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Page Last Updated: 03/09/2012
Subjectively censorring data is restrictively banned in science communities. Some bad apples in science communities used cencored data to achieve their personal goals, and if been found out the bad apples are banned hardly.
However, we have a data censoring case presented by FDA in coducting ANCHOR AdCom. Intentionally or not, I don’t know. But the data censoring in ANCHOR case stands still.
First at all, let us look at the data in its entirity.
Triglyceride, Placebo Data Only, ANCHOR Study
Screening (6 Weeks)____|__Randomized Treatment (12 Weeks)
No Treatment _________|___Placebo (mineral oil 4 mL/d)
* Triglyceride Level, censored in FDA’s Briefing
# Triglyceride Level, presented in FDA’s Briefing
| vertical bar, division of screening phase and treatment phase
Note that there was two phases, screening phase (no treatment at all) and treatment phase. In the Briefing, FDA only presented the baseline (pre-dose, I suppose) and median of the treatment phase. The entire screening phase data and the pattern shown by the data entirety in treatment phase were censored.
I am using placebo data, because FDA’s Briefing negated ANCHOR by the issue of “mineral oil” altering placebo inertness (below), and this issue carried a heavy doubt on ANCHOR’s effectiveness and influenced panelists in ANCHOR AdCom Meeting on Oct 16.
In page 58 of FDA’s Briefing, FDA stated:
“The changes in lipid and lipoprotein parameters from baseline to Week 12 in the mineral oil placebo group are rather atypical for a trial that included a stabilization period for diet and lipid-lowering therapy, raising the possibility that mineral oil may not be as inert as assumed. If true, the treatment effects observed with AMR101 may be overestimated.”
If FDA could present screening phase data to panelists, even only baseline and median of the screening data, the panelists would see an elevation by time in the screening phase. The panelists would say “Ah Ha, triglyceride do elevate by time without any treatment. Thus, nothing seriously happened with mineral oil.” If FDA could present placebo data in its entirety (say, by graphic, a very simple way), panelists would see a strong linearity (a straight line) in the data consistently through from the start of screening phase to the end of treatment phase. Comparing with Vascepa data (see Blair O’Neill’s Seeking Alpha article “Amarin Corp: An Oversold Investment Opportunity”), the panelists would have a correct answer for the efficacy of ANCHOR.
Another important endpoint is LDL-C. I don’t have the access to review the LDL-C data in its entirety. However, the level of LDL--C and the level of triglyceride in HTG (high triglyceride) patients with CHD risks are highly correlated. FDA’s data censoring may cause misinterpreting LDL-C data as well (heavily damaged ANHOR’s credibility).
I don’t know what are the legal consequences of a government agency gains its purpose by censoring data. I am not a lawyer. Anyway, the FDA’s censoring data in ANCHOR AdCom is horrible to me, a US citizen.
In FDA's Summary Review on Vascepa approval:
"There was one reported death in the hypertriglyceridemia database; a 64-year-old male died from a myocardial infarction while participating in the ANCHOR trial. He was randomized to placebo."
I wonder what would happen if that 64-year-old male was randomized to Vascepa. He probably survived as other hundreds patients (a total of 1,322) randomized to Vascepa did. And I believe there is a good chance of having an early success in REDUCE-IT at any coming day -- one death is too much.
Actually, Vascepa is a goose which produces golden eggs.
Lovaza will be genericized for sure. However, Lovaza has lower rank in treating severely high TG, and Lovaza is nothing in treating common high TG and mixed dyslipidemia. In fact, not only Lovaza is in genericizing, but also other 3 blockbuster TG-killers, Tricor, TriLipix and Niaspan (all from ABV), are suddenly genericized in the same time, September, 2013. The dying down marketing activities will help Vascepa to penetrate the market.
The Vascepa’s sales have multiple catalysts: AdCom Meeting in October, PDUFA in December, particularly REDUCE-IT outcomes in a coming year. If approved, the ANCHOR indication may bring Vascepa to be a multi-billionaire in a few years. And positive REDUCE-IT may seat Vascape to the top of entire drug market. BTW, AMRN is not a one-pony company. The clearest one is the combination of Vascepa + Atorvastatin -- the next catalyst followed REDUCE-IT.
Talking of the combination of Vascepa + Atorvastatin, PFE will automatically jump in sight. PFE's interesting in the combination is naturally unforgettable. So, PFE is a potential suitor to buy out AMRN. Due to that all three recently genericized TG-killer are ABV's. ABV (spinning off from Abott labs) suddenly lost 3 blockbusters at the same time. And their thousands sales REPs have nothing to sell. Naturally, ABV is another potential suitor to buy out AMRN. Sure, GSK is also in the champ of potential suitors.
With a successful AdCom Meeting, buying out AMRN is not an "if," but "when" and "how much."
The events may take a few years to be spinning off. So, stay tune for the full story of a fish, or the full story of a goose producing golden eggs.
