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Hi Kiwi,
Short summary:
“[Note: Sealed] Information regarding product launch planning is manifestly confidential business information. Amarin’s request to make public … of this nature is especially troubling”. – AZN’s argument on 09/11/2014 Doc #21. (I agree with AZN.)
AZN has 2 arguments:
1.) Epanova does not infringe the patent, since change from baseline is greater than 20% – “funny”, the patent is “against baseline or placebo” and diff. is less than 20% compared with placebo.
2.) Epanova is not on the market
I do not know the exact claim of AMRN, but the ruling could be:
- Dismissal
- AZN will be restricted to market Epanova
Are you joking?
This is the worst management ever. They proposed compromises to the FDA for the last 10 months meanwhile faild to accept / turned down FDA great, acceptable proposal. Do you really do not see how bad they are?
And honestly, how could you compare a public forum (CC) with this board? How do you know that the participants were from Amarin? The folks on the CC could be anybody.
If you could not appreciate this board, leave it and stay at your stock (AMRN)
Jl,
If I understand you correctly, you said:
The director of the review division could determines that a substantial scientific issue essential to determining the efficacy of the drug if new substantial information effecting efficacy of the drug arose and the director is not entitled to reevaluate their assumption without it.
LDL-C is/ was a validated surrogate endpoint and all other lipid-parameters (in this case HDL and TG are relevant) was considered reasonably likely to predict clinical benefit. Accumulation of the scientific information led FDA to conclude that HDL cholesterol could not be used as a surrogate end point for cardiovascular risk reduction and adopted a more conservative approach than previous applied for biomarker based approvals targeted towards cardiovascular risk reduction.
However, they were not entitled to use the same conclusion for all lipid-parameters, and they have to use the previous assumption regarding TG, could not adopt the new, more conservative approach, since they have to evaluate all lipid-parameters individually.
“FDA has right to make such a clinical decision in the abscence of an SPA agreement”, but not if the SPA is exist, because the SPA does not contains this possibility and it overwrites the law. FDA have to use different approach for biomarker based approvals at the same time one for SPA supported and one for w/o SPA.
Is it a correct interpretation?
Agree, as
I say "could I jump?" they say "yes!" or "no!", I say "how high?"
Good point, agreed.
a.) CRL letter will be issued "now" and after / during Amarin will continue to engage FDA.
b.) Amarin will continue to engage FDA and after the negotiation (w or w/o agreement) the CRL letter will be issued - it's better, since if they will agree, Amarin could communicate the CRL and the new sNDA at the same time.
If they could agree
a.) ANCHOR data on the label or
b.) "new" indication and ANCHOR data on the label
Amarin will submit a new sNDA and hopefully, as you wrote, FDA will offer priority review since it's essentially just a label changed to their satisfaction, as the rest of the package would be nearly identical, if not 100% identical.
(I did not and won't check the regulation - use of the current sNDA -, since the outcome is the same.)
Thx, but I am still interested in JL's view (I am not 100% sure, it's just my view.
One addition, Amarin CC transcript:
In the October 2013, Vascepa advisory committee meeting, FDA stated that to approve an indication based upon triglyceride lowering in statin treated patients with triglyceride levels below 500 mgs per deciliter, it needs to be confident that triglyceride lowering will result in cardiovascular risk reduction.
As previously disclosed, failed results of the cardiovascular outcome studies of other drugs, fenofibrates and the ACCORD-Lipid study and nicotinic acid in the AIM-HIGH and HPS2-THRIVE studies, reduced FDA's confidence in the use of triglycerides alone as a surrogate for regulatory approval of a drug focused on cardiovascular risk reduction in this population, such that the FDA would like to see outcomes data to confirm cardiovascular reduction benefit.
This is a regulatory policy focused issue for the FDA. The FDA has considered against the backdrop of HDL rising drugs that fail to show cardiovascular benefit.
In our communications with FDA, it is clear that in the backdrop of these HDL studies, FDA has revaluated the situation and has adopted a more conservative approach than previous applied for biomarker based approvals targeted towards cardiovascular risk reduction. FDA expressed to us that the accumulation of the scientific information that led FDA to conclude that HDL cholesterol could not be used as a surrogate end point for cardiovascular risk reduction occurred in the same timeframe as its decision to rescind the ANCHOR SPA agreement.
FDA noted to us that this illustrates that the science related to the use of drug induced changes in lipid parameters as surrogates for cardiovascular risk reduction remains unstable and fluid. FDA noted an exception for LDL cholesterol for which there have been successful outcome studies. So, they went onto mention that even for LDL cholesterol, there may be new answers which come out of future studies.
