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I found these:
Development of Therapeutics for Heart Failure
Stopping Randomized Trials Early for Benefit and Estimation of Treatment Effects
- Every long-term trial has a interim analysis and a stopping guideline.
- DMC could recommends to stop the trial
- Decision is company's responsibility
- Bassler et al rather arbitrarily suggest that the threshold should be 500 events
I don't know that the stopping guideline is for the interim analysis only or for the entire duration of the trial, so could be applied anytime.
What's your thought?
I see the following scenario for the upcoming three weeks till Aug. 15:
1.) AMRN received or will receive the answer next week and they will announce on Aug 4/5 the release of 10-Q by Aug. 8. 10-Q will includes: decision was uphold.
2.) They will wait as long as possible with 10-Q (deadline Aug. 15.)
a. 10-Q: decision was uphold
b. 10-Q: decision delayed (“we may hear something late summer or early fall” by AF)
c. 8-K will released before 10-Q: SPA reinstated
1. - 45%
2.a - 30%
2.b - 15%
2.c - 10%
See post #28220 and Guidance for Clinical Trial Sponsors, but shortly:
- "To avoid any influence of interim data on consideration of protocol changes, FDA staff will also generally remain blinded to the interim results."
- "In rare cases, we [FDA] may wish to interact with a DMC ..."
Two more:
Chart - 60% / 967 event
Chart - 100% / 1.612 event
Note: all charts are with 5% event rate
Not 100% accurate - Date of 500 events for eff. 15%-50%
Chart - 500
One correction: it was May and not March 2013.
DR. KETCHUM / AdCom:
"In relation to the projected event rate, we amended the SPA and protocol in May of this year to enrich the mixed dyslipidemia population. This change raised the minimum triglyceride threshold from 150 to 200 milligrams per deciliter. Our rationale aligns with our trial hypothesis that higher triglyceride levels increase the risk for a cardiovascular event in these at-risk patients. Since the implementation of the triglyceride threshold amendment, the median triglyceride level of newly-enrolled patients is 230 milligrams per deciliter. It is our belief that this will help to achieve the projected event rate, which the DMC will continue to monitor."
JL,
My assumption behind 5,0%:
- around March, at least 4.000 was enrolled (since they submitted sNDA)
- they increased the TG (from 150 to 200) due to lower than expected (5,2%) event rate and I think if they thought the modification is necessary the difference was significant (0,5%) so the event rate was 4,7%
- March 13 - YTD add. enrollment is app. 3.250 and rate for these is 5,4%
Total event rate: 5,01% as (4.000*0,047 + 3.250*0,054) / 7.250
I could accept info based on facts (source or “wording”). Sometimes it reasonable to blind the source. In this case, two opinion exist:
- and CHD or … equal with CV reduction (by sts66 – unless he agree w my post 31185)
- it’s not equal (mine, but I am not professional)
I am open to accept that Amarin refused an acceptable label, IF somebody write a label, which:
- cover ANCHOR population
- includes the “same” indication as Niaspan and / or Trilipix
- significantly different compare to the proposed indication
Until:
- it did not happened
- the proposed label was unacceptable
ps.:
JL & everybody: I understand your opinion, but please if not "necessary" do not qualify the other posters. (I did it once with BioB re bickering, but I tried to be polite and as I saw it was not a problem for BioB, he did not take it as an insult.)
Kiwi: 60% = 967, 100% = 1.612. One more data - app. average follow-up: 506 days / 17 bmonths / 1,4 years
Reread again
It's an assumption, the design is for 5,2%: "I decreased from 5,2% since the March 13 modification - TG min. 200, instead of 150 - based on lower than expected events"
btw: unblinded events number (total, not separated by arms) known by Amarin
Sorry, but I could not catch it? What would you like to say?
