2013 IVFE Workshop and survey results
The FDA is having a public workshop on intravenous fat emulsions (i.e., TPN lipids) on October 29th, 2013 -- there is a survey to collect information on the patient experience with IVFE's that could potentially provide valuable information for this workshop. Here's those links again:
- http://www.fda.gov/Drugs/NewsEvents/ucm369044.htm -- info about the workshop, which will be webcast
- https://cuboulder.qualtrics.com/SE/?SID=SV_79Q2irnC52R0iHz -- anonymous patient survey -- please submit results by Oct 12 to be included in the presentation for the workshop. Results will be presented on this website.
Results of Survey
83 complete responses were submitted. Initial major results are shown here -- thanks to everyone who responded!! These data very strongly confirm the general sentiment in the patient community that IntraLipid can be very damaging for a significant proportion of patients, and that Omegaven is very safe, and should merit FDA approval. Here is a draft of the Patient Perspective presentation for the workshop, incorporating this data, and all the wonderful comments that people submitted: Media:oreilly fda pres wkshop 2013.pdf -- please send any feedback to: randy.oreilly [at] colorado [dot] edu. Thanks!
Summary of Workshop
Slides from workshop available here: http://www.nutritioncare.org/Professional_Resources/FDA_ASPEN_IVFE_Workshop_Syllabus/
Basic Fatty Acid Science
- There are two competing metabolic pathways for processing fatty acids: the omega-6 and omega-3 pathways. Omega-6 is pro-inflammatory (heightened immune response), and Omega-3 is anti-inflammatory (suppressed immune response)
- The omega-6 pathway starts with 18:2 (18 carbons, 2 double bonds) Linoleic Acid (LA): http://en.wikipedia.org/wiki/Linoleic_acid
- The most pro-inflammatory step in the omega-6 pathway is Arachidonic Acid (AA)
- The omega-3 pathway starts with 18:3 (18 carbons, 3 double bonds) Alpha-Linolenic Acid (ALA): http://en.wikipedia.org/wiki/Α-linolenic_acid
- Theoretically this leads to production of EPA and DHA, which are the main anti-inflammatory fatty acids, but this pathway is actually not very productive so that consumption of "raw" ALA does not produce very much EPA and DHA. Thus, it is beneficial to obtain EPA and DHA directly in the diet.
- omega-3 also improves the metabolism of other fats -- very good to have some of this in the mix!
Soy oil contains over 50% Linoleic Acid (LA) and is thus strongly pro-inflammatory.
Fish oil contains large proportions of EPA and DHA and is thus strongly anti-inflammatory
MCT (medium chain triglycerides) e.g. from Coconut oil are not very "bioactive" like the above LCT's, and are primarily a source of energy -- easily oxidized and converted into energy. http://en.wikipedia.org/wiki/Medium-chain_triglyceride
Olive oil contains mainly Oleic acid http://en.wikipedia.org/wiki/Oleic_acid -- it is not clear exactly how it stacks up -- overall perhaps less bioactive and more like MCT -- a neutral energy source?
Summary: very clear basic science for why pure soy oil is imbalanced. Pure fish oil is similarly imbalanced the other way. SMOF which contains soy, MCT, Olive, and Fish oils is probably a reasonable balance, and has been very successful in reducing incidence of liver disease and other negative side effects in Dr. Jon Shaffer's large intestinal failure practice in Manchester, UK.
For kids on pure omegaven fish oil, the strong imbalance toward anti-inflammatory will produce suppression of the immune response, and thus these kids will be more susceptible to catching diseases. Also, the one thing that LA is particularly important for is fluid transport across cells, and LA depletion will result in scaly, dry skin. Thus, it probably makes sense after primary liver disease symptoms have been ameliorated to reintroduce some level of soy oil into the mixture, especially if the level of enteral intake is otherwise low. The new availability of the 80% olive oil / 20% soy oil Clinolipid from Baxter could be used to make a SMOF-like combination together with omegaven (SOF actually) that would be more balanced.
Existing Clinical Trial Data
Overall, there are SOME statistically significant results of various alternative IVFE formulations on clinical outcomes such as length of stay in the hospital, rates of infection, etc, but the effect sizes are not large, and results not strongly reliable across studies.
The point was made that there have been a number of drugs specifically targeting the anti-inflammatory or pro-inflammatory pathways directly, and these have failed to show clinical benefits as well. Thus, the idea that the relatively weak manipulation of diet could have some kind of benefit here is, on this basis, not very credible.
Everyone agreed that getting beyond pure soy was likely to be beneficial in many ways, but often the use of IVFE is limited to a short duration and doesn't really matter that much.
Dr. Abrams (Baylor) emphasized that just reducing the dose of soy oil IVFE does NOT prevent liver disease in many patients. Furthermore, reducing these nutrients is deleterious for patients in many ways. Thus, we really do need new formulations!
Conclusions and Way Forward
The final debate centered around the following key question:
- Can a new IVFE product just demonstrate non-inferiority compared to existing product, and safety as a nutritive source of fat and calories, or does it have to demonstrate some kind of superiority in a well-defined clinical outcome?
It seems clear from the FDA's slides and some comments from the FDA that they would prefer to have a superiority claim. But this is a much higher hurdle to achieve, because it likely requires longer-term TPN patients and longer-term studies -- these are smaller populations, and the longer duration of the study makes it more expensive. And the points above about existing clinical trial outcomes are very relevant. Nutrition is a relatively weak tool for achieving strong clinical outcomes.The strong consensus from most of the participants seemed to be that a simple non-inferiority demonstration focused on the safe delivery of essential nutrients would be the most reasonable way to proceed, to give clinicians a range of options, and enable further studies going forward. Given the extensive use of these newer IVFE formulations in other countries, it would seem that this data is already in hand, and, if the FDA were to proceed with this approach, things could happen relatively quickly, as was the case with the recent Clinolipid approval, which also relied largely on existing data.