Sunday, June 02, 2019 11:03:40 AM
https://medicalresearchcollaborative.com/reports
1.5.1 Log-transformed hs-CRP Data
A line in the supplement to the NEJM paper on REDUCE-IT cites the result of an analysis of log-transformed hs-CRP data, which showed a highly significant 21.8% reduction in IPE group, and no change from baseline in the placebo group. The sponsor’s website provides the following explanation:[1]
However, with a study as large as REDUCE-IT, and with nine separate fasting lipid panels performed on average per subject to ascertain levels,[2] log-transforming biomarker data is unnecessary, and analyses based on such data could be misleading.
The Central Limit Theorem (CLT) states that the sampling distribution of the mean of any independent, random variable will be near normal if the sample size is large enough. Thus, the means of large samples will closely follow a normal distribution, whatever the distribution of the observations themselves.[3] Generally, this is considered true in samples of modest size where skewness and kurtosis are low, but certainly in samples of over 500 subjects when skewness and kurtosis are high.[4]
As the CLT stipulates that for large samples the mean can be approximated by a normal distribution even if the population is non-normal (i.e. data are skewed), then if the sample size is large, it is appropriate to use a t-test.[5] With over 4,000 subjects per arm in REDUCE-IT, and with the added benefit of so many repeat lipid panels performed, untransformed hs-CRP data will follow a normal distribution (mean and median approximately equal). Essentially, REDUCE-IT is over-sized and over-powered when doubling as a biomarker trial, i.e. there were 1,612 major coronary events, but >8,000 biomarker “events.” The percent changes noted in the study are based on median values, which reflect the central tendencies of the robustly sized groups. And because of the large size of each treatment group, the geometric mean and median hs-CRP values will be near equal, and the kurtosis near 3.[6] Skewness will also affect both groups approximately equally, and thus, any subsequent regression to the mean will equally impact both arms.
As the previous citation also enumerates, log-transformation has been shown to have major drawbacks. It can cause right-skewed data to become left-skewed, and may even increase skewness; it can often increase—instead of reduce—the variability of data, whether or not there are outliers; it can lead to inaccurate estimates of the true population mean of the original data; it can cause significant errors in hypothesis testing, and is prone to numerous user errors as well. There is also little value in comparing the variability of original versus log-transformed data because they are on different scales. Log-transformed data therefore cannot usually facilitate inferences concerning the original data, since it shares little in common with the original data.[7] Therefore, an analysis based on classical statistical methods or generalized estimating equations is most appropriate.
Lastly, and as was also seen in JUPITER and CANTOS, hs-CRP values were highly consistent between lipid panel tests over years in both arms of REDUCE-IT (after the initial post-randomization changes had occurred). It has previously been shown that hs-CRP levels are as consistent over time as total cholesterol and blood pressure.[8] This adds to the reliability of interpretations based on observed levels.
The above considerations make drawing conclusions based on log-transformed hs-CRP data from the REDUCE-IT trial potentially misleading. Comparing the percent median change between groups using untransformed hs-CRP data is an accurate and reliable way to analyze these data.[9]
***
1.7 Confirmation of an Adverse Impact of Mineral Oil on Drug Absorption
The elevation of all atherogenic and inflammatory markers measured in MO placebo group in the REDUCE-IT trial was previously observed to a similar degree in a separate study—the ANCHOR trial, also sponsored by Amarin Corp.