For Amarin, reduce it or answer a less regulatory legal and more patient focused questions that goes well beyond the validity of triglyceride as a surrogate, specifically, whether the cumulative effects of Vascepa will result in cardiovascular risk reduction in the high risk patient studied. The effects of Vascepa including improvement in triglyceride level and other lipid lipoprotein and inflammatory biomarkers that were demonstrated in the ANCHOR trial, as well as potentially other effects not yet fully studied, but explored and described in the scientific literature. The safety profile of Vascepa that was established in the completed Phase 3 studies is comparable to placebo and compares favorably to existing drug therapies for use as [indiscernible] to statin therapy in treating this at-risk patient population.
Although for regulatory approval purposes, FDA's confidence in the use of triglycerides is a cardiovascular risk to surrogate was lowered by the cited studies of different class drugs. FDA could not and specifically did not rule out that triglyceride lowering effects of Vascepa could result in cardiovascular risk reduction in the ongoing REDUCE-IT study. We discussed with FDA that REDUCE-IT's future success might also be attributable to other favorable effects of Vascepa and its unique single active ingredient, EPA.
The ANCHOR SPA agreement remains rescinded. There has been no determination on the ANCHOR sNDA. We tried to engage FDA on the ANCHOR sNDA with every available opportunity over the last 10 months and offered a number of compromises. But FDA maintained the SPA appeal and sNDA are two separate matters and did not address the ANCHOR sNDA in our communication on the ANCHOR SPA appeal.
Amarin continues to believe that approval of an indication based upon the ANCHOR clinical trial results is in the best interest to patient care. As a reminder, Vascepa achieve all primary and secondary endpoints in the pivotal ANCHOR Phase 3 study. As previously disclosed, prior to completion of a successful outcome study, we see FDA approval of an ANCHOR indication and approval of ANCHOR data in the label as an uphill battle.
As to steps forward, aside from stating that we're again reaching out to FDA for resolution on the sNDA, we will not detail our plans on this call. We have continued to consult with our nationally recognized regulatory clinical and legal advisors who share our passion for approval of the ANCHOR indication.
JL,
What do you think about the following? Two notes to the below. I had the view, FDA has only a limited right to rescind the SPA (it should be based on a valid / good reason) but has the right, so the question they exercised their right correctly or not. I am not a physician I don’t know / could not evaluate the science.
“the director of the review division determines that a substantial scientific issue essential to determining the safety or efficacy of the drug” – I read it as the director determines that the available scientific issues are not enough due to reevaluation and improved understanding of the relevant scientific knowledge (w or w/o new substantial scientific issue arose) since the ANCHOR trial began.
I do not know (we do not have exact information) that “FDA concluded that in its view the totality of scientific data and information” includes or not the new data and information became available after the SPA rescission as acc. to the Formal Dispute Resolution “Because all FDA decisions on any dispute must be based on information already in the relevant administrative file (§ 10.75(d)), no new information should be submitted as part of a request for reconsideration or appeal. If the sponsor has new information that may affect the original decision, any appeal should be deferred until the new information has been submitted to the administrative file and reviewed by the division.”
Theravance’s case (Vibativ) is not exactly the same, however it looks like similar: Fair is Fair; But Science is Science
JL,
I detailed it the simplest way as I could in #34665
re your post:
"is not a new scientific issue casting doubt of Vascepa's efficacy."
Agree, however FDA did not set-up a new science, TG never was a validated surrogate end point and still not and they not approve something without validation from now.
"And the reason I ask that is that the proposed label is to treat a surrogate endpoint, as you say, with the presumption that there's clinical benefit. But the issue on the table today is whether we should approve something as a surrogate endpoint." (AdCom)
b-
It's my fault as drrc1949 pointed correctly I am not always crystal clear, understandable. Let me approach it differently.
We agree: FDA did not notify Amarin within a reason able time, it could be a basis of a suit (I never said anything else reg. the timing)
We did not agree: FDA breach or not the SPA.
FDA did not breach the SPA as they have legal authority to rescind it if they have a reason. The question is that the reason is good or not.
I hope we could agree, except the LDL-C, none of the lipids are validated as surrogate endpoint and this is the key point.
FDA approved lipid-altering drugs based on their assumptions that favorable changes in the lipid profile would translate into a benefit on clinical outcomes. Based on other studies they feel that this assumption is weaker now (at the time of the rescission) and required validation. They did not say TG could not be a validated surrogate endpoint, they just do not know yet.
According to Amarin PR: ”However, FDA concluded that in its view the totality of scientific data and information, including its reevaluation and improved understanding of the relevant scientific knowledge since the ANCHOR trial began, does not support use of decreases in triglycerides as a validated surrogate for cardiovascular risk reduction in the proposed patient population.”
or with other words it was not a validated endpoint and still not.