One more addition from Trilipix's label:
"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"
I do not want to bickering - - with you, just present other view:
Facts:
1.) To approve any drug as a combination with statin in TG =>200 mg/dL and =<500 mg/dL population is for CV risk reduction
“I could think of to lower triglycerides or raise HDL or change LDL composition, Apo B levels, particle size -- the only reason to want to do that is to prevent cardiovascular events” (Dr. Hiatt / AdCom)
2.) AdCom was not ANCHOR’s AdCom since “the issue on the table today is whether we should approve something as a surrogate endpoint.” (Dr. Hiatt / AdCom). It's - at least - more than unfair, unacceptable to discuss this during the AdCom of SPA supported drug, 2 months before PDUFA date.
3.) Vascepa label with or without ANCHOR includes and will includes (till R-IT approval):
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 has not been determined.
4.) This part of the proposed indication could not be questionable (also on Niaspan’s and Tripilix’s label):
„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”
Question / Discussion:
„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.
CHD risk equivalents comprise:
o Other clinical forms of atherosclerotic disease (peripheral arterial disease,
abdominal aortic aneurysm, and symptomatic carotid artery disease);
o Diabetes;
o Multiple risk factors that confer a 10-year risk for CHD > 20%”
My view:
- it’s not indicate CV reduction, it’s the target population and as I remember JB said it was worded based on existing, FDA approved label
- Trilipix’s label includes exactly the same wording: (1.1 - Trilipix label) and Trilipix is still approved – after ACCORD-Lipid and Trilipix’s AdCom (see Vascepa FDA BD page 81)
Reduce-IT
With eff. 25% and 5,0% events rate (I decreased from 5,2% since the March 13 modification - TG min. 200, instead of 150 - based on lower than expected events) app. YTD data:
- Enrollment: 7.250
- Events: 439 (188 Vascepa - 250 placebo)
I could not find any guidelines or standard for DMC driven early stop, but using Kiwi's determination "DMC's usually want at least 500 events and up to 25% separation of event lines before advising co" the 500th events will be around beginning of Oct 2014. (I could not calculate the exact power, but based on Biwatch calculation for different number of events - used in #28220 - it will be more than 90%)
We also know that the DMC meeting occurs quarterly (let's assume they will meet just before the 500th events, so they will recognize it at the next meeting).
So if the 500 events and 25% is enough for early stop DMC will advise it by end of 2014 / beginning of 2015.
SPAs are different:
=500 mg/dL (MARINE): It’s always approved based on surrogate endpoints, since „It's hard to imagine an event-driven pancreatitis trial for super-high triglycerides.” (Dr.Hiatt / AdCom)
=200 mg/dL and <500 mg/dL (ANCHOR & REDUCE-IT): Both evaluate the same high risk patient population, however ANCHOR was to improve atherosclerotic markers, including triglycerides, non-HDL-C, Apo B, and hsCRP without having a detrimental effect on LDL cholesterol (surrogate endpoints), meanwhile REDUCE-IT is to demonstrate Vascepa efficacy to reduce cardiovascular events. It is an event-driven trial.
FDA rescinded the ANCHOR’s SPA as improvement of these markers is not enough to determine the efficiency.
I do not say that the FDA will not try to null the R-IT trial, however they could not ignore / null the result since it’s events.
Same as on Monday: "07/25: TRx - 8764, NRx - 3899 Refill - 4866"
sNDA and SPA are two different items. The SPA was rescinded and appealed by AMRN.
sNDA is pending.
BB,
It's not a bickering, it's a discussion (and as I see Kiwi does not have a problem with it)
This board is for discussion, sharing thoughts and info. Full respect for your activity, however meanwhile you are criticizing the “system” sometimes you have the same behavior and would like to tell / dictate what have to be done, have to think by everybody. Again respect your activity I do not think that you are the only one who know the truth, the solution: a lot of people on this board have good view and thought.
Finally sometimes "Less is more" - keep it in mind when post the same type of message within 10 minutes or different statements for the same topic / issue within short period ...
Kiwi,
It's not the first round between us, regarding when and what is due to Pharmakon
All my statement is based on this:PURCHASE AND SALE AGREEMENT and company's 10-Qs & 10-K.
The "loan" was 100M, repayment is 150M, the difference - 50M - is the interest.
