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Agree!
Strength had Epanova at 4g dose.
This is what the description says. Please don't tell me that AZ is making and dispensing "oxidized" EPA , where as Amarin is dispensing " not oxidized" EPA.
The amount of EPA is lower and there is significant amount of DHA. The question is not whether patients took EPA but is the presence of DHA responsible for no effect.
EPANOVA, a lipid-regulating agent, is a coated soft-gelatin capsule containing 1 gram of fish oil-derived free fatty acids, designated “omega-3-carboxylic acids,” with at least 850 mg of polyunsaturated fatty acids, including multiple omega-3 fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA] being the most abundant).
The empirical formula of EPA free fatty acid is C20H30O2, and the molecular weight of EPA free fatty acid is 302.45. The structural formula of EPA free fatty acid is:
The empirical formula of DHA free fatty acid is C22H32O2, and the molecular weight of DHA free fatty acid is 328.49. The structural formula of DHA free fatty acid is:
The reason for the neutral finding of STRENGTH trial and the positive REDUCE-IT trial is likely due to the different drugs studied. The latter trial studied a purified formulation of high-dose EPA, which resulted in much higher EPA levels. The prior JELIS trial had also studied pure EPA and was positive. The STRENGTH trial used omega-3 CA, which is a combination of EPA and DHA, and it is possible that DHA could counteract the benefits of EPA though, sub-analysis did not find a harmful association among those with the highest achieved DHA tertile vs. placebo.
Strength was acombination of EPA and DHA. Nobody claims it was oxidized EPA and DHA.
EPA - there is only one EPA.
ICOSAPENTENOIC ACID ETHYL ESTER.
Eicosapentaenoic acid (EPA) is an omega-3 polyunsaturated fatty acid (PUFA) with 20 carbon atoms and 5 carbon-carbon double bonds.
When oxidized, it is no more EPA.
If the product in the clinical trail is not EPA, the two trials ARE DIFFERENT.
The drug is EPA. The issue is there is also DHA in the study.
If the investigators says that the strength trial did not adminster EPA, story ends. Two different drugs, different results. But if the investigators say it was 4g EPA ( plus DHA), then it is EPA. The question still remains what is the role of DHA in presence of EPA.
Just saying that EPA is oxidized, does not cut it. Happy to back down if you can prove that the drug in the strength trail was different from 4g- EPA .
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4147761/#!po=37.8049
EPA - there is only one EPA.
ICOSAPENTENOIC ACID ETHYL ESTER.
Eicosapentaenoic acid (EPA) is an omega-3 polyunsaturated fatty acid (PUFA) with 20 carbon atoms and 5 carbon-carbon double bonds.
When oxidized, it is no more EPA.
If the product in the clinical trail is not EPA, the two trials ARE DIFFERENT.
The drug is EPA. The issue is there is also DHA in the study.
If the investigators says that the strength trial did not adminster EPA, story ends. Two different drugs, different results. But if the investigators say it was 4g EPA ( plus DHA), then it is EPA. The question still remains what is the role of DHA in presence of EPA.
Just saying that EPA is oxidized, does not cut it. Happy to back down if you can prove that the drug in the strength trail was different from 4g- EPA .
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4147761/#!po=37.8049
Again, can EPA oxidize? YES.
But was the product ised in the strength trial oxidized? There is no evidence to make that claim. If there is evidence to suggest that patients did not get the correct drug, we have a issue with the trial.
Again, the interpretation of strengh trial are JUNK. That guy is trying to defend his turf, nothing more. He has been shut down by other cardiologist calling the bluff.
How do I explain to you
EPA = Ethyl eicosapentaenoic acid = icosapent ethyl = Vascepa
Vascepa is nothing but ethyl ESTER of the acid. Most drugs are made into salt forma or easter.
The salt is NOT patented.
GNC can make it . But GNC products are NOT FDA approved and their quality is NOT guaranteed. Herbal products , nutritional supplements can not make health claims and no provider can be serious in using them for their patients fo manage heart health.