The basis of the whole "debate" was that Amarin "has to" appeal / sue or not.
I said not, due to the reason above and because of the duration of the appeal / legal process (ruling could be around mid-2017 only).
It's an uphill battle for me , but good to see that your opinion about SPA/sNDA and negotiating/compromise talk closer to mine now. Keep the direction and we will meet. I will not move
sts,
FDA refused to negotiate while the SPA appeal process was ongoing since if SPA exists their evaluation primary has to based on the ANCHOR study and they "have to" approve. Until the SPA appeal process was ongoing they "did not know" ... how could they act regarding the sNDA. Now, they do not have to use the ANCHOR study as a primary basis so they could be flexible. (?): #34552
Why is it still a possibility: #34637
I do not know the real possibility, however this is that I said several times since the CC ...
I do not know, it 's not finance / match / business / legal. JL has a lot of great post about it.
JL,
I agree with you that FDA's opinion on trigs is wrong and I did not argue(d) regarding this area with you or anybody else and it is not a question that FDA was far away from “in notifying the sponsor of such issues within a reasonable period of time after FDA becomes aware.” The question: Did they breach the SPA or not? My opinion is business / “legal” view:
As I wrote “it was not a classical contract, it is an agreement”. In a classical, business contract both parties have rights and obligation. In this case:
The sponsor’s
- obligations: run the study according to SPA (design and size)
- rights: submit a marketing application based on the (successful) study
The FDA’s
- obligations: use the study as the primary basis of an efficacy claim
- rights: ? nothing
The classical, business contract could not be terminated based on single party decision without breach by the other side.
In this case FDA could rescind the assessment (not terminate, not the contract, not the agreement, or as exactly described-“A clinical protocol assessment will no longer be considered binding”) “if the director of the review division determines that a substantial scientific issue essential to determining the safety or efficacy of the drug has been identified after the testing has begun.”
FDA acts according to regulation and to law as they have ability to rescind a SPA according to these. My view they did not breach anything.
„Clearly the FDA is exceeding its authority in Amarin's case”
You have right “there is no conclusive evidence that trigs won't lower CVD risks”, however there is no conclusive evidence that trigs will lower CVD risks, it is not a validated surrogate endpoint. The FDA did not set-up new science.
Congress adopted the 1962 Drug Amendments, which included a provision requiring manufacturers of drug products to establish a drug’s effectiveness by "substantial evidence." Substantial evidence was defined in section 505(d) of the Act as “evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested inthe labeling or proposed labeling thereof.” Nevertheless, FDA has been flexible within the limits imposed by the congressional scheme, broadly interpreting the statutory requirements to the extent possible where the data on a particular drug were convincing.
Unfortunately in this case FDA was not flexible. I also think that if FDA announce their current assumption (favorable changes in the lipid profile, would translate into a benefit on clinical outcomes is questionable) about lipid-altering drugs in 2012 (shortly after AIM-HIGH and ACCORD-LIPID), I think we would have a different discussion today…
Again, their decision is wrong (the reason is weak), was not within reasonable time, but it was legally ok, they did not breach anything and did not exceeded their authority. They could request validation of effectiveness anytime.
BB,
Do not forget, we will know the eff. of V after R-IT as "in combination with a statin", we will not know the eff. of V alone.
I do not think that a trial V alone vs placebo will be initiated ever, since nobody will agree to study patients without statin within this population.
NCE:
We do not know the timing, however (I think) the judge knows that the NME will be expired by July 26, 2015, so it "should" be finished before that, ergo: max. 10 months.
r-
I am not a lawyer, but:
„SPA, a written commercial agreement representing an investment of capital”
Investment was not based on SPA, SPA was based on proposed investment and no policy or law exists regarding the "substantial scientific issue".
Amarin could sue FDA based on two reason:
a.) the rescission itself (reason behind it)
b.) the timing
a.) With rare exception, FDA has historically considered granting approval for lipid-altering drugs based on favorable changes in the lipid profile, with the assumption that these changes would translate into a benefit on clinical outcomes, however it is not required by any law or regulation. It was the FDA’s practice. Furthermore, as lipids (except LDL-C) never was a validated surrogate-endpoint, the past practice does not obligate FDA to approve evry lipid-altering drug based on surrogate endpoint(s). It’s at least not a slam dunk.
b.) It could be ruled in favor of Amarin, since two of the referred studies was known more or less 2 years (the 3rd app. 10 months) before the rescission, so it was not within the reasonable period of time.
However if Amarin win the case – based on both reason or on b.) - it could be around mid-2017 only.
