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This is the clearest expression of intellectual excreta possible. It should be disposed of in the waste basket of pure bullshit:
a. Vascepa will be approved based on both of the following criteria:
NOTE THE COMMAND TO OBEDIENCE
1) Used for cardiovascular risk reduction
ABOUT THE ONLY JUSTIFICATION IF THE TG<500 MG/DL
-AND-
2) Documentation of positive clinical response to therapy
WHAT DOES THIS MEAN--SHOW US THAT THE TG WENT DOWN? OR THAT THEY ARE STILL ALIVE BECAUSE THEY HAVEN'T SUCCUMBED TO AN MI?
-AND-
3) Patient is on an appropriate low-fat diet and exercise regimen
WHAT IS APPROPRIATE? WHO DETERMINES THIS?
-AND-
4) Patient is receiving maximally tolerated statin therapy
THIS IS WHATEVER A PHYSICIAN OR PATIENT SAYS IT IS
-AND-
5) Prescribed by or in consultation with one of the following:
a) Cardiologist
b) Endocrinologist
c) Lipid specialist
PRESUMABLY, NO INTERNIST OR FAMILY PHYSICIAN IS CAPABLE OF EXERCISING THEIR BRAIN ACCORDING TO UNITED HEALTH! (PRIMARY CARE PHYSICIANS SEE MOST OF THE CASES ANYWAY-PERHAPS THAT IS THE POINT)
Great posts BB and Ski-entirely agree
Market reform is long overdue.
HK
DK,
My response to insurers playing silly buggers with the TG>150 requirements, is to order a non-fasting lipid panel and tell the patient to have a large repast underneath the golden arches of Mickie D before sampling blood--never had a problem after that...when monkeys set the rules, one has to play games also...
HK
My take exactly
thanks for posting sts
So we will see the evidence pile on in the coming year: LDL and lipid effects are known to be deleterious in direction but there are also a lot more direct cell membrane effects that run in the opposite direction to EPA: vis a vis cell membrane fluidity, cholesterol domain formation, free radical generation, lipid peroxidation and nitric oxide generation by endothelium to mention just a few.
I agree with you in a way--I meant it makes strategic sense to do this for UHC. I agree TG>500 pancreatitis is a low prevalence disorder and elevated moderate TG are seen in acute pancreatitis along with other causes such as gallstones, alcohol, medications such as NSAIDS etc..
Amen Raf-all these other suggestions are educated lunacy and about as practical as wrapping your arm around your head to touch your nose. These third-party payors have turned thinking prescribers into thoughtless paid monkeys.
This is a flawed analysis on many levels.
(1) There is a continuum of risk for pancreatitis that expresses itself above 500mg/dl and increases dramatically over 1000 mg/dl in most cases
(2) There is a continuum of cardiovascular risk for TG>150 and increases proportionately (though not linearly) thereafter and exists both above and below 500mg/dl.
A dichotomous > and < 500mg/dl approach to risk: benefit analysis that relegates a pancreatitis risk to above 500 and a CV risk to below 500 is therefore illogical.
Further, the pancreatitis "risk" that we are treating in TG>500 is an idiosyncratic one albeit correlated with the chronicity of the TG>500 exposure. So we would have to continue the Lovaza "ad infinitum" to prevent pancreatitis and stopping it arbitrarily after 12 weeks would not serve any purpose.
Lastly, the adverse risk of the DHA in Lovaza has hitherto been ascribed to the LDL rise that DHA containing drugs elicit. It has been portrayed as being negated by co-administering statin. In fact, there may very well be a direct deleterious effect of DHA independent of the LDL effect, just as there is an independent beneficial effect of EPA independent of its LDL effects. This being the case, a prolonged duration of consuming DHA containing products would neither be desirable for the patient or ethical for the prescriber. If we wish to treat pancreatitis risk and maintain CV risk lowering simultaneously the logical choice for TG>500 is Vascepa, albeit with a 10% lower TG lowering c/w Lovaza that could be mitigated by just increasing the EPA dosage. As an aside, once the TG risk gets above the 750mg/dl range there is always a need for polypharmacy (just as with severe hypercholesterolemia where statin or statin plus ezetimibe will not cut it if your starting LDL is >250mg/dl)
HK.
