Sunday, February 11, 2024

Patient Advocates Argue Exercising Bayh-Dole "March-In" Rights Reasonable to Ensure Ongoing Supply of an Insulin Novo Nordisk Intends to Discontinue

Back in 2016 (when President Obama was still in office), the trade group known as the Pharmaceutical Research and Manufacturers of America (better known by the acronym PhRMA) claimed in an organization-published white paper (see https://web.archive.org/web/20161022175500/https://phrma.org/sites/default/files/pdf/bayh-dole-act-white-paper-summary.pdf for an archived copy of that paper from PhRMA; note that it has since been removed from PhRMA's website, hence I found a copy on the Internet Archive) the PhRMA championed the Bayh-Dole Act of 1980. 

Understand that what PhRMA really wants to prevent a particular provision of the Bayh-Dole Act from ever operating in order to address prescription drug prices. That provision is known as "march-in" rights. To do this, the PhRMA trade organization made a variety of baseless assertions about Bayh-Dole that could not be supported with any data or involved data that had absolutely nothing to do with Bayh-Dole. In fact, its entire opposition to Bayh-Dole "march-in" provisions is having the government use those provisions over drug prices. 

But what about reasons other than price? PhRMA would prefer to not acknowledge the possibility of such a thing happening. But the industry has discontinued products before, and that is currently happening in the insulin space. Specifically, refer to my recent blog post about the November 8, 2023 announcement from Novo Nordisk so it could instead redeploy internal manufacturing capacity to making drugs for the indication of obesity without Type 2 diabetes because it cannot keep up with demand.

A well-written summary of the PhRMA debate over using "march-in" rights under Bayh-Dole can be found at https://researchenterprise.org/2016/09/29/phrma-loves-bayh-dole-but-cant-say-why/ (just note that it's link to the PhRMA white paper noted above is now dead; I accessed a copy on the Internet Archive) which essentially refuted every asserted claim made by PhRMA in its 2016 white paper. At issue is whether prescription drugs which are created based on inventions made (at least in part) with public funding enable drug companies to receive the benefit of federal research funding and then can do pretty much what they want with the results. That's essentially what the pharmaceutical industry argues and believes it is entitled to. 

For its part, the Biden Administration in 2023 did propose a roadmap that would potentially allow the federal government to grant licenses to third-parties (such as generic and biosimilar manufacturers) for products which were developed (at least partially) using federal funds if the original patent holder does not make them available to the public on what are deemed "reasonable terms." The basic idea was that "reasonable terms" could potentially be interpreted as price for the first time ever even though the outline never mentioned price.

But in the case of the product withdrawal and discontinuation of Levemir (again, see my coverage of that announcement at https://blog.sstrumello.com/2023/11/novo-nordisk-to-discontinue-levemir-in.html and also https://blog.sstrumello.com/2024/01/the-business-case-for-biosimilar.html for more), that in the case of Levemir (insulin detemir), no one is even suggesting that the government exercise of Bayh-Dole "march-in" rights should be used to address price. Instead, patients are seeking continued availability for a still-efficacious insulin which the manufacturer announced that intends to stop making and selling. In my mind, discontinuing a product sounds like "reasonable terms" for the government to exercise "march-in" rights in order to ensure that the molecule (developed in part with U.S. taxpayer money) remains available to the patients who need it from biosimilar manufacturers instead of Novo Nordisk which announced it won't even make it after December 2024.

Novo Nordisk expects patients to simply switch to is newest, patent-protected basal insulin branded as Tresiba or alternatively to Sanofi's patent-expired Lantus or a growing number of biosimilars of that particular product (right now, copies are already made and sold by Biocon and Lilly, but in 2024, Sandoz, Amphastar Pharmaceuticals, Lannett Company, and CivicaScript have biosimilars pending FDA approval decisions on Lantus biosimilars (a third company known as Meitheal Pharmaceuticals has one expected a few years from now). 