Again in the strength trial unless there is clear evidence that the product given to the VOLUNTEERS was NOT EPA and DHA in the indicated doses, we have a different argument .
Just saying that the product is oxidized without any support is silly.
I do not agree with #Strength interpretation . It is junk.
All am saying is oxidation is irrelevant unless we agree that the trial was provided clinical doses NOT approved by FDA and did not meet the standards.
Any data to show that this is True and FDA still approved the clinical material ?
Do you have a issue with Costco cetrizine or CVS minoxidil? Are you worried they are oxidized?
If not, it does not do matter what Bhatt or you think.
BTW, I fix sprinklers.
These are the facts. Here , it does not matter what Dr Bhatt thinks.
Was the drug used in the Strength trail not upto FDA standards? Possible. Was the drug in strenght trial not what was claimed in the protocol. Possible.
It needs to be proven or the facts taken at face value. Again Oxidation is irrelevant!
https://www.fda.gov/media/83670/download
It is irrelevant. The questions still remain.
How low was EPA dose? Why were blood levels similar? Even if drug levels were low what does it mean.
Again EPA was not the issue.
The question thAt strength did not answer was the effect of high DHA when Epa levels were high.
Saying EPA does not work despite knowing DHA may have a role to play is dumb.
Strength wasall about DHA not EPA
GSK V TEVA
In its 2-1 decision, the Federal Circuit sided with GSK: "[P]recedent makes clear that when the provider of an identical product knows of and markets the same product for intended direct infringing activity, the criteria of induced infringement are met."
It is “possible”. What did he base it on ? How low was the drug conc? It was comparable to vascepa.
The issue was not EPA but concurrent high level of DHA .
Epalevels in strength was not disputed. The q was around high level of DHAnegating the effect of HIGH EPA
See 341272
The act of supplying for theCV indication is an act of induction.
"Cheer on , you have our back " logic.
The following Q need to be answered by Hikma.
1. For any given drug what % sales are for off label use? Minimal .
2. Of the off label use , what % is for a patented use? None.
3. What % sales of gV are for off label use beyond TG?
Majority.
That is specualtion.
It is possible that the drug conc was less than 4 g total.
This means the product administered in below the stated quantity . That is a drug supply issue.
FDA required stability studied to show that the drug maintains it's conc during the whole period of stability and during patient use. Expiration of a drug product is there for a reason.
No. Is Hikma aware their product is being used in infringing manner? Are they inducing it by ignoring infringement?
How do you prove it? Sales as a function of indication. What% of Hikma sale is for TG?
10% ,50% , 90% ?What is the rest for?
By actively supporting infingement by SUPPLYING drug , you are inducing.
.
Your statement , Hikma does not know what doctors will do with drug has limited standing. They know doctors WILL infringe.. they are allowing it via supply.
Free radicals are different from oxidation products. You are talking about blocking free radicals. Nothing wrong with oxidized products
This is the reason the court will not dismiss the infringement case:
Notes for Teva v GSK
"generic drug companies improperly relying on the skinny label strategy to profit from "off-label use" by physicians for the very indication excluded by the skinny label carveout. "
While not expressly discussed by either the majority or the dissent, there is a hint that the majority was concerned with generic drug companies improperly relying on the skinny label strategy to profit from "off-label use" by physicians for the very indication excluded by the skinny label carveout. The majority extended the scrutiny regarding this stratagem perhaps farther than it can reliably be stretched, not requiring the level of promotion of the carved out indication that would be expected to attract inducement liability. And the dissent argued strongly regarding the impropriety of the policymaking consequences of the majority's decision usurping Congress's role in deciding the extent to which a generic drug company can use the skinny label strategy to avoid infringement inducement liability. It is likely that (at a minimum) the Court will hear this case en banc; perhaps less likely but certainly within the realm of possibility is Supreme Court review in light of the important policy considerations raised by the majority and even more strongly by Chief Judge Prost's dissent.
https://www.patentdocs.org/infringement-contributory-or-induced/
This is true. Payers are equally powerful.