I think they will not cover genV or V for any form of HyperTG period. There is only genLovaza or fibrates. If you want to use Vascepa one would need a prior auth for the only valid indication that UHC appears to acknowledge for Vascepa--CV event reduction BUT only with a prior auth. Interesting to see what gets you the prior auth authorized ie what variant of the R-IT entry criteria they have gerryed up to raise the barrier for endorsement. Incidentally, note the term used in the left column. It says "cholesterol or lipid-lowering" not cardiovascular event reduction, presumably, that is assumed in which case we can throw out every alternative drug except the statins in the right column.
HK
These are critical points that North makes:
Makes total strategic and medical sense:
Great find RDH, any chance of finding Brinton's reference. In any event, we are about to see courtesy of PreatonMason and Viet Le all the evidence basic and clinical that we need to say DHA is not just a diluter but a disaster.
HK
I believe that Du's quest for doing the right thing politically biased her towards H-W's thrust that generics prevailing is always a good outcome for society. The logic is good and I agree with Marjac:
Thanks, Eight--all points are well taken. I can't blame Singer for the rule 36 debacle--he was ambushed, corralled and slaughtered before he could utter a decent word..." so very sad to see a court do that. As to the skinny label issue being sub judice by the appellate division...well I guess time will have to tell the outcome.
HK
Thanks, Eight--all points are well taken. I can't blame Singer for the rule 36 debacle--he was ambushed, corralled and slaughtered before he could utter a decent word..." so very sad to see a court do that.
HK
Thanks Ratna,
I agree with your suggestion..after all, we have all seen what concerted mass effort (misguided or otherwise) can do when concertedly applied by the Redditt crowd.."
Thank you for compiling his outstanding summary CaptBeer
Eight
Amarin's case is a poster child for the two most pressing problems in patent law in general and drug patent protection and 2021 H-W applicability in particular. I speak of course of the issue of parsing the prima facie and secondary objective indicia for obviousness determination (last visited in Graham vs Deere) and the issue of policing the skinny label boundaries. Possession being nine-tenths of the Law, it becomes essential to rapidly and conclusively define where the carve-out ends and the skinny label begins. Given the solicitor general's job is to bring this to the SC's attention, we had better hope (nay pray) that this is not someone with some political or "social" agenda like Henry Waxman. There is an imminent danger of idolatry in the way our judges and the legal system is starting to look at H-W. H-W is a stab at social justice in drug pricing. It has served a purpose but desperately needs better defining. H-W was not meant to be carved in stone like the ten commandments or even the Magna Carta. I realize that Judges like Prost and politicians like Waxman ( the retired representative) would sooner pen an amicus or a dissent to preserve the status quo, than stop to reflect where the pendulum of change has swung since 1984 when Reagan signed it, to now? As in all things American and politics especially, we swing eternally between extremes. We have swung from one extreme of inequitable drug pricing to the other equally vile extreme of depriving innovation/incentivization at great societal cost. Amarin's legal case is a truly worthy contender for the hallowed 2.8% that reach the gaze of the SCOTUS.
HK
There are nuances to this excellent idea that are worth mulling over.
(1) Yes, it is true that Lovaza is already partially nibbling at Vascepa's lunch. But, this has occurred where mostly gen IPE supply ran out and Vascepa substitution has defaulted to the least expensive "alternative" in third party payor/pharmacy policy -Lovaza. There is also a deep historical base of ever-reliable knowledge deprived prescribers stuck in the ice age of developmental therapeutics, who blissfully commit murder (perhaps manslaughter) by Rx. It will take Time, ruthless Guideline enforcement and more than the average dose of shaming to elicit change here.
(2) It may be true that the FDA has an open ear for a PFE or JNJ but it is also the case that GSK has a vast team of representatives who have established access to the ear of physicians already. The same may be said of PFE JNJ Novartis etc...However, targeting their own Lovaza prescribers to upgrade to Son of Lovaza may be a good selling strategy (coupled with the knowledge of why this matters to patients).
(3) In the end, for prescribing habits to change the majority of physicians must be convinced of two things categorically and scientifically: DHA is detrimental and EPA is incrementally beneficial. That time is nigh as we will see from the ACC presentations this month. The time is also pressing when a review of this half century's most significant cardiovascular achievements (by 3 cardiology grandees) cannot blatantly and shamefully ignore the immense cardiovascular achievements of Vascepa and REDUCE-IT.