Novo Nordisk has retired no fewer than six insulin varieties over my lifetime (actually more if one considers both porcine and bovine-sourced insulins sourced from pancreas glands derived as a byproduct of meat production). For example, the entire porcine and bovine Lente series consisting of Semilente, Lente and Ultralente [at the time, bovine Ultralente was considered the most effective long-acting basal insulin for most patients, while the shorter-acting porcine varieties tended to be favored for their effectiveness by many others; remember that porcine insulin is actually much closer in genetic structure to human insulin than are Novolog and Lantus, which introduce two amino acids which do not exist in insulin found in nature in order to have a desired impact on absorption, distribution, metabolism, and excretion, aka "ADME" properties], and then again when the company discontinued the newer Novolin biosynthetic "human' insulin variety of Semilente, Lente and Ultralente a few years later, and patients who used those products were left with no alternative than to use something else. 

At the time, Novo Nordisk intended for patients to switch to its $#!tty mid-range insulin variety known as insulin isophane/Neutral Protamine Haegdorn referred to by the acronym "NPH" but branded as Novolin N, but many patients switched to Sanofi's Lantus or an insulin pump using prandial only insulin programmed to be delivered in tiny amounts all the time as a basal rate. 

In other words, the patent and intellectual property rights for Levemir (insulin detemir injection) which Novo Nordisk views as its exclusive property could, under the Bayh-Dole "march-in" provisions be used to encourage other manufacturers to make insulin detemir instead. That is essentially what patient activists are seeking: to create an "open license" for any remaining patents on Levemir (most of the original Levemir patents expired in 2021) to ensure biosimilar manufacturers realize the potential and won't be sued for patent infringement by Novo Nordisk.

As I noted in my previous blog post entitled "The Business Case for a Biosimilar Company to Bring a Copy of Levemir to Market" https://blog.sstrumello.com/2024/01/the-business-case-for-biosimilar.html last month, PhRMA remains committed to ensure that Bayh-Dole "march-in" rights are never ever exercised under any circumstance. But for the reasons I've already acknowledged, there really is no substance behind the effort. It's just what the pharmaceutical industry feels entitled to: government welfare for the pharmaceutical industry.







No offense to PhRMA President Steve Ubl, but a) march-in rights have never been exercised in 44 years, and b) prior to Bayh-Dole, government research never sat on the shelf; the pharmaceutical industry routinely mined it for new drug ideas). However, it is not abuse when the government reclaims rights which it paid for in the first place when a company forfeits its rights by discontinuing a product.

A scrappy patient advocacy organization known as Alliance to Protect Insulin Choice (APIC) has been on a nonstop lobbying campaign in Washington, DC meeting with dozens of federal lawmakers. They have a Facebook group located at https://www.facebook.com/groups/3901021673560624 (which, if you're a patent upset over Novo Nordisk's latest product retirement might be a place to find like-minded people).








The real question is whether exercising Bayh-Dole "march-in" provisions in order to provide patients who use that insulin with an ongoing supply in the form of biosimilars is a reasonable use to use the rights enshrined in a 44 year-old law.

PhRMA claims the drug industry does NOT consider a product withdrawal to be a "reasonable" use for the government to exercise "march-in" rights under Bayh-Dole (and that no reason is ever considered "reasonable" use), and that the patents and intellectual property rights given to Novo Nordisk by U.S. taxpayers under Bayh-Dole should continue to belong to Novo Nordisk exclusively. But PhRMA also believes and argues that Bayh-Dole "march-in" provisions should never, ever be exercised. 

The thing is that the Secretary of the U.S. Department of Health and Human Services may not be given the luxury of siding with PhRMA. The reason is because anyone or any entity with a vested interest in the matter is permitted to petition the HHS Secretary, and by law, the HHS Secretary is legally obliged to both consider the petition itself, and render a decision on the petition. 

But will the federal government agree when patient activists file a petition with the Secretary of the U.S. Department of Health and Human Services which argues that ensuring continued availability for a drug might be a "reasonable" use to exercise those rights? We may soon find out!

