In my recent post on the FDA, I mentioned a story about a fish-oil-based infant nutritional fluid called Omegaven. The FDA took too long to approve it, and lots of infants died.
I plucked that from the anti-FDA blogosphere, where it had been floating around for a while in various incarnations. I tried to check it before publishing, but only enough to confirm the basic outline. A concerned reader sent me a Cochrane paper suggesting that the fluid was no better than previous treatments, which would potentially exonerate the FDA. This was concerning enough that I decided spend a longer time trying to figure out the specifics.
After more research, I’ve concluded that the story I told is basically true, although I got a few details wrong. I want to go over it at more length here to set the record straight and see what we can learn from it. My main source will be Dr. Kathleen Gura, the pharmacist most responsible for getting Omegaven approved. She won an award for her work, she gave a very long acceptance speech describing her adventure, and the transcript of her speech is where I’m getting most of this information.
Omegaven is a fluid for parenteral nutrition. If your digestive tract doesn’t work (a problem frequently associated with newborn babies), then you risk starving to death. Doctors can avert this by pumping nutrients directly into your veins through an IV. This is notoriously hard, because food has lots of nutrients, and if you try to put together a complete replacement for food you will probably miss something. The US standard is a nutrient fluid called Intralipid, which uses soybean oil as its main fat. Because of the usual random cross-national differences in medicine, Europe used a formulation with fish oil as the main fat (though I’m not sure whether they used it along with soybean or on its own). In the early 2000s, nobody thought there was any interesting difference between these.
Parenteral nutrition is notoriously tricky. Food has lots of different chemicals in it - vitamins, minerals, etc. Scientists haven’t discovered exactly which ones are biologically necessary, and if you forget one in your fluid then your patient will get some kind of inexplicable disease. One of these diseases is called PNALD - Parenteral Nutrition Associated Liver Disease. Lots of people on parenteral nutrition get PNALD. Some need liver transplants. Others die. Doctors assumed there was something they were missing, but they weren’t sure what.
In 2002, Boston Children’s Hospital needed to give IV nutrition to a kid with a soy allergy. The hospital only had soybean-based fluid, and tasked our hero Dr. Gura with finding a solution. She asked a bunch of experts and “put the question on various nutrition listserves”, and finally some nutritionist who attended European conferences mentioned that Europe had a fish-oil based fluid, Omegaven. If they could get permission to import Omegaven from Europe, they could maybe save this kid. They asked the FDA for permission, filled out the relevant forms, and (to its credit) the got approved within 48 hours. They were able to get an emergency shipment of Omegaven from Europe and the kid got better.
Meanwhile, a team of researchers at the same hospital, including a certain Dr. Puder, were trying to figure out what was going on with PNALD. They pumped lab rats full of various combinations of nutritional fluid, trying to see which rats got liver disease and which ones didn’t. Dr. Gura was helping this team get their IV nutrients, and on a whim:
I asked Dr Puder to humor me and use the leftover Omegaven in my office for the mouse model.
The Omegaven turned out prevent liver disease! (in rats). She continues:
We were confident we were onto something and began to discuss our findings with others at BCH. The response was not what we expected. We were told “Everyone knows it's not the lipids because liver disease happened with them and without them.” Some individuals would even pull me aside to ask “Are the results real?” Dr Folkman was totally supportive of our research methodology and our findings and said we should ignore the naysayers and needed to expand our research to other animal models.
We wrote almost 20 different grant proposals to a variety of funding sources including ASPEN, American College of Clinical Pharmacy, and the Gerber Foundation. The response was always the same…. “Everyone knows it's not the lipids.” Even Fresenius, who held the rights to Omegaven, was not interested in sponsoring our research. One rejection letter from a pharmacy organization noted that I wasn't qualified to do translational research, Dr Folkman (the father of angiogenesis) was not a suitable mentor, and Harvard was not the proper place to train a pharmacist in scientific research!
Luckily, BCH, the Departments of Pharmacy and Surgery, and the Vascular Biology Program (Dr Folkman's' lab) saw value in our work and funded us when no one else would. That is one of the reasons BCH is so special and why I believe that this discovery could not have happened anywhere else.