Takeda Vs Hikma ruling will be very use in Amarin case.
https://content.next.westlaw.com/8-611-9329?__lrTS=20210104221410287&transitionType=Default&contextData=(sc.Default)&firstPage=true
Will the label with AB rating lead teh physician prescribe off lable use of Hikma drug for CVD? YES
Are their treatments that decrease risk of CVD other than icosapent ethly that are approved with statins? NO
will doctors forgo any other treatment (if any) in favor of off-label use of icosapent ethyl? YES
Is there evidence that if icosapent ethyl is used for CVD, is there evidence that they will inevitably prescribe Hikma product?
YES
@marjac thoughts?
The Federal Circuit also noted that even if it looked beyond the label, there is no evidence that the label would necessarily lead treating physicians to prescribe the off-label use of Hikma's drug to treat acute gout flares because:
Alternative treatments of gout flares exist and there was no evidence that the physicians would forego these treatments in favor of the off-label use.
Even for treating physicians who would prescribe colchicine for acute gout flares, there was insufficient evidence that these physicians would inevitably prescribe Hikma's product.
At the federal level, gun sellers have access to databases on criminal records. If the buyer presents legit id and the seller checks against it and finds that the buyer can not own a gun, it will be a crime to sell the gun. Here we are talking of a database of criminals who can not own guns. ALL FEDERALLY licensed sellers need to perform the check. If they sell a gun after a failed check , they are liable
We are not taking state or private sale laws here.
Similarly, if a mfg sells a product despite knowing they are being used for unapproved indications should be considered as a party in direct infringement.
Oxidation (addition of O2) is one of the many processes by which drugs degrade.
Oxidation by itself does not mean anything. Oxidized product is the endpoint. If the product strength is 1 g, as long as EPA stays above 0.9 g (900 mg) before it expires, the product is considered stable during storage. Companies are also required to do studies to prove that the degradation products are not toxic. Those are generally as part of intial drug development and submitted as part of NDA. Generics do not need to do these studies.
The point I am making is generic have to do adequate studies to establish product stabilty. Fishy smell, change of color are all cosmetic endpoints. As long as the core product meets the shelf life specifications, there are no issues.
Every product has a shelf life / expiration date. The product should degrade less than 10% during this period. All drugs undergo chemical change in storage. As long as the degradation is less than 10% at the end of shelf-life, there are no issues. What makes you believe that the oxidation is greater than 10%
Ralphey- this is a API issue. The efficacy is irrelevant. If the drug degrades more than 10% , even though it is effective, it will be treated as a quality control issue and the drug needs to be pulled off the shelf immediately !
Consultation is required in most states. The language goes something like this. The patient can decline the offer .
. Pharmacists will now be required to provide verbal counseling prior to dispensing a prescription to a new patient; a new medication to an existing patient; and any medications where the dose, strength, route of administration, or directions for use has changed. The new rules are a departure from the previous requirement that a patient merely be offered counseling. Under the new rules, an offer to provide counseling must still be made on all other prescriptions where counseling is not mandated.
What percentage of Vascepa sales are for > 500 trig after the new indication
From what I know , it is 10 %
How likely it is that Hikma took 100% of Trig market in 1 quarter? ZERO CHANCE!
As a clarification, in the opioid crisis, the provider and pharmacies were charged because they have a legal obligation to the well being of their patient. They knew that indiscriminate prescribing and dispensing is bad for their patients. They put their profits over their patients, hence they were implicated.
This is not the case with icosapent ethly. For the doctor and pharmacist there is no professional or ethical conflict . They are not liable for prescribing and dispensing the drug for the right use .
The pharmacist has to consult on new prescription. Yes , it is the law . But they do not have to worry about consulting on generic vs branded icosapent ethyl.
They are consulting the patient on the drug and not the patent. The drug is approved for CVD use . So no malpractice.
