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As your first sentence (Of course the SPA is about approval.) is totally wrong it does not makes sense to reply.
I am not writing about science ...
When did they lose? In a science dispute.
Welcome in the real world ...
I am not a lawyer, but it is not a question that FDA has ability to rescind a SPA agreement "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".
50% enrollment was a condition to submit the sNDA - not for approval - and FDA accepted the sNDA for review.
The results of the Anchor study will be evaluated and the answer will be "it is not enough to approve the sNDA" according to the current approach of FDA.
TG reduction is not “just for fun”, the only reason to treat these mid-range triglycerides is to prevent heart attack, stroke, and death. The SPA was signed in 2009 and at that time FDA 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.
FDA has reevaluated the situation and has adopted a more conservative approach (proof of benefit on clinical outcomes) in 2013 than previous applied for biomarker based approvals targeted towards cardiovascular risk reduction.
SPA meaning: agreement on the design and size of clinical trials intended to form the primary basis of an efficacy claim in a marketing application. Nothing more, nothing less.
Did V reduce TG without side effects? – Yes
Would this change translate into a benefit on clinical outcomes? – Looks like, BUT we do not know
Was FDA “fair”? - No
Could FDA apply a new approach? – Yes
Could FDA rescind the SPA? – Yes
I do not like this also, but we do not have to be blind.
The situation is not good, however ANCHOR was not a final target ever. It’s “only” a tool (increase script / finance operation) to get R-IT approval.
The SPA contract for Anchor was predicated on Vascepa efficacy in lowering triglycerides on patients taking statins with the assumption that it will further reduce CVE. SPA isn't about approval, it's about the study and (in this case) the condition to submit the sNDA.
Its somewhat like the prospective buyer (the FDA) telling a prospective seller(Amarin); "I will buy your house on the condition that the seller puts a mountain of money into it to fix it up and assume that all necessary permission will be granted. Then, after Amarin spends a fortune on the house, The FDA says; "I want the necessary permission before I buy, because regulation was changed and I did not get the permission in case of other seller/ house."
As you agree, FDA won’t drop the lipid approach and won’t focusing on inflammatory for many, many years, why you think (why I am wrong) that after successful R-IT, TG won’t be validated as surrogate endpoint and FDA will care the secondary endpoints, lowering inflammatory biomarkers.
It looks like for me that FDA will approve any drug based on validated endpoint(s) only. As Vascepa is not “LDL-C drug”, TG or inflammatory biomarkers have to be accepted for approval.
Based on your (and JL’s) post I still think that after successful R-IT, TG will be validated as surrogate endpoint (FDA does not care inflammatory biomarkers currently) and new TG lowering drug could refers to R-IT and could get approval without own CVOT.
Your statement was “At this time, the FDA was already in possession of data from other studies on totally different drugs that, by inference, made them question the efficacy of EPA.” I reacted regarding this, as it was false.
It is not about EPA or Vascepa, it is about TG lowering therapy. TG lowering is not a aim / target, it is the tool to avoid CVE. “So the only reason to treat these mid-range triglycerides is to prevent heart attack, stroke, and death.” (AdCom).
I believe that an unbiased jury of people experienced in the science would not accept that failed studies on totally different drugs, with totally different modalities of action, with totally different safety profiles and with totally different patient populations would serve as the basis for PROOF of NON-efficacy of Vascepa.
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) 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.
A special protocol assessment (SPA) for ANCHOR was completed and accepted on July 6, 2009.
ACCORD-Lipid result: 2010
AIM-HIGH result: 2011
AdCom:
"The first was for the treatment of severe hypertriglyceridemia, levels of 500 or greater, where the principal concern with these folks is that you want to get their triglycerides down in an attempt to avoid acute pancreatitis."
"the division has historically approved drugs for severe hypertriglyceridemia on the premise that treating severe elevations in triglycerides would be expected to reduce the risk of acute pancreatitis. There are estimated to be approximately 3.4 million adults in the United States with severe hypertriglyceridemia."
"It's hard to imagine an event-driven pancreatitis trial for super-high triglycerides."
"In addition throughout the SPA appeal, we have been aware of considerable outreach from physicians, investors, and industry groups to the FDA into elected representatives aimed at reinstatement of the ANCHOR SPA and approval of the ANCHOR sNDA.
