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Just want to cordially offer some information (previously discussed):
Regarding niacin:
THRIVE results were released on March 9, 2013[51]. THRIVE principal investigator Prof. Jane Armitage said about niacin “…the unwanted side-effects outweighed the benefits. This is important information for all the people who have been using this or similar medicines for many years.” From the THRIVE press release headline[52]: “NIACIN CAUSES SERIOUS UNEXPECTED SIDE-EFFECTS, BUT NO WORTHWHILE BENEFITS”
[51] THRIVE trial website (niacin): http://www.thrivestudy.org/
[52] THRIVE trial press release: http://www.thrivestudy.org/press_release.htm
Vascepa vs Lovaza: http://www.buyvascepa.com/why-vascepa/vascepa-vs-lovaza-which-is-better-safer-more-effective/
What has a lot of us up in arms is that the so-called new science is bogus, they cite failure of some outside trials to strongly support V efficacy. That is an excuse for FDA to justify their anti-Vascepa agenda, those trials are mostly irrelevant and to the small extent they are slightly relevant they are supportive. If FDA wants to cite outside trials to break the SPA, they need something that succeeds at supporting that V is ineffective or the Anchor trial design (that FDA approved) is inadequate. They don't have that. Their lack of justification is why they turned the adcom into an ambush, and minimized the possibility of properly focused discussion (changed the goal post after discussion was over).
"If Vascepa's efficacy is proven with REDUCE-IT, then the FDA will be responsible for the many lives lost. … that is a position I would not want to be in."
That is exactly correct, and I think we need to let the individuals involved at FDA know that we are watching, and we will remember and hold them responsible for what they do, by strictly legal and ethical means (by continuing to bring the facts to the public’s attention, now and for years to come.
"slide 32 Limitation of Jelis Study
FDA was well prepared. "
Funny that FDA did all that research to find limitations of JELIS, but they forgot to mention a key limitation: JELIS only used 1.8 grams of EPA, less than half the Vascepa dose, and we know that EPA benefit is dose dependant, so that's a reason to expct Vascepa to exceed JELIS benefit.
"I don't think lawyers being on furlough or not would have made a wit of difference wrt what went on at the AC - those documents were prepared and probably finished, or close to it, before the furloughs started ..."
I think that's right, I believe the FDA guidelines (not legally binding) are for the panel to have briefing materials from both FDA and AMRN 55 business days prior to the meeting. FDA didn't give AMRN their materials until they were released to the public about 2 business days prior (actually more like 1.5).
I think FDA has gotten complacent, since the primary means of appeal for AMRN is just back to FDA, and most companies are, with good reason, terrified of annoying the FDA and walk on eggshells. I think FDA felt pretty much unaccountable to anyone and crossed a line with behavior that is indefensible several different ways. At a certain point it becomes an irresistible story for the media, and I think we will be there if FDA doesn't reverse the rescission and approve at least a large part of the label expansion. Failed outcome trials for niacin and fibrates being used as an excuse to keep Vascepa off the market (for Anchor indication) while niacin and fibrates are kept on the market, with serious safety and efficacy issues, is just a little too crazy. The science is so bad a layperson can understand it in a few seconds. And the parsing and other chicanery is very transparent, and the failure to even consider the pro-Vascepa evidence is over the top.
zoo - Thanks for writing the letter and sharing it with us. A couple quick thoughts: when you mention subgroups, it might be more clear if you said subgroups of subjects with high triglycerides (those are the only subjects with any possible relevance to Anchor). And, I think it's important to hammer them about he inappropriate criterion they use, that outside studies "fail to support." My old first grade homework papers also fail to support Anchor approval. Because they're irrelevant. To rescind the SPA, FDA needs to cite new science that succeeds at supporting that Vascepa is ineffective or the Anchor trial design they approved is flawed.
"The provision seems designed to prevent pin head bureaucratic geeks from making shit up to fit their agenda. "
I think you're exactly right. IMO, the primary motivation for this "sound science act" is probably related to the apparent intent to impose ultra expensive carbon footprint control by the EPA via regulation, without legislation that environmental activists were unable to pass. Believe it or not, if you actually look objectively at it, the science supporting the possibility of catastrophic human caused global warming is about as sound as the science behind the SPA rescission. The reason the issue doesn't really get debated based on science is that it is not really debatable, if you actually focus on the relevant questions and follow known facts and rules of logic known since Aristotle. As with the FDA and Amarin, the primary tactic is avoiding properly focused debate, and counting on a lack of scientific literacy and common sense. Sadly, that is quite effective.
There is desperate need for sound science in government, but, sadly, history indicates the odds of achieving it are very, very slim. But, I'm glad to see an effort.
One other thing to bear in mind is JELIS used only 1.8 grams of EPA, less than half the Vascepa dose, and we know EPA benefit is dose-dependent. Also, JELIS subjects were pretty healthy and ate lots of fish, which is likely to reduce the benefit observed, so REDUCE-IT with lots of fat-eating Ukranians should presumably show even more benefit from EPA. Of course, we won't really know until the fat lady sings (or enough of the fat ladies and gentlemen have cardiovascular events). It's unfortunate REDUCE-IT doesn't have an arm with just Vascepa, so it could be evaluated head to head against the statin, as well as as an add-on.
The FDA left out of the adcom minutes the single most important thing, that changed the vote and gives the excuse for not approving. They verbally changed the voting question before the vote, to outcomes, which the Anchor trial was not designed to measure.
From page 285 of the transcript and 1:45:30 of the final video clip of the panel:
“DR. SEELY: Are we voting on whether … Vascepa will effectively lower triglycerides -- because that could be one interpretation of the voting question … Or … that the medication is indicated for CVD prevention?
DR. COLMAN (FDA): I think you need to … decide if … the changes that have been observed in the ANCHOR trial, for example, lead you to believe that … it will reduce the risk for cardiovascular disease. …
DR. SEELY: Okay. But it's not how the vote question is written.”
A short time later (at 1:49:05 in the video clip, page 288 of the transcript):
“Dr. Parks (FDA): …We do not want to change the wording [of the voting question] and part of the reason why is that a lot of thought has been put into this prior to this meeting …”
Anchor advisory committee meeting transcript link: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM376102.pdf
Anchor advisory committee meeting, Oct. 16, 2013 links to video recordings:
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM370983.pdf
Barry "The Zone" Sears is on record liking EPA over DHA, for example:
http://www.prweb.com/releases/fish_oil/omega_3/prweb4725774.htm
I suppose a lot of people take both because fish oil contains both and it's expensive to remove the DHA.
My latest version of letter
I continue to send letters to various people in government and the media. Here’s my most recent version, a brief initial letter with detail in an appendix, in layman’s terms. I welcome comments.
I apologize for being slow with this, I was delayed by a family emergency. My wife’s mother had a cancer scare (on top of a heart condition) that exploratory surgery revealed as a false alarm.
If Anchor is not approved on Dec. 20, as seems likely, that will have the silver lining of making our grievance more clear, and a more compelling story for the media. I wouldn’t want to be the FDA having to defend their junk science and chicanery as attention grows.
Senator XXXXX
We are very concerned that the FDA is not serving the public interest in an irrational, unfair, and harmful way. Their actions are indefensible scientifically and ethically, and some attention from congress may help motivate them to do what is right.
This is about the FDA breaking an agreement they made with a small company (Amarin) to approve their drug for helping prevent cardiovascular disease (CVD), the primary killer of Americans (over 700,000 US deaths annually by strokes and heart attacks). This will unnecessarily delay approval about five more years, on top of the five years the company already spent meeting all the requirements FDA had agreed to. FDA acknowledges the drug (called Vascepa) is exceptionally safe and effective for its stated purpose (reducing triglycerides, which is fat in the blood widely recognized to increase risk of CVD). Vascepa is badly needed because it avoids serious side-effects and limitations of drugs currently used by millions of Americans.
The FDA was deceptive and surprised Amarin with this very late in the game, denying them a fair chance to prepare and present their case. The FDA gave indefensibly flawed reasons that are easily debunked with just a little common sense, which explains why they sidestepped a fair debate. They convened an advisory panel of experts for a non-binding vote, several of whom supported Amarin and questioned FDA’s actions to no avail. FDA asked them the wrong question, and refused to change it when they asked, so they had little choice but to vote no. Other drug developers have not been treated this way. Amarin’s CEO correctly said “Right is on our side,” and bravely attempted an appeal, which FDA refused to hear.
After spending five years doing everything the FDA asked of them, Amarin lost most of its value overnight, laid off half its employees, and must now fund a $100M+ trial (about half the current value of the company) without access to about 90% of their market. More important, of course, delaying access to a superior life-saving drug for half a decade, and discouraging new drug development generally, will cost lives, when disease prevention is supposed to be a priority. This is an important part of the bigger issue of a power-hungry agency and a government mismanaging healthcare as it takes more control over it.
For brevity here, I defer details to an appendix (the story fleshed out to three pages in layman’s terms, plus supporting notes and references). My interest in this is three-fold: my wife and I believe in Vascepa, so we want access to it and we invested in Amarin. And, we don’t like irrational injustice to go unchallenged. I know you don’t either. The FDA approval decision is due soon (December 20, 2013). While they’re intention to deny approval now seems clear, it might help if you can make inquiries to them before then.
Sincerely,
Name, town, state, phone number, email address
PS I’m not a doctor, but I know some very smart doctors who are very enthusiastic about Vascepa.
APPENDIX
The Story of Vascepa, Amarin, and the FDA (in layman’s terms)
Why Vascepa is good for people
First, a little history will help show why Vascepa is safe, effective, and badly needed.
