As expected, no rejection at all.
To me, the most impressive in the PR is no mention of binding ANCHOR approval and REDUCE-IT completion. In fact, "t(T)he FDA also communicated to Amarin that it now views Amarin's appeal of the ANCHOR SPA agreement rescission and the ANCHOR sNDA as separate administrative decisions worthy of separate consideration. FDA plans to complete its review of Amarin's request to re-instate the ANCHOR SPA agreement and plans to convey its decision to Amarin no later than January 15, 2014. The FDA provided no additional information on when it expects to complete its review of the ANCHOR sNDA. " However, the correlation of the two is much stronger than the separation: a restated SPA guarantees an immediate approval of ANCHOR sNDA. Therefore, the January 15 is the "semi-PDUFA" date: if the SPA been restated, then a Class I (2 months for labeling adjustment) follows.
The placebo data of ANCHOR Study revealed that triglyceride keep elevating, about 100 mg/dL per year in a linear pace averagely, in patients with mixed dyslipidemia and residually high serum triglyceride levels (200-499 mg/dL). The patients supposed to be in REDUCE-IT for 4-6 years. Therefore, triglyceride in most patients with placebo in REDUCE-IT will shoot up above 500 mg/dL. Even though “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” (I believe that FDA will change their tune very soon), they already recognized that serum triglyceride greater than 500 mg/dL causing greater cardiovascular risks. Therefore, no doubt MACE (major cardiac event) keep elevating in REDUCE-IT patients with placebo.
The treatment data in ANCHOR Study revealed that Vascepa 4 g/d reduced 20% more serum triglyceride from placebo in a 12 week timeframe. As serum triglyceride keep shooting the roof in REDUCE-IT patients with placebo, the relative reduction in serum triglyceride of V 4g/d vs placebo will be greater and greater.
This scissor-type dynamics guarantees REDUCED-IT’s success.
May much earlier than what you have thought.
In fact, the primary endpoint of REDUCE-IT is MACE: a composite of CV death, MI, stroke, coronary revascularization, and hospitalization for unstable angina. The protocol of REDUCE-IT aimed 1,627 CVE, and 60% is the threshold for an interim analysis. I.e., no data un-blinding before 976 CVE happened. But, how about a CV death? FDA and DMC (Data Manage Committee) will monitor any death case in any clinical trial closely. With a CV death in REDUCE-IT, FDA and DMC will be immediately looking at the case and finding out it is with placebo or treatment. I.e., there is no blinding with a death case. MI and stroke are with high death rate. For death cases, it is easy to design a computer program of 2 X 2 table statistic test. Whenever, the death with placebo is statistically greater than that with treatment, the program will alarm, and then the Study will be terminated. Therefore, I expect that REDUCE-IT will be terminated much earlier than the 976th CVE.
The primary endpoint of REDUCE-IT (RI) is MACE (major adverse cardiac event, including heart attack, stroke, cardiovascular surgery, hospitalized angina). In OCT 2013, FDA’s estimate of MACE rate in RI population was 5.2%. The rate should go up gradually in patients with placebo (due to high-triglyceride progressing) and go down gradually in patients with Vascepa 4g/d (due to treatment effect proven by ANCHOR). The RI protocol requires the size of 8,000 patients with high triglyceride. MACE cases target 1,726 to distinct placebo from treatment by statistical significance, and an interim analysis will happen as MACE reached 976 cases.
Counting on the size of 6,400, the annual total MACE cases is expected to be 333, based on 5.2% rate. RI started in Nov 2011, the size gradually reached 6,400 in Dec 2013. Assuming, conservatively, there were 350 cases MACE occurred in RI prior to the end of 3013, thus there will be 683 MACE cases accumulated at the end of 2014, and 1,016 accumulated cases at the end of 2015. Therefore, an interim analysis of RI would be occurring in late 2015
However, deaths may change the timetable. In ANCHOR Study (702 patients in total), there were four CVE in two patients (including one death caused by MI) with placebo, one CVE with Vascepa 2 g/d, and 0 CVE with Vascepa 4 g/d, in a 12 Week timeframe. Converting to annual death rate, it was 0.6% (a point estimate, not reliable). Whenever, death number can distinct the two arms (placebo and Vascepa) with statistical significance, FDA will terminate RI and announce the conclusion.