Icosapent Ethyl either as Vascepa or as a generic or as a derivative improved product will save millions of lives and prevents countless more strokes, heart attacks, heart failure, but it will take a legal system that doesn't destroy the incentives for innovation and trial, as well as an equitable access to that medication in whichever country of the world.
HK
Reference:
https://www.nejm.org/doi/pdf/10.1056/NEJMp2033115?articleTools=true
Politics are the festering unavoidable corruption that flows through the noble spirit and flesh of the American legal system. It is perhaps the price we pay for representation, in the hope of equitable application of the Law. Judge Moore is no doubt highly qualified, but nonetheless, actions reveal the inner thinking, and I withhold judgement as to whether this Judge is another Portia come to justice.
HK
Onerag
It’s always about ego and dominion and provenance... it was ever the human failing.
True true all true
10 mg lipitor in my image
Full disclosure
Maybe 10% of my patients are on that dose
Still horse pills kiwi
And just for counterpoise here is Henry Waxman the not-so-retired congressman of Hatch-Waxman fame:
https://accessiblemeds.org/resources/blog/thank-you-rep-henry-waxman
Great post and analysis LB and DK,
Both effects are likely in play
A. The Federal Circuit’s Burden-Shifting
Test Violates This Court’s Precedents.
The point of the obviousness inquiry is to identify
advancements that are so slight or trivial that they
would have occurred without the need for patent
protection. See Hotchkiss v. Greenwood, 52 U.S. 248,
267 (1850) (concluding that a clay doorknob was not
entitled to patent protection because the improvement
was merely the “work of the skillful mechanic, not that
of the inventor”). Section 103 of Title 35 directs that a
claim is obvious “if the differences between the subject
matter sought to be patented and the prior art are
such that the subject matter as a whole would have
been obvious at the time the invention was made to a
person having ordinary skill in the art to which said
subject matter pertains.” 35 U.S.C. § 103. The burden
of proving obviousness is supposed to remain at all
times with the patent challenger. “[B]y its express
terms, [35 U.S.C.] § 282 establishes a presumption of
patent validity, and it provides that a challenger must
overcome that presumption to prevail on an invalidity
defense.” Microsoft Corp. v. i4i Ltd. P’ship, 564 U.S.
91, 100 (2011).
As interpreted by this Court, federal law requires
a court asked to invalidate a patent to take account of
all relevant factors, including objective indicia of nonobviousness. See Graham v. John Deere Co. of Kan.
City, 383 U.S. 1, 17–18 (1966). The factors bearing on
obviousness are to be considered in their totality,
weighed together with the burden of persuasion
squarely on the patent challenger. See KSR Int’l Co.
v. Teleflex Inc., 550 U.S. 398, 406 (2007); Graham, 383
U.S. at 17–18. In rejecting the position that a patent
challenger is capable of “shifting both the burden of
production and the burden of persuasion” to the
patentee upon a certain showing, Microsoft, 564 U.S.
at 103 (internal quotation marks omitted), this Court
has affirmed that “a defendant raising an invalidity
defense b[ears] ‘a heavy burden of persuasion,’
requiring proof of the defense by clear and convincing
evidence,” id. at 102 (quoting Radio Corp. of Am. v.
Radio Eng’g Labs., 293 U.S. 1, 8 (1934), as modified
on denial of r’hrg (Oct. 8, 1934)).
Instead of anchoring its analysis to the
presumption of validity and a patent challenger’s
burden to show obviousness clearly and convincingly,
the Federal Circuit’s approach relies on an improper
burden-shifting framework. Under that approach, as
long as the patent challenger makes a prima facie
showing of obviousness, the burden of production—
and in effect persuasion—shifts to the patent holder to
prove that secondary considerations refute that prima
facie showing. See App. 81a; see also Pet. 26, 29. By
shifting the burden and discounting objective indicia
of non-obviousness, the Federal Circuit’s test raises a
particular risk of impermissible hindsight bias. Under
the Federal Circuit’s approach, patents on even the
most novel inventions risk being invalidated when
challenged.
B. This Case Presents an Ideal Vehicle for
Addressing the Question Presented.