“Section 119(a) of the Modernization Act amends section 505(b) of the Act (21 U.S.C. 355(b)). New section 505(b)(4)(B) of the Act directs FDA to meet with sponsors, provided certain conditions are met, for the purpose of reaching agreement on the design and size of clinical trials intended to form the primary basis of an efficacy claim in a marketing application.”
“Upon specific request by a sponsor (including specific questions that the sponsor desires to be answered), the agency will evaluate certain protocols and issues to assess whether the design is adequate to meet scientific and regulatory requirements identified by the sponsor” at the time of the assessment.
“If an agreement is reached, the Agency will reduce the agreement to writing and make it part of the administrative record. An agreement may not be changed by the sponsor or FDA after the trial begins, except (1) with the written agreement of the sponsor and FDA, or (2) if the director of the FDA reviewing division determines that "a substantial scientific issue essential to determining the safety or effectiveness of the drug" was identified after the testing began (section 505(b)(4)(C) of the Act).”
“The Committee is aware of FDA’s ability to rescind a SPA agreement reached under section 505(b)(5)(C)(ii) of the Food, Drug, and Cosmetic Act only if it demonstrates that ‘‘a substantial scientific issue essential to determining the safety or efficacy of the product has been identified after the testing has begun.”
„The Committee also expects that, as a matter of public policy and fundamental fairness to the sponsor, FDA should be accountable for continued diligence in identifying issues that bear on the continued enforceability of a SPA agreement and in notifying the sponsor of such issues within a reasonable period of time after FDA becomes aware.”
„To ensure agreement over the standard to rescind a SPA, the Committee directs FDA to report to the Committees on Appropriations of the House and Senate within 60 days of enactment of this Act regarding the standard by which FDA would rescind a SPA. Lastly, to ensure agreement over the standard to rescind a SPA, the Committee directs FDA to revise and re-issue, after public comment, its existing guidance regarding SPA agreements to clarify the agency’s interpretation of the statutory standard regarding SPA agreements and the rescission of such agreements.”
Enclosure: PDUFA Reauthorization Performance Goals and Procedures
Guidance for Industry: Special Protocol Assessment
As Senate and House Lawmakers Slog Through FDA Appropriations Bills, FDA’s To-Do List Grows
D-
My 'basis' was management secondary target and Lovaza's previous label (the 200-500 study was removed just earlier this year).
Boost or not? Maybe, hopefully. With data / study on label sales reps and the company will have "easier" job to sell as they could talk about ANCHOR as part of the label.
CC was not about sNDA - they definitelly said "we not share our plan regarding sNDA during this call" - but it sounds as next phase.
The question: when?
As FDA did not deal with ithe sNDA during the SPA appeal process, I hope that the management will send a letter / confirmation to FDA regarding "no more appeal", otherwise FDA will wait till Oct 11 (AMRN has 30 days to appeal). Hopefully FDA evaluated the sNDA already and "just" the label is remaining and we could see something within a 3-4 weeks.
I do not give high possibility, but
- FDA STILL not accept TG as a VALIDATED end-point - so it is just a no change as they see TG
- FDA does not have any confirmation that TG lowering therapy is NOT lower CVE - I see it as a small change compare with DMEP that said that below TG 500, therapy is not necessary as the aim within this poplation is CVE reduction and TG did not reduce CVE
Altogether, OND (FDA) current view: we do not know, "please" finish the R-IT, since we would like to know.
They will not approve the claim as it is, but at least b.) - just data/study on label - not a irreale possibility and if FDA take into account "everything" they could accept / propose / agree modified indication.
Under the current circumstances it is the best for everybody:
- AMRN could sell V in 200-500 with approved indication
- FDA could say we did not approve ANCHOR since not confirmed CVE, but we approved differently as the drug is safe and we will see at R-IT result.
-------
raistthemage,
No real reason to appeal:
- it was not a classical contract, it is an agreement and it just a primary base of the claim, not the one and only
- it is not slam drunk, since FDA change his practice / approach regarding lipid surrogate-endpoints and not any law or policy
- the case easily could run till mid-2017 (at that time R-IT will be stopped already or will be finished few months later) as they could submit the case around beginning of Q2 2015.
----------
BB,
I do not think it could be 150-500. Do not forget R-IT is also about 200-500 now, since the SPA was modified in May 2013 (min TG from 150 to 200)
If 1,612 events occur in Dec 2017: placebo event rate / Vascepa eff.
4,4% / 0-3%
4,6% / 9-11%
4,8% / 17-19%
5,0% / 24-26%
5,2% / 31-33%
5,4% / 37-39%
5,6% / 43-45%
5,8% / 48-50%
6,0% / 53-55%
6,2% / 58-60%
BB,
We will not get ANCHOR.
short-term: maybe (?) we will get modified label (for 200-500), but not ANCHOR
long-term: if R-IT successful, we will get R-IT
The original ANCHOR over by the decision of OND.
