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sts
I look at carve-out as what is being carved OUT (ie R_IT indications)and the skinny label is what is left behind for the generic.IF we cannot legally define and respect what is in the carved out indications, then H-W becomes a government authorized takings scheme where the government robs Peter to pay Paul, and the generics help themselves to an all indications plunder. I am not debating the economics of whether generic drugs can save money. They may in some circumstances, do so validly. I believe where governments bulk buy and distribute drugs for infectious diseases, HIV, HTN etc indications in developing countries, this works well.(eg CIPLA and Ranbaxy selling HIV drugs to S Africa). In the USA, the balance between drug pricing and innovation is in serious jeopardy. H-W reform is long overdue but it won't occur with politicians and judges pushing generics at all costs, even when there is no real cost-saving, and where the valid intellectual property in the carve-out is stolen.
HK
sts,
I think there are differences in absorption (including variation in concomitant food consumption), variations in compliance and chronicity of dosing, differences in sampling times post-dose and thus steady-state levels vary considerably. Bear in mind patients in short term 12 week PK studies are followed and reminded closely by the trial coordinators--not so people in an 8000 pt trial running over many years. Another thing that is interesting is that despite the touted enhanced absorption of EPANOVA the EPA levels in STRENGTH were really mediocre even in the highest tertile, in actuality much less than 130ug/ml. In STRENGTH EPA levels were parsed according to tertile of percentage rise of EPA levels c/w baseline. It would have been better if they stuck to absolute levels, but the mean EPA level overall was 89.6 ug/ml (46.7 to 131.5)c/w REDUCE-IT at 144 and JELIOS even higher >160 ug/ml. Levels matter, but raising DPA and giving DHA may matter also.
HK
I saw this, even discussed this directly with the author. Nothing new argument wise has arisen, since this was posted in Sep 2020. The errors are profound visible and easy to see. The fundamental premise of this author's analysis is I believe correct. The scale of the blunders in statistical analysis and scientific logic enacted (unchallenged) by HIKMA/ Heinecke is of monumental proportions. How a court accepted this, and how plaintiffs allowed it to happen remains an unsolved mystery.
HK
From the methods paper:
Artificial intelligence and machine learning to the rescue Raf
VuBru
I agree that this is clearly "propensity score matching" which is a second-best technique in my mind, forced upon the MITIGATE trialists because they need a large n for power, have a small n for Vascepa supply and for "pragmatic" reasons have to employ an open-label design. Since propensity matching utilizes an artificial control group by matching each treated unit with a non-treated unit of similar characteristics the estimate of the impact of the Vascepa intervention is dependent on accurate matching. However good the "matching" may be, it is only as good as the propensity risk factors one recognizes, hence the need for placebo-controlled randomization (not possible of course for reasons outlined above).
There are other problems.
The entry criteria state:"Eligibility criteria include men and women age >50 years, established ASCVD (i.e., defined as prior myocardial infarction [MI], percutaneous coronary intervention [PCI], coronary artery bypass graft [CABG], ischemic stroke, and/or peripheral artery disease [PAD]), no prior history of confirmed COVID-19". This means there will be people who have had flu-like illness possibly covid19 who had no EMR record of covid 19 recruited into the treatment group. All recruitment being done through an EMR search of ICD 10 codes. There is no laboratory testing of covid serology pre-randomization so there is no way to know if the propensity matching worked. If skewed this might inflate Type II error.
The "viral primary endpoint includes a nebulous component "The first of the co-primary endpoints is the incidence of moderate-to-severe confirmed viral URIs (i.e., COVID- 19, seasonal flu, and other known viral respiratory pathogens) based on laboratory testing leading to an urgent care appointment, emergency department (ED) visit, or hospitalization with a SpO2 ?94% on room air (RA) and/or requiring any form of supplemental O2". the problem is that the trial entry criteria have no requirement for laboratory testing but the endpoint criteria utilizes it. Thus a patient who has a positive covid test and presents for whatever reason to the clinic would add to the co-primary endpoint...some care is required here to determine who actually had a moderate to severe URTI. A baseline lab test for viral serology is important. The timing and extent of how and when lab serology is obtained in both arms is unclear in the methodology paper.