In the 1970s, scientists found that Inuits in Greenland had very little cardiovascular disease (CVD), apparently due to eating fish. Other studies confirmed eating fish reduces CVD. Over the last several decades, there has been a vast amount of research on the benefits of fish oil and its various components, especially the omega-3 fatty acids EPA and DHA [1-10]. Vascepa is EPA, purified from fish oil.
Inflammation is increasingly recognized as the underlying cause of many ailments, including CVD[11,12,45]. EPA is anti-inflammatory, and has been applied, sometimes in combination with DHA, to myriad ailments ranging from CVD, arthritis, asthma, and diabetes to cognitive problems and dry eye syndrome[4-10,13,44,45]. Some prominent experts believe EPA (Vascepa) is very important (e.g., Dr. Barry Sears, biochemist and best-selling author of books about “The Zone”[14,15]). EPA has been used in Japan for decades, with extensive data confirming its safety and efficacy there[22,10], and millions of Americans take dietary supplements containing EPA.
Lovaza, a drug consisting of both EPA and DHA, was approved by the FDA for reducing very high triglycerides. Lovaza was denied approval for moderately high triglycerides because it increases bad cholesterol. Its adverse side-effects also include atrial fibrillation[16,17]. Other widely used CVD drugs also have serious side-effects and limitations (details below). FDA trials confirmed that Vascepa is exceptionally safe and avoids the cholesterol problem and other adverse side-effects, while still improving triglycerides and several other CVD risk factors[17]. Vascepa is superior for helping prevent the primary killer of Americans, and it is badly needed[54].
The FDA and other drugs
Next, some background to help explain FDA behavior that is not always in the public interest.
The FDA balances drug risks and benefits, hopefully for the public good. Unfortunately, their incentives are skewed toward excess caution and over-regulation, especially for widely-prescribed drugs. It’s been said the polio vaccine would have trouble getting approved today because, with so many taking it, even very rare adverse effects occur enough to get noticed, and they tend to get more attention than the millions saved. FDA seems to find ways around congressional reforms intended to rein them in and enhance drug access and development[18].
In recent years, FDA has approved CVD drugs that demonstrated improved risk factors (such as lowered cholesterol levels), with outcome trials to be completed a few years after approval to confirm CVD risk is actually reduced. (CVD outcome trials can take six years or more and can cost hundreds of millions of dollars, generally funded with profits.) This turned out very well for statins, which many consider to be among the most successful drugs ever[29].
It was a different story for niacin and fibrates, which were approved after demonstrating they improved CVD risk factors. Their post-approval outcome trials, on people also taking statins, failed to show improved outcomes. These trials also had high rates of serious side-effects, many requiring hospitalization (niacin[20,52], fibrates[21]), and causing up to 25% of subjects to drop out (niacin[19]). However, years later, they remain available and widely used while a new fibrate trial is run [36]. This was embarrassing for the FDA, which sometimes seems to have difficulty withdrawing approval.
Doctors need better alternatives, like Vascepa, but FDA seems more interested in avoiding any risk of another embarrassment and, as always, generally tightening their grip and raising the bar. So they seem to be punishing Amarin (and the public) for the shortcomings of unrelated drugs[26].
The FDA and Amarin
The FDA agreed to requirements for approval and reneged after Amarin satisfied them.
In 2008, Vascepa approval was sought in two parts, called Marine (for people with very high triglycerides, about 10% of the market), and Anchor (for people on statins with moderately high triglycerides, the primary market). FDA entered into special protocol assessment (SPA) agreements that spelled out the requirements for approval. (Legally binding SPAs were established by congress to stop FDA from moving the goalposts during the game[43].)
Requirements included successfully completing two 12 week trials to confirm triglyceride-lowering, and launching a major six year outcomes trial (called REDUCE-IT) before applying for Anchor approval. The outcomes trial (measuring CVD risk) was to be completed after approval, as usual. Amarin met all requirements, and started REDUCE-IT in 2011. Marine was approved in 2012, and the Anchor approval decision is due by December 20, 2013.
In October 2013, FDA convened an advisory panel of experts for discussion and a non-binding vote on Anchor approval. In a surprise move, FDA focused the panel on outcomes instead of just triglycerides, contrary to usual practice and the SPA agreement[39]. (FDA guidelines advise against speculating about outcomes, which the Anchor trial was not designed to measure[34].)
FDA seemed biased against Amarin, strictly limiting their responses[31], calling the five extra years of delay short[32], and, remarkably, vigorously downplaying the importance of Vascepa’s superior safety[33]. They largely avoided a fair debate by giving no hint they were moving the goal post and fundamentally changing the topic until two days prior to the panel meeting[38]. They postponed making this profound change fully clear until after Amarin’s presentation, public comments, and the panel discussion, minimizing properly focused debate.
The FDA’s carefully crafted voting question was confusing about whether approval should be based on triglycerides, as agreed, or outcomes [27], and FDA declined to change it[28]. Several panelists expressed support for Amarin and opposed requiring outcomes[29], and agreed Vascepa effectively lowers triglycerides[30]. At the last moment, the voting question was verbally clarified (fundamentally changed) to be about outcomes, and the panel had little choice but to vote no[28].
Shortly after the panel meeting, FDA rescinded the SPA, citing new science[40], and refused to hear an appeal[41]. Their new science is years old and indefensibly flawed under even mild scrutiny, which explains their determination to avoid a fair debate. They clearly want to delay approval until after completion of the REDUCE-IT outcomes trial.
The FDA’s bad science
The FDA apparently intends to lengthen Amarin’s approval process from 5 years to 10 based on bad science that is easily debunked in a few moments with layman’s common sense.
The FDA claims the SPA is nullified by a substantial new scientific issue essential to determining Vascepa’s effectiveness. They cite three outcome trials for niacin and fibrates, which lowered triglycerides but did not improve CVD outcomes, and they implied that reducing high triglycerides does not reduce CVD risk[40]. That would have been an important discovery if it were true, but it is not true.
Vascepa is labelled for lowering the triglycerides of certain patients with high triglycerides. The FDA must decide if Vascepa is effective for those patients. Naturally, all three Vascepa trials were designed, with FDA oversight, using only subjects with high triglycerides. But, almost 90% of the niacin/fibrate trial subjects didn’t even have high triglycerides[46]. It’s not surprising there was little or no benefit from lowering triglyceride levels that were already normal.
The few niacin/fibrate subjects that did have high triglycerides (the only subjects possibly relevant to Vascepa) showed substantially improved CVD risk (by 28% and 37%), although there weren’t enough of them to be fully conclusive[46]. So, those trials are mostly irrelevant to Vascepa, and what little relevance they have is supportive. They also displayed the previously discussed dangers and limitations of niacin and fibrates, further bolstering the case for prompt Vascepa approval as a safe alternative.
If FDA can nullify a SPA because irrelevant outside trials of unrelated drugs on crucially different subjects fail to support it strongly enough, is any SPA safe? Evidence deemed substantive and essential enough to break an important contract should be relevant and negative, and the FDA should defend it with fair, open scientific debate, not misleading parsing. Weakly positive evidence is portrayed as negative by saying it fails to support (an inappropriate criterion). Careful reading reveals that the FDA simply changed its mind and wants more proof (as usual), without ever actually saying, let alone proving, that there is a scrap of valid evidence that more proof is needed[40].
FDA downplayed or ignored supportive outside studies far more relevant than the niacin/fibrates trials. For example, JELIS (a major 5 year Japanese trial with several thousand subjects on statins) showed significant cardiovascular risk improvement with EPA, despite using less than half the Vascepa dose[22,10]. Another recently published study also confirmed that high triglycerides cause increased CVD risk[48], contrary to the FDA position. Current medical guidelines recommend treating high triglycerides, and Vascepa also improves several other CVD risk factors[49].
Fibrates and niacin failed their outcome trials, which showed serious and dangerous side-effects. Years later, they remain approved while fibrates take a mulligan. FDA even approved a new fibrate within a few days of breaking Amarin’s SPA[47]. So, a failed fibrate trial is about to stop safe, effective Vascepa dead in the water for 5 years while fibrates never skip a beat. It’s an amazing world.
The FDA has almost unlimited power over drug developers, especially small ones. They routinely make life and death decisions that can cripple or destroy companies trying to save lives, unconstrained by normal rules of civilized justice. It seems outrageous to knowingly leave apparently ineffective drugs with dangerous side-effects on the market, while unfairly denying access to a safe, effective alternative. To be fair, the formal approval decision isn’t due until December 20, 2013, but FDA intent seems clear.
Bottom Line
Something protected the Innuits from humanity’s primary cause of death, and after decades of research EPA (Vascepa) seems to be the most promising candidate. Americans deserve the right to choose it. The FDA should stop its unfounded, irrational, dishonest, and devastating attack on the small company that played by the FDA’s rules and risked everything to try to provide it. FDA should follow the law and the facts, should allow a fair hearing of Amarin’s appeal, and should approve Vascepa by the December 20, 2013 deadline.
Notes and References
[1] Dyerberg J, Bang HO, Hjorne N (1975). "Fatty acid composition of the plasma lipids in Greenland Eskimos". Am J Clin Nutr 28 (9): 958–66. PMID 1163480.
[2] Kromhout D, “N-3 fatty acids and coronary heart disease: epidemiology from Eskimos to Western populations,” J Intern Med Suppl. 1989;731:47-51, http://www.ncbi.nlm.nih.gov/pubmed/2650698
[3] Wang C, Harris WS, Chung M, Lichtenstein AH, Balk EM, Kupelnick B, Jordan HS, Lau J., “n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review,” Am J Clin Nutr. 2006 Jul;84(1):5-17, http://www.ncbi.nlm.nih.gov/pubmed/16825676
[4] “Fish oil in recent onset rheumatoid arthritis: a randomised, double-blind controlled trial within algorithm-based drug,” usehttp://ard.bmj.com/content/early/2013/09/30/annrheumdis-2013-204145.short
[5] Ruggiero C, Lattanzio F, Lauretani F, Gasperini B, Andres-Lacueva C, Cherubini A (2009). "Omega-3 polyunsaturated fatty acids and immune-mediated diseases: inflammatory bowel disease and rheumatoid arthritis". Curr Pharm Des 15 (36): 4135–48. doi:10.2174/138161209789909746. PMID 20041815.