As you replied my post #34535, you can read what I wrote about ANCHOR within it:
a.) NCE will expire by 2017 ...
b.) patents in 2030
Agree.
During the CC AMRN said "it is/was clearly regulatory policy process issue" (something like this).
#34492 - it was "funny" to read how to evaluate the FDA (and the same folks) the ACCORD-Lipid study 2 years ago and now.
I did not lost anything. It's just worth less currently ...
If it will not be a CRL, we could see something like this::
Possible label change:
----------------------
VASCEPA is an ethyl ester of eicosapentaenoic acid (EPA) indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (= 500 mg/dL) hypertriglyceridemia.
VASCEPA® (icosapent ethyl) is indicated as an adjunct to diet and in combination with a statin to reduce triglyceride (TG) levels, in adult patients with mixed dyslipidemia = 200 mg/dL and <500 mg/dL).
Limitations of Use:
•The effect of VASCEPA on the risk for pancreatitis in patients with severe hypertriglyceridemia has not been determined.
•The effect of VASCEPA on cardiovascular mortality and morbidity in patients with severe hypertriglyceridemia and mixed dyslipidemia has not been determined.
and 14.1 Mixed dyslipidemia (details and data of ANCHOR study)
----------------------
Maybe, some (all) of the following will be included: non-HDL-C, Apo-B, TC, and VLDL-C, but definitely not the LDL-C.
ANCHOR indication:
“Co-administration Therapy with Statins for the Treatment of Mixed Dyslipidemia
VASCEPA® (icosapent ethyl) is indicated as an adjunct to diet and in combination with a statin to reduce TG, non-HDL-C, Apo-B, LDL-C, TC, and VLDL-C in adult patients with mixed dyslipidemia and CHD or a CHD risk equivalent.”
Crestor label contains:
“Patients with primary hyperlipidemia and mixed dyslipidemia as an adjunct to diet to reduce elevated total-C, LDL-C, ApoB, nonHDL-C, and TG levels and to increase HDL-C (1.1)
Yes, interim event will be at x% around mm/yy:
15% - Nov/15
25% - Jan/2016
if the placebo event rate is 5,2%. If it is less ie.: 4%
15% - Aug/16
25% - Oct/16
ps.: BB - check your inbox
??? I just answered your question. It was not based on CC. AMRN do not want to give any estimation (early / mid / end of 2016) during the CC as it is premature.
Yes, IF the 967th will be in July 2016. However, we do not know when it will be. AMRN do not want to give any estimation (early / mid / end of 2016) during the CC as it is premature.
b-
Today CC has several message (suggestion):
1.) R-IT will be continued: no stop, no modification. However, it was not a real decision, since they do not have any other choice. Without R-IT they will never get the requested indication. btw: ANCHOR will not be approved anytime. If R-IT will be successful (early or at the end) R-IT will be approved.
2.) The SPA appeal process was only about the SPA rescission / reinstatement. Nothing about sNDA or label.
3.) Meanwhile they did not talk about further appeal, they mentioned the sNDA process. It suggests that they will not appeal to JW. It is totally realistic, (as DewD wrote pragmatic) since if OND did not reinstate the SPA higher level will not (especially as JW is a member of MPC). Maybe they have a chance at court, but that phase could run till mid-2017, when R-IT will be stopped already or the final result just few months away.
4.) sNDA is the next action and they have plan.
A lot of people is still do not understanding the meaning of SPA. . SPA intended to form the primary basis of an efficacy claim in a marketing application (sNDA). However it is not a mandatory for efficacy claim, sNDA could be approved without SPA.
What is the possible scenario?
a.) CRL for everything
b.) ANCHOR data on the label
c.) modified indication and ANCHOR data on the label
d.) indication as requested and ANCHOR data on the label
Possibility (as my view)?
a.) 45%
b.) 30%
c.) 25%
d.) 0%
Meanwhile some folks expected bad news (and as pps looks some think that R-IT cont. is bad) all of these are good.
I still keep my opinion, they are know what they are doing and they are focusing on the right thing at the right time. To the appeal YTD, to the sNDA from now.
If the 967th will be in July 2016 at 5.2% placebo event rate, then the V eff.% is 53-56%, (event rate 2.29-2.44%)
You have right: I had to use "Maybe" instead of "Definitely". So, Was any BO offer? Maybe. Was it high enough? I do n....
"I never see any realistic / logical version from anybody". Still valid - inc. Ajax.
"SPA back on the table" and "BBW" are not within the realistic / logical version and nothing else was mentioned. I am not talking (requesting) about the proof or the exact proposals just an example.