Finally, as I have outlined in my prior post, using the event rates quoted in REDUCE-IT and assuming similar risk populations, we have a 4.3% and 5.7% incidence rate per 100 patient-years (respectively Vascepa: Placebo) i.e.there would be assuming 1500:15000 randomization, ~65 events to 855 events. The primary composite endpoint curves separated in R-IT for around 2 years. Even assuming a higher event rate in a secondary prevention cohort (as c/w mixed primary /secondary in R-IT), this trial would either need more n or longer duration(?how long) to show CV endpoint differences, IMHO.
Assuming, the trial is positive for the covid/URTI endpoint, it is unclear how an FDA approval system will view such a trial design for purposes of drug approval.
HK
https://documentcloud.adobe.com/link/review?uri=urn:aaid:scds:US:d2c0b603-c121-40e0-81b6-70c8e99e7353
I agree the whole ENHANCE - IT result exposition has been an exercise in hype and high drama to drum up institutional funding for a phase 3 trial. As you and Fermi suggest, there is more smoke than fire. MTNB may have overreached with the DPA. Just showing “superior” EPA levels or TG reductions is not proof of principle. There are NO surrogates for a CV phase 3 outcomes based randomized comparison against placebo. If it was good enough for Amrn after ANCHOR and MARINE it’s good enough for MTNB after ENHANCE- IT.
I agree the whole ENHANCE - IT result exposition has been an exercise in hype and high drama to drum up institutional funding for a phase 3 trial. As you and Fermi suggest, there is more smoke than fire. MTNB may have overreached with the DPA. Just showing “superior” EPA levels or TG reductions is not proof of principle. There are NO surrogates for a CV phase 3 outcomes based randomized comparison against placebo. If it was good enough for Amrn after ANCHOR and MARINE it’s good enough for MTNB after ENHANCE- IT.
PDude
I agree that someone conducted a retrospective review of the data using a matching analysis for equal comparison of underlying morbidities. It may well have suggested the prospective study as you suggest. The problem is that a retrospective review with subject matching for balanced comparison of comorbidities is subject to all sorts of selection bias . Better is a randomized allocation to test therapy and a prospective evaluation of outcomes. Of course limitations of resources have forced a 1:10 randomization to Vascepa vs. usual care. I think because of numbers assigned 1500 vs 15000 some disproportionate randomization of comorbid conditions is inevitable and will require balancing by matching- no way out. 1:1 randomization of thousands of patients is better but not “ practical “ because of limited Vascepa supply presumably.
HK
Sleven,
I agree --I cannot see how a CV endpoint analysis could be powered to produce an answer within a year--see my last post
HK
Zip,
Kiwi
I agree with much of your DD.
The interesting thing is the endpoint here is the incidence of mod-severe URTI's an 18% RR reduction at a power of 80% (alpha=0.8). The end-point ambition of the trial is quite wide: a reduction in the incidence of the common cold as much as the covid19 URTI. Imagine if Vascepa could diminish the incidence of the common cold in the age >50 vulnerable comorbid patients. I was puzzled about the power for CV event reduction, though I understand this was powered to look at the denovo incidence of mod-severe URTI's in a vulnerable patient population. MITIGATE as far as I am aware is a 1:10 randomization between Vascepa IPE intervention to best "usual medical care" randomization prospectively of 16500 patients. Using the event rates quoted in REDUCE-IT and assuming similar risk populations, we have a 4.3% and 5.7% incidence rate per 100 patient-years (respectively Vascepa: Placebo) i.e. there would be assuming 1500:15000 randomization, ~65 events to 855 events. The primary composite endpoint curves separated in R-IT around 2 years, so my question: Is there power for CV endpoint definition on this basis and if so how do we calculate that? I asked Dr GO (the Kaiser PI)and he replied that the power calculations and trail design/analysis details were undergoing peer review and would be published soon... so I have no answers as yet.
Certainly, this is a novel trial design by all accounts. Matching for susceptibility to URTI and comorbidities will also be a tricky issue.
HK
I have learnt a lot of law and investing here Mr1979. Good people here.
HK
JB
It looks they are randomizing 1:10 IPE Vascepa to usual care and then later adjusting for age and comorbidities between the groups for moderate-severe URTI (including Cov-19)outcomes comparisons. Interesting will be the issue of how vaccination incidence and its effects will be adjusted for in the analysis.