[6] Fortin PR, Lew RA, Liang MH, Wright EA, Beckett LA, Chalmers TC, Sperling RI. (1995). "Validation of a meta- analysis: The effects of fish oil in rheumatoid arthritis". J Clin Epidemiol 48 (11): 1379–1390. doi:10.1016/0895-4356(95)00028-3. PMID 7490601.
[7] http://icelandicfourmula.com/blog/omega-3/short-term-omega-3-epa-dha-supplements-improves-dry-eye-symptoms
[8] http://www.nutraingredients.com/Research/Omega-3-EPA-triumphs-over-in-DHA-for-anti-asthma-potential-Study
[9] http://ezinearticles.com/?Type-1-Juvenile-Diabetes-And-Omega-3&id=1199676
[10] “Eicosapentaenoic Acid (EPA) Reduces Cardiovascular Events: Relationship with the EPA/Arachidonic Acid Ratio,” J Atheroscler Thromb, 2013; 20:000-000.
https://www.jstage.jst.go.jp/article/jat/advpub/0/advpub_18002/_pdf
[11] http://www.ncbi.nlm.nih.gov/pubmed/16470012 Am J Clin Nutr. 2006 Feb;83(2):456S-460S, “Inflammation and cardiovascular disease mechanisms,” Libby P, Harvard Medical School and Brigham and Women's Hospital.
Abstract “The traditional view of atherosclerosis … crumbles in the face of extensive and growing evidence that inflammation participates centrally in all stages of this disease … we now understand that at least some of the cardiovascular benefits attributable to medical treatment and lifestyle modification … may result from reductions in inflammatory processes.”
[12] Willerson JT, Ridker PM. Inflammation as a cardiovascular risk factor. Circulation. 2004; 109 (suppl II): II-2–II-10.
[13] Study evaluating EPA and DHA for dry eye syndrome: http://www.ncbi.nlm.nih.gov/m/pubmed/24190233/
[14] Dr. Barry Sears re cognitive benefits of EPA http://www.prweb.com/releases/fish_oil/omega_3/prweb4725774.htm
[15] Dr. Barry Sears re inflammation and EPA. http://www.drsears.com/ArticlePreview/tabid/399/itemid/68/Default.aspx
[16] Lovaza atrial fibrillation warning: http://www.drugs.com/labeling-changes/September-2012/lovaza-omega-3-acid-ethyl-esters-capsules-3051.html
[17] Vascepa vs Lovaza: http://www.buyvascepa.com/why-vascepa/vascepa-vs-lovaza-which-is-better-safer-more-effective/
[18] Documentation of previous problems with the FDA is found here: http://i.bnet.com/blogs/cert-fda-letter-to-the-president-4-2-09-and-trans-team-1-7-09.pdf
[19] HPS2-THRIVE niacin trial: adverse effects, 25% drop out, and no improved outcomes http://www.eurekalert.org/pub_releases/2013-02/esoc-hts022513.php
[20] AIM-HIGH and THRIVE niacin trials – THRIVE adverse effects (3% serious, most requiring hospitalization) and outcomes not clearly improved for either trial http://finance.yahoo.com/news/adverse-effects-aim-high-trial-191500575.html
[21] FDA re ACCORD fibrates trial safety information http://www.fda.gov/Drugs/DrugSafety/ucm278837.htm
[22] Simple summary of the JELIS CVD outcome trial (Japanese EPA), with links to more in depth scientific papers. http://www.medscape.org/viewarticle/518574
[23] Anchor advisory committee meeting transcript link: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM376102.pdf
[24] Anchor advisory committee meeting, Oct. 16, 2013 links to video recordings:
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM370983.pdf
[25] Anchor advisory committee meeting briefing materials http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm331504.htm
[26] FDA said at Amarin’s advisory committee meeting, the Vascepa discussion would be different if the niacin and fibrates trials had been successful[23 (p. 258)].
[27] The advisory panel voting question, as written [25]: “Taking into account the described efficacy and safety data for Vascepa, do you believe that its effects on the described lipid/lipoprotein parameters are sufficient to grant approval for co-administration with statin therapy for the treatment of patients with mixed dislipidemia and CHD or CHD risk-equivalent prior to the completion of REDUCE-IT? Please provide the rationale underlying you recommendation.” This was “clarified” (actually fundamentally changed) verbally shortly before the vote[28].
[28] Verbal clarification of the voting question by FDA shortly before the vote [23 (p. 285)], 24 (video clip #4 at 1:45:30) ]:
“DR. SEELY: Are we voting on whether … Vascepa will effectively lower triglycerides -- because that could be one interpretation of the voting question … Or … that the medication is indicated for CVD prevention?
DR. COLMAN: I think you need to … decide if … the changes that have been observed in the ANCHOR trial, for example, lead you to believe that … it will reduce the risk for cardiovascular disease. …
DR. SEELY: Okay. But it's not how the vote question is written.”
A short time later (at 1:49:05 in the video clip, page 288 of the transcript):
“Dr. Parks (FDA): …We do not want to change the wording [of the voting question] and part of the reason why is that a lot of thought has been put into this prior to this meeting …”
During discussion panelist Dr. Seely said the voting question was confusing and inconsistent with the discussion question [23 p. 261], but FDA chose to delay this crucial clarification until after discussion was finished. In the more than two years since unsuccessful niacin and fibrate outcome trials presumably motivated FDA’s policy change, FDA had many opportunities, and in fact obligations, to inform Amarin. Instead, they delayed at every possible opportunity, minimizing properly focused discussion of a policy change profoundly important to Amarin and patients, and denying the opportunity to plan for it.
Amarin trusted the FDA and counted on the approval they had earned. They ramped up their supply chain and marketing instead of pursuing alternative income sources, and started the uber-expensive REDUCE-IT trial with borrowed money they expected to pay back with sales. The FDA made a bad situation far worse for Amarin by not giving them notice.
[29] Numerous panelists said FDA set the bar too high or otherwise expressed support for Amarin or Vascepa:
“DR. HIATT: I'm just puzzling a little bit over -- switching to the efficacy side, …if you go back to the approval of statin drugs that this division has a history of approving drugs in this space because they change lipid parameters in a presumably favorable way. It was later that the statin trials showed dramatic clinical benefit, and that was a great thing on your part to collectively make that decision to let those drugs on the market. …as I observe the data from this meeting, it appears the sponsor [Amarin], I think appropriately, has committed to a cardiovascular outcome trial, which is terrific, by the way, and I think you guys are doing us a public good, no doubt …
So my question to begin this thinking is … is a cardiovascular outcomes trial really part of the program here? The label simply says, this drug lowers triglycerides in people at risk, which literally is true. …
Because literally, this drug does a terrific job lowering triglycerides. It makes the other real lipid fractions look good, pretty much. But there's uncertain clinical benefit, and they actually have a trial launched to
answer that question.” [23, p. 254-255] [Despite many very positive comments, Dr. Hiatt voted no.]
“DR. RASMUSSEN: … I think we all commend the company for having initiated the REDUCE-IT trial and have gotten this far. I'll just say that on behalf of all of industry, setting a bar that's higher and drawing a line in the sand right now, saying future agents will likely have to demonstrate cardiovascular risk lowering through hard outcomes, will significantly impair innovation. These types of trials cost several hundreds of millions of dollars, and I'm not sure companies the size of Amarin would endeavor into this kind of activity if that was the future. “ [23, p. 266]
“DR. GREGG: I thought the efficacy from both ANCHOR and MARINE were actually quite acceptable, as well as the risk profile. But … Given that there's an ongoing trial underway, it makes sense to wait for those outcomes.” [23 p. 308] [He voted no.]
DR. HIATT: It would seem to me unfair to the sponsor [Amarin] … Why would you suddenly change the bar? The sponsor’s done everything you’ve asked them to do.” [23 p. 295] [He voted no.]
DR. SEELY: . … we need small companies to be developing medications. And the concern that we are setting a high bar, .. may be too high for a number of small companies to meet…this company, … really did everything that anyone would have asked them to do, and we usually like to reward that. …companies are depending on interim approvals to be able to support the cost of studies.” [23 p. 309] [She voted no.]
[30] Most panelists said they were confident triglycerides were lowered. Dr. Seely’s remarks were typical:
“DR. SEELY: …I voted no based on that I think the medication has effective triglyceride-lowering benefit, but that the new data that was presented today shows that it's not clear that triglyceride-lowering
necessarily translates to a CV benefit. And I took the vote to mean that there would be an implied CV benefit. And that was my reason for voting no. “ [23 p. 309]
[31] The moderator seemed intent on limiting Amarin responses at key moments, e.g., [24 (video clip 4 at 1:24:35)] (Faulty science had just been promoted unchallenged. Amarin briefly and articulately summarized their case.)
And, [23, p. 277], [24 (clip 4, 1:35:45)]:
DR. WILSON: …So that seriously affects my thought as I'm trying to make a decision, going back and forth. I'd like somebody to convince me otherwise [regarding a specific concern about Vascepa] …
DR. KETCHUM (Amarin): Dr. Smith, could I be recognized to have some address Dr. Wilson's --
DR. SMITH: [cutting off Dr. Ketchum] I would like to keep the discussion here for now.