Top of it, the today CC confirms my view: the appeal process is not about negotiation / compromise, AMRN could not discuss the sNDA in the process (it was "forbidden" by FDA as these are separate issues.)
One item could be negotiated only: the label. Nothing else.
btw: Barack rebutted the January meeting during the last night dinner, so 1:1 regarding the meeting.
Piece of history …
With rare exception, FDA has historically considered granting approval for lipid-altering drugs based on favorable changes in the lipid profile, with the assumption that these changes would translate into a benefit on clinical outcomes. Both epidemiological studies and controlled interventional trials of lipid-lowering agents, including omega-3 FA, supported the hypothesis that pharmacologically-induced improvements in the lipid profile are cardioprotective. These studies also informed professional society guidelines that promoted the consumption of EPA and DHA with the goal to reduce cardiovascular risk.
Trilipix (fenofibric acid) was approved in the United States on December 15, 2008, with
similar indications given to previous fenofibrate products:
• As monotherapy to reduce TG in patients with severe hypertriglyceridemia
• As monotherapy to reduce elevated LDL-C, Total-C, TG, and Apo B, and to increase HDL-C in patients with primary hyperlipidemia or mixed dyslipidemia
However, Trilipix was the only fenofibrate product to receive the following indication:
• In combination with a statin to reduce TG and increase HDL-C in patients with mixed dyslipidemia and CHD or a CHD risk equivalent who are on optimal statin therapy to achieve their LDL-C goal
The approval of Trilipix was supported by the findings from three 12-Week randomized, controlled clinical trials, comparing the effect of therapy with fenofibric acid and a statin versus fenofibric acid monotherapy or statin monotherapy on key lipid parameters. The primary endpoints in these trials were TG and HDL-C changes with the combination of a statin and fenofibric acid as compared to fenofibric acid monotherapy.
During a pre-IND meeting with the applicant in July 2008, however, the Division noted that there was a lack of prospective, controlled clinical trial data demonstrating that pharmacological reduction of non-HDL-C (or TG) with a second drug, in patients with elevated TG levels at LDL goal on statin therapy, significantly reduces residual cardiovascular risk. The Division referenced trials ongoing at the time (e.g., AIM-HIGH, ACCORD-Lipid - Trilipix) that, while not able to assess the effect of specifically lowering non-HDL-C (or TG) on clinical outcomes, would be expected to provide important information on the incremental benefit of adding a second lipid-active drug to statin therapy.
FDA agreed with Amarin regarding the SPA (12-week study with lipid endpoints as well as initiate an appropriately designed cardiovascular outcomes study. (Note: as I know it was a first time when one SPA was linked to other SPA).on May 2009 and the study was started December 2009 (the study database was unblinded in March 2011.)
ACCORD-Lipid study was released in March 2010 and FDA held an AdCom on May 19, 2011 (FDA Participants (Non-voting): Iffat Chowdhury, M.D., Eric Colman, M.D., Solomon Iyasu M.D., M.P.H., Mary H. Parks, M.D., Curtis Rosebraugh, M.D., M.P.H).
Trilipix AdCom materials
“Although there was no significant additional cardiovascular benefit with the use of statin plus fenofibrate as compared to statin monotherapy, a subgroup analysis raised the possibility that patients with TG greater than 204 mg/dL and high density lipoprotein cholesterol (HDL-C) below 34 mg/dL might benefit from the addition of fenofibrate to a statin. (FDA’s BD)
“Many members expressed a concern that the trial was not specifically designed to address the questions at hand regarding coadministration with statin specifically in statin treated patients with high triglyceride- low HDL lipid profile, and thus did not provide adequate data with which to fully evaluate the benefits of coadministration”. (Summary Minutes)
“The committee commented that subgroup analysis is always of concern when the trial as a whole is negative. They acknowledged that the findings from this subgroup are of a clinically important magnitude, consistent with other trials and with the current written risks indications.” (Summary Minutes)
The committee voted unanimously to require an additional clinical trial (Note: Is it done or ongoing for Trilipx?) and allowed continued marketing of Trilipix’s indication for coadministration with a statin with revision of the labeling to incorporate the principal findings from ACCORD-Lipid.
The trial was stopped prior to its planned conclusion based on the recommendation of the Data and Safety Monitoring Board because interim results had crossed a conservative pre-specified boundary for lack of efficacy: in AIM-HIGH participants, Niaspan did not demonstrate a beneficial effect on the primary endpoint. The AIM-High study was released in December 2011, however FDA did not organize an AdCom and Niaspan’s label still contains “In combination with simvastatin or lovastatin: to treat primary hyperlipidemia and mixed dyslipidemia when treatment with NIASPAN, simvastatin, or lovastatin monotherapy is considered inadequate”. (More presentation and publication about AIM-High here.)