So they plodded on, testing the Omegaven in more and more kinds of animals, getting great results each time.
In 2004, the children’s hospital got an patient named Charlie, a newborn baby with a condition called gastroschisis which required IV nutrition. They gave him the nutritional fluids, he developed liver disease, and they were stuck - he would die if they took him off the IV, but he would also die if the liver disease continued. They were super out of options. So:
[Charlie’s surgeon], Dr Rusty Jennings, isn't one to follow the status quo. Some may call him a “cowboy,” but he is one of those guys who just won't give up. He came to Dr Puder and me one afternoon and asked us to do the mouse experiment using our “fish squeezings” on his patient Charlie. It was during this time that we couldn't get funding for additional animal studies. In fact, in our last submission, we stated, “if these experiments prove to be successful, they will provide additional evidence to translate this work into clinical studies in humans.” It was our hope to buy Charlie time to gain the necessary weight to make him eligible to undergo a multivisceral transplant.
Although Dr Puder was hesitant about doing this, because the only other case of fish oil monotherapy was that of my soy allergy patient 2 years' prior, he agreed. I retrieved all of my old soy allergy paperwork and began the process of developing a protocol that included informed consent. I also began to prepare the required FDA materials. Additionally, I contacted [pharma company] Fresenius and spoke with Dr Schlotzer, the inventor of Omegaven. Although initially hesitant, they ultimately agreed to provide a new supply of Omegaven, especially for Charlie for as long as he should need it. Charlie's parents understood that this was a long shot, but they felt they had no other options. They knew Charlie was the first baby, and the first patient with liver disease, to receive Omegaven. The only request they made was that if it worked we would offer it to other children just like Charlie.
Since you’re hearing this story, you can guess how it ended. Charlie made a miraculous recovery.
After this, Boston Children’s Hospital and the FDA kind of became pen pals - every time BCH got a new PNALD patient, they would ask the FDA for permission to import Omegaven from Europe, the FDA would grant it, and the patient would make a miraculous recovery. Eventually they worked together with the FDA to get something called an IND, which meant their hospital only was allowed to use Omegaven in the context of investigating and studying it.
But studying things is hard. The BCH team tried submitting case reports to journals, but none of the journals were really interested, and they didn’t have the funding for anything bigger. In 2006, the FDA itself donated enough money to do one small weak randomized trial, which found that Omegaven cut mortality by a factor of four. But this got them stuck in a rut. One small weak randomized trial wasn’t enough evidence for anyone else to care. But it was enough evidence that BCH refused to do larger studies, because that would require putting some babies in the control group, and obviously those babies were going to die, and that would be unethical. Someone else in Hong Kong tried to do a randomized controlled trial, but ran into the same problem - halfway through, the parents figured out what was going on, demanded their babies be put in the Omegaven group, and nobody had the heart to say no to them.
(This is where the Cochrane paper that my reader sent me comes in. It evaluates fish oil-based nutritional fluids on a lot of different dimensions, and this is one of them. Its only conclusion is that there was only one weak study showing it worked, so formal evidence is poor.)
People started yelling at the FDA to maybe start the process to approve Omegaven anyway. The FDA very reasonably protested that nobody had asked them to. Usually a pharma company would submit an application to the FDA, pay the fees, and do the paperwork. But Fresenius, the European pharma company that made Omegaven, had no interest. PNALD was rare, Omegaven was cheap, the FDA approval process was expensive, and this just wasn’t a winning business proposition for them.
Dr. Gura and her team, by her own description, started a “media war” to “encourage” (her quotation marks) Fresenius to change their mind. In 2012, they finally agreed and submitted their application. In 2018, the FDA finally approved it.
There still have not really been any great large-scale studies proving that Omegaven works better than older nutrient fluids, though my impression is that everyone who uses it believes it does.
UpToDate, the US gold standard medical evidence aggregator, says:
Accumulating evidence suggests that changing from a conventional soybean oil-based lipid emulsion to a fish oil-based lipid emulsion helps to reverse IFALD [another name for PNALD] in infants who require ongoing parenteral nutrition. The proposed mechanism is that soybean-based emulsions are thought to promote hepatic triglyceride synthesis and inflammation because of their high content of omega-6 fatty acids and phytosterols, compared with fish oil, which is rich in omega-3 fatty acids and contains no phytosterols...