Thursday, January 25, 2024

The Business Case for a Biosimilar Company to Bring a Copy of Levemir to Market

My readers may recall that in November 2023, I blogged that Novo Nordisk announced it plans to retire (stop making) its first "Lantus killer" known as Levemir (insulin detemir injection) in the U.S. in 2024 (catch my post at https://blog.sstrumello.com/2023/11/novo-nordisk-to-discontinue-levemir-in.html for more). At the time I learned of the announcement, I was on vacation in Amsterdam, so I just made a note of the development and blogged about it a few weeks later upon my return.

Like other patients my age, I have endured the company's previous insulin "retirements". Novo Nordisk's time-frame for withdrawing this particular insulin from the market is happening unacceptably fast. For example, the company said that Levemir FlexPens were expected to be unavailable by mid-January 2024 — a matter of weeks following the announcement. Exactly why anyone without a visual impairment needs an expensive insulin pen injection device (pens were devised for dosing prandial insulin on-the-run, not for daily-dosed basal insulin) for a basal insulin which only needs to be dosed once per day is unclear to me (I suspect the real reason manufacturers even sell insulin pens for basal insulins is because pharma aims to make insulin injections less threatening for insulin-naive Type 2 patients), but compared to Novo Nordisk's prior insulin retirements (for example, when it stopped making the entire Lente series consisting of Semilente, Lente and Ultralente) which were announced about three years before they actually stopped selling those products, they are pulling the plug on Levemir in less than a year.

Why the big rush?

The company cited "manufacturing constraints, reduced patient access and available alternatives" as the reasons it had decided to stop making and selling Levemir. In reality, there was only a shred of truth to any of the reasons the company cited (specifically, the one about manufacturing constraints, because Novo Nordisk really wants to deploy its internal manufacturing capacity to produce weight-loss GLP-1 inhibitor drugs for obesity without Type 2 diabetes which it can sell at a premium price instead of making insulin which has become commoditized where lowest prices wins sales). 

Nevertheless, we should all be upset that the arrogant Danish company is prioritizing profits in order to sell a product GLP-1 inhibitor product which is not even a WHO-designated "essential medicine" as insulin is in order to sell a drug for people without diabetes to lose unwanted pounds/kilograms. The only motive is profit. In reality, as a pharmaceutical company, Novo Nordisk could easily quadruple its manufacturing capacity instantly by using one or more contract manufacturers, so no pharmaceutical company has a capacity constraint to speak of.

The more plausible explanation for its haste to stop making Levemir is that a) Levemir lost all U.S. patent exclusivity in April 2021, and b) not coincidentally, in March 2023, Novo Nordisk also announced that it would cut the price of Levemir by about 65%, effective January 2024. Then, just weeks before the new Levemir price cuts were to take effect, the company just decided to stop making Levemir instead. That is shameful corporate behavior IMHO.


We do know that there are already laboratory companies based outside the United States already making biosimilars of Levemir right now. That means biosimilars of the product are a viable option.

For example, China's Hangzhou Jiuyuan Gene Engineering Co. Ltd. is already selling the Active Pharmaceutical Ingredient (API) in bulk for Levemir right now (see the link for the manufacturers' insulin detemir API at https://www.jiuyuangene.net/ap/recombinant-diabetes-api/insulin-detemir-diabetes-diabetes-bulk-cas-no.html for more). It happens to sell them in bigger-sized 3 mL vials (most insulin patients buy insulin sold in 1 mL vials). All it would take to sell a copy in the U.S. is for a company operating in the U.S. market to sign a supply agreement with Hangzhou Jiuyuan Gene Engineering and then conduct some small clinical trials for the FDA in order to prove that the insulin is bioequivalent to actual Novo Nordisk Levemir. No one is saying it would not cost anything. But the REAL REASON that Novo Nordisk is discontinuing Levemir so fast is it does not want any other company to make and sell patent-expired insulin detemir. By discontinuing it so fast, it intends to force patients to switch to another basal insulin instead, and with any luck, that would be Novo Nordisk's patent-protected basal insulin called Tresiba.