November 16th in Dallas, new guidance will be published. Mark your calendar! That is important much more than those studies on fen fibrates and niacines.
I have recalled the AdCom meeting. Because the chopping input from FDA's website, it is not a complete one. Today, I just post a summary of my recall. I may do a better one over the weekend.
Seemingly, Hiatt and Seely are co-speakers of the penal. Both are very smart. From FDA's voting question, it is clear that FDA wants a "NO" vote. So, both are very picky in evaluating all the materials. Not too many other members #$%$ out in the meeting. I heard something from Britton (Card?) and Wilson (Biostat).
Hiatt's and Seely's main point is the effectiveness on lowering TG is not enough to evidence Heart Benefits. Niacin study has been mentioned very often in the meeting. Seely dis-qualified JELIS study hardly. They didn't mention Copenhengan study and Demark study (two strong evidences to correlated TG-lowering and heart ben
Turning to safety, the weather was changed from winter to spring. As the chair (Smith voted YES) switching the subject, Hiatt insisted discussing safety, and he said kind words on that -- giving an impression that he may change on the fence. Hiatt and Seely pointed out that the company did everything that FDA asked. Seely worried funding for completing REDUCE-IT and talked about Federal Fund to the company. Seely asked if approved but REDUCE-IT failed, what FDA will do? Very interesting question indicates "YES" was struggling in their mind, though a "NO" is clearly pre-set by the voting question. FDA answered that they can force the company to change the label even via legal path with lawyers. Another interesting point from FDA is "prescribing V off label is legal" -- a strong nod to physicians.
The most interesting thing followed the discussion about safety and what FDA can do if approval but REDUCE-IT fails, a few members ask FDA to change the voting question. FDA's ironical answer is "We don't change the voting question. ALL SET!!!! 9 NO and 2 YES (Smith and Herral).
I think that this recallation may be already enough.
Very interesting, all old blockbuster TG-killers (Lovaza, Niaspan, Tricor, TriLipix) got generics in the same month: September, 2013.
Vascepa is the new generation of TG-killers, and to be the first in the class.
The disadvantage is generics are cheap, but the serious side-effects of those old guards will stay with the generics. The superiority of Vascepa make it distinguishing to the old guards.
The generics may help the commercialization of Vascepa. The marketing efforts of the old guards will be dying down soon. The TG-killer sales forces in ABV and GSK has nothing to sell now. Seemingly, the best for AMRN may be establishing a relation with GSK or ABV to fill the marketing vacuum.
Lovaza contains 47% EPA and 38% DHA.
In matching 4G EPA, one needs to take 8-9 G Lovaza, including 3+ G DHA -- that will cause CVD, prostate cancer, ......
My First Finding:
"The question presented for a vote should have minimal qualifiers, not be leading, and should avoid the use of double or triple negatives. When presenting a question for a vote, the Chair, DFO, or other senior agency officials should solicit and answer questions about its meaning before the vote begins. The objective is to reduce any potential confusion and maximize the meaning of the voting results by ensuring that the votes are based on a consistent and collective understanding of the question at issue."
From GUIDANCE FOR FDA ADVISORY
COMMITTEE MEMBERS AND FDA STAFF
Voting Procedures for Advisory Committee Meetings
FDA violated its own Guidance, particularly Roberts
(to be continued)
It took me 3 hours to go thro the transcript.
Primary impression: the meeting is well designed and controlled by FDA and panelists performed with their wisdom.
Due to the complexity of the subject, no simple answers beyond the symbolic 9 No 2 YES ("birds in cage")
AMRN is still fight for reinstallation of rescinded SPA. It is also a symbolic move -- no way. I suggest AMRN to be out of that "hard way" soon and to start negotiation with FDA in a soft way. FDA won't kill ANCHOR. Oppositely, they wish REDUCE-IT doing its job: to define "Vitamin EPA" or "Next Lipitor". Recent changes in labeling Niaspan, TriLipix, TriCor and Lovaza may indicate a "controlled" label for ANCHOR still has its chance (but no ordinary "conditional approval" for ANCHOR, by Mary Park).
From ANCHOR data, there were 4 CVE events in two placebo patients (including one death), 1 CVE in V 2g/d, and 0 in V 4g/d. No statistic meaning, but hint thousands death may ocur if FDA simply delay ANCHOR for FOUR MORE YEARS. FDA would do something to help AMRN to test the "historical high bar" -- it's in public interesting and in FDA's interesting as well.
FDA's Brief and the company's Brief together gives us a clear picture:
Actually, ANCHOR is about coming COMBO and REDUCE-IT. AdCom and FDA should realize that an on-time approval of ANCHOR will bring the massive benefits of COMBO and REDUCE-IT coming on-time. The delay of ANCHOR, so of COMBO and REDUCE-IT, costs life among millions patients.