Sleven,
my understanding is that Phase 4 only designates a prior approval of Vascepa for a different indication (CV TG)
No worries Mr1979, I was just adding color to the conversation. I believe new indications may certainly be pursued as a result of data derived from Phase 4 trials. "The goals of the Phase IV activities are to explore new formulations, new indications, and other patentable innovations. "
The good news that the toxicity and dosing issues are out of the way.
The ENHANCE-IT trial needs to be seen in the context of what has been already shown for efficacy and levels in other Omega 3 trials i.e. JELIS, REDUCE-IT, STRENGTH, PK TRIALS of VASCEPA and MARINE/ANCHOR. While it is tempting to oversell limited PK study of 90 odd patients the EPA levels achieved in the ENHANCE-IT trial over 28 days are essentially of a similar range to that achieved at one year after consistent Vascepa administration and compliance. The DHA levels are perhaps equally important given Preston Mason's lab findings regarding the differing lipid and cellular effects of DHA and EPA. For one thing, STRENGTH having negative results may be as much a function of too much DHA elevation as it is inadequate EPA elevation. The effects of DHA in the MTNB preparation is unknown though the DHA levels seen are not much different between the Vascepa and Lypdiso arms. The biological benefit of raising DPA levels is unknown. I do not believe that ancillary biomarker effects on hs-CRP can be used as a corollary for CV benefit effects. There will be no answer until they perform an actual phase 3 trial which is what they are angling to do as suggested by John Kastelein. All else is but shadows and dust...
Our prayers and best wishes are with Montana at this very difficult time.
Thank you for informing us Irishman.
HK
Phase 4 trials to previously approved drugs--while frequently described as post-marketing surveillance trials, this is not necessarily so. In this case in MITIGATE, Vascepa is being used in a prospective, open-label, parallel-group, randomized, pragmatic clinical trial. The MITIGATE Study was designed to evaluate the real-world clinical effectiveness of pre-treatment with icosapent ethyl (IPE) Vascepa®, compared to the usual standard of care to prevent and reduce the sequelae of laboratory-confirmed viral upper respiratory infection (URI)-related (i.e., COVID-19, influenza, and other known viral respiratory pathogens) morbidity and mortality in a high-risk cohort of adults with established atherosclerotic cardiovascular disease (ASCVD). Thi sis still a randomized trial and has all the obligations of proving efficacy that a phase 3 trial has--only its being done with a drug previously approved for another indication.
It is not "basically paved for approval"
HK
Exactly
Why would you buy out anything or bargain a price until (1) EU approval was secured and (2) All your ducks are in a row regarding Covid trials, China, and EU launch “ GIA” Germany ?
That is my reading of it. Anyone who sees it differently should point out why. I have highlighted all the evidence in my prior posts.
HK
Bravo Navitus: must be getting a better financial deal after all the contractual obligations using Vascepa.Doubt this is the considered judgement of therapeutic benefit by Aetna.
Kiwi
Envolve is the contracted PBM for Healthnet. They follow the tiering policy and generic pricing mandates set by Healthnet. They make their money as the contractor between the third party payor and the consumer.
HK
Lemm
It means I believe that after first inserting a section viii statement for purposes of ANDA approval HIKMA then removed the CV limitation of use statement to encourage broader infringing use of the generic. The FDA didn’t opine on the necessity for cv such an action. Hikma did it anyway!
Yes sleven, that is my understanding. To me the GSK vs Teva ruling does not speak to what is being alleged specifically here in Delaware with regard to Healthnet and Hikma
Not that it matters, but this brief is actually better written and defined cleanly and more definitively even than the Appeals brief at CAFC after Nevada, that was so disconcertingly kicked out of the park by Dyk and brethren using the Rule 36 judgement. It helps that Singer knew the territory from the prior GSK trial. Never underestimate the Hikma lawyers --they are nothing if not inventive in their deceptions.
HKL
Judging by the torrent of Healthnet/Envolve approvals for generic IPE (mandated) for CV risk reduction Vascepa petitions, I am getting in my office--I would say they have decided full speed ahead and damn the torpedoes...
HK
The request for Amicus decision for GSK vs. Teva is due tomorrow. This will be important. I still think Amarin's case is related but NOT determined (except in tangential part) by GSK vs. teva.