In my lifetime with autoimmune Type 1 diabetes, Novo Nordisk has habitually discontinued insulin products and effectively tried to force patients to "upgrade" to its newest, still patent-protected products. However, in those days, biosimilars were not a viable option. But I never did what Novo Nordisk wanted me as a patient to do. Instead, I just started using the same product made by a different maunfacturer (Eli Lilly & Company).  Tresiba (insulin degludec injection) was Novo Nordisk's second attempt to sell a "Lantus killer" since Levemir was never really as successful as Sanofi's Lantus was in the basal insulin space (that's because Novo Nordisk was more than five years late to market with Levemir).

Novo Nordisk also happens to be a notorious "patent troll" whereby the company takes out numerous U.S. patents (many not even backed by actual science, but for ideas the company has) for "intellectual property" and then uses its vast army of lawyers on-staff (and on retainer) to sue any other company over supposed patent infringements. In my view, if Novo Nordisk chooses to withdraw Levemir, then it should also forfeit the rights to any intellectual property associated with the product. It is incumbent on our lawmakers to ensure any company that aims to bring a biosimilar of the product to market will not be sued by Novo Nordisk for patent infringement.

U.S. taxpayers have the right already enshrined in law to ensure that happens. The 1980 Bayh–Dole Act (known officially as the Patent and Trademark Law Amendments Act of 1980) enables any company which receives the benefit of U.S. taxpayer dollars to help commercialize a pharmaceutical or biologic to market (and Novo Nordisk deducted certain business expenses from its U.S. tax liabilities when it brought Levemir to market, hence it did so), then the U.S. could theoretically use what are referred to under Bayh–Dole as "march-in rights" to the intellectual property associated with the drug or biologic which our tax dollars already helped pay for. 

Since the Bayh–Dole Act became law in 1980, however, the U.S. has never once used "march-in rights". But lawmakers including former House Speaker Nancy Pelosi and President Joe Biden have threatened to do so. That prospect of lawmakers using "march-in rights" scares the crap out of the pharmaceutical industry. 


Right now, the pharmaceutical industry trade group known as PhRMA is making ominous but unfounded threats about using "march-in rights". But it is not abuse; rather the law has always said that if pharma takes taxpayer dollars, the government reserves the right to reclaim patent exclusivity on those products. PhRMA's CEO Steve Ubl has been making repeated warnings on social media about "march-in rights" (on December 13, 2023, he Tweeted that using march-in rights would be a huge loss for innovation and for patients). Don't believe his hyperbolic threats; they are bull$#!t.

Insulin Detemir (Levemir) Is Viable for Biosimilars

Some believe that Levemir is too small and insignificant for any company to even bring a biosimilar of that product to market. The reason is because right now, only the three bestselling insulins have any pending biosimilars with the most being for Lantus copies.

But it's hardly the case that Levemir is too small or insignificant to warrant any biosimilar copies.

We know, for example, according to the diaTribe Foundation (via data derived from the company which started the diaTribe Foundation, a firm which makes it money by consulting on behalf of businesses operating [in or interested in] pursuing business in the diabetes space known as Close Concerns) that "Levemir generated $649 million in revenue in 2022" (see https://diatribe.org/levemir-long-acting-insulin-be-discontinued-novo-nordisk for diaTribe's coverage of the Levemir "retirement").



In terms of how many patients use Levemir, according to data derived from the U.S. Government's MEPS prescribed medicines database (see https://www.ahrq.gov/data/meps.html from the U.S. Agency for Healthcare Research and Quality for access), that as of 2021, Levemir ranked as the 117th bestselling drug in the United States (see a more conveniently-organized list of the 200 bestselling drugs in the U.S. at https://clincalc.com/DrugStats/ for data and search under "insulin detemir" to quickly find the Levemir data; the tool is used by professors to help pharmacy technicians to memorize the bestselling prescription drugs) with a total of 5,214,067 U.S. prescriptions for insulin detemir were filled in 2021, serving 1,027,442 individual patients as of 2021. Also, Levemir's sales rank among the bestselling drugs sold in the U.S. had increased 7 places compared to the preceding year (2020). 