For infants with marked progressive IFALD (direct or conjugated bilirubin >2 mg/dL), despite optimization of the general measures described above, and who are predicted to require PN for at least an additional 30 days, we suggest changing the lipid source to a fish oil-based lipid emulsion (Omegaven). As of 2018, this lipid emulsion was approved by the US Food and Drug Administration for use in pediatric patients with IFALD (defined by a direct bilirubin level >2 mg/dL after exclusion of other causes of cholestasis). This preparation is also available in many countries outside of the United States.
So although this is couched in the appropriate level of uncertainty, they do seem to believe it works better and they do recommend the new product.
My earlier version of the story made at least the following mistakes:
It discussed adding fish oil to nutritional fluids, whereas the real advance was switching to a different fish-oil-based nutritional fluid.
It said that the problem was that fish oil was necessary for infant development, whereas it actually has to do with this which fats cause this specific liver problem. I can’t find good sources about whether the issue is that soybean oil causes the liver problem, or that fish oil prevents the liver problem.
It didn’t mention some potentially exculpatory factors, like that there weren’t that many studies in favor (also, although I didn’t get into this above, some people thought the fish oil based fluid might cause bleeding, although this turned out not to be true).
I’m sorry for these errors and will add a link to this post on my Mistakes page.
Still, I think the basic structure was right - the new fluid was better than the old fluid, this was pretty clear in terms of miraculous recoveries, and it took 14 years between the first patient saved and full FDA approval.
You’ll notice that in Dr. Gura’s story (whose tone I tried to reproduce in Part II) it’s not obvious that this is an anti-FDA morality tale at all. Dr. Gura gently criticizes other doctors and hospitals for not realizing the value of Omegaven fast enough. She criticizes funding agencies for refusing to fund Omegaven studies, and journals for refusing to publish Omegaven articles. She even criticizes Fresenius, the pharma company behind Omegaven, for failing to advocate hard enough for its own product.
The FDA, in comparison, comes out looking pretty good. They approved the first few original single-patient exemptions to import Omegaven from Europe. They (eventually, after a lot of work) approved the Investigational New Drug application that let Boston Children’s Hospital keep using it (I’m still unclear whether any other hospitals got INDs for this). They even contributed a little funding to get one small study done. It wasn’t enough, but the FDA is not primarily a funding body, actual funding bodies dropped the ball on this one, and so it’s really impressive that the FDA went above and beyond to try to move Omegaven through the pipeline. Dr. Gura seems to have been left with the impression that the FDA was one of her few allies during this fight, which I think is fair.
I mentioned in a section of my recent post, “Sympathy For The Devil”, that I think the FDA as an agency is often quite good. They’re smart, caring people, and they usually carry out their mandate well - so well that the few exceptions, like aducanumab, are highly newsworthy. I have no objection to Dr. Gura’s mostly-positive portrayal of them.
My problem is: doing anything in medicine is illegal until you clear a giant hurdle. To clear the hurdle, you have to pay millions (sometimes billions) of dollars, fill in thousands of pages of forms, conduct a bunch of studies that can be sabotaged for reasons like “this drug is too good so it would be unethical to have a control group”, and wait approximately ten years. You have to clear this hurdle to do anything, even the most obviously correct actions. Everything starts out illegal, and then a tiny set of possible actions is exempted from the general illegality. The easiest name for this hurdle is “the FDA”, since they’re the agency charged with enforcing it.
Given the existence of the hurdle, various people come off looking like villains, eg:
Yes, funding agencies look bad, insofar as they refused to provide enough millions of dollars to clear the hurdle. But there’s no funding agency so rich that they can can give hurdle-clearing amounts of money to every promising new treatment.
Yes, the pharma company involved looks bad, insofar as it balked at the time and expense involved in starting the approval process for its product. But who made the hurdle so high that even a pharma company - one with a great drug and the chance to make millions of dollars off it - took one look at the amount of time/energy/expense involved and said “no thanks”? And if pharma companies are intimidated by the process, what hope does anyone else have?