In ANCHOR, over 700 subjects (all of whom were on background statin therapy) were randomized 1:1:1 to either 4 g/d MO arm, 2 g/d EPA arm (which included 2 g/d MO in addition to 2 g/d EPA[10]), or 4 g/d EPA arm. The trial was designed with an extensive lead-in period to stabilize lipid and lipoprotein values before randomization. The median percent changes in parameters from baseline to 12 weeks per group were as follows:
An extensive wash-out and stabilization period should help control against errant swings in markers between the three robustly sized groups (approximately 230 randomized per arm). The lead-in period protocol details from the ANCHOR trial are outlined below:
After examining the ANCHOR trial data, an FDA reviewer stated the following in the briefing documents:
In his book Dyslipidemia: Pathophysiology Evaluation and Management, 2015., Dr. Garg writes,
Although the most profound elevations in markers were observed in the 4 g/d MO arm, the 2 g/d arm exhibited a muted effect compared to what might be expected from this dose of concentrated EPA. For example, in the ORD study, comparing TAK-085 (a POM3) with EE-EPA, the 1.8 g/d EPA arm (n=195) showed an 11.2% reduction in triglycerides at the end of 12 weeks of dosing.[11] However, in ANCHOR, 2 g/d EPA combined with 2 g/d MO resulted in a more tepid 5.6% reduction in TG. Importantly, mean TG levels at baseline were similar between the two studies (272 mg/dL in the ORD study and 262 mg/dL in ANCHOR).
In fact, the 5.6% reduction in TG in the 2 g/d arm is similar to the reduction seen in the 4 g/d olive oil placebo arm in the ESPIRIT trial, which enrolled subjects of similar background therapy and baseline TG levels as ANCHOR. There, a 5.9% reduction from baseline in TG level was observed in placebo group.[12]
Was concurrent dosing with MO somehow negatively impacting the efficacy of EPA, or perhaps hindering statin absorption, thus attenuating the overall TG lowering effects observed in the ANCHOR 2 g/d group? The same incongruency is observed in other markers as well, for example non-HDL-C was reduced by 5.7% in ORD (1.8 g/d arm), but increased by 2.4% in ANCHOR (2 g/d arm).
From the MARINE trial data (~25% of whom were on background statin therapy), which also tested 4 g/d EPA against 4 g/d MO or 2 g/d MO+2 g/d EPA in subjects with very high triglycerides (>500 mg/dL), an FDA reviewer commented on the wild fluctuations in mean triglyceride levels in the two arms that received MO, while no fluctuation in the 4 g/d EPA arm that received none. This is consistent with the notion that MO causes some form of interference with drug absorption.[13]
Interestingly, in the ANCHOR and REDUCE-IT placebo groups there was a 4.8% and 4.7% increase in HDL-C respectively, both significant. Counter-intuitively, HDL-C has been shown to increase more from a lower versus higher atorvastatin regimen.[14]
The increase in HDL-C in both placebo groups might therefore be expected if the dose was effectively lowered due to malabsorption. In the MARINE trial, where the vast majority were not on statin therapy, HDL-C was unaffected in either the 4 g/d MO or 2 g/d MO+2 g/d EPA groups.
In the REDUCE-IT trial, highly significant increases in atherogenic markers also appeared in the MO placebo group quickly (at the next blood draw 4 months later) and remained elevated throughout the study. Meanwhile, in those randomized to IPE arm, there was little change (i.e. LDL-C moved down slightly from 85.8 mg/dL at baseline to 83.6 mg/dL at month 4, then back up to 85.3 mg/dL at year 1 and to 85.5 mg/dL at year 2)—except in markers known to be impacted by EPA, such as TG and, to a lesser extent, non-HDL-C.
Regarding the differences in risk reduction seen between subjects on low (HR 1.12), medium (HR 0.76) and high-intensity (HR 0.69; p=0.12, significant for interaction) statins in the REDUCE-IT study, a related phenomenon surfaced in ANCHOR.
However, this was “compared to placebo.” The “decreased hs-CRP” as stated was not due to an observed reduction in hs-CRP levels in IPE group from baseline (-2.4%, p>0.05), but instead due to the highly significant increase in hs-CRP levels in the MO placebo arm. The breakdown is given as follows:
But why would IPE—compared to MO placebo—have such differential effects on CRP, depending on the intensity of the background statin therapy of the subject? We can see that IPE had no measurable impact on CRP levels from baseline in those dosed with it; therefore, whatever impact on CRP is likely coming not from IPE, but from an adverse effect of MO on placebo group subjects.
High-intensity statin regimens produce the largest reductions in CRP levels, followed by moderate and then low-intensity regimens.[16], [17] Therefore, if MO attenuated the efficacy of statin therapy, we would expect those on high-intensity statins to show the largest increase in CRP levels, followed by those on moderate-intensity, with the least change in those on low-intensity regimens. And that is what the ANCHOR trial data show.