The doc is prescribing icosapent ethly which is approved for CVD, so no malpractice.
Hikma "may not" be even inducing the doctors.
The issue is they are infringing on a patent by willingly supplying the drug for a use for which they are not approved. Same with the payer.
Similar to the fire arm seller- if the seller knows or suspects the gun is being sold to a criminal and they still go ahead with the sale, it is a criminal offense and illegal.
If the manufacturer knows that their product is being used for an indication that they are not approved for, they can not keep supplying the drug. They can not claim innocence by saying we don't know what the doctor is using the drug for . They have the data at their finger tips. It is their job to not infringe by denying the pharmacy the supply of the drug.
Also with opioid, the drug makers were willingly supplying the drug despite knowing the truth. Same applies here.
Pharmacist is just a transfer agent. They are supposed to verify if the prescription is correct , if the prescribed drug at a proper dose and is for the right patient. They do not even need to verify if the drug for the right indication, though they can always confirm with the provider.
What they DO NOT need to worry about to verify patents on drugs. That is not their job.
However, just as the payer can deny prescription coverage for a drug for whatever reason, they need to APPROVE the payment for the drug for a given indication. If there is reason to believe that the drug can not be approved for a certain indication , they should not allow the authorization of payment. They have to know what the drug is approved. If they choose to authorize it, they are willfully infringing on the patent. The reason for doing so is obvious- conflict of interest in relation to economic savings
For the manufacturer, if a pharmacy is demanding supply of massive amount of drug and the Mfg has good reason to believe that it is being used for an indication for which it is not approved, they are infringing the patent by allowing the supply of the drug.
Hikma and HN are not only intending to infringe they are willingly doing it by supplying and approving the use of the drug for a indication which is protected under patnt.
See section below of gun control law applies to the patent litigation:
It is UNLAWFUL for a person to sell a firearm IF THEY KNOW OR HAVE REASONABLE CAUSE TO BELIEVE.....
It shall be unlawful for any person to sell or otherwise dispose of any firearm or ammunition to any person knowing or having reasonable cause to believe that such person—
(1) is under indictment for, or has been convicted in any court of, a crime punishable by imprisonment for a term exceeding one year;
(2) is a fugitive from justice;
(3) is an unlawful user of or addicted to any controlled substance (as defined in section 102 of the Controlled Substances Act (21 U.S.C. 802));
(4) has been adjudicated as a mental defective or has been committed to any mental institution;
(5) who, being an alien—
(A) is illegally or unlawfully in the United States; or
(B) except as provided in subsection (y)(2), has been admitted to the United States under a nonimmigrant visa (as that term is defined in section 101(a)(26) of the Immigration and Nationality Act (8 U.S.C. 1101(a)(26)));
(6) who?[2] has been discharged from the Armed Forces under dishonorable conditions;
(7) who, having been a citizen of the United States, has renounced his citizenship;
(8) is subject to a court order that restrains such person from harassing, stalking, or threatening an intimate partner of such person or child of such intimate partner or person, or engaging in other conduct that would place an intimate partner in reasonable fear of bodily injury to the partner or child, except that this paragraph shall only apply to a court order that—
(A) was issued after a hearing of which such person received actual notice, and at which such person had the opportunity to participate; and
(B)
(i) includes a finding that such person represents a credible threat to the physical safety of such intimate partner or child; or
(ii) by its terms explicitly prohibits the use, attempted use, or threatened use of physical force against such intimate partner or child that would reasonably be expected to cause bodily injury; or
(9) has been convicted in any court of a misdemeanor crime of domestic violence.
This subsection shall not apply with respect to the sale or disposition of a firearm or ammunition to a licensed importer, licensed manufacturer, licensed dealer, or licensed collector who pursuant to subsection (b) of section 925 of this chapter is not precluded from dealing in firearms or ammunition, or to a person who has been granted relief from disabilities pursuant to subsection (c) of section 925 of this chapter.
I agree. Teva GSK ruling will have a lot to bring to the table.