Based on the last known date (01/17), timeframes (30 days for appeal, FDA reaction and 14 days for meeting) and take into account the weekends my calculation (no delay included):
Jan-17 DMEP decission
Feb-14 AMRN appeal
Mar-14 ODEII letter
Mar-28 Meeting
Apr-25 ODE II decision (AMRN said "late April")
May-23 AMRN appeal
Jun-20 OND letter
Jul-04 Meeting
Aug-01 OND decision
Kiwi, please! BioPharma deal is clear:
They have a quarterly CAP (equal with 10% of Net Revenue) and they could delay the difference till 2017 AND CAP will be applied for the delayed amount also. CAP will be exist in every quarter (inc. 2017 and beyond) till 10% of Net Revenue is lower than the scheduled payment.
Regarding label:
- I am not a medical professional, but for me without "and CHD or a CHD risk equivalent" it's a larger indication ...
- "change labels": agree w u, label change is a "daily" practise
HPS2-Thrive press release yesterday:
Everybody - inc. me - expected that additional info, subgroup analysis will be released, but it was the same as it was presented earlier (no new info, no new data) just on paper.
No, I missed by more. It's my calculation / prediction for tomorrow.
07/18: TRx: 8.451, NRx: 3.875, Refill: 4.576
Did you see the background of it?
"Another intriguing observation is lack of efficacy in individuals with mixed dyslipidemia (elevated TG and lower HDL) in HPS2-THRIVE."
I could not find any source / data for it, just the two element separatelly (and TG is 151 and not 200)
HDL cholesterol <35, 388 / 399 (ERN / Placebo)
or
Triglycerides =151, 461 / 483 (ERN / Placebo)
but noting about HDL cholesterol <35 AND Triglycerides =151
More than a year after its public presentation, the Heart Protection Study 2—Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) is now in print ...
To be honest I expected some new info (ie.: sugroup of low HDL high TG) but this release is not new, all info was available at the public presentation (inc. the TG >150 data).
I think it's totally meaningless (except if "Lloyd-Jones D. Niacin and HDL cholesterol—time to face facts. N Engl J Med 2014; 371:271-273." contains some new info / data, however I do not think.)
The other one ... Niacin and HDL Cholesterol — Time to Face Facts
I could not read the original NEJM articles, but it was based on that:
HPS2-THRIVE: As Niacin Fails, HDL's Role Is Debated Anew
It looks like no new data for "ANCHOR population", however my favorites:
"Nobody does trials as well as the Oxford group, let me say that, but when you look at the baseline LDL- and HDL-cholesterol levels in this trial, who on this planet would ever throw 2 g of nicotinic acid at a patient with that lipoprotein profile? No one. No one would do that."
"I think that when trials are so removed from what we do in daily clinical practice, it becomes silly. If you're a patient and you have those [baseline] lipids on statins, I would say, 'Wow! I'm done.' You can see how these trials are becoming too far removed from reality."
"My problem with both trials [AIM-HIGH and HPS2-THRIVE] is that they have so vigorously pretreated with statin therapy that baseline lipids were essentially normal. This means that any change you induce with an agent is, by definition, going to be minimal."
Berger also said the clinical trials could still be designed if researchers are able to identify a subgroup of patients where niacin might be beneficial, such as the patient with low HDL cholesterol and high triglycerides or high LDL-cholesterol levels. "I think we have to think about high-risk groups, not entire populations," said Berger. "We need to move away from that."
Niacin might have a part as a fourth-line agent—after lifestyle changes, fibrates, and pharmaceutical-grade fish oil—in patients with high triglycerides who are at risk of pancreatitis.
genetic mutation in APOC3 not only have lower plasma triglyceride levels but they also have a decreased risk of developing coronary heart disease. "This has resulted in a swing back toward triglycerides, but not with the old drugs,"
So AZN management should be replaced also? They turned down BO offer.
At the time of $20 offer from AZN the market valuation / estimation was at least 4bn / $23 ps, so at least 15% higher. If u have a house valued for $100k and the market is growing are you sell it for $87k? I think no.