So don't believe the bull$#!t about Levemir being a small, dying product. 

That is hyperbolic nonsense that Novo Nordisk is claiming in order to persuade everyone that its product withdrawal was perfectly legitimate (which it is not).

With that said, while I believe it's entirely feasible to bring a biosimilar of Levemir to market, doing so will likely require about 4 years which explains why Novo Nordisk hopes to stop selling it in a matter of months. Unless they use an insulin pump with prandial insulin-only programmed to deliver small amounts of prandial insulin regularly as their "basal" rate. Novo Nordisk is HOPING that patients who use Levemir will simply switch to Tresiba instead.

But one of the very reasons Novo Nordisk is discontinuing Levemir so fast could also help make to biosimilars of Levemir an even more attractive business opportunity.

This part is a little confusing for people who don't follow the intricacies of how pharmaceuticals are commercialized, so please bear with my explanation.

Pembroke Consulting and Drug Channels Institute President Adam J. Fein reported about insulin "For 2021, average rebates and discounts for insulin were about $5,400 per-patient annually, while net drug costs were less than $1,100." 

In other words, the dollars generated by legally-exempted rebate kickbacks paid by insulin-makers to PBMs in order to secure formulary placement exceeded the cost of insulin itself by a substantial margin. It was the PBMs who were to blame for runaway insulin prices. This has been validated by peer-reviewed academic research undertaken by the University of Southern California as well as a study undertaken by the U.S. Senate Finance Committee. 

It is hardly a secret anymore.

Big PBMs' Incoherent Strategies in Response to Lilly, Novo Nordisk and Sanofi Price Cuts

Adam Fein subsequently acknowledged that Lilly, followed by Novo Nordisk and Sanofi and their collective insulin price cut decisions which were announced in March 2023 will soon mean that health plans will no longer be able to subsidize premiums using money derived from insulin rebates, and he also acknowledges that PBMs also will no longer be able to earn fees based on insulin list prices. No one should (except maybe the insurance-company owned PBMs) be crying over their losses. Besides, as I've written about previously, they've already moved on to rebate aggregation on continuous glucose monitors (CGMs) instead anyway.

The March 2023 announcements of insulin list price cuts bankrolled by disintermediating the PBMs was the first positive direction we have seen on insulin prices in years. But even Adam Fein observes there's more at work (see https://www.drugchannels.net/2023/03/drug-channels-news-roundup-march-2023.html for more) before we see growth in biosimilars. 

Adam Fein opines that (see https://www.drugchannels.net/2024/01/the-big-three-pbms-2024-formulary.html for his observations) "The simultaneous list price reductions [on insulin] have limited (but not eliminated) PBMs' ability to block lower list price products. The cuts also popped the gross-to-net bubble for insulin, which gave PBMs little choice but to cover the lower priced products." But, he cited the three largest PBMs' divergent approaches to insulin market developments. 

One thing he acknowledges is the genuine impact of the American Rescue Plan Act of 2021 which capped Medicaid rebates at 100% of the Average Manufacturer Price (AMP). Adam Fein expanded on that slightly by saying: "Medicaid rebates are linked to the bogus list price, which has been inflated by the gross-to-net bubble. The 100% cap on Medicaid rebates ends next year [in 2024], which means that some companies with high-list/high-rebate products [such as insulin] may have to pay Medicaid to use their products, i.e., negative prices. Anti-pharma zealots complain that insulin manufacturers are somehow 'avoiding' Medicaid rebates. In reality, the manufacturers are rationally responding to Congressional incentives that encourage drugmakers to avoid having to pay the government for the use of their products."

OK. I also agree with his assessment that this was not really due to any grand strategic plan from lawmakers in Congress. It basically happened by accident, combined with a boatload of biosimilars pending FDA approval right now.