And, just before the vote:
“DR. KETCHUM [representing Amarin]: Dr. Smith, could I just have
DR. SMITH: Yes. I would prefer at this point not to have that further input.“
[23 (p. 302), 24 (clip #4 at 2:05:10, Dr. Ketchem off mike)]. (Dr. Ketchum did eventually make a very brief comment apparently uninvited.)
[32] FDA gave the impression the REDUCE-IT trial would be done soon. (It would actually delay approval about 5 years, a large part of the useful patent life and a crushing blow to Amarin and patients Vascepa might save.)
FDA: “it [REDUCE-IT] will get done fairly quickly. If the folks feel that it shouldn’t be approved at this point, the trial’s up and running and we still will get that data fairly shortly” [23 (p. 258), 24 (clip 4 at about 1:13:00)].
[33] In what should be a risk/benefit trade-off, FDA omitted Vascepa’s exceptional safety from its presentation and FDA’s Dr. Roberts was very evasive when asked about it, aggressively downplaying the importance of Vascepa’s superior safety to currently used drugs. She finally acknowledged Vascepa is a safe drug from a safe class of drugs [23, pp. 158-161]. When pressed, FDA acknowledged Vascepa’s safety again later [23, pp. 181-182].
[34] FDA document – “Guidance for Industry Advisory Committee Meetings – Preparation and Public Availability of Information Given to Advisory Committee Members” (These guidelines are not legally binding.)
From page 8: “We emphasize that a sponsor’s submissions should include only information related to the issue being discussed by the committee. Statements or suggestions that could be viewed as misleading or promotional (e.g., statements that go beyond study conclusions or speculate about clinical or commercial implications not supported by the data) are inappropriate for inclusion in the briefing materials.”
These FDA guidelines advise against speculating about outcomes, which the Anchor trial was not designed to measure. (It measured the lowering of high triglycerides Vascepa is labelled for.) FDA focused the advisory committee on speculation about clinical implications of outside trials of unrelated drugs (fibrates and niacin) to subjects fundamentally irrelevant to Vascepa because close to 90% of them didn’t have high triglycerides. FDA cynically said these outside trials failed to support the benefit of lowering high triglyceride, even though the few relevant subjects with high triglycerides had substantially improved CVD outcomes, although there were too few of them to be fully conclusive [23,40].
[35] ACCORD-lipid fibrates trial and subgroup analysis for high triglycerides http://www.medscape.com/viewarticle/721569
[36] New fibrate trial undertaken after failed ACCORD trial (see end of article) http://www.medscape.com/viewarticle/745407
[37] Niacin subgroup analysis info http://seekingalpha.com/article/1745132-will-cardiovascular-concerns-jeopardize-amarins-upcoming-fda-advisory-panel
[38] Amarin spokesman Joe Bruno.
[39] Panels are briefed by both the FDA and the company, with the briefing materials submitted months in advance. The company, however, doesn’t get to see the FDA’s briefing materials until two days in advance. The stakes are immensely high, but there don’t seem to be the guarantees of justice a civilized society provides for a traffic ticket, such as knowing the question to be decided, a fair chance to prepare and present your case and question witnesses, and the right to appeal injustice.
[40] Forbes.com article, which includes a link to Amarin’s form 8-K filed with the SEC on October 29, 2013 announcing the FDA rescinding the SPA agreement. http://www.forbes.com/sites/larryhusten/2013/10/29/fda-throws-more-cold-water-on-amarins-hopes-for-vascepa/
From the 8-k: “ the FDA has rescinded the ANCHOR study special protocol assessment agreement because the FDA has determined that a substantial scientific issue essential to determining the effectiveness of Vascepa in the studied population was identified after testing began. Specifically, consistent with discussion at the Advisory Committee meeting, the FDA cited results from the ACCORD-Lipid and AIM-HIGH outcome trials, as well as the publicly presented results from the HPS2-THRIVE outcome trial, which the FDA stated in its October 29, 2013 notice to Amarin, fail to support the hypothesis that a triglyceride-lowering drug significantly reduces the risk for cardiovascular events among statin-treated patients with mixed dyslipidemia and residually high serum triglyceride levels (200-499 mg/dL). Thus, the FDA stated that it no longer considers a change in serum triglyceride levels as sufficient to establish the effectiveness of a drug intended to reduce cardiovascular risk in subjects with serum triglyceride levels below 500 mg/dL.”
[41] FDA refuses to hear appeal.
http://sg.finance.yahoo.com/news/amarin-shares-continue-slide-fda-194648740--finance.html
[42] Amarin November 7, 2013 earnings call.
Transcript: http://seekingalpha.com/article/1820862-amarins-ceo-discusses-q3-2013-results-earnings-call-transcript?page=2
Near the end, the CEO says “right is on our side.” The transcript mistakenly says light instead of right. Audio available at: http://investor.amarincorp.com/events.cfm
[43] The FDA Modernization Act of 1997 introduced SPAs to help address “moving target” approval requirements. It is much discussed, including here:
http://www.devicelink.com/mddi/archive/98/03/011.html
[44] A study suggesting EPA can help memory http://www.ncbi.nlm.nih.gov/pubmed/19968753?dopt=Abstract&holding=f1000,f1000m,isrctn
[45] Men’s Health fish oil article: http://www.menshealth.com/health/governments-big-fish-story
[46] The three niacin/fibrate outcome trials were: the ACCORD-lipid trial (fibrates ) the AIM-HIGH trial (niacin) and the HPS2-THRIVE trial (niacin). For all three trials subjects were selected without regard to triglyceride levels, and the vast majority did not have high triglycerides. While they did not demonstrate improved CVD risk overall, the subgroups with high triglycerides had substantial improvement (by 28% for ACCORD and 37% for AIM-HIGH). The significance of the subgroups is limited by the small number of relevant subjects. There were not enough THRIVE subjects with high triglycerides for meaningful analysis.
The ACCORD-lipid trial results were published in 2010 [35]. The AIM-HIGH trial results were published in 2011[50]. Only 12.9% of AIM-HIGH subjects had high triglycerides. THRIVE results were released on March 9, 2013[51]. THRIVE principal investigator Prof. Jane Armitage said about niacin “…the unwanted side-effects outweighed the benefits. This is important information for all the people who have been using this or similar medicines for many years.” From the THRIVE press release headline[52]: “NIACIN CAUSES SERIOUS UNEXPECTED SIDE-EFFECTS, BUT NO WORTHWHILE BENEFITS” See [53] for additional comments from a doctor (unverified).
[47] New fibrate approved Oct. 22, 2013 within about a week of Vascepa’s October 29. 2013 SPA recission
http://pharma.financialexpress.com/latest-updates/2842-lupin-receives-us-fda-approval-for-antara-capsules
[48] Study finding that triglycerides cause CVD: http://www.broadinstitute.org/news/5292
[49] Risk factors improved by Vascepa: http://www.buyvascepa.com/why-vascepa/benefits-of-vascepa/
[50] AIM-HIGH trial (niacin) December 2011:
http://www.nejm.org/doi/full/10.1056/NEJMoa1107579
[51] THRIVE trial website (niacin): http://www.thrivestudy.org/
[52] THRIVE trial press release: http://www.thrivestudy.org/press_release.htm
[53] A doctor’s comments on FDA’s bad science (anonymous and unverified but credible. Informative, but I formed my conclusions independently of these remarks): http://seekingalpha.com/article/1848051-why-the-fda-got-it-wrong-and-why-it-will-approve-vascepa-for-anchor-snda-submission
[54] A website with information about Vascepa, advocating for its approval: EPADrugInitiative.com
Partial transcript of pre-vote clarifying questions.
From final video clip of Amarin October 16, 2013 Adcom meeting.
[Here, FDA finally, unambiguously clarifies the voting question to be about outcomes, Dr. Seeley observes that’s not how the voting question is written, and FDA declines to reword it.]
[1:45:30]
Dr. Seeley: So, are we voting on whether the sponsor has shown us sufficient information that Vascepa will effectively lower triglycerides, because that could be one interpretation of the voting question, in this population, or are we voting that the medication is indicated for CVD prevention?
Moderator: I think you need to take into account the efficacy and the safety data, and then decide if you believe that the changes that have been observed in the Anchor trial, for example, lead you to believe that when this is co-administered with a statin, it will reduce the risk for cardiovascular disease. Now, if you’re confident that’s the case, you would vote to approve it now, if you are not confident then you would say
Dr. Seeley: OK, but it’s not how the vote question is written.
FDA Male: Is it clear how people should, do we need to change the wording?
FDA Male: I’m open to that if you are. … We’ll come back to that
…
[1:49:05]
Dr Mary Parks : I just want to visit the question about whether or not the wording of this voting question should be changed. We do not want to change the wording and part of the reason why is that a lot of thought has been put into this prior to this meeting and we recognize that there are a lot of imperfect data when you come to this meeting. The indication as written up here is the indication has been proposed by the company. So if there’s any uncertainty about that, if that’s going to weigh into your vote, then state that, you have the opportunity to state that when you explain your vote.
Part 2 - partial transcript of adcom discussion (continued from previous post)
[1:12:19]
Moderator: but when we started to get into companies wanting to target this lower range of TG it was clearly with the goal of selling it to reduce the risk for cardiovascular disease. So, back in 2007, 2008 we weren’t in a position to say there’s no way you’re going to get this approved without doing a cardiovascular outcomes trial and completing it and then coming back to see us. We knew these other trials were ongoing: Accord, Aim high, Thrive. While not the same compound, we knew they would add some information. So we felt it was very reasonable to say look: do a lipid endpoints study for 12 weeks so we get to see what the lipid profile looks like but we want you to at least have the outcomes trial up and running with 50% enrollment. So that we know that even if we approve it now it will get done fairly quickly. If the folks feel that it shouldn’t be approved at this point, the trial’s up and running and we still will get that data fairly shortly. I also think that if Accord lipid and aim high and Thrive were positive, I think we would have a different discussion today.
