I sent this statement (PDF) to the FDA Panel administrator as she instructed. She was apologetic for misinforming me in a prior email that I could submit the actual study. I requested confirmation my statement would be made available to the panel. This is a text only copy, formatting lost.
Dear Stephanie,
As you advised, I am writing this statement to be submitted for review and consideration by the Advisory Committee convening October 16th 2013 Endocrinologic and Metabolic Drugs Advisory Committee Meeting for NDA 202057/S-005.
There has been much deliberation and discussion written about the effects of fish oil and its derivates on cardiovascular outcomes and these studied effects have been at best confusing and often contradictory. With the exception of the JELIS study, most such trials published to date have shown no material association of the consumption of fish, fish oil supplements or its derivates. This is of course concerning as it related to NDA 202057/S-005 if it were not for one conspicuous factor that is common among those trials that failed to show positive outcomes. That factor is both the dose studied and a scientific understanding of how EPA is metabolized and the relationship of metabolized EPA to AA and how that ratio between EPA and AA is correlated to CVD risk factors and outcomes Putting aside those that studied diets containing ordinary fish in diet, and considering only those studies in which dose are closest to, or similar to that of Vascepa (4 grams of icosapent ethyl) , we are left with only a small number of studies that can be considered as comparative by scientific measure. The reason is simply because the dose in every study was fractional to what is contained in Vascepa. For example, fish oil supplements contain comparatively small amounts of icosapent ethyl (EPA eicosapentaenoic acid), usually found to be between 300- 500mg on average. The one study in which utilized icosapent ethyl EPA (eicosapentaenoic acid) in a similar dose to trials conducted and the currently approved Vascepa drug, was the JELIS study. Upon reading the JELIS study and subsequent follow on reviews and meta analysis, it appears obvious to me that the effectiveness of icosapent ethyl / (EPA eicosapentaenoic acid) at reducing cardiovascular events is dose dependent. And therefore dose dependency should be considered material to any discussion among the advisory committee for NDA 202057/S-005 when any outcomes are considered.
The 5 years JELIS study, composed of 18,645 Japanese produced fascinating results especially in a cohort of those with TG > 150 mg/dl where the reduction of major coronary events was 53%. The obvious disparity between this study and all other outcome studies is the 1.8 grams dose of pure icosapent ethyl (EPA eicosapentaenoic acid) as opposed to unrefined, mixtures of much smaller doses . The results of both the Marine trials and Anchor trials included both 2 gram and 4 gram dose. A review of the Marin and Anchor data will clearly show that 4 grams of icosapent ethyl (EPA eicosapentaenoic acid) was required to produce meaningful and material improvements in lipid parameters and confirm dose dependency.
The EPA to AA ratio correlation to CVD outcomes
But what should be even more important to the committee beyond dose dependency is the relationship between EPA and Arachidonic Acid which has recently been discovered to be strongly correlated to such a sizable reduction in cardiovascular events as was found in the JELIS study .
A very timely and important paper titled “Eicosapentaenoic Acid (EPA) Reduces Cardiovascular Events: Relationship with the EPA/ Arachidonic Acid ratio” addresses this relationship of EPA and AA and the ratios effect on CV events. I have attached the study to this letter as you requested. This timely and critically important study should be made required reading by the advisory committee since it is the first such study to scientifically explain the disparity among past studies that have shown positive outcomes and those that do not. This paper was published in the Journal of Atherosclerosis and Thrombosis Vol 20 and made available online September 18th, 2013. This paper explains the clinical efficacy of EPA and exposes with exceedingly strong correlation the ratio of EPA to AA to incidence of cardiovascular events. The importance of this study is germane to the decision being made the advisory committee and critical when considering the decision is made on behalf a very large segment of the US population whose lipids beyond LDL-C are largely untreated; the 20 million diabetics at risk for CVD.
The study I am referencing concludes that the difference between EPA and DHA is the metabolism of EPA to bioactive PGI3. It is assumed that similar to PGI2, PGI3 inhibits platelet aggregation, vascular contraction, myocardial ischemic injury and arteriolosclerosis. It was speculated that the CVD risk reduction induced by EPA is associated with the effects of PGI3 in addition to numerous effects of EPA itself such as TG reduction, inflammation inhibition, and improvements in plasma membrane fluidity. This hypothesis is confirmed by the following findings; an increased CVD risk was found to be associated with a reduction in the EPA/AA ratio, and the EPA/AA ratio was found to be positively correlated with the (PGI2+PGI3)/TXA2 ratio.
In closing, I would find it concerning and frankly alarming that this esteemed advisory committee would not be given access to this study by the FDA in advance of making a decision that could potentially improve the longevity and quality of life for millions of Americans who are at most risk for events and possibly death from CVD.
I eagerly await on your confirmation that this critical material I reference is to be made available to the advisory committee in advance of the meeting on October 16th 2013, Endocrinologic and Metabolic Drugs Advisory Committee Meeting for NDA 202057/S-005.
Sincerely yours,