Shortly after Lilly, Novo Nordisk and Sanofi cut insulin prices by disintermediating the PBMs from the sale (hence it cost the manufacturers no money to slash their insulin prices), Adam Fein wrote (see https://www.drugchannels.net/2023/03/drug-channels-news-roundup-march-2023.html for his article) "The simultaneous list price reductions also limit PBMs' ability to block the lower list price products (as they did with Semglee, the interchangeable biosimilar of Lantus)."

But, he subsequently observed in January 2024 of diverging PBM strategies from United Healthcare's OptumRx, Cigna's Express Scripts and Aetna/CVS Health/Caremark (see https://www.drugchannels.net/2024/01/the-big-three-pbms-2024-formulary.html for details).

Below were his observations (with a few tiny edits on my part):

  • [United Healthcare's] OptumRx has placed all insulin products at parity the first formulary tier, which has the lowest out-of-pocket costs for patients. (Great move, IMHO.) All products on this tier have same copayment or the same coinsurance rate. However, a patient’s actual out-of-pocket costs will vary for benefit designs with coinsurance, because the list prices vary among the products.

    OptumRx's formulary includes both Lilly's Humalog product as well as the unbranded version. OptumRx placed the brand-name Lantus product and the Rezvoglar biosimilar on tier 1, while the Semglee biosimilar has been excluded from the formulary.

  • [Cigna's] Express Scripts' biggest formulary includes the brand-name Humalog along with the lower list price insulin lispro. Its formulary also includes the basal insulin Semglee, the high-list-price interchangeable biosimilar of Lantus, but excludes the identical unbranded, low-list-price unbranded insulin glargine-yfgn product as well as the Lilly Rezvoglar biosimilar. Express Scripts didn't reply to his request for a comment on its love of higher list prices.

  • CVS Caremark's [of which, the insurance company Aetna is also a part] formulary includes brand-name versions of Novolog, and excludes Humalog and Apridra. It includes Lantus and excludes the follow-on biologic Basaglar. However, it doesn’t mention Semglee, unbranded Semglee, or Rezvoglar.
His article acknowledge "Insulin exclusions vary among the PBMs. Biosimilar insulins still face challenges."

All of that suggests that big PBMs aren't really clear yet on how they intend to handle biosimilars and their strategies are, putting it kindly, incoherent. But since big insulin no longer pays multi-million dollar rebate kickbacks to PBMs, and so far, they do not appear to have figured out a coherent way of managing that. He seems to believe that United Healthcare's OptumRx is likely the most coherent strategy (he commented: "Great move IMHO"), but the reality is that until we have more than a dozen biosimilars on the market, and patients will be free to buy less costly insulins (including varieties which are not "preferred" by their insurance company's PBMs) with cash, we won't yet see what happens.

But, in 2024, we will have a bunch of Lantus, followed by nearly as many Novolog biosimilars, with a smaller number of Humalog biosimilars. If I had to guess, I'd say that we should expect Novo Nordisk to stop making Novolog soon, too, only there are already a number of biosimilars for that already pending approval decisions. One reason there are only a few Humalog biosimilars pending approval (three in total, although the third won't come for another 5 years, along with the Admelog biosimilar manufactured and sold by Sanofi) is because when Lilly learned that more than one-third of domestic Humalog sales was the unbranded, unrebated (to PBMs) version, it decided to cut prices on unbranded Humalog even further. Consequently, Lilly's Humalog prices are really cheap at $35/vial right now. Biosimilars aren't sure they can beat Lilly's prices (rest assured, they most certainly CAN, catch my post HERE which shows the cost for them to make a vial of insulin lispro in China is $8.68 per vial).

Which brings me to the business case for Levemir biosimilars.

The reality is that biosimilars of that product won't possibly have a chance to hit the market before Novo Nordisk stops making the product (which is why Novo Nordisk is discontinuing Levemir so quickly). That will force patients and doctors to find alternatives. But it won't guarantee that those patients will automatically switch to Tresiba, especially if they have a choice of a 8 or 9 glargine biosimilars to choose from at prices even lower than $35/vial. 