[1:13:45]
Dr. Hyatt: I appreciate that, I’m still just wrestling a little bit with The only reason I can think of to lower triglycerides, or raise HDL, or change LDL composition, APOB levels , particle size, the only reason to want to do that is to prevent cardiovascular events. I can’t think of any other reason to do that. And, by the way, I agree with you, it’s hard to imagine an event-driven pancreatitis trial for super high triglycerides. I kind of smiled when you think about that, because that’s just by inference that it’s actually going to be good, we don’t know that really. So the only reason to treat these mid-range triglycerides is to prevent heart attack, stroke and death.
So, let me ask the question another way. Why not require every new lipid drug coming on to be reviewed to demonstrate that it has a biomarker benefit that looks good, i.e., changes levels appropriately, but that’s just a surrogate endpoint towards the actually clinically meaningful event driven trial.
And then like if you’re developing a new anti-thrombotic drug, whether it’s anticoagulant or anti-platelet, you’d be in the same position. It sounds like you’ve gone there, but it’s not clear to me.
[1:15:00 ]
Moderator: Well, you know, when we’re dealing with compounds that if you could call them more pure LDL lowering compounds, that’s where we feel the most comfortable in terms of using that as a surrogate. I think the further we get away from LDL, and start getting into TG, or LPa or even Non-HDL
We have in place, if your compound is primarily raising HDL cholesterol, you do have to complete an outcomes trial before you can submit your application. So we do have that requirement for HDL raising drugs based on the recent experience with C ETP numbers
But again, this is the first case with triglycerides, so this is a test case. We weren’t in a position back in 2008 to feel like we had the proper support and data to say to Amarin There’s no way you will ever get this indication unless you complete an outcomes trial. We thought there was enough uncertainty to give them the advice we did, and as it turns out we’ve had additional studies that have been completed that I think do play into today’s discussion.
Moderator: We’re going to have a comment back from Dr Seeley. Dr Seeley first
[1:16:30]
Dr. Seeley – So, I’m still kind of stuck on the I think there’s a contrast between the discussion and the vote that’s hard for me. So, we don’t know whether this is going to translate into meaningful reduction until this current study is completed. But we could have confidence that in the patient population with people with CHD and CHD risk-equivalent, it will effectively lower triglycerides. So I think that’s why the question of do we also need to know that it will reduce CVD risk is part of the indication. Because, I think we’ve seen effective data that in the population that the company wants the drug approved in, it will lower triglycerides. I just don’t know if it’s going to lower CVD risk. So I could approve it for lowering triglycerides if that’s the way the question was phrased. So, I’m very confused about how the voting question is phrased in contrast to the discussion question.
[1:17:43]
FDA male: Do we want to get into the voting question before we finish with the discussion?
FDA male: I would recommend we defer that, but if I forget remind me that we ought to have a little discussion before the vote about this question and perhaps others that come up.
FDA male: to help inform the discussion point though, Dr Parks and others can correct me if I’m wrong, but what defines our effectiveness requirement for a drug is not laid out by statute, it is actually covered by case law, and really comes down to what’s a clinically meaningful endpoint. What that means to each person around this table might be different. And that’s why we want to hear your discussion. Because some would argue that, for example, if you saw a 40% reduction in LDL, I’m confident that that’s a clinically meaningful endpoint, a clinically meaningful result. But what we’re asking you to do is to look at the lipid changes in front of you that were demonstrated in this trial and say how confident are you that that’s a clinically meaningful result? We know that there’s an outcomes trial that’s ongoing. We’re not going to be able to say anything definitive about cardiovascular risk until it’s completed. So the question is, is how confident are we that this is clinically meaningful, now?
Female voice: And that’s what I answered, and I think maybe
Moderator: Dr. Everett
Dr Everett: To echo Dr. Seeley’s comments, I think that in my view the epidemiology for on-statin triglycerides being an important risk marker for future cardiovascular events is mixed. It is not unequivocal or totally clear. There are certainly some positive studies which we’ve heard about, there are some others which suggest other things, like BMI or APOB are better markers of that risk. Secondarily, it’s not necessarily clear that reducing, to me, triglycerides, is going to impact that risk. In particular, I think you know we all talk about statins and use LDL as the cannonical marker, and that if it goes down, cardiovascular risk will go down. Quite frankly, outside of statins, that assertion has not really been demonstrated to be true. The ongoing improve-it study of ezetimibe may give us some insight, but it’s enrolled well over 25,000 patients, it’s not like it was stopped early for efficacy, and we don’t know, we just don’t know. And unfortunately for the average cardiologist, the field of adjunctive agents is littered with failures. We’ve heard about a bunch of them this morning, such as niacin, and ezetimibe, at least in my view up until this point is another example, and the fibrates are another.
And so, to echo Dr. Seeley’s comments that a how important is triglycerides I think is an interesting topic, you could take either sides of that issue. The actual risk reduction associated with lowering triglycerides, frankly for lowering any of these biomarkers, apart with with a statin, is not clear to be of substantial benefit to me.
Moderator: Dr. Rasmussen
Dr. Rasmussen: So I think today is a particularly difficult discussion to have. I think we can all agree that, despite standard of care with statins, there is still a significant residual risk that has been difficult to address. So I’m not sure that statins, I mean when they were introduced that’s the bar to set for future innovations within lipid lowering. It may be that differences from now on will be incremental. It’s going to be a bit of a stretch, we don’t have the outcomes data to substantiate that triglyceride lowering will be the next biomarker to manipulate, but it’s a good candidate, I think we can all agree on that, and I think we all commend the company for having initiated the REDUCE-IT trial and have gotten this far.
And I’ll just say that on behalf of all of industry, setting a bar that’s higher and drawing a line in the sand right now saying future agents will likely have to demonstrate cardiovascular risk lowering though heart outcomes will significantly impair innovation. I mean, these types of trials cost several hundred millions of dollars, and I’m not sure companies the size of Amarin would endeavor into this kind of activity if that was the future.
[1:22:50]
Moderator: Thank you. And, Dr. Wilson
Dr. Wilson: So I think we have There’s one slide I keep looking back at and it was Michael Miller’s slide number 21 if you have a handout. And it’s, stare at it several times cause it’s really summarizes an awful lot of what we’ve been saying, what Brendon’s just talked about. Even in these other trials that have statin on board and those LDLs are typically what we’re seeing in modern clinics basically starting on the hundred and lower. You can use non-HDL if you want. They lower triglycerides. They lower triglycerides to the same degree that is seen with Vascepa. So, it’s pretty hard to say, you know, that this is going to necessarily translate into a clinical difference. I share Dr. Seeley’s optimism, let’s see the results with an outcomes trial, that’s really where the proof in the pudding is from my perspective at this point.
[1:24:35]
Moderator: If we could have a response, I see someone from the sponsor would like to make a statement, again just very relevant to this point in a way that might help us address some of these questions [moderator clearly very intent on limiting Amarin response]
Amarin spokesman: Yes, yes, I’ll just touch a little bit on each of these comments. So first, Dr. Hyatt, this program was designed upfront to be comprised of three different studies: Marine, Anchor and REDUCE-IT. It did represent actually a new kind of standard in terms of working up front collaboratively. Those special protocol assessment agreements were vital, as a small company, to get the clarity so we could marshal forth the human and other resources to put this program into play. And Marine and Anchor were conducted in parallel, as has been described. The Marine original submission had both the Marine and Anchor safety data reviewed and included and REDUCE-IT was actually started shortly thereafter.
And, I think, to Dr. Brittain’s comment, I want to accentuate that, when we look at those numbers that Dr. Wilson had up there, those were TG lowering and patient populations that may not have been at risk by virtue of their TG levels, so we have to at least keep that in mind when we look at the table 1 in the FDA questions relative to those failed outcome trials and what we, by virtue actually of a lot of collaboration with the FDA, we were aware of some of the limitations of ACCORD, AIM-HIGH, and HPS2Thrive. They’ve been built into REDUCE-IT.
And we need a balance between patient care access and the science, and Amarin is stepping up to the plate and filling what we’re all saying is a very murky situation that needs to be met head-on. And that’s the challenge for us, as a small company, putting in play what is a huge clinical operations effort. 11 countries, 450 plus sites, as was mentioned, triple digit millions of dollars, to get the answer. And we think that, when we look at elements of ACCORD, elements of AIM-HIGH, elements of HPS2 Thrive, elements of JELIS, along with our Anchor lipid and lipo-protein benefits and our safe and tolerable profile, we think when you look at it there’s manageable risk.
And we don’t gloss over, Dr. Hyatt, the risk, we take post-marketing surveillance very seriously. We have a great opportunity to look at all these adverse events of interest in REDUCE-IT, whether it’s bleeding, glucose metabolism, worsening new-onset diabetes, that’s part of our commitment to the ongoing patient safety and so, I just want to leave you with that message, that we have this safe and tolerable drug, with these signs across these various domains of what we consider to be plausible benefit. Yes, some of the lessons are hypothesis-generating, agreed, but you really do need companies like Amarin to step up to the plate and tackle these important scientific issues, and I will just leave it to that.
[FDA uncharacteristically changed topic instantly, to repeating and adding more emphasis to concerns about placebo, with no moment for questions, discussion, or thought. The articulate Amarin spokesman abruptly meekly tapered off, as if given a firm signal to stop.]
I transcribed, by hand, pretty carefully, a few key parts of the adcom meeting. I share some here, relating to the discussion question. Part 1 of 2.