NCE: what's the role of the management?
1.) apply for it, if they think that the product is eligible for it - DONE
2.) After denial go to court - DONE
What are you expect from the management in this case? If the court ruling will be negative, yes they a mistake and misinterpreted the law. In this case, I did it also.
Jan negotiation: I am not challenging it, I do not need proof (btw: pps are not the proof), but I still could not imagine any proposed labelling by FDA which allow to AMRN to market 200-499 population and they refused it. Vascepa proposed / requested indication is as follows:
“Vascepa (icosapent ethyl) is indicated as an adjunct to diet and exercise and in combination with a statin to reduce triglyceride TG, non-HDL-C, ApoB, LDL-C, TC, and VLDL-C in adult patients with mixed dyslipidemia and CHD or a CHD risk equivalent.” – more or less the same as fibrates and niacin. (ie.: Niaspan)
Help me and please write a label for Vascepa which is for 200-499 and significantly different than the proposed indication and acceptable.
Moiety is not relevent, since the NCE is depends on ingredient.
"The controlling statutes grant 5-year exclusivity to any new drug, no “active ingredient (including any ester or salt of the active ingredient)” of which has been previously approved by FDA. It is undisputed that the “active ingredient” of Lovaza is an undifferentiated fish oil mixture. That mixture is not the same as Vascepa’s active ingredient (icosapent ethyl). Nor is the mixture an ester or salt of icosapent ethyl, or vice versa. In refusing to recognize Vascepa’s 5-year statutory exclusivity, FDA has improperly substituted the words “active moiety” for the statute’s words (“active ingredient”).
Moiety is relevant in case of submission of NDA or ANDA:
"to submit any NDA or ANDA for drug product that contains the same active moiety as in the new chemical entity for a period of 5 years from the date of approval of the first approved new drug application"
NCE case
I am not a lawyer and I do not know the full Food, Drug, and Cosmetic Act, but after analyzed the documents:
Doc1: Amarin's Complaint
Doc2: Amarin's Complaint Exhibit 1 (FDA's letter)
Doc3: Sec. 355 - New drugs
my conclusion:
- FDA agreed with Amarin that Vascepa and Lovaza have different active ingredients
- The controlling statutes grant 5-year exclusivity to any new drug, no “active ingredient (including any ester or salt of the active ingredient)” of which has been previously approved by FDA
- The controlling statutes prohibit to submit any NDA or ANDA for drug product that contains the same active moiety as in the new chemical entity for a period of 5 years from the date of approval of the first approved new drug application (Doc2 page 5)
Maybe I am wrong / missed something but it looks like for me that FDA mixed the exclusivity and the new submission part.
Conclusion:
- drugs with the same active moiety are entitled for NCE – after 5 years from the date of approval of the first approved new drug application – if the active ingredient is different
- Vascepa is entitled for NCE, although the active moiety is exist in Lovaza, however the 5-year period was expired and the active ingredient is different.
a.) I will not check it, I believe in you (but not mix press release with cc)
b.) it's still irrelevant, since If – theoretically – management said f’d you FDA during the meeting, but Vascepa eligible for NCE status, FDA has to grant it.
“precedent setting NCE case” – it’s arouse my interest and try to find out what’s behind this. I could not find it, but I found something else …
First Post-FDAAA “New Active Ingredient” Election and Grant of NCE Exclusivity Made With the Approval of FETZIMA (ANRN included it in their filling)
Sorry I could not recognize the topic of the "high level meeting with the FDA regarding NCE pre-Vascepa approval", but it's irrelevant since NCE is purely about facts (no science involved). It looks like for me that FDA delay the decision to issue new guideline and try to retroactively apply it for Vascepa. As I remember after GSK's statement "The entire fish-oil based mixture in Lovaza-not just the ethyl esters of omega-3 fatty acids-constitutes the active ingredient." and FDA's denial of CP everybody thought that they will get the NCE. Yes, EPA is part of Lovaza as JL referred and it could be a valid argument now, but not in 2012. We will see. Good to get, but not a big issue if not.