Regarding the difference in changes in hs-CRP levels between the ANCHOR (+17% at 12 weeks) and REDUCE-IT (+32.3% at year 2) studies, Bonnet et al. (2008)[18] showed that after an initial sharp decrease in CRP levels from statin therapy, high-dose therapy further lowered levels over a 26-week follow-up period; i.e. atorvastatin 10 mg/d produced a 25% decrease in hs-CRP over a 5-week period, which was maintained at 26 weeks (-24.3%), whereas the 80 mg dose produced a 36.6% decrease over 5-weeks, which then continued on to a 57.1% decrease at 26 weeks. Thus, even in this regard, the ANCHOR and REDUCE-IT studies mirror what might happen at different time points if statin therapy was attenuated in one group of randomized high-risk subjects, but not the other.
Having two clinical trials testing the same therapies (IPE vs MO) in back to back succession, reproducing the findings in one other, adds to the reliability of the evidence presented. In this case, the evidence suggests that MO adversely impacted the efficacy of concomitant therapies.
***
3.2 Critique of Amarin’s U.S. ITC Complaint
Regarding the Complaint brought to the ITC by Amarin against high-purity omega-3 manufacturers (initially dismissed, but being appealed currently[19]), which side-stepped the FDA’s ministerial role on what constitutes a dietary supplement vs. a drug, other authors have previously offered extensive reporting on the issues involved.[20] It is clear to us that high-purity EPA-E was in use as a dietary ingredient well before the Investigational New Drug Application (IND) for Vascepa (no. 102,457 [21]) was granted. Thus, code 21 USC 321(FF)(3)(B) of the FD&C Act[22] does not preclude high-purity EPA-E as a dietary ingredient in that regard. If Amarin had developed and received an IND for a fully synthetic or otherwise unique EPA analogue (vs. the semi-synthetic prodrug EPA-E), which thereafter was made into and sold as a dietary supplement, they would have a case under 21 USC 321. However, Amarin is arguing more broadly that ethyl ester forms (and thus also rTG forms that use an EE step) of EPA and/or DHA are not dietary supplements as defined by the FD&C Act, and further, that their use historically as such only came after these semi-synthetic versions of EPA and DHA were granted INDs.[23]
To reiterate, FDA defines a “dietary supplement” as that containing one or more “dietary ingredients,” further defined as follows:[24]
This includes synthetic or semi-synthetic forms of vitamins, minerals and amino acids. However, synthetically or semi-synthetically produced botanicals, and even esterified omega-3s (as well as other esterified nutrients) at some point may not be deemed to be dietary ingredients (FDA hasn’t issued final guidance on this yet). In their natural forms, EPA and DHA are considered essential fatty acid nutrients, fitting in the category: “a dietary substance for use by man to supplement the diet by increasing the total dietary intake…” But in esterified form, they may not be deemed thus.
From the latest FDA-draft guidance on this topic as of 03-2019:[25]
The language in the above mention seems to suggest that an esterified product is not deemed to be a dietary ingredient, but it is not definitive. It asserts only that the esterified form is a “new substance” and that this “new substance is not considered to be a dietary ingredient merely because it has been altered from a substance that is a dietary ingredient…” It does not explicitly state that this new substance “is not a dietary ingredient,” only that it is a “new substance” that cannot be deemed a dietary ingredient solely (aka “merely”) on the basis that its unaltered form is a dietary ingredient. That does not preclude other rationale for it to potentially be considered a dietary ingredient. As such, some or all esterified products could still fall in line with the requirement to be reported as a New Dietary Ingredient (NDI), which is the main subject matter of this draft guidance document the mention is found in, entitled, “Dietary Supplements: New Dietary Ingredient Notifications and Related Issues: Guidance for Industry.”