A summary of highlights: Dr. Hyatt probed the FDA about moving the goal posts from triglycerides to outcomes, seeming to take Amarin’s side and commending Amarin for doing a public good. FDA said ACCORD and other studies added information, even though they used different drugs. (Of course, elsewhere they reject the added information of much more closely related studies favorable to Amarin, like JELIS or high-trig subgroups.) FDA says it is dubious of biomarkers other than HDLC, and it would be a different discussion if ACCORD etc. had been successful, and REDUCE-IT will be done “fairly quickly.” (Delaying approval from about 2 months to about 5 years doesn’t seem fairly quick to me.) Dr. Everett points out the limitations of biomarkers, including LDL cholesterol. FDA says efficacy is defined by case law as clinically meaningful, which is subjective. Dr. Seeley asked for clarification of the voting question and said she could vote for approval if that just meant trig lowering. Dr. Rasmussen was very sympathetic to Amarin, and said raising the bar would impair innovation. An Amarin spokesman gave a few articulate and persuasive remarks, strictly limited by the moderator.
Amarin October 16, 2013 Advisory committee meeting -
Discussion question (last video clip, starting around 1:05:15)
Moderator: So, this is our discussion question for today, and I’m reading this as a lead-in to comments specifically related to this issue or things that you think are strongly related. So, please discuss the efficacy results from the Anchor trial, including the clinical significance of the observed changes in lipid/lipoprotein parameters and your level of confidence that these changes will translate into a meaningful reduction in cardiovascular risk among the target population. Dr. Seeley
[1:05:58]
Dr. Seeley: So, I have a few comments in this regard. So, I’m concerned about the table and there being so many measurements listed. In terms of when we say the observed changes in lipid/lipoprotein parameters, the study seems like it was powered for the outcome of triglycerides and the others are secondary and exploratory, and it’s nice they go in the same direction but I’m concerned about putting a lot of emphasis on secondary and exploratory outcomes and I personally would focus on the triglyceride lowering. And, in just focusing then on the triglyceride lowering, I think there is effective triglyceride lowering in this new group of subjects with the four grams a day. It’s limited in terms of knowing the full magnitude because of the changes in the placebo group which are of concern to me, and I’ve seen no data that tells us that this will translate into a meaningful reduction in CV risk among the target population.
I don’t think the JELIS study, we can say that the JELIS study is different and point out the differences, but then come back and say we expect to find the same benefit. As was pointed out, it was an open label study, the cut offs for entry of the lipid levels were very different than what we’re looking at for the indication.
So, I am, I would be, I mean I’m really glad an ongoing study is happening and I will be incredibly thrilled if the results of the efficacy study with outcomes shows that Vascepa added to a statin decreases cardiovascular risk, I think it’s a really important study, I’d be thrilled with those results, but I don’t think we have that information today.
[1:08:10]
Moderator: Other comments? Yes, Dr. Brittain
Dr. Brittain: I’d agree with what Dr. Seeley said. I guess to me the fact that there are a number of studies in which we see the triglyceride change, but we don’t see evidence of a treatment effect on cardiovascular endpoints to me is the key.
[1:08:40]]
Moderator: Dr. Hyatt
Dr. Hyatt: I’m just puzzling a little bit over switching to the efficacy side. The history of what got us here. So that, I recognize, if you go back to the approval of statin drugs that this division has a history of approving drugs in this space because they change lipid parameters in a presumably favorable way. And it was later that the statin trials showed dramatic clinical benefit and that was a great thing on your part to collectively make that decision to let those drugs on the market. Now we’re in a different space of add-on therapy. We’ve had these discussions a few years ago around the fibrates. And, as I sort of observed that the data for this meeting, it appears that the sponsor, I think appropriately, has committed to a cardiovascular outcome trial, which is terrific by the way, and I think you guys are doing us a public good, no doubt, because of the wide use of these medications off-label or as supplements, which is earlier discussed in the open public hearing.
So, my question to begin this thinking is: Has the division made a decision that if you’re going to go beyond a triglycerides of 500 mg/dl if you’re going to get into this more kind of range where there are more patients, they’re at risk, is a cardiovascular outcomes trial really part of the program here? I mean the label simply says this drug lowers triglycerides in people at risk, which literally is true. (1:10:22)
But in fact, the behavior would suggest that they’re going to have to initiate, and they’re in the middle of a large cardiovascular outcome trial, which would imply to me that any new lipid drug add-on to statin would really need the same approach which would suggest that a guidance might be forthcoming or something to help us understand a little bit more what’s expected. Or are you just doing this because ultimately they want to have a label that says this drug actually works in terms of Clinical benefit?
I guess I’m asking you all, where do you stand in this regard? Because literally this drug does a terrific job lowering triglycerides, it makes the other lipid fractions look good, pretty much, but there’s uncertain clinical benefit and they actually have a trial launched to answer that question.
So where are you in terms of the state of developing any drug that’s add-on to statin to alter hdl or triglycerides or other lipid fractions?
Moderator: If we just stick with this particular compound. Remember that our discussions with the company started back in 2008 and we’d had conversations with similar companies in 2006. Where it was primarily a triglyceride lowering drug and for a long time people were getting the indication of severe hypertriglyceridemia over 500 based on just triglyceride lowering alone.
Dr. Hyatt: Right
Moderator: And if you read the guidances, most people would agree that the first priority is to try to prevent pancreatitis.
We’ve talked about could we actually have a development program where Pancreatitis was the endpoint, and I think that would be probably tough to do.
Dr. Hyatt: Yup
[1:12:19]
Here is a transcript I made of part of the adcom where panelist Hyatt noted that FDA hadn’t presented safety, and when he asked about it, it took him several attempts to get an answer from Mary Parks, who kept saying to emphasize efficacy, not safety, and to not consider that Vascepa whether is safer than other drugs currently in use.
Second Amarin Oct. 16, 2013 adcom video clip at around 37:15
“Clarifying questions”
Dr. Hyatt: I’d like to ask the FDA whether you think the Anchor safety database is adequate. And the reason I ask that is that the proposed label is to treat a surrogate endpoint, as you say with the presumption there’s a clinical benefit, but the issue entailed today is whether we should approve something on a surrogate endpoint. In my mind, if that’s the question, the safety database has to be really good. And it should rule out things that were mentioned earlier today, such as worsening glycemic control, transitioning people from pre-diabetes to diabetes or causing major or minor bleeds. And the background in both your and the sponsor didn’t say much about it. And I just want to know if you all think it’s adequate for approval for this indication.
Dr. Roberts: If I hear you correctly, you are asking if the safety database is adequate to approve this indication?
Dr. Hyatt: Correct.
Dr. Roberts: Well, I think that, first, I would want to look first at the efficacy of the trial first to make sure you are comfortable with the observed lipid lipo-protein changes that you have seen with the anchor trial. I definitely think safety has to play into it in part, but I wouldn’t necessarily want to give somebody a pass because they feel like the safety may be not as significant as some other drug. I would want to focus first on whether or not I was comfortable with looking at the changes, and whether or not I thought the changes I observed would translate into a clinically meaningful benefit first, and then I would look into the safety database. Part of the reason we have you guys come is to look at it with new eyes, to look at the cardiovascular, look at the safety database. Certainly what I’m hearing from you today is that there may be concern about some of the glucose changes and I can say that it may not be in a 12 week study that may not be enough time to formulate your final conclusions about the glucose changes that you’re observing. Certainly the reduce-it trial is going to give us more information about that, but thus far what we have are two 12 week studies that we’ve looked at. I can show you, in the initial evaluation, just a second, hold on
40:05
Dr Hyatt: I get that. That’s not my question. My question is, at the end of the day, we’re going to judge something on risk and benefit, right? So clearly the drug sig lowered TG levels, and you focused on efficacy, and that is fine. My question is, from a regulatory perspective, do you think the safety database is adequate? You didn’t even present it, and I’m asking you to judge collectively, you know, why we’re here today if we’re trying to prove something on a surrogate endpoint, not a clinical endpoint, a surrogate endpoint with a really sparse safety database, and we can discuss what is concerning about it later in the day, and I think we probably will, but I want to ask you again, do you think the safety has been adequately described to approve this label indication?
41:10
Dr Roberts: I think that, based on the information that we have available today, there wasn’t upon our review a concerning safety signal that would seem to be new, based on the class and on this particular drug, so that’s what I
41:35
Dr Hyatt: That’s what I figured. And just to point out though, it’s a short exposure, it’s not many patients, there aren’t many safety events, and therefore you’re sort of assuming the absence of evidence is evidence of safety, and just I’m asking that question. I guess I can just table it for now, but that’s my concern.
ranjo - Yes, it's me. Good to hear from you.
Over the last several years I've had long-term holdings of EXAS and AMRN. I had some luck moving some funds between the two as they ebb and flow. I bought a lot of my EXAS around $1 years ago and sold a lot of it around $12 to buy AMRN between $5 and $7, which seemed cheap at the time. I also sold some $4 AMRN puts before the adcom, so I've got lots of AMRN now. I didn't risk what I couldn't afford to lose, but, like a lot of us here, I pushed it to the limit and am hurting. At least I didn't use margin.
Trying to chip in to do something about it, this just seems too wrong to stand on several levels. If you were writing a novel, this plot wouldn't work. As I think Mark Twain said: "Truth is stranger than fiction. Fiction has to be plausible." This is unbelievable. I'm making it a project to see that the people responsible are exposed to scrutiny.
Angelo - That FDA guideline document is clearly marked that it is non-binding legally. But, violating it would be embarrassing, and the SPA is legally binding, with escape clauses that it is not clear have been satisfied.
I think FDA often figures they can get away with things that wouldn't pass muster in court, because they have infinite resources of time and money compared to a small company, and the company can't afford to anger the FDA. Sadly, it seems like they are often right. I figure our best bet is to shine light on them with their hand in the cookie jar, with the pressure not coming directly from Amarin (congress etc.), so the FDA hopefully doesn't start a vendetta with them.