Amarin announced submission of ANCHOR sNDA for Vascepa on February 26, 2013 as 12-week study was completed and R-IT was more than 50% enrolled.
More than 2 years after ACCORD-Lipid’s AdCom and 20 months after AIN-High study release, the FDA held the AdCom on October16, 2013, regarding Vascepa / ANCHOR indication, however the discussed issue was FDA’s approach (policy). The Adcom discussed and voted as “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 outcome study, based on surrogate endpoints.” is not adequate. (FDA Participants (Non-voting): Jean-Marc Guettier, MD., Eric Colman, M.D., Mary H. Parks, M.D., James P. Smith, MD, MS, Mary Dunne Roberts, MD).
FDA rescinded the ANCHOR SPA – Oct 2013
DMEP uphold – January 2014
ODE II uphold – April 2014
Amarin presented post-hoc analyses of Marine and ANCHOR
New studies related to reduced triglyceride (TG) levels and reduced cardiovascular (CV) risk were published – June 18, 2014 (NEJM)
The Lancet, published a review article regarding “Triglycerides and cardiovascular disease“– August16, 2013
NLA) launched a nationwide triglyceride campaign – September 2014.
OND (with MPC) uphold – September 11, 2014 (and urged Amarin to complete the REDUCE-IT cardiovascular outcomes study.
FDA concluded that in its view the totality of scientific data and information, including its reevaluation and improved understanding of the relevant scientific knowledge since the ANCHOR trial began, does not support use of decreases in triglycerides as a validated surrogate for cardiovascular risk reduction in the proposed patient population.
Maybe they will fully understand some time …
L-
Are you sending a letter to BOD (inc. JZ & JT) to remove JT? …
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“None of this happens until there is a change in management at the company. NONE. I really don't understand how you still do not see this yet.”
I do not see it, since I do not see anything that confirms it. We have a different view on different topic:
I could agree, if they stop R-IT they are incompetent, however I do not think it, since the company / Vascepa was and is about R-IT always. Not Marine, not ANCHOR – these are just tools.
PPS is a sentiment of the market about the potential of the company, so conclude anything regarding the management based on the level of it is false.
PPS was high due to Marine approval and BO expectation. Based on Marine only nobody value the company for $10+ on a short-term. Was any BO offer? Definitely. Was it high enough? I do not know. As of today we could say, yes it was high, however – maybe – two years later we will say good move to turn down that silly $20 offer. We do not know yet, that it was bad or good decision, it just looks like as bad now. I am sure that the company made a valuation and refuse the offer due to low offer. A lot of people will booo, but management “lost” more than any of us: insiders still own 6,7M shares …
Really, what was the mistake done by the management during the ANCHOR sNDA? Refused the FDA’s offer in January? I never see any realistic / logical version from anybody (including you) about it. SPA modification? Joke – study was done, data analyzed and SPA is not about indication. BBW? Are you really think that if it is the diff. between them, AMRN refused it? They want R-IT label? Assuming that any company running a trial would like to include it in the indication is not realistic.
I do not think that they will appeal or if yes, it worth anything, but if they will I am sure that they will have a good reason to do it.
Suing FDA? They will not, since could not before go through the whole appeal process up to MH.
CRL: I am give a minor chance for other outcome, but based on FDA past action it has the highest possibility, so I will not be surprised.
NCE: How is it management related? AMRN developed the new drug V, it has a new active ingredient (FDA agreed), FDA based on their regulation (active moiety approach) did not grant NCE, however the statue contains active ingredient and based on previous case I think that the court will reverse the decision. But let me know, how any other management could get NCE status for the V?
„It is not the FDA's fault this stock is trading at $1.44.” – really? Meanwhile, FDA “noted that there were ongoing cardiovascular outcomes trials -- ACCORD-Lipid, and AIM-HIGH, to name two -- that these trials would provide important information on the incremental benefit of adding second lipid-altering drug to statin therapy.” during the pre-IND meeting in 2008 and the studies were published in 2010 & 2011 they could not conclude anything till the BD. The study result were irrelevant regarding of V. Why not cited a study about adverse effect of fishing? That has more relevancy …
Are they hating AMRN’s management, were they irritated by any of them or by the management bonus plan? I do not think. But if we accept it for a second, how could be the approval of a safe, effective drug influenced by person, against the most science?
So, is it FDA’s fault or not? It looks like yes.