As an aside, we wonder here if FDA did not instead mean transesterification [26] when they wrote “esterification” above, as the latter is also a natural process and frequent result of human metabolism[27] (as is “re-esterification”[28]). In fact, any process (metabolic or otherwise) that results in an ester being made is an ‘esterification process.’ This occurs when, for example, a fatty acid is combined with an alcohol (such as ethanol, glycerol, etc.).[29] Trigycerides are thus fatty acid esters of glycerol, formed as a result of esterification.[30]
The “It depends” mention in the draft guidance above relating to metabolites might therefore still be applicable to esterified forms of EPA and DHA, but not ethyl ester forms, which cannot be achieved as a result of human metabolism (no naturally occurring ethanol). However, so called “monoglyceride omega-3s” would appear to fit the excepted clause.[31], [32], [33], [34], [35], [36] Also, “rTG” forms appear to be applicable, as we will elaborate on forthcoming.
The draft guidance clarifies that if a product was in use before Oct. 1994, it may be “grandfathered in,” and not required to be reported as a “New Dietary Ingredient” (NDI). Yet, the guidance also states that an ingredient must first be defined as a “dietary ingredient” to then be either an NDI or not. Thus, the main question (and it is an open question) is whether or not the FD&C Act precludes ethyl ester forms (and potentially rTG forms that first rely upon a transesterification step) of EPA and DHA being deemed “dietary ingredients.”
Another mention by FDA in a letter to AIBMR Life Sciences brought up in Amarin’s appeal is also relevant.
[To AIBMR]:
However, once again we are met with open-ended phrases such as “it is unclear if…” and “FDA cannot determine, at this time, whether your product contains a dietary ingredient (DI)…” FDA clearly acknowledges the ethyl ester forms of EPA and DHA lie outside the statutory definition of a DI, but do not go one step further and outright state they are not DIs. They conclude only it is “unclear” and “cannot be determined at this time.” That at least leaves the door open to a future determination by FDA that EPA-E and DHA-E are DIs.
According to the FD&C Act as interpreted by FDA, synthetic vitamins, minerals, and amino acids are considered dietary ingredients despite their synthetic nature. But that does not mean all other synthetic ingredients are precluded as DIs. For instance, FDA mentions “vanillin” and “cinnamic acid” as synthetic botanical constituents that are considered “dietary ingredients,” due to their long-standing use in food products and very safe track record. The same could possibly be said of ethyl ester omega-3s included in food products for many years now.[37]
In a warning letter to an “ethyl ester creatine” merchant, there is found no mention of the substance itself being deemed as not qualifying as a dietary ingredient, only issues regarding labeling and quality control.[38] If FDA deemed ethyl ester creatine to not be a DI, it would be most straightforward for them to have notified the merchant that they were selling a “drug,” not a “dietary ingredient.” The omission of such is in one respect a concession.
The following from the draft guidance in question may allow reconstituted (aka “re-esterified”) TG (rTG) forms, which return EPA-E/DHA-E to their original TG-form components as found in nature (plus some metabolites) and absent any ethanol, to be considered DIs:
Contrariwise, it could be said that “components that were present in the original plant” that are part of the “new material” are dietary ingredients, despite the semi-synthetic nature of the composition.
A description of rTG is as follows:[39]
Nordic Naturals’ products take advantage of a process that yields an even higher percentage of TG in the final composition:[40]
They also provide helpful graphics to illustrate the components and their metabolism:
Thus, the rTG form is a mixture of what exists in the “original” fish oil, with a lesser percentage of the components that are known metabolites as the body breaks down TGs into free fatty acids and monoglycerides, with some diglycerides also present.[41] Re-esterification is part of this natural metabolism process, with ethanol absent in the final composition.[42] Thus, by our reading of FDA guidance, rTG forms of EPA/DHA should pass muster as dietary ingredients, due to being comprised of 1) mostly TG forms, which are present in the “original” nutrient source (i.e. anchovy, sardines), and 2) metabolites of a dietary ingredient: monoglyceride and diglyceride EPA/DHA. The process also need not take place in the human body.