We're thankful for this outreach and also thankful for the efforts of the many elected officials to ensure that this matter is seriously considered by regulatory authorities. We are certain that the FDA has considered not only the positive ANCHOR study results in this analysis. But also more recent data such genetic studies, which as Steve will discuss, add to our confidence and the positioning of REDUCE-IT to be successful." (Sept.16. CC)
Thx.
So if you want to play on the FDA's playground, you are going to have to play with the statins..'as an add on".
Trying to initiate a trial base on the notion that atherosclerosis is an inflammatory disorder and not a lipid disorder is far to radical for the FDA.
a.) I do not hate idioms
b.) It's exist here also.
c.) I did not argued with sts66 regarding his statement "treating inflammation, not TG, is the key to success." I just pointed that TG is the first and lowering inflammatory biomarkers is the secondary endpoint.
Maybe you know the answer: If lowering inflammatory biomarkers is more important than lowering TG why it is secondary and not first endpoint?
Erm, no. Just wrote about this in another post - the secondary endpoints, lowering inflammatory biomarkers, are the key here - TG is a sort of red herring, as in treating inflammation, not TG, is the key to success.
Erm....no....because the proposed ANCHOR label apparently has something along the lines of "reduces CVE risk if taken in combo with statins"....something ANCHOR did not prove, what R-IT is for....if it didn't have that language, FDA would have no basis for rescinding SPA.
Why hurry? 35472
"...They are awaiting response from FDA..."
And the fact is that V is approved for MARINE without a CVOT coz of other drugs successful trials and validated science. So the situation is more or less same for the news drugs.
As a marketing Amarin has to approach Guinness Book and claim first in class (?) status for:
- the first SPA (Anchor) that was linked to other SPA (R-IT)
- the longest delay with PDUFA date
Smart? FDA? ... as smart as fair ...
P-
It' not my area, I let the answer to JL or sbody else.
My two cents:
Good question, but do not forget that the genetic studies according to Amarin "provide encouraging new data connecting reduced TG levels to reduced CV risk."
HD are you saying after FDA issues a CRL, Amarin can continue appeal on original SPA since it's a separate matter?
if so, why didn't they just do that to begin with instead of dragging sNDA out a year by appealing SPA ?
wellingtons = gum-boots
I am OK with your EPA definition.
What do you think about this?
After successful R-IT, TG will be validated as surrogate endpoint. New TG lowering drug could refers to R-IT and could gets approval without own CVOT.
I wrote: It's science, so I try to be careful, so no more comment from me.
But regarding the water replacement ... The good stomach is like a wellingtons, don't let the water in
I believe Establishment of TG's as valid surrogate biomarker would hurt Amarin somewhat as the newer TG lowering drugs will be able to enter the R-IT market without doing a CVOT.
z-
It’s an interesting, „good” situation. “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.” No appeal was submitted, sNDa is the open issue only. FDA technically could delay the determination on the ANCHOR sNDA forever, however they “have to” issue it in the near future (already overdue by 9 months and they could not refer to ongoing appeal). Since there is no deadline to submit a next level appeal, Amarin could wait for the determination and based on that – if no compromise - they could submit the next level appeal and they have an option to file a complaint after the end of the appeal process.
So, Can you please share how did you derive the dates?
I believe Establishment of TG's as valid surrogate biomarker would hurt Amarin somewhat as the newer TG lowering drugs will be able to enter the R-IT market without doing a CVOT.
I don't think. It's not about the study itself. FDA has a guidance ( Guidance for Clinical Trial Sponsors) with recommendation for interim analysis / data. The new guideline contains more, exact recommendation (condition) for handling of interim info. As I see, the result will be: more cost (due to more staff), lower risk of bias (the study won't be changed based on interim data).
Without emotion: I agree with the purpose.
It's not the perfect answer (as it's within SPA guidance), however I assume the same is true for appeal process.