CVS, for example, has a business unit called Cordavis which will sell biosimilars (it will start with a Humira biosimilar), and presumably that could also include insulin biosimilars at CVS for low cash prices. We shall see on Cordavis; its Humira biosimilar will likely be more expensive than one sold by Mark Cuban Cost Plus Drug Company, so its unclear what will happen when there are lower-cost choices on insulins, but I'd bet we'll see many of them sold under the pharmacy's brand as private-label insulins.

But the prospect of a different basal insulin biosimilar of Levemir might be unique enough to be able a manufacturer to capture sales (and at a slightly better price) simply because it is different. Hence, the very market forces which Novo Nordisk was hoping will force patients use its Tresiba might actually HELP biosimilars of Levemir to differentiate themselves on the market.

Watch this space!

Thursday, January 11, 2024

Consider Bypassing Your Health Insurance to Afford Certain Type 1 Diabetes-Related Medicines and Supplies

Since it's January (a new year), and about half of all Americans with employer-sponsored healthcare insurance plans have some deductibles to satisfy before their healthcare insurance really kicks-in to cover much of anything, and also because deductibles reset on January 1, I thought perhaps this might be a good time to write a little about my own experience with high-deductible insurance plans and discoveries of some intelligent work-arounds, some of which I've used successfully myself. 

Who knows? You might (as I did) find you actually like using a particular brand or variety of insulin which is not "preferred" by your insurance's PBM, or maybe you find a competing CGM brand has some features which you like better. Or maybe you like saving money, or are forced to do so.

Read on for more!

It may seem counterintuitive (after all, health insurance is supposed to help pay for our medical care), but the data is clear: it is frequently wiser for many patients to bypass their own insurance to purchase medicines and medical devices used in the treatment of autoimmune Type 1 diabetes (especially true if you have deductibles to satisfy before your pharmacy benefits become effective; disregard the myth [and it IS a myth] that paying artificially-inflated prescription prices contributes meaningfully toward satisfying deductibles, because your insurance is only applying their deeply-discounted PBM-"negotiated" prescription prices towards your deductible, not the much higher price you'll actually pay at the pharmacy checkout counter). 

This post provides notes on insulin, glucagon, and Continuous Glucose Monitor (CGM) sensors. Note: Type 2 diabetes is a disease with a different etiology from Type 1 diabetes, and there are vastly more prescriptions approved to treat that particular disease (Type 1s have a choice between insulin or death), and that also means that many drugs used to treat Type 2 diabetes still remain protected by patents. I make no effort to address those here; that is beyond the scope of this post (but I welcome others to use this as a model for your own blog posts).

The Facts:

Peer-reviewed academic research data shows a few undeniable truths. 

The main reason Americans pay more for prescriptions is not because the greedy pharmaceutical industry prices their drugs vastly higher in the U.S. while selling them for a lot less in other countries (the reason is because their realized "net" prices after discounts are about the same in the U.S. as they are in Europe and elsewhere). University of Southern California (USC) researchers found that (see https://healthpolicy.usc.edu/article/more-than-half-of-insulin-expenditures-going-to-middlemen-new-usc-schaeffer-study-finds/ for more) between 2014-2018, Pharmacy Benefit Managers (PBMs) were taking home more than half — about 53% — of the net proceeds from the sale of insulin, a percentage which had increased from just 30% in 2014. Meanwhile, at the same time, the share going to insulin manufacturers had simultaneously fallen by one-third. In a different USC study (see more at https://mann.usc.edu/news/in-the-news-paying-cash-for-prescriptions-could-save-you-money-23-of-the-time-usc-analysis-shows/), researchers also found that U.S. pharmacy customers would be better off paying cash nearly a quarter (23%) of the time, most often on generic and biosimilar drugs (although not limited exclusively to those).

We now know the reason Americans pay more for prescriptions is because the massive cash discounts called "rebates" (which totalled more than a quarter of a trillion dollars in 2022, estimated at $236 billion at the time) which is being paid by drug, biotech and medical device companies to PBMs for formulary placement are instead being misdirected rather than for lowering patient prices. That is a complicated way of saying that intermediaries like PBMs (and to a slightly lesser extent drug wholesalers), are taking money which really should be going toward reducing the prices U.S. patients pay.