The only hitch we can see is the last sentence in the above, which might exclude rTG forms in a very strict reading, as an intermediary transesterification process does occur that breaks off the glycerol “backbone” and causes the resultant free fatty acids to cleave to ethanol. This greatly helps concentrate the EPA and/or DHA present in the crude batch via subsequent molecular distillation. But the final rTG product form contains only natural EPA-TG and/or DHA-TG and metabolites of EPA-TG/DHA-TG. This may be enough to convince the ITC (especially given this is an unfinalized draft guidance), even if it might take an eventual citizen petition to persuade the FDA:
Whether ethyl ester forms of EPA and DHA (whereby the free fatty acids remain cleaved to ethanol) are dietary ingredients would not be defensible by this argument, however. Yet by extension, it may be. FDA has stated the following with regard to ethyl alcohol in goods or in the manufacture of foods:[43]
Also, the human body metabolizes the consumption of alcohol and fatty acids to make “fatty acid ethyl esters” (FAEE), which in this case cannot then be considered synthetic.[44]
Beyond these observations, there may also be some room for interpretation of the following mention from the current draft guidance:
For example, a synthetically produced amino acid, i.e. L-carnitine, which is often taken as a weight-loss supplement,[45] is considered a DI based upon its ability to provide L-carnitine to the human body, and the identification of L-carnitine as a “nutrient” itself—as opposed to a synthetic botanical such as echinacea, which cannot in and of itself be considered a “nutrient”—and furthermore, “A substance that has been synthesized in a laboratory or factory has never been part of an herb or other botanical and, therefore, is not a dietary ingredient under section 201(FF)(1)(C) of the FD&C Act.” But EPA-E and DHA-E were “part of” a natural food source, and further, are directly assimilated in and used by the human body as nutrients (essential fatty acids). Therefore, it may be more apt to consider EPA and DHA in a similar category as “vitamins, minerals and amino acids,” or perhaps more succinctly for them all: nutrients. Certainly, the end result is the same—500 mg of EPA-E and 500 mg of NTG EPA will both result in increases in serum EPA levels. It is similar to various forms of vitamin E, in fact, available in natural, synthetic and semi-synthetic forms.[46], [47]
Furthermore, one could argue that since semi-synthetic and synthetic fats of various kinds have long been used as dietary ingredients, such as hydrogenated oil (common fat bound to hydrogen) and “Olestra” (a sucrose polyester), and because EPA/DHA are fatty acids themselves, that a semi-synthetic modification of these falls under the same category of DI.
Amarin’s goal is to get the Federal Circuit to remand the Complaint back to the ITC, charging them to investigate the matter and rule one way or the other. The ITC must then decide whether to infer from the draft guidance or not, and whether it should be concluded that EPA-E is not a dietary ingredient, but rather, a drug, from its interpretation of the FD&C Act. But that is a tall order considering the open-ended nature of the mentions in the draft guidance, and the major changes FDA has historically made to previous drafts to arrive at its final guidance—even omitting entire sections from draft-only versions.[48] Furthermore, FDA is not even legally bound by its own final guidance in making specific decisions that may at times contradict its own guidance.[49] And, most importantly, Congress has solely charged FDA with the ministerial role of interpreting and applying the FD&C Act.[50]
FDA issued a comment to the ITC on the case, stating:[51]
FDA is also working on a master list of those “grandfathered-in dietary ingredients,” including all products that are considered “dietary ingredients” and are exempted from reporting as NDIs by FDA.[52] If ethyl ester forms of omega-3s make it onto the list, then that would absolve manufacturers of the same.
And so, we await the outcome.[53] At worst, supplement manufacturers would be restricted to producing concentrated free fatty acid, natural triglyceride and monoglyceride forms of EPA and DHA (and we think rTG forms would also be allowed), all of which do appear to be better absorbed than ethyl ester forms in any event.[54] Of course, being disallowed to produce EE forms would certainly be a setback to the omega-3 supplement industry, and at least a short-term victory for Amarin. However, we think there is a high likelihood that the Federal Circuit upholds the ITC decision not to take up the case, as the subject matter requiring its ruling lies outside its jurisdiction, and abides only with the FDA.