C. Personnel Changes
Changes in personnel on both the Agency's review team and the sponsor's development team are common during drug development. Personal preferences of new individuals on either team should not affect any documented special protocol assessment.
sts66 & BB,
Both of you has right, talking about the same thing with different word. As I see:
CRL will be issued with recommendation (previously I mentioned the CRL w/o recommendation, however I think it won't happen.). The possible version of recommendation:
a.) Complete the R-IT and resubmit based on the result of it.
b.) Resubmit with modified indication of usage and / or with modified label (other studies: ANCHOR).
In case of (b.), it will be classified by FDA as Class1 (2 months), Class2 (6 months),or new review cycle (10 months).
FDA could issue the CRL anytime, but hopefully they will do it after discussion with Amarin and issue the CRL as b.). It won’t contains the “negotiated label”, however bothers the re-submission.
Sec. 314.110 Complete response letter to the applicant.
"Do you believe a CRL is being held until SPA appeal is finished?" - FDA maintained the SPA appeal and sNDA are two separate matters and did not address the ANCHOR sNDA (Amarin CC) - I do not think they changed their approach / mind now
SPA vs CRL - yes. Without SPA they could be more "flexible"
Oct 12 - I could imagine that Amarin send a declaration (informal drop), however I do not know (did not and won't check) that they could or could not drop the appeal legally before the end of the official expiration. I don't think they will appeal to JW
Amarin update the IR Presentation once in a month (no update in July) usually, but twice (10 & 18) in September. The key changes are:
- no detailed goals for ANCHOR
- sNDA history replaced by "Future Potential Expanded Indications"
- new slide: "Studies Supporting a Correlation Between Triglycerides (TG) and Cardiovascular (CV) disease"
- updated investment highlights: "Multi-billion dollar potential with REDUCE-IT"
- "Important Potential Upcoming Operational Milestones" was deleted
- not mention SPA at all
-----------------------------
Based on these and the CC, my short-term assumption (did not confirmed):
- no more appeal (maybe declared it to FDA)
- try to compromise on ANCHOR
- FDA will send the CRL (w or w/o recommendation and / or allow data on label) on or after Oct 12. (Despite of possible declaration by Amarin, they will wait till the appeal will be ended officially. AMRN has to file appeal till Oct 11 if they want to go further.)
-----------------------------
Ajax: Thx.
We need to get to 25% efficacy vs placebo to stop the trial ....Do we all agree on that .?
If trial is not stopped on or by interim , Co is out of $ ....Do we all agree on that ?
The current event rate is in line with the expectations, however we and Amarin do not know the exact "reason". (ie. lower placebo rate and V eff.%, higher placebo rate and eff%., exactly as anticipated)
It was not a "clear" dupped by the FDA and I do not expect anything similar. R-IT primary endpoint is CVE and not lipid changes. If it will be successful, TG will be validated as surrogate endpoint.
Ajax,
I did not take your posts personally.
“The DSMB can stop a trial but only FDA can approve the drug.” –agree, however I commented a different statement: “FDA …, doesn't allow DSMB … to stop the trial.„. I know you see the difference. I do not want to espouse anything.
„$20 offer” - Yes, I “referred” to it as IF any, we could not judge yet, and it was a good decision IF any offer was exist at the time (different valuation said, that the market value is $4M+ or $23+ / share.)
A lot of posters add a real value to the board (ie.: JL about science) and I would like to do the same WITHIN my profession. I am not bickering with anybody just for fun or to espouse anything. If I have a different view it’s always based on my interpretation of data / facts. I never argue with JL about science (and funny to read his posts about legal /finance). I do not have to and do not want to prove anything about me, I am fine thanks. Some posters know exactly who I am and what is my working experience. I run more US-subsidiaries and read more contract under US law then some (lot of) other posters.
Management (it’s for ladavis23 also):
I never said it’s the best management, however definitely not the worst I am fine with them, since I saw one mistake (appeal to OND in 2013) only. This will be the mistake ever, independently from pps. There is one other (2012-2014 Notes conversation) that I do not like – it was premature – however I do not have every info, I could not judge it.
Ladavis22 approach, “logic” method is not mine, L has a 22-catch logic: pps is low due to bad management, how we know that management is bad: pps is low. Top of it is easy to come to different conclusion x months later and criticized the decisions. If R-IT will be stopped based on interim result and pps will be significantly higher, all of his verdict will be nulled.