Patents: Sorry, but "WHAT'S UP?" The company is doing very well regarding patents. They have one of the most patent protected drug. Based on AZN excuse - no drug on the market and not challenging the patent - I think their patents (at least in case of Epanova) are strong.
It’s not white or black, but the answer: NO
NCE: How is the NCE decision linked to management’s performance? They did all that they can: requested NCE and went to court after denial. NCE is a little bit meaningless no – agree with sts66 – but it could generate some positive (and only positive). If the judge’s ruling against or for AMRN it will not effect the pps significantly or constantly, but If it’s for AMRN:
- we could delay legal cost
- we could use it as a marketing tool
SPA: How is the SPA decision linked to management’s performance? Without details (it’s discussed several times) the SPA rescission was a non-sense. How could anybody avoid it? (The only step – and it’s delaying the hole process at least by 1 month – that they did was to appeal to OND immediately. It was stupid, they could not ignore the official route.)
AdCom / Plan B: I do not say they were fully prepared for negative vote, however I guess they had a plan “on paper”, since I do not think they figured out the staff cut during that 5 days (16-22 Oct) and within 3 months after “confirmed” rescission (21 Jan) they agreed with KOWA.
Dilution in July: It’s a valid point / good question. Why they agreed with Pharmakon for 100M only and not more or dilute in the same time. I have one guess only: they thought that Pharmakon will be enough: yes, it’s a mistake.
GIA: No confirmed info, but the rumor was that GIA was decided after refused $20 BO. Let’s see it separately:
- $20 BO: in Dec 2012, the PPS was $12-14 and a lot (maybe all) of valuation said that the company worth at least $23-25 or more. So I do not think that the no for BO offer (if any) was a mistake.
- GIA: after no BO agreement they had two option a.) do not do anything and wait till ANCHOR b.) GIA. If they had chosen option a.) we are in more problematic situation today and the company value is less. Currently we have some really good company value belongs to GIA:
o the product on the market
o impressive HCP coverage (200M+ and 100M+ in Tier 2) which is much faster than any other drug in the past
o growing sales (yes it could be better)
Again it’ not easy to answer your question, but I think the best solution is go with current management (Please note that Board of Directors and Management are two different bodies. BOD are an advisors only and the Management run the company on a daily basis.)
JL,
I still believe that the FDA does not want court ruling on this rescission and the next two level do not want to be involved, so OND will reinstate the SPA or - and this is the best solution for everybody - DMEP will approve the ANCHOR sNDA before official OND decision.
(btw: the HPS2-Thrive subgroup analylis hopefully will be released in July)
It's not my day: sorry for misquote.
Hopefully I will not be wrong again: as I remember it was not posted yet
Lawmakers Push FDA To Clarify Special Protocol Assessment Rescissions
First of all: I think FDA was wrong and Vascepa should be approved for ANCHOR and hope it will be in the near future, meanwhile I would like to see / analyze the whole situation with cool head and check all aspect.
cmm3rd: science is not equal with reasonable chance or assumption. The SPA guidance does not require “new substantial scientific issue”, just a “substantial scientific issue”. FDA did not conclude that there is substantial scientific evidence that the underlying assumption was no longer valid, they said it’s still not confirmed, so in case of Vascepa they would like to see substantial scientific issue to determining the efficacy.
ladavis23: sorry, I did not read your post carefully: yes, you wasn't suggesting that the FDA would stop R-It.
sts66: TG reduction is not the target it’s the tool, TG “just” a surrogate endpoint. Yes, ANCHOR was for TG reduction and Vascepa met with primary and secondary endpoints, however FDA does not have to approve any drug based on surrogate endpoint, it’s just a possibility for them. I disagree with JL and FDA legally rescind the SPA as “substantial scientific issue essential”, HOWEVER they do not have any reason to do it and they did not act as reasonable, so:
- Could they rescinded it legally? – Yes
- Have they a good reason to rescind it? – No
Agree with JL: “The FDA is looking at some very difficult problems if this goes before the courts.”