The short timeframe, from Dec 20 to Jan 15 including holidays, indicates that FDA already has had a draft solution. Seemingly, higher leaders in FDA has been touched by recent grass-roots movement. I expect a positive outcome on Jan 15.
The mortality rate with MACE is quite high. E.g, the death rate with heart attack is about 10%. Counting on 5.2% MACE annual-rate in general RI population and assuming the overall death rate with MACE to be 5% annually, the annual MACE death rate in RI population would be 0.026%. There was 0 death in ANCHOR patients with Vascepa (2 or 4 g/d), though a minimal rate should be expected.
For the RI study, there would be about 17 MACE deaths per year based on 6,400 enrollers, and about 21 MACE deaths per year based on 8,000 enrollers.
For the RI population (36 M), there would be about 93,600 MACE deaths per year without a safe and effective treatment. That would be FDA's burden if they don't approve ANCHOR in tome.
I don't believe that FDA will simply say NO on Dec 20 -- not a single panelist suggested a rejection at Oct 16 EMDAC Meeting. Most possibly, a CRL -- clarifying the stipulations.
The situation has been well discussed a few months ago:
A 3y NP (New Product) exclusivity to July 2015 for MARINE. ANDAs can be filed thereafter with Paragraph IV certification and then 30 Month Stay to January 2017. If ANCHOR can be approved before 2017, another 3y NP should be granted (and another 30 month stay). Parallelly, REDUCED-IT, if succeed, should be granted a new kind of exclusivity might longer then 3y (then 30 month stay). Here, the outcomes of patent-lawsuits have not been counted.
Vascepa makes blood thinner for flowing to whole body easier and smoother than ever. Placebo-like safety plus the anti-inflammatory effect will make Vascepa to be a more acceptable drug than Aspirin.
Oct 16: EMDAC voted 9 : 2 against of approval for ANCHOR indication.
Oct 29: FDA rescinded ANCHOR SPA and 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.
Nov 22: FDA refused to accept the appeal for review at a level above the review division.
Dec 16: JZ retired.
Dec 20: FDA plans to complete its review of Amarin’s request to re-instate the ANCHOR SPA agreement and plans to convey its decision to Amarin no later than January 15, 2014. The FDA provided no additional information on when it expects to complete its review of the ANCHOR sNDA.
The primary endpoint for REDUCE-IT is MACE (major adverse cardiac event, a composite of cardiac death, heart attack, stroke, open heart surgery and hospitalized angina). MACE rate in REDUCE-IT, per FDA, is estimated to be 5.2% annually (less with Vascepa, greater with placebo), and mortality rate with MACE is about 4% annually. Therefore, there will be 300,000 deaths in 36 M high triglyceride patients in FOUR MORE YEARS, if FDA delays ANCHOR approval.
FDA rejected to discuss the Appeal at review division level on Nov 22, but FDA announced, on Dec 20, that it will convey to the company about the Appeal no later than Jan 15. It indicates the recent decision was made by upper level. Dec 20 was the PDUFA date for ANCHOR sNDA. However, the Dec 20 announcement didn't have any offer regarding the sNDA (even no new PDUFA) but focusing on SPA Appeal. If FDA intend to reject the Appeal, they can reject the sNDA at the same time -- no separation is needed. The separation of Appeal and sNDA is trending to positive -- Appeal Acception and then Labeling Negotiation.