UPDATE:
The Federal Circuit has issued a ruling against Amarin Corp., 2-1, with the dissenting opinion not disagreeing with the ruling of the majority necessarily, but only in that the dissenting justice viewed the case to be outside the Federal Circuit’s jurisdiction, that the grounds upon which an appeal to the decision by the ITC weren’t even met. The Justice’s view pertains to a subtlety of law, whereby only the ITC’s “final determination” may be appealed, not their decision “not to institute an investigation.”[55] The majority ruled that the ITC was correct in not instituting the investigation as the subject matter lied outside their jurisdiction. And, importantly, they (reiterating the ITC decision) left open the ability for Amarin to try their case again after the FDA issues a determination on whether or not the FD&C Act (FDCA) precludes ethyl ester forms, and forms that use a transesterification step, as drugs and not dietary ingredients. In essence, it was a majority verdict against Amarin.
Amarin may attempt to spend more resources appealing to the Supreme Court, but there is very little chance that their ruling differs.
***
SOURCE: https://medicalresearchcollaborative.com/reports
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[1] https://amarincorp.gcs-web.com/static-files/97e31858-1936-43da-80ea-2f78bb7e7260
[2] https://www.nejm.org/doi/suppl/10.1056/NEJMoa1812792/suppl_file/nejmoa1812792_appendix.pdf
[3] Douglas G Altman. Statistics notes: The normal distribution. BMJ 1995;310:298.
[4] Thomas Lumley, Paula Diehr, Scott Emerson, and Lu Chen. The Importance of the Normality Assumption in Large Public Health Data Sets. Annual Review of Public Health. 2002 23:1, 151-169
[5] Hui Jin, Xuejun Zhao. Transformation and Sample Size. Hogskolan Dalarna. 2009.
[6] DeCarlo LT. On the Meaning and Use of Kurtosis. APA. 1997.
[7] Feng C, Wang H, Lu N, et al. Log-transformation and its implications for data analysis. Shanghai Arch Psychiatry. 2014.
[8] Robert J. Glynn, Jean G. MacFadyen, Paul M Ridker, et al. Tracking of High-Sensitivity C-Reactive Protein after an Initially Elevated Concentration: The JUPITER Study. Clinical Chemistry. 2009.
[9] Geraci M1, Alston RD, Birch JM. Median percent change: a robust alternative for assessing temporal trends. Cancer Epidemiol. 2013.
[10] Bays HE, Ballantyne CM, Doyle RT, et al. Icosapent ethyl: Eicosapentaenoic acid concentration and triglyceride lowering effects across clinical studies. Elsevier. 2016.
[11] Tatsuno, Ichiro et al. Efficacy and safety of TAK-085 compared with eicosapentaenoic acid in Japanese subjects with hypertriglyceridemia undergoing lifestyle modification: The omega-3 fatty acids randomized double-blind (ORD) study. Journal of Clinical Lipidology. 2013.
[12] Maki KC1, Orloff DG, Nicholls SJ, et al. A highly bioavailable omega-3 free fatty acid formulation improves the cardiovascular risk profile in high-risk, statin-treated patients with residual hypertriglyceridemia (the ESPRIT trial). Clin Ther. 2013.
[13] https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202057Orig1s000MedR.pdf
[14] Agrawal D, Manchanda SC, Sawhney JP, et al. To study the effect of high dose Atorvastatin 40 mg versus 80 mg in patients with dyslipidemia. IHJ. 2018.
[15] Bays HE, Ballantyne CM, Braeckman RA, Stirtan WG, Soni PN. Icosapent ethyl, a pure ethyl ester of eicosapentaenoic acid: effects on circulating markers of inflammation from the MARINE and ANCHOR studies. Am J Cardiovasc Drugs. 2013.
[16] Zamani B, Saatlo BB, Naghavi-Behzad M, Taqizadeh-Jahed M, Alikhah H, Abbasnezhad M. Effects of high versus low-dose atorvastatin on high sensitive C-reactive protein in acute coronary syndrome. Niger Med J. 2014.
[17] Scott Kinlay , Gregory G. Schwartz , Anders G. Olsson, et al. High-Dose Atorvastatin Enhances the Decline in Inflammatory Markers in Patients With Acute Coronary Syndromes in the MIRACL Study. Circulation. 2003.