I am guessing courts will put heat on FDA to clarify therapeutic equivalency rating in context of indication approved and patents.
Another thing that the courts need to take up with regards to patent infringement is on prescription writing.
When a doctor's writes a prescription for a off-label indication , it is in their right to do so for an indication that has not been clinically approved or validated. Eg- corticosteroids in covid, colchicine (gout drug) for pericarditis, viagara for female sexual enhancement , etc. This is true OFF-LABEL use.
Doctor can prescribe generic Vascepa for CVD. The question to ask is if EPA for CVD is a off label use?
IT IS NOT! It is a clinically PATENTED use by Vascepa.
The doctor does not know need to know that patents. They can prescribe it. The pharmacist does not need to know, they can dispense it.
The payer NEED to know that they can not cover it . The manufacturer needs to know that they can not supply it for this use.
So by paying for it and by supplying the demand , both the payer and manufacturer are infringing on the patent!!
The argument is not induction of patent infringement but contributing directly to patent infringement !
The analogy here could be to selling guns. A person is on a national no gun sale list and does not clear background check. Can the gun seller claim that selling guns to this person is legitimate because he asked for a gun ?
If the doctor writes a prescription , a pharmacist dispenses it (they do not need to know patents) , can the payer and manufacturer claim innocence and just say that they asked for the drug and we gave it to them clearly knowing that the drug was dispensed for CVD? Did the intentionally violate the rights of the patent holder?
Hikma has gone to great length to protect themselves from patent infringement accusation
https://www.hikma.com/media/2944/2021-hikma-non-injectable-product-catalog.pdf
See page 26
They GOT RID OF AB rating from their product catalog and also put this disclaimer
†
Hikma’s generic version is indicated for fewer than all approved indications of the Reference Listed Drug.
Does anyone know where the transcript will be posted?
FDA desire to address patented indication in the orangebook
https://www.engage.hoganlovells.com/knowledgeservices/news/fda-to-consider-patent-listing-therapeutic-equivalence-and-other-orange-book-issues-agency-will-issue-draft-guidance-documents-seek-public-comment.
Second, Dr. Gottlieb stated that FDA will be soliciting public comment on Orange Book use and potential enhancements, including a re-examination of the types of pharmaceutical patents that must be listed in the Orange Book. Listing patents in the Orange Book that claim the approved drug or method of using the drug is a key part of the Hatch-Waxman balancing of interests between pioneer and generic drug sponsors, affecting procedural protections and incentives for both sides. Dr. Gottlieb indicated that FDA plans to consider novel issues associated with new technologies, such as whether an application holder for a drug product that has been approved for use in conjunction with a digital application should be required to list any patents associated with that app. This will be a key issue in a rapidly emerging area of pharmaceutical product development.
In context of Teva v GSK
"promotion by the generic drug sponsor of the Food and Drug Administration's (FDA) therapeutic equivalence (TE) rating was evidence that the company induced physicians to prescribe the generic for the same indications as the Reference Listed Drug (RLD), including the indication that had been carved-out of the generic’s labeling."
It is in the briefing document
There is email communication between Health Net and Amarin regarding formulary when Vascepa was approved for Reduce-It.
This communication will be used to prove that Healthnet was aware of the patent before the lawsuit was filed
I did not understand your statement? Who should not worry?
All I am saying is that Hikma label has no issue. What we need to show is for what indication generic Vascepa being prescribed.
Hikma and Amarin should be able to produce the data. If the data says it is for CVD, then Hikma is "knowingly" fulfilling the demand for EPA, despite knowing that the indication is patent infringement.
Hikma can not pleas ignorance to this fact and they are inducing themselves to supply thus infringing the patent.
Furthermore, the >200 study in the label was in reference to adverse events. The clinical pharmacology section on discusses 500 to 2000 values
It is not on their label as a indication. What they are providing is literature that is already in the public domain not generated by them
They are just quoting the trial that was conducted. It is a fact and can not be constituted as an infringement