What will be a next step? I do not know. Of course as all of us I am speculating. Maybe:
- they will appeal further (I do not think)
- they got an answer as based on the info at the time of the rescission it is uphold, bur submit the new info (post analysis of V, NEJM articles) to DMEP and we will see
- they will try to modify the R-IT’s SPA to make an earlier interim analysis
We will know soon. I understand your feeling and thinking, just do not agree. We have to "step back from the fray for a bit to regain a proper perspective." (c) - not mine, but agree.
Still not agree, however I am confused now: What is your goal?
"Change the management" & "All communication efforts should be made directly to the BOD."
AMRN management is the Executive Team (3 members):
John Thero – President and Chief Executive Officer
Joseph T. Kennedy – SVP, General Counsel and Secretary, Chief Compliance Officer
Steven Ketchum, PhD – President of Research and Development, SVP
They could be removed / replaced by the BOD
BOD (8 members, including JZ and JT): They could be removed / replaced by the shareholders meeting.
Seriously, did you really think that FDA is acting based on management bonus schedule ...
No compromise will be happen. Not because of management and not because of the FDA. Appeal process (and all process at every authority) is not about negotiation.
Sponsor / client submit a request (appeal, application, etc.) and the authority grant or deny. That is it.
Short term we could see (with very low probability):
- DMEP approves the sNDA due to new study results (NEJM and ApoIII) since the rescission or
- grant ANCHOR's data on label
JL,
Maybe it's worse and FDA did a 180 before the submission of the sNDA application ...
No problem.
I never said the my assumption for the calculation will be always correct. I used ie.:
- the Total Operating Expenses as Q2 (no additional decrease)
- GM% also as Q2 (60,14%), since as the first time it was lower than the previous period (Q1 2014). Meanwhile I hope it will be higher.
With my assumption, parameters (Based on Q2 2014):
Net revenue / script: $134,67
GM%: 60,14%
KOWA fee: 9% of Gross Margin
BioPharma: 10% of Net Revenue
Total Operating Expenses: as Q2
Notes interest: 3,5%
One-time expenses (ie.: $8.5 million license fee of ANCHOR to Laxdale) excluded
the break even script number (40,233 / week) is correct. If they could increase the GM% and / or decrease the OPEX (I do not think they could significantly increase the Net revenue / script) the break even script number will be less.
One correction:
I could imagine (but not think) one scenario only when the reason could be important, if the reason is that the rescission at the the time of it was appreciate. As no new information could be submitted during the appeal process JJ decision have to be based on info as of Oct 2013 and could not consider the new studies' result.
Technically, since the SPA is not a mandatory condition of sNDA approval, DMEP could say, that based on the ANCHOR study and new information (studies) became available after the rescission they approve the sNDA.
"Because all FDA decisions on any dispute must be based on information already in the relevant administrative file (§ 10.75(d)), no new information should be submitted as part of a request for reconsideration or appeal. If the sponsor has new information that may affect the original decision, any appeal should be deferred until the new information has been submitted to the administrative file and reviewed by the division. New analyses of data previously reviewed should be considered new information, and therefore should be submitted to the division for review before being submitted as support for an appeal."
The new MARINE and ANCHOR Post-Hoc Analyses came out in May (after rescission and after the decision of ODE II). The new studies' result came out in June after the submission of the appeal to OND (May).
Agree. The mineral oil will not be an issue:
- it is event driven, not based on lipid parameters
- maybe the official wash-out is 4-6 weeks also, but technically the whole trial is wash-out period for placebo arm
north,
We know „everything”. We know that the rescission was uphold. It is totally irrelevant what the exact reason of JJ was. Maybe he had a bad day or he hates AMRN.
Not as a shareholder (meanwhile I have):
Their reason of rescission (because the “healthy” patients in the citied studies did not benefit, the sick (sub-group) will not also) was more than poor, it is against any comparison standard.
The current science suggest the benefit of TG lowering therapies and V does it. I guess everybody – except FDA – could agree that the possibility of successful R-IT (confirms the CV outcome) is high.
Top of the science - assuming that the company did not submit the sNDA if they have any clue about it - it is still not understandable why the FDA announce / confirm their intension to approve this type of indication based on outcome study only and not on surrogate endpoints in BD / AdCom only. They had years to do it, ie.: as included in the BD the AdCom of Trilipix (Accord-Lipid 2010) said: “several members recommended that the FDA consider requiring a different level of evidence for future lipid altering drugs, transitioning away from surrogate endpoints to relevant clinical CV outcomes especially for add-on therapy to statins.” and Trilipix is still approved for this indication …
So anything was the exact reason within the decision, it could not be strong. It looks like JJ approach: if FDA said the sky is green and the grass is blue and everybody say the opposite, they are stand on their heads.
It is remind me of the classic joke:
Radio: “Everybody drive carefully on route 66, since one foolish is driving in the wrong lane.”
Driver: “One?! All of them!”