[18] Bonnet J, McPherson R, Tedgui A, et al. Comparative effects of 10-mg versus 80-mg Atorvastatin on high-sensitivity C-reactive protein in patients with stable coronary artery disease: results of the CAP (Comparative Atorvastatin Pleiotropic effects) study. Clin Ther. 2008.
[19] https://investor.amarincorp.com/static-files/a39c4d56-8aa5-424c-9490-8f7b43777f19
[20] https://www.raps.org/news-and-articles/news-articles/2018/7/update-on-the-amarin-itc-case-and-the-issues-at-st
[21] https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202057orig1s000clinpharmr.pdf
[22] https://codes.findlaw.com/us/title-21-food-and-drugs/21-usc-sect-321.html
[23] https://investor.amarincorp.com/static-files/a39c4d56-8aa5-424c-9490-8f7b43777f19
[24]https://www.fda.gov/downloads/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/UCM515733.pdf
[25]https://www.fda.gov/downloads/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/UCM515733.pdf
[26]https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Supplemental_Modules_(Organic_Chemistry)/Esters/Reactivity_of_Esters/Transesterification
[27] https://www.ahajournals.org/doi/full/10.1161/01.atv.15.11.1819
[28] http://www.jlr.org/content/31/8/1423.long
[29] https://www.sciencedirect.com/topics/food-science/esterification
[30] https://chem.libretexts.org/Courses/University_of_Kentucky/UK%3A_CHE_103_-_Chemistry_for_Allied_Health_(Soult)/Chapters/Chapter_14%3A_Biological_Molecules/14.2%3A_Lipids_and_Triglycerides
[31] https://pubs.rsc.org/en/Content/ArticleLanding/2018/CP/C8CP04256J#!divAbstract
[32] https://link.springer.com/article/10.1007/BF01569662
[33] http://thriveveteranscenter.com/wp-content/uploads/2018/08/Fish-Oil.pdf
[34] https://patents.google.com/patent/US5935828A/en
[35] https://store.amymyersmd.com/products/complete-omega-3-softgels
[36] https://neptunecorp.com/en/what-we-do/ingredients/maxsimil/
[37] https://onlinelibrary.wiley.com/doi/pdf/10.1002/lite.201400004
[38] https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2014/ucm421502.htm
[39] http://apjcn.nhri.org.tw/server/APJCN/19/4/499.pdf
[40] http://www.promedics.ca/site/downloads/Nordic%20rTGtrifoldLOW.pdf
[41] http://www.jbc.org/content/281/1/491.full.pdf
[42] https://www.ncbi.nlm.nih.gov/pubmed/2280183
[43] https://www.fda.gov/ICECI/ComplianceManuals/CompliancePolicyGuidanceManual/ucm074550.htm
[44] http://www.jlr.org/content/42/7/1025.full
[45] https://www.ncbi.nlm.nih.gov/pubmed/27335245
[46] https://www.naturalproductsinsider.com/heart-health/many-forms-vitamin-e
[47] https://acgrace.com/natural-vs-synthetic-vitamin-e/
[48] https://www.fda.gov/regulatoryinformation/guidances/
[49] https://www.fda.gov/forindustry/fdabasicsforindustry/ucm234622.htm
[50] https://www.fda.gov/about-fda/fda-basics/what-difference-between-federal-food-drug-and-cosmetic-act-fdc-act-fda-regulations-and-fda-guidance
[51] https://wlflegalpulse.files.wordpress.com/2017/11/fda-letter-to-usitc.pdf
[52] https://www.fda.gov/downloads/Food/NewsEvents/WorkshopsMeetingsConferences/UCM581835.pdf
[53] https://mofoatitc.mofo.com/statistics/appeals/
[54] https://www.ncbi.nlm.nih.gov/pubmed/20638827
[55] http://www.cafc.uscourts.gov/sites/default/files/opinions-orders/18-1247.Opinion.5-1-2019.pdf
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- Form 8-K - Current report • Edgar (US Regulatory) • 07/29/2024 09:30:08 PM