If I was in a position of the management I do the same thing as, ie.
- if any, refuse a $20 offer, when the approval of the ANCHOR was reasonable and based on that the pps could be significantly higher than $20
- appeal to FDA till (OND) it could be useful
Meanwhile JT does not have a CEO experience, based on his CV’s summary he could be good. He has a strong finance and operation background. The CFO (at every company) knows the most about the company as he see all invoices and payment. The best CEOs does not know too much details about the different area (except their own) of the company, but they do not have to. They have to hire the perfect department heads and see the total picture.
I understand people who has a huge loss on their investment (it is theoretical till they do not sell), however their expectation are unrealistic (ie. what and when should be released), they do not know exactly what is their rights as a shareholder and most / all of them do not have a management experience.
I have a huge loss (on paper only as I did not sell), but it was my decision, based on my DD. It’ my fault. I blame FDA, but not for their decision as a first reason, but how (when) they did it.
I think that based on publicly available info (about Vascepa, about the science, FDA earlier actions – ie. after failed Accord-Lipid study did not change Trilipix’s indication) nobody could conclude the current situation. All negative outlook should be based on internal info from FDA and / or pessimism.
I am still believe in V and in a brighter future.
CRL is coming – I am “sure” – however hopefully with some compromise. If not, the chance for increasing script is good. It looks like a winner lottery one year ago, but it will take more time.
BioC,
sts66 has right. You wrote 2,2% in your post, but it was the absolute diff. (10,9-8,7) not the %. The % diff. was 20% (2,2/10,9)
You had not been saying anything ever. Your strongest argument was "it's b.llsh.t." I am not remember who was that, but said that everybody look genius beside you ...
Yes I had wrong assumptions about the future (as all of the longs have YTD), however my conclusions about the past were supported at least by logic always, however usually by exact source also.
Ajax,
The simple solution for a bright guy like you is to simply read ... it’s rocket science for some folks ….
Maybe it was forbidden to them by FDA, since they could do everything, as you wrote: “FDA (Who never gives away Ice in the wintertime), doesn't allow DSMB (correct term) Data Safety Monitoring Board to stop the trial.„ meanwhile DSMB (correct term) DMC was appointed by Amarin …
You are knocking on the wrong door: ladavis 23 said: “If you have done any DD into the plumbing of WS and IB you would know that a deal was very much there for AMRN for the taking in late 2012. AZN was front and center at the time.„
I never said that any offer was submitted. I said IF any we could not judge yet. I used a wrong word in 34455 as “Was any BO offer? Definitely. Was it high enough? I do n…” Corrected it in 34528 (re sts66 note): You have right: I had to use "Maybe" instead of "Definitely". So, Was any BO offer? Maybe. Was it high enough? I do n....
btw: I hope that during your discussion, you called JT to account for his words during the CC “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.” and he asked your forgiveness, as he did not want that anybody think that you are lying about MLK weekend.
“it's not about looking for a different management expecting different results. It's about knowing the difference between a minor league and major league team” by ladavis23. It's essence of ladavis23's thought ...
It is already recommended by the current guidance. If it will be regulated: no problem. The data is not essential for the sponsor if they trust in the DMC and SC.
Exactly, and 10 consecutive business days above $1 reset the clock. Is it new for anybody?
http://nasdaq.cchwallstreet.com/NASDAQTools/PlatformViewer.asp?selectednode=chp_1_1_4_3_10_3&manual=%2Fnasdaq%2Fmain%2Fnasdaq-equityrules%2F
r- sorry, it isn't a reply to you, I would like to post it as a new ...
Relax! It's not too simple to force the delisting ...
"(A) Bid Price
A failure to meet the continued listing requirement for minimum bid price shall be determined to exist only if the deficiency continues for a period of 30 consecutive business days. Upon such failure, the Company shall be notified promptly and shall have a period of 180 calendar days from such notification to achieve compliance. Compliance can be achieved during any compliance period by meeting the applicable standard for a minimum of 10 consecutive business days during the applicable compliance period, unless Staff exercises its discretion to extend this 10 day period as discussed in Rule 5810(c)(3)(F)."
As of today the earliest "possible" date for delisting is May 5, 2015 ...