This case presents an ideal vehicle for the Court
to clarify the proper standards for determining when
a patented invention is obvious. The case brings into
sharp focus the serious consequences of the Federal
Circuit’s burden-shifting approach, which relaxes the
standards for demonstrating obviousness. There also
can be no doubt that the time is ripe for this Court’s
intervention. Despite the extraordinary importance of
this case, the Federal Circuit views its burden-shifting
approach to be so entrenched that it summarily
affirmed without even issuing an opinion.
If Amarin’s drug is not entitled to patent
protection, no drug manufacturer can be confident
that its patented inventions will withstand an
obviousness defense. Amarin’s drug indisputably
addresses a previously unmet medical need and took
hundreds of millions of dollars to develop.
I agree North-this article was a snooze in every respect.
I think you are going to see evidence at ACC 2021 that DHA containing drugs like Lovaza and Epanova directly negate the clinical benefits of EPA, independent of any change in LDL. This "give statin to neutralize LDL rise of Lovaza" is spurious reasoning. This is because while we do have a correlation of LDL levels and CV event rates, the CV clinical benefit of Vascepa IPE which was both considerable and statistically significant in REDUCE-IT had no correlation whatsoever with LDL levels or TG levels or HS CRP levels--this was a unique direct biological effect of the EPA. By analogy, the detrimental effect of DHA is a direct one that interferes with the beneficial biological effects of EPA. There is no other way to explain the lack of clinical benefit of DHA/EPA combo drugs in every clinical trial thus far, most especially STRENGTH.
HK
I would only add that while COVID has been a discussed focus of this MITIGATE trial--it actually aims at a mitigation of all lower respiratory tract viral infections including influenza.
HK
Fingers crossed
It is shocking the delays in implementation into guidelines of what we consider in retrospect o be obvious recommendations. Three years for Entresto means 2022 for Vascepa? It will be a lot shorter for Vazkepa that for sure.
HK
Iryo,
It is remarkable when I think back to ACE inhibitors enalapril/lisinopril or Carvedilol, how ridiculously slow the uptake of Entrsto was in comparison despite widespread acclaim for its benefits and widespread guideline endorsement.
You would think a 20% reduction in mortality on top of full CHF therapy is compelling:
Kiwi
That being the case, how about this scenario for nirvana?
MD's can still write off label but the courts should mandate that where there is a skinny label-carve out indication conflict: (a) the physician stipulates the indication and (b) the pharmacy filling documents the filed indication and (c) the third party payor cannot mandate a generic substitution for an infringed indication
This is just my wishful thinking...
HK
Exactly John I agree with Sleven:
HDG
eight and Sleven,
This is how I see it:
(1) Teva vs GSK is seeking confirmation/denial as to whether a skinny label with no disclaimer of the benefits of the carved out patented indications, (whether or not they were forced to include carve-out indication side effect and contraindication label verbiage required by FDA), is tantamount to induced infringement with or without evidence of direct inducement shenanigans such as incentivization or advertising etc...
(2) In Hikma's specific case with Amrn regarding generic IPE, they committed 2 faux pas: (a) They omitted the "not for CV event reduction" disclaimer which had been on the label when they submitted it for approval to the FDA (B) They maintained the AB rating designation on the post-ANDA approval label without the disclaimer and retained all the FDA required listings of contraindications and warnings that could, of course, make the prescriber aware that this might be used for CV event reduction (thereby promoting inducement) which is not in the ambit of the skinny label from the git-go. The AB implies bioequivalence which is pharmacokinetic and structural bioequivalence rather than therapeutic equivalence which is inferred but never proven. All the elements were in place to induce infringement by design.
(3) The issue with Healthnet covers another separate issue and that is despite knowing the skinny label restraints of the HIKMA product, Healthnet nevertheless mandated the substitution with generic IPE for known CV event reduction Vascepa prescriptions--this was so as many of these scripts were initiated and documented prior to the gen IPE release, and were documented on pre-authorizations as being for CV event reduction per R-IT indications. In effect, Healthnet colluded with HIKMA and the intermediary PBM's to defacto the substitution while HIKMA feigned a clean hands attitude while all the while supplying the inducement stopping only when their API ran out. Incidentally, Blue Shield (of CA) is doing the same as Healthnet as of two weeks ago.
All of this would be equitably decided for everyone's good if only our courts weren't the feckless institutions they are and have the courage to penalize the generics that flout the law and stray out of the generic skinny label box and punish the PBM's and third party insurers that casually infringe for their own fiscal profit motives. These cases are truly seminal cases for our patent law system...
HK