Yes, the other doctors who didn’t really care about this potentially life-saving treatment look bad. But in their defense, they would have had to go through the FDA special-exemption import process to even begin testing this on their own patients. I once had a patient who needed an unusual European drug not available in this country. briefly considered the FDA special-exemption import process, and decided to do the reasonable thing and walk my patient through the process of ordering it illegally on the Internet. I am not super proud of this, but at least the patient got their drug, which is more than you can say about most of the times this kind of thing happens.
…and given the existence of the hurdle, the FDA (as an agency) comes off looking good. They helped coach Dr. Gura through the process of filling out forms. They helped fund Dr. Gura’s study. They worked extra hard to process the Omegaven application as fast as they could. Good for them.
But as long as this giant hurdle sits in the path of medical practice, lots of people will inevitably be villains, and lots of other people will need to display an unusual and not-fair-to-expect-of-them level of heroism to get anything approved at all.
Partly this is about Dr. Gura having to move heaven and earth (and become something of a political activist) to gather the coalition that eventually got Omegaven approved. But partly it’s about - did you notice how unlikely the discovery of Omegaven was? It required:
Dr. Baker, a BCH nutritionist, was in touch with the European medical establishment and had learned about their alternative nutritional fluid.
Dr. Gura, a BCH pharmacist, had a patient with a soy allergy and needed some solution.
Dr. Puder, a researcher, was doing mouse studies on the causes of PNALD
Dr. Jennings, a surgeon, had a patient with such a severe case of PNALD that they would obviously die without a miracle, and might as well just try a random thing that seemed to work in mice.
…all to be in the same place around the same time.
And I was tickled to hear Dr. Gura describe Dr. Jennings as a “cowboy”, because I’ve been trying to make the case that the point where “cowboy” (used metaphorically, to mean someone who is willing to take initiative) went from complimentary to pejorative marked the beginning of the end for our civilization, and we need to make it a compliment again. All four of these doctors needed to at least kind of be “cowboys”, willing to try crazy things that weren’t the standard of care. If you imagine there’s a 10% chance of each link in this chain being around in any given situation and being able to do their cowboying successfully, the chance of an Omegaven-level discovery is 10% * 10% * 10% * 10% = 0.01%. This is one of the reasons science is so hard.
But the hurdle makes it harder. Dr. Gura didn’t just need to have a patient with a deadly soy allergy. She had to fill in a bunch of forms begging the FDA for the right to import something from Europe. Dr. Jennings didn’t just need to be a “cowboy”, he needed to have the right combination of cowboyness and willing-to-go-through-an-arduous-special-exemption-approval-process-to-get-the-right-to-try-his-crazy-idea-ness. If even half the people in these situations would be turned off by these kinds of trivial inconveniences, our chances go down to 5% * 5% * 5% * 5% = one sixteenth what they were before. Discoveries are made by weird tinkering, but it’s really hard to weird-tinker when everything is default-illegal except a small set of officially permitted actions.
(it’s easy to say that since lives were on the line, you should fill in the paperwork regardless of how onerous it might be. I agree this is what a good person might do, but I myself am not that good a person - I gave up on what I thought was an important study because an IRB placed so many obstacles in my way that it would have driven me crazy to continue. I take some slight comfort in knowing that even Dr. Gura, part of the tiny pantheon of people who successfully advocated for new drugs, seems to have gotten close to this - in her acceptance speech, she thanks “Eileen Sporing, the VP of patient services at BCH, who successfully advocated for me when the IRB would not let me consent patients for my own drug study.” Maybe if I’d had an Eileen Sporing, I would have continued my project - but Eileen is another one of the heroes who we can best honor by making their sacrifices less necessary in the future.)
I realize the hurdle is there for a reason. What would a default-yes medical world look like? What would a still-default-no-but-the-hurdle-is-smaller medical world look like? I have thoughts about this which I hope to address in future posts.
For now, I think the real story of Omegaven is that a lot of really great and heroic people, both inside and outside the FDA, worked really hard to fight for a lifesaving treatment, and should feel good about themselves. Meanwhile, it still took fourteen years, and hundreds to thousands of babies still died preventable deaths. It will be really hard to change the system radically enough to make it possible to do better, but I still think we should try.