HK
Sleven,
This is an unclear territory. This is an attack on H-W by extension because Hatch-Waxman is a clear license for generics to infringe valid legal patents by inducing off label use--the third-party payors and PBM's are complicit in this because they mandate the substitution and incentivize it financially ostensibly for the patient's benefit but in reality their own. What our own BB likes to call a legalized takings scheme.
Now in GSK vs. Teva, there was a period of tacit infringement by generic carvedilol Teva (ostensibly for HTN postMI lv dysfunction) and Coreg (for CHF), then the HTN/LV dysfunction patents expired and the new 000 CHF patent was instated. Then labelling mandates forced disclosure of the CHF uses and side effects which were adjudicated as inducing infringement indirectly if not definitively.
Here in Amarin vs. Hikma, we have direct infringement by Healthnet and concerted synergistic incitement to infringe by both Hikma (via press releases and investor PR (goes to motivation) and de facto removal of section viii statement present on the pre-approval ANDA as compared with the post ANDA marketing labels (goes against all prior demonstrated practice for Vascepa and Lovaza in the MARINE era).In my opinion, this is not nebulous in intent like GSK vs. Teva. It is very concrete. It will fall out on the parsing of the meaning and intent of HIKMA's PR labels, the post-approval drug labels, and the comparison to the pre-approval ANDA proposal from Hikma with the section viii statement in...
This is in IMHO a just assault on H-W egregious abuse by generics and third-party payors. That it is, is evidenced by Waxman himself petitioning the Delaware court by Amicus to strike it down with lots of emotional word play...
HK
My three other favorite places are nearby ARLES ( van gogh the “ bridge at Arles”); Aix en Provence ( atelier cezanne), and Avignon ( sur le pont Avignon.. palais de papes)
Iryo and sleven,
(1) HEALTHNET straight up infringed on a patented indication ( CV risk reduction)
They have used the prior authorization to MANDATE generic IPE substitution for Amrn Vascepa’s carved out indication of CV risk reduction
(2) HEALTHNET induced infringement using the financial incentives of the TIER system applied inappropriately to the patented carved out indication
(3) HIKMA induced infringement by deleting the section viii statement “ not indicated for CV risk reduction “ from their post ANDA approval launch label
HK
CBB
sts,
I do not believe HIKMA ever included the "not for CV event reduction" disclaimer after the ANDA was approved by the FDA. They had to do this initially, prior to issuance of the ANDA, because section viii demands this statement for clarification that the generic is not aimed at a patent protected indication.
This is slightly nuanced IMO compared with GSK-Teva; In GSK the lack of discussion of product indications is used by Prost to dissent against the majority saying "AB" rating alone is not enough. Singer turns it around for Amarin-HIKMA in Delaware saying: (1) HIKMA knew their indication was a very clear cut carve out YET unlike Lovaza and Vacseepa before who both put in the section viii "not for CV risk reduction" disclaimer--HIKMA put it in to get the FDA ANDA approval and then took it out later (just like Kurabaysahi in Nevada).
Then there is Prost's point about: AB rating "is an indication that the product is therapeutically equivalent when used as labeled" and [not] with respect to the off-label uses.". Here the uses of Vascepa vis a vis HyperTG reduction and CV reduction have been deliberately obscured by deletion of the section viii statement requirement "not for CV event reduction".
tm100
So far I have not seen a redirection by Healthnet toward Lovaza--such a course would not be supported by science or logic because Lovaza being a DHA containing omega -3 ethyl ester has been demonstrated to have ZERO CV risk reduction ability. All trials (ORIGIN OMEGA ASCEND VITAL AND RECENTLY OMEMI) of primary and secondary CV risk reduction using omega 3 combos in 1-1.8 g doses have been negative. So while Lovaza retains a TG lowering (presumably for pancreatitis) indication... I could make a case for medical negligence in prescribing if Lovaza is prescribed fo CV risk reduction (primary or secondary) and the patient develops Afib and has a subsequent stroke....just saying.
The odd thing is Healthnet has declined to cover genric IPE for some of my patients with diabetes on insulin with max tolerated stain and all the TG and LDL requirements BUT UNDER the age of 45. Apparently, CV risk only becomes manifest on the day of your 45th birthday...Of course, all this lunacy is in the hands of people who barely understand logic or science, but try to follow Healthnet high command orders.
HK
Vascepa PI:
John the whole pre-auth is one BIG FAT LIE!
I sent it to Thero for what its worth.