Connecting the dots:
The Oct 16 EMDAC Meeting was specifically set up for "rationalizing" SPA rescission on Oct 29 (however, what a mess!). Nov 22 refusal was FDA's defensive move (trying to limit the influences), and Dec 16 JZ resignation was AMRN's offensive move (getting "lean" in dealing with FDA). The fraudulent "sciences" employed by the reviewing division made the division losing all credibilities. Originally, Dec 20 was set up as ANCHOR PDUFA. However, the action was focusing on SPA, and no new PDUFA. Dec 20 action should have been decided by FDA's higher level. Now, the probability of re-instating ANCHOR SPA on Jan 15 is greater than 50% and ANCHOR approval will be a natural extrapolation of re-instated SPA -- no new PDUFA is needed.
Amarin's statement on pulling out of the J.P. Morgan conference:
Key Words: respond on the SPA reinstatement question, the date on making determination on the ANCHOR sNDA, sensitive dialogue, significant updates
As previously disclosed, the FDA has communicated its plan to respond to Amarin on the SPA reinstatement question not later than January 15, 2014 and the FDA has not informed Amarin of the date on which it will make its determination on the ANCHOR sNDA. Because Amarin and the FDA may engage in sensitive dialogue related to such ongoing matters during such time, Amarin does not currently plan to meet with investors or to have discussions with investors until after Amarin makes an appropriate public disclosure following significant updates from the FDA. Amarin is no longer scheduled to present at the J.P. Morgan annual healthcare investor conference.
IMV, it is almost impossible that FDA will reinstate the original SPA. I expect FDA will modify the SPA and conditionally approve the ANCHOR with label changes (with certain restrictions related with REDUCE-IT). Now the "sensitive dialogue" is ongoing. We will know the outcomes in WEEKS.
Thank you, Speed. The CP is a powerful way to force FDA to "do something". Glad to see the flowers of grass-roots.
One suggestion: allow those who missed to sign onto the CP to add on their signatures at epadruginitiative website, even the first official version has already been sent out.
The CP is well written. It is beyond me.
I intend to agree with you. The timing and keeping JZ in BD, both have something behind. Anyway, only 3 days to get there, my take: CRL -- some kind of "delay."
Even though main-street sciences recognize that excessive triglyceride causing greater CHD risks, current Vascepa's Prescription Information didn't seek any reducing CHD risks advantages:
"Limitations of Use:
•The effect of VASCEPA on the risk for pancreatitis in patients with severe
hypertriglyceridemia has not been determined. (1)
•The effect of VASCEPA on cardiovascular mortality and morbidity in
patients with severe hypertriglyceridemia has not been determined. (1)"
Although ANCHOR Study is targeting the population with residual CHD risks and ANCHOR data implicates potentially reducing residual CHD risks for patients with triglyceride between 200 - 499 mg/dL, in fact I believe the ANCHOR sNDA hasn't seek explicit labeling of reducing residual CHD risks. Actually, in Prescription Info of TriLipix, Niaspan and Lovaza, all for treating TG greater than 500 mg/dL, all included clinical data in population with residual CHD risks treating by combination with Statin(s).
In the ANCHOR case, 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.
First at all, the finding of that TriLipix and Niaspan failed to demonstrate reducing cardiovascular risk in subjects with serum triglyceride levels below 500 mg/dL doesn't have any natural correlation to what other TG-lowering chemicals can or cannot do in reducing residual CHD risks.
(to be continued)
Seemingly, FDA made the turn in early Dec. Why? Pressures from grass-roots (particularly CPs and scientific documents) be a significant factor. However, FDA is not such a agency to compromise easily. Any other factors? I will try to understand that in another separate thread.
Thanks for your kindness of help.
The refill rate is at 62.8%, record high -- patients satisfactions, a comprehensive index of effectiveness and safety.
I don't expect any dramatic advances in AMRN's business. I hold my position standing along the side line. May add some, if PPS down to around $1.5. I have no doubt on V, and no doubt to the bright future, just doubt to any kindness from FDA.
The appeal is ongoing at the second level. The expectation is low till, at least, the next level.
I don't expect any quick pop on V's sales -- AMRN won't suicide by promoting V off label without ANCHOR approval.
Though the company said they are considering terminating RI, I don't take it seriously -- it is just another way of suicide.
The view from side line is "business as usual."
However, don't forget the underneath energies. Explosion may happen any time.