying, “everyone knows it’s not the lipids” causing the liver disease. And there were safety concerns.

“We were going against dogma,” says Gura. “People thought you’d get bleeding, people thought you’d get an essential fatty acid deficiency if we used Omegaven as the only lipid source.”

But one by one, Gura and Puder began using Omegaven in patients with IV-nutrition-related liver disease on a compassionate-use basis, with good results. Patients began arriving from all over the country to receive it.

Puder, Gura and colleagues began publishing case series, first in two infants with short bowel syndrome (including Charles) who had IV-nutrition-related liver disease, then in another 18 infants. To date, there have been more than 70 publications.

A hospital steps up

Though almost all infants got better with Omegaven, the FDA remained unconvinced.

“They wanted us to do a randomized controlled trial, which Kathy and I refused to do because we saw such good results with Omegaven,” says Puder.

In addition, Fresenius Kabi wasn’t interested in pursuing testing of its emulsion in the U.S., especially in gravely ill infants. In fact, the package insert for the product in Europe said Omegaven was contraindicated in liver disease. It was being used only in adults, as a supplemental anti-inflammatory agent, for periods of less than two weeks.

But Puder and Gura convinced the company to keep providing it, and Boston Children’s made Omegaven available to any child who needed it, at its own considerable expense. (As an “experimental” treatment, it wasn’t covered by insurance.)

“We received a lot of support from the nurses in particular,” notes Gura. “Back in the day, a lot of nurses transferred to other units because it was so hard to see children die slowly of liver disease.”

Saving lives

Finally, in December 2017, Puder, Gura, collaborators and the company had assembled enough data to go back to the FDA, which has become more willing to expedite their reviews in cases of dire need. Less than nine months later, the agency approved Omegaven for children with liver disease associated with parenteral nutrition.

Omegaven emulsion for infusion
PHOTO: FRESENIUS KABI

“Prior to this, all lipid emulsions had a ‘black box’ warning, saying they could cause fat overload syndrome that could be fatal,” says Gura. “We convinced the FDA that Omegaven doesn’t cause this side effect, and we were able to have the black box removed.”

The prospective study is still enrolling, and to date, more than 280 patients have received Omegaven under compassionate-use guidelines. Most have done well. The vast majority are still alive, including Charles Rolfe, now 14. He still receives IV feedings, but is doing well, loves fishing and the outdoors and will enter a technical high school this fall. The Rolfes still keep in close touch with Boston Children’s and visit every four to six weeks.

Now that Omegaven has FDA approval, other hospitals can readily obtain it for their patients.

“It’s kind of crazy that Charlie’s 14 and it’s taken 14 years to get it approved,” says Alyson. “It’s good that other people are being saved.”