Also, I like to see Amarin working the off-label route more via non-traditional marketing (publicists, search engine ads, etc.) and expanded pipeline (dry eye, etc.).
" I have never been more wrong (thus far) on an investment in my entire life. And many other very intelligent folks I know are in the same boat."
Well said. I'm in that boat with you, and I'm not going to sink without some flailing around. Plenty of crazy things happen in this world, but this seems just too crazy to not get at least partially straightened out. Let's hope, and do what there is to be done.
Correction re FDA obligation to give Amarin briefing docs – In the first version of my letter to members of congress, I mentioned FDA was required to give Amarin their adcom briefing documents 14 days prior to the panel. I was wrong about that.
In the FDA document “Guidance for Industry Advisory coommittee meetings – Preparation and Public Availability of Information Given to Advisory Committee Members”, the policy of giving Amarin the FDA briefing documents 14 business days prior to the panel seems clearly included in the Appendices:
“We will send a copy of our briefing materials (or relevant portions thereof), as prepared for public release, to the sponsor to review.” [14 to 21 business days before the meeting]
However, these guidelines are non-binding, plus elsewhere in the document it says that this timeline applies only if there is material that is exempt from disclosure.
“When we have prepared our briefing materials, we will review them to determine if they contain information that, under certain circumstances, could be considered to be exempt from disclosure under FOIA (specifically, confidential commercial or trade secret information belonging to a sponsor). If the materials do not contain information that, under certain circumstances, could be considered to be confidential commercial or trade secret information belonging to a sponsor, the portions of the timelines (see Appendices) that pertain to sharing our briefing materials with sponsors will not apply. “ (page 13, Section F)
I apologize for the error.
The only other guideline I find regarding informing the sponser is the following (and, again, the entire guidelines in non-binding):
“For open advisory committee meetings that involve sponsor-prepared briefing materials, approximately 55 business days before the meeting is scheduled to occur, FDA intends to notify a sponsor that an advisory committee will consider an issue that is directly relevant to the sponsor. We will explain the meeting’s focus to the sponsor and also may advise the sponsor about the information it may wish to include in its briefing materials.
…
We emphasize that a sponsor’s submissions should include only information related to the issue being discussed by the committee. Statements or suggestions that could be viewed as misleading or promotional (e.g., statements that go beyond study conclusions or speculate about clinical or commercial implications not supported by the data) are inappropriate for inclusion in the briefing materials. “
So, they were supposed (not legally bound) to explain the meeting’s focus 55 business days prior.
It seems especially twisted that, apparently without warning, FDA changed the focus of the panel from trig lowering to speculation about outcomes, and the guidelines directed Amarin not to speculate about outcomes.
Thanks birzinho for your suggestions for my letter and helping me find that error. I'm reworking it, and including some ideas of yours and others.
Quote: "I think AMRN should submit trial design to FDA for dry eyes. that should get much interest from WS. Imagine the potential. I don't know anyone who doesn't have dry eye in SO CA"
Agree 100%. As JL pointed out, an outcomes trial could be done in a few weeks with a small number of subjects for low cost. As an SNDA, there would be expense and delay, but a lot of the heavy lifting has already been done (safety, manufacturing issues already handled). Approval should be possible years before Reduce-it, and good publicity immediately.
Management should take the salary of one of the laid-off sales people and hire a publicist to help generate buzz and goose off-label sales before approval. Clever publicity could get both the dry eye and cardiovascular angles covered in the same story (maybe even some of the other ailments, like arthritis, diabetes, etc.). cautiously within the rules, of course.
This sure seems worth doing to me.
Expert advice about letters to congress
I sent a letter to Senator Grassley. My wife was on his staff years ago, and sometimes helped screen such letters. She gave me some advice. I had carefully written a letter that made sense to me, much of it focused on science. It was a good letter but I completely redid it after my wife pointed out the following:
1. Keep it short. Make the primary point in the first sentence or two, flesh it out just briefly, preferably with 2 or 3 bullets that help focus attention. You can follow that with a few details, which may not get read. As frustrating as it is, it is best to keep it under a page.
2. Neither legislator nor their staff is probably a scientist. What they can understand and take action on is violation of process (e.g., not giving Amarin briefing documents the required two weeks ahead).
I include a copy of the letter I ended up with (still a bit longer than my wife preferred). I’ll probably modify it slightly and send it to others.
Senator Chuck Grassley
Knowing about the concerns you’ve had regarding the FDA, I wanted to let you know about their recent conduct regarding Vascepa, a drug developed by Amarin. My wife, Barb, worked for you years ago, and she suggested I tell you about this as the situation is important for multiple reasons:
? Vascepa, a drug for prevention of heart attacks and strokes, has scientifically been shown superior to current drugs on the market (avoiding serious side-effects), and its approval could help millions.
? Perhaps more importantly here, the FDA has violated its own processes, adding years of unneeded delay and crippling costs to a small company without adequate notice or opportunity for discussion, and establishing new precedents that are likely to discourage future drug development.
A brief history:
Amarin, a small company with operations in Connecticut, developed Vascepa and negotiated a formal agreement with the FDA, specifying the requirements for its approval. That approval was expected in December 2013, after a five-year effort during which the company delivered on all FDA requirements.
In October 2013, FDA convened an advisory committee meeting to review Vascepa and take a non-binding vote. The FDA did not provide their briefing documents to Amarin two weeks in advance as required. The voting question was artfully crafted to be ambiguous, and was clarified verbally, after Amarin’s presentation, in such a way as to materially change its meaning and renege on their agreement, surprising Amarin and effectively denying them a fair opportunity to fully prepare and present their case. In other official communications FDA was also not forthright about their intended major policy change that profoundly affected Amarin. FDA cited “new” information they’d had for years and gave scientifically flawed reasons, which is presumably why they sidestepped a fair debate. The FDA conduct of the meeting was biased, not mentioning Vascepa’s exceptional safety, for example, and being very evasive when asked about it. Panel members questioned the process to no avail.
The FDA acknowledges that Vascepa is safe and effective for its intended purpose – lowering triglycerides (widely recognized as a risk factor) – however, the FDA now insists on confirming it reduces heart attacks prior to approval. The vote, as architected by the FDA, was negative for the company, and the FDA rescinded the SPA agreement. Recordings show that panelists agreed that triglycerides were reduced (that’s what the vote was supposed to be on), but that reduced heart attacks were not yet proved (that’s what the FDA changed the question to).
New requirements were added, delaying approval about five more years. Amarin had already started the requested multiyear trial, but the FDA had previously agreed it could be completed post-approval, funded by profits, as has been done for previous drugs. These events set a bad precedent – one that will discourage future R&D – and deny millions access to a superior life-saving drug. I would be happy to provide more information. For now, I wanted to focus your attention on an agency gone rogue, abusing its regulatory processes.
I hope you will look into this before the December 20 approval decision, as the future of Vascepa still hangs in the balance.
Sincerely,
Charles ***** and Barbara ***** (formerly Barbara *****)
(Sent by both fax and email)
“why didn't the FDA come to them behind closed doors and say hey, were changing things, lets discuss and modify? … Why so unfriendly towards AMRN? …What (if anything) makes you think the FDA might modify the label “
FWIW, clearly the FDA wanted a negative adcom vote, and did whatever it took to get that. As JL pointed out, they stacked the panel. They omitted Vascepa’s superior safety from their presentation, and were evasive when asked about it. They wrote an ambiguous voting question, and then “clarified” it verbally just before the vote, changing it definitively to outcomes instead of trigs. So, when Amarin presented, they still didn’t fully realize the question was completely changed.
Of course, if the FDA had wanted to be fair, they would have told Amarin the real question weeks or months (or a year or two) earlier. As it was, FDA maneuvered deceptively so they would face only a partial defense. They needed to, since there was a lot wrong with what they did, including flawed science.
Why did they want a negative adcome vote? As others have said, they had egg on their face from failed outcome trials, made worse by their inability to recall those drugs. When there’s a problem, it’s human nature to want to be able to point to something you’ve done about it, even if what you did wasn’t actually helpful. Plus, the FDA often seems overly reluctant to approve drugs, especially when intended for wide use, because it exposes them to criticism if the drug causes harm. They don’t get much credit when drugs help people, and they usually don’t feel much heat for restricting access to good drugs. So, they have incentives to seek more control and higher burdens of proof.
It’s possible FDA could be prodded into approval with a modified label (a reasonable outcome) by having enough attention brought to their indefensible behavior. It is also possible FDA just wanted to strengthen their bargaining position for a compromise. I hope so, but I consider December approval a long shot. Nonetheless, I’m writing congress and signing petitions.
speedrunner
I have 70K shares
My wife was on Senator Grassley's staff years ago, and we are working on our letter to him. Hope to send it in the next day or two. Multiple letters couldn't hurt.
<<Does anyone know wtf is going on here? I sure don't.>>
Yo – Good post. I don’t claim to understand all this, but I’ll toss a couple thoughts into the mix.
The public is best served by a reasonable balance between protecting against bad drugs and hindering access to good drugs. The FDA responds to their perceived incentives, which distorts this balance since FDA is criticized if a handful of people are harmed by a drug, even if that drug benefits many thousands, and FDA doesn’t benefit much when good drugs help people.
So, to protect themselves, the FDA seeks ever more control, more stringent regulations, and higher burdens of proof, especially for widely used drugs. This has a chilling effect on drug development. I’ve heard it said the polio vacine might not have been approved by today’s FDA. Congress has tried to address this problem with reforms over the years, but FDA seems to find ways around the reforms.
In AMRN’s case, I believe FDA wanted to require outcome trials prior to Anchor label expansion for two reasons: to reduce their responsibility and risk, and in response to the failed niacin and fibrates outcome trials. FDA’s inability to remove niacin and fibrates from the market was frustrating, and they want to be able to point to something they’ve done to address the failed outcome trials problem.