Short-term volatility (painful) doesn't darken the long-term prosperity. Long-term investors will laugh at the last.
The invalidation is due to that FDA employed censored data and an inductive voting question (the solo voting question) to lure 9 NO 2 YES from the AdCom. If I can have a transcript of the AdCom meeting, I can show it in details.
Third Finding from the same Guidance:
"Briefing materials provided to advisory committee members as background materials before an advisory committee meeting should be thorough and, to the extent possible, include the questions that will be voted upon by the committee. The objective is to maximize the meaning and utility of the voting results by ensuring that the voters have had ample opportunity to study background materials before the day of the meeting."
The background materials (Briefing) omitted most relevant data (all screening data and most treatment data), and only statistics based on two occasions were in the Briefing. And FDA wrongfully made "placebo inertness" in doubt. It leaded panelists misunderstanding the true efficacy in the entirety of data.
(to be continued)
Both ANCHOR and REDUCE-IT are targeting residual CHD risks of satins caused by excessive triglyceride. It is a brilliant idea.
Yes, statistically statins reduce CHD risks. However, CHD risks still quite high in statin population (about 6%, per FDA). No matter what FDA said, literatures proves that excessive triglyceride is a cause of CHD risks, and the risks somewhat beyond statins (in ANCHOR study, there were 4 CHD events and 1 death in 223 statin patients with placebo, 0 with 4 g/d Vasceap, in 12 weeks). I.e. statins are not enough to control the CHD risks by excessive triglyceride. Recently, AHA guidance suggests to expand statins usage significantly. It actually is good news for Vascepa's potential. ANCHOR data proves, even with statins triglyceride still staedily raises 1.7 gm/dL weekly, i.e., about 100 gm/dL annually. However, triglyceride drops more than 20% with Vascepa. Without ANCHOR (or conditional) approval, FOUR MORE YEARS will raise triglyceride 400 mg/dL more averagely in statin population without Vascepa treatment. And, whether other TG-lowering drugs can lower TG in satin population is unknown.
(to be continued)
Optimistically speaking, AMRN may be the Apple in the Pharmaceutical Kingdom.
One reported death in ANCHOR study with placebo is a micro-REDUCE-IT;
V + S COMBO.
The most importance is from the anti-inflammation effect of Vascepa. Inflammation is a nursery of many kinds of diseases. Thus, Vascepa may become an efficacy enhancer for many drugs. The possible COMBOs, the Smart Phones in the Pharmaceutical Kingdom, include:
V + anti-diabetic
V + antidepressant
V + anti-dermatitis
V + anti-hypertension
V + anti-insomnia
V + COPD treatment
V + anti-opioid addiction
With Vascepa's patents, AMRN has enough time to develop dozens COMBOs. BTW, usually, fixed dose COMBO has its own patent independently, and this kind of patent is strongly defendable.
To sum up, the breakout continuation of the Cup and Handle will keep going on for YEARS.
I am a senior scientist. Usually, I leave financial to others. However, seemingly, financial is one of the keys for AMRN moving forward, even though the company has an approved product with nice potential. I did some non-professional DD as follows:
The company's cash position was $270.5M as of June 30, and debt was $236.7M. The expenses run at about $180M annually, and could reduce to $150M in 2014. The sales run at about $10M quarterly, and could run at $20M quarterly in 2014.Vascepa gross margin is about 48%, and could increase to around 70% in 2014 (average about 60%). For the $100M financing last Dec, the company should pay $2.5M in Nov, and another $2.5M in Q1/2014. After that, $8M quarterly for rest of 2014, $10M quarterly in 2015, and $15M quarterly in 2016, ...... till totally $150M been paid. REDUCE-IT costs $40M to have the enrollment done, then $20M to run annually (a total of $100M in 4 years, but could be cut by early achievement).
Tight, but not in desperation. More sales is a must. More fund by any means would be helpful very much.
Just my non-professional view.
I am interesting in what FDA will do.
A CRL is almost for sure. But previous models don't fit ANCHOR/REDUCE-IT.
Previous CRL models:
b) Approvable, but need
a revised label -- Class I, two month delay, or
additional data -- Class II, six months delay;
ANCHOR won't be approved or rejected, and Class I and II both are not suitable to the ANCHOR case. However, FDA has enough creativity to create a brand new solution.
The observed CVD events were 4 in 2 placebo patients, and only 1 in 1 patient with V 2g/d, of course 0 with V 4g/d. It was a reduction of CVD events with V. I have calculated the p value of the event-difference of V vs. Placebo: p = 0.18 (below 0.05 then significant). Tossing a coin, p = 0.5. With p = 0.18 (small patient number -- ANCHOR had 223 placebo patients, 236 with V 2g/d and 233 with V 4g/d), it is not significant yet, but not far away -- the success of R-IT is not far away neither. I think that I have dug into ANCHOR deep enough. Only R-IT counts, FDA.