- Amarin Receives National Reimbursement for VAZKEPA® (icosapent ethyl) in Portugal • GlobeNewswire Inc. • 07/17/2024 08:15:00 PM
- Amarin to Report Second Quarter 2024 Financial Results and Host Conference Call on July 31, 2024 • GlobeNewswire Inc. • 07/17/2024 12:00:00 PM
- Amarin Partner EddingPharm Receives Regulatory Approval for VASCEPA® (Icosapent Ethyl) in Mainland China for Cardiovascular Risk Reduction (CVRR) • GlobeNewswire Inc. • 07/08/2024 11:30:00 AM
- Form 8-K - Current report • Edgar (US Regulatory) • 06/04/2024 11:30:10 AM
- Amarin Board of Directors Announces CEO Transition • GlobeNewswire Inc. • 06/04/2024 11:30:00 AM
- Amarin Receives National Reimbursement for VAZKEPA® (icosapent ethyl) in Greece and Announces Exclusive Marketing and Commercialization Agreement with Vianex S.A. • GlobeNewswire Inc. • 05/28/2024 12:15:23 PM
- Amarin to Present at H.C. Wainwright 2nd Annual BioConnect Investor Conference • GlobeNewswire Inc. • 05/06/2024 12:00:00 PM
- Amarin Reports First Quarter 2024 Business Update and Financial Results • GlobeNewswire Inc. • 05/01/2024 11:00:00 AM
- Amarin Applauds HealthyWomen’s Citizen’s Petition Urging FDA To Take Further Action On Fenofibrate Prescribing in Patients at Risk of Cardiovascular Event • GlobeNewswire Inc. • 04/24/2024 06:00:01 PM
- Amarin Announces Results of Annual General Meeting of Shareholders • GlobeNewswire Inc. • 04/22/2024 12:00:25 PM
- Amarin to Report First Quarter 2024 Financial Results and Host Conference Call on May 1, 2024 • GlobeNewswire Inc. • 04/15/2024 12:00:00 PM
- Amarin Highlights Key Data Providing Mechanistic Insights into Eicosapentaenoic Acid (EPA) at ACC.24 • GlobeNewswire Inc. • 04/08/2024 12:00:00 PM
- New REDUCE-IT® Analyses Show VASCEPA® (Icosapent Ethyl) Benefit in High-Risk Cardiovascular Disease Patient Subgroups • PR Newswire (Canada) • 04/08/2024 10:30:00 AM
- New REDUCE-IT® Analyses Show VASCEPA®/VAZKEPA® (Icosapent Ethyl) Benefit in High-Risk Cardiovascular Disease Patient Subgroups • GlobeNewswire Inc. • 04/06/2024 07:30:00 PM
- Amarin Provides Update on VAZKEPA® (Icosapent Ethyl) Intellectual Property Portfolio in Europe • GlobeNewswire Inc. • 04/03/2024 12:00:00 PM
- Research Evaluating Benefits of VASCEPA®/VAZKEPA® (icosapent ethyl) to be Presented at the American College of Cardiology’s (ACC) Annual Scientific Session & Expo • GlobeNewswire Inc. • 03/25/2024 12:00:00 PM
FEATURED Cannabix Technologies and Omega Laboratories Inc. Advance Marijuana Breathalyzer Technology - Dr. Bruce Goldberger to Present at Society of Forensic Toxicologists Conference • Sep 24, 2024 8:50 AM
FEATURED Integrated Ventures, Inc Announces Strategic Partnership For GLP-1 (Semaglutide) Procurement Through MedWell USA, LLC. • Sep 24, 2024 8:45 AM
Avant Technologies Accelerates Creation of AI-Powered Platform to Revolutionize Patient Care • AVAI • Sep 24, 2024 8:00 AM
VHAI - Vocodia Partners with Leading Political Super PACs to Revolutionize Fundraising Efforts • VHAI • Sep 19, 2024 11:48 AM
Dear Cashmere Group Holding Co. AKA Swifty Global Signs Binding Letter of Intent to be Acquired by Signing Day Sports • DRCR • Sep 19, 2024 10:26 AM
HealthLynked Launches Virtual Urgent Care Through Partnership with Lyric Health. • HLYK • Sep 19, 2024 8:00 AM