Having decided what they wanted for selfish or political reasons, FDA needed a strategy and an excuse to achieve it. Their scientific/public interest justification was too weak to survive a fair debate, so they avoided one by blindsiding Amarin at the adcom. They apparently didn’t give Amarin the briefing documents 2 weeks ahead of adcom, as required, and the voting question was carefully constructed to be ambigous, as panelist Ellen Seely pointed out. It wasn’t until just before the vote that, in response to Seely’s question, FDA made completely clear the vote was to be about outcomes, not triglycerides. So Amarin did not have notice to prepare their case to defend against this devastating major change in policy, and did not fully know about it when they gave their adcom presentation. They were apparently also not allowed to discuss Vascepa's anti-inflammatory effects. (Can anyone tell me the source for this?) I think it's inexcusable FDA did not raise their concerns with Amarin a year or two ago.
I am hoping that if enough congresspeople contact FDA to shine light on this sordid episode, FDA may realize that some middle ground compromise is in their best interest. Better for the heat to come from congress than Amarin (let them be the ones that poke the lion with a stick). I also think dry eye syndrome should be pursued immediately, and with a clever publicist, off-label scripts could be accelerated prior to formal approvals.
I am hurting too, but what happened is not the fault of any poster. The FDA behaved inexcusably.
JL - Great letter. I do just want to point out that the adcom had one discussion question (more like a topic), and one voting question, and I think you may have interchanged the two. I cut and paste from a previous post from I forget who, and they I believe were quoting Redacre:
<<The gist of question 1 is:
Please discuss the efficacy results from the ANCHOR trial, including the clinical significance of the observed changes in lipid/lipoprotein parameters and your level of confidence that these changes will translate into a meaningful reduction in cardiovascular risk among the target population.
this is a non-voting question meant to solicit discussion from the AD COMM members.
Question 2 is the voting question:
Taking into account the described efficacy and safety data for Vascepa, do you believe that its effects on the described lipid/lipoprotein parameters are sufficient to grant approval for co-administration with statin therapy for the treatment of patients with mixed dyslipidemia and CHD or CHD risk equivalent prior to the completion of REDUCE-IT? Please provide the rationale underlying your recommendation.>>
(Back to my remarks) The net effect is to clearly give the impression the question is about outcomes, but perhaps convoluted enough for deniability. Also I believe and FDA spokesman verbally gave a different version verbally just before the vote, and one of the panelists commented that what he said did not match the voting question. Certainly in their comments, several no-voting panelists agreed that TGs were lowered, and some said they were optimistic outcomes would be improved, but that just wasn't proved yet.
I believe (from second hand reports of the ZGNX adcom) that the FDA was not pushing the panel to vote against, when ZGNX had done all that was asked of them. The panel seemed to go rogue on their own, worried about abuse as a safety issue. So, not exactly comparable to the AMRN situation, but I still find it encouraging as an example of FDA approval after an overwhelmingly negative panel vote.
I think our best bet is to find FDA officials higher up the food chain who don't like the lower level FDA hijinks surrounding the adcom. I'm hoping members of congress inquiring about this case might help, and hopefully our various letters will help get the ball rolling. I worry that angering FDA staff more than necessary could have repercussions, so I hope we all tread carefully, and stay on the high road.
"From AFs blogging, it was a simple electronic vote and "class dismissed". "
AF didn't comment on everything, they did go around the table and comment after the vote. I just listened to it.
Most of the no votes believed that trigs were lowered, but did not think there was convincing evidence lowering trigs improves outcomes. Some of the no voters also said they were optimistic Vascepa would improve outcomes, but that it hadn't been shown yet. Pam McCallister said she was unconvinced of clinical benefit and the placebo was not inert. Acouple of the no voters expressed sympathy for Amarin, since they had done what was asked. Only one or two seemed concerned about the immense cost, and there didn't seem much discussion of the several years delay, and it's impact on the company and patients. Several no voters said the large population made them more cautious. One of the yes voters said he was really just 60% yes, almost on the fence, so we just barely got him.
My wife worked for senator Grassley (quite a few years ago), and we intend to send him a letter. I also intend to send it to our representative and senators from Virginia where we now live, and also to the various physicians serving in congress. I want to keep it simple and short (improves the odds of it ever getting read), and provide references to the key science. I'm working on it in what little spare time I have.
I'll post a draft, and will appreciate any feedback. (I'm not a doctor.)
I appreciate everyone's efforts, prefer to do it mostly in my own words. Let's turn this into a flood of letters.
"Right now, if I was the company, I would be designing a trial for dry eye syndrome (DES)"
I think that makes a lot of sense. The evidence EPA helps DES is far more than just anecdotal, and is both theoretical and empirical. There have been several studies with apparently compelling clinical results of improved DES OUTCOMES within a month or so. These studies seem pretty convincing to me, despite verying degrees of rigor and some being apparently motivated to sell supplements.
Amarin is in a good position to take this to the major leagues. Nothing is ever easy, fast, or cheap with the FDA involved, but safety and manufacturing issues are already handled, an outcomes trial should only require a few weeks of treatment, and the statstics are such that it seems like no more than a few hundred patients should be required for definitive outcome results. (No waiting a long time for enough people to have heart attacks, no surrogate markers.)
With estimates of as many as 30 million Americans affected by DES, and limited competition, it seems like it might help bridge the gap if Anchor really is delayed several years.
http://www.dhaomega3.org/Eye-Visual-Health/Omega-3-Supplementation-Found-to-Alleviate-Dry-Eye-Syndrome
http://www.drmichaellange.com/research/proper-nutrition-and-dry-eyes/
(mentions inflammation and omega 3)
http://www.dhaomega3.org/Eye-Visual-Health/Short-term-EPADHA-Supplementation-Improves-Dry-Eye-Symptoms
http://allaboutdryeye.com/2011/11/04/draft/
The link to check for briefing documents:
http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm331504.htm
A careful look at the CaPre PR shows for the LDL decrease they report, they are NOT comparing to the control arm, so they are reaping the benefit of initiating statin treatment for those with high LDL. In contrast, they compare against the control arm for HDL, and cherry pick whether to mention 4 or 8 week results. This was a clever, and somewhat misleading, spin of the PR and design of the trial IMO, by having the control arm initiate statins instead of already being on them, and claiming credit for statin benefits on LDL when the DHA in CaPre actually increases LDL.
AMRN is up today, so the market doesn’t seem worried about these results.
The relevant excerpt from the PR:
<<After 8 weeks of treatment, patients under a daily dose of 4g of CaPre(R) had a mean LDL decrease of 8.3% and non-HDL decrease of 14.3%, while lower doses did not show deleterious effect on LDL or non-HDL. Moreover there was, after a 4 week treatment, a statistically significant HDL increase of 11.1% between the Standard of Care and the 4.0g CaPre(R) treatment groups.>>
The CaPre (krill oil) PR released this morning about successful Phase 2 study results reports reduced LDL as well as reduced triglycerides. That seems surprising since it includes DHA, and JL has commented that previous results were suspect since they violated the Friedwald equation. As far as I can tell, that was because for this trial the treatment was krill oil in addition to whatever other treatment the physician recommended, which often included statins. So, there was lipid improvement from that, including in the control arm of the trial.
I’m eager to hear the opinions of board experts. An excerpt from the PR:
<<Trial Highlights
• Primary objective was met: CaPre was shown to be safe and effective
• Statistically significant reduction in triglycerides: achieved greater than 20% reductions
• Efficacy of CaPre(R) increases from 4 to 8 weeks
• CaPre(R) efficacy at all doses facilitates dose adjustment for better patient management, providing potential advantage over other competitive omega-3 drugs
• Statistically significant HDL increase
• Reductions in LDL and non-HDL
The primary objective of the study was to evaluate the safety and efficacy of CaPre(R) at different doses over a 4-week treatment period in patients with mild to severe hypertriglyceridemia as compared to Standard of Care alone. Standard of Care could be any treatment physicians considered appropriate in a real-life clinical setting and included lifestyle modifications as well as lipid modifying agents, such as statins, ezetimibe and fibrates. Demographics and baseline characteristics of the patient population were balanced in terms of age, race and gender. Over 230 patients completed the 8 weeks treatment, which exceeded the targeted number of evaluable patients. From this patient population, 88% had mild to moderate baseline triglycerides between 200 and 500mg/dL (2.28 to 5.7 mmol/L).
The study met its primary objective showing CaPre(R) to be safe and effective in reducing triglycerides in patients with mild to severe hypertriglyceridemia. After only a 4-week treatment, CaPre(R) achieved a statistically significant triglyceride reduction as compared to Standard of Care. Patients treated with 4g of CaPre(R) a day over 4 weeks reached a mean triglyceride decrease of 15.5% from baseline and an absolute mean improvement of 18.1% as compared to Standard of Care.
Results also showed increased benefits after 8 weeks of treatment, with patients on a daily dose of 4g of CaPre(R), registering a mean triglyceride decrease of 21.6% and an absolute mean improvement of 14.3% as compared to Standard of Care, in which, due to lipid lowering medication adjustment, a significant improvement in triglyceride levels was observed during the trial between 4 weeks and 8 weeks.>>
nofan - I'm not sure who you refer to when you say "we" don't need or want more science, but many of us greatly appreciate the science from JL and others. It helps us understand the fundamental value of the company.
What was reported was not related to the outcomes trial, it was a phase 1 trial of a combination product of Vascepa and a statin.
Should Amarin be pursuing additional patents for additional conditions including scleroderma?
I could not help laughing when I noticed the drug with the second highest uptake on the graph is for involuntary bursts of laughing or crying.
You can not judge a marathon from the first quarter mile. I am very long, bought a little more here, and feel good about it. It is good to hear from others who feel the same way.