The PBM industry euphemistically calls those "misaligned incentives", but it really should be called theft. As of June 7, 2022, the U.S. Federal Trade Commission (FTC) was studying PBM "business practices" with a comprehensive 6(b) study (FTC Matter No. P221200), (see https://www.ftc.gov/news-events/news/press-releases/2022/06/ftc-launches-inquiry-prescription-drug-middlemen-industry for the bipartisan study announcement). Upon that FTC study's conclusion, it may result in litigation against the PBMs and their insurance company parents (Aetna/CVS Health/Caremark being a slight role-reversal). Until the FTC acts on PBMs, here are some practical tips to navigate the shark-filled waters of buying prescriptions for Type 1 diabetes in the U.S.

Drug, biotech companies and medical device manufacturers are aware that the rebate-contracting sales model promoted by the largest PBMs often means patients pay far more money than they should be for their products, but they felt powerless to abandon the PBM rebate-contracting model because of veiled threats they received from the big PBMs about "formulary exclusions" for all of their drugs (not limited to insulin). A good overview of what happened in the case of insulin can be read HERE.

But a number of manufacturers (including CGM-makers) now offer discount coupons enabling patients to buy their products (as long as patients are NOT submitting the same purchases as claims to commercial health insurance or government healthcare plans; check the fine-print for details). In the past, manufacturer discount coupons were limited in size, not available to all, were difficult to use, and some were only available for a limited time. As of 2024, for Type 1 diabetes prescriptions at least, manufacturer discount coupons are no longer limited-time offers (they are part of the manufacturers ongoing "marketing" expenses), available to most anyone and can substantially reduce the amount patients are charged.

The following contains a brief description of different manufacturer discount coupons along with links of where those coupons can be found. 

Dexcom Manufacturer Coupon:














Download a Dexcom manufacturer coupon to save $200 per 30-day supply of sensors (and an additional $200 on each 3-month transmitter on the G6 model). Manufacturer coupons work for both those insured with high-deductibles to satisfy as well as cash-payers. Generally, to evaluate whether a coupon saves you money, compute your daily cost of wearing a CGM sensor in order to determine if it might be less costly to use a manufacturer coupon rather than the pharmacy benefit of your insurance. While competing CGM sensor brands cost about the same, your cost must be evaluated by how many days you can actually wear each CGM sensor. Dexcom coupons can be used without insurance. However, some patients find that Dexcom's Automated Insulin Delivery (AID) partnerships with insulin pump manufacturers may still make Dexcom their preferred choice for them in spite of its slightly higher cost.

Abbott Freestyle Libre eSavings Voucher:


 






If you're commercially insured and asked to pay more than $75 for two Freestyle Libre 3 sensors, call Abbott customer care at 1-855-632-8658 (M-F from 8-8 ET) to ask for an eSavings voucher to be emailed to you. Abbott eSavings vouchers expire at the end of each calendar year, but they can be renewed by telephone at the beginning of each new year. Note that some Libre CGM models feature 14-day wear-time. Generally, less frequent sensor changes save patients money unless your insurance assumes some portion of the cost, but do the math to find out. To do so, take your monthly CGM cost and divide that amount by the number of sensors in each refill (generally, 3 for Dexcom or 2 for Libre). Then, divide that figure by the number of days each sensor can be worn. My Aetna/CVS Caremark plan covers 37% of the cost of Dexcom sensors pre-deductible, yet I still found the Libre 3 model to be less costly with the Abbott eSavings voucher due to the longer wear-time of the sensors if I if I buy them at Costco Pharmacy. Abbott Freestyle Libre coupons can be used without insurance. Although Libre 3 currently has no pump partnerships in the U.S. (it has some in Europe), the Libre system nevertheless has several advantages over Dexcom G6/G7 including its lower cost due to its longer wear-time, as well as updating new readings every minute compared to Dexcom reading updates every 5 minutes. That translates into 1440 new CGM readings each day with Libre 3 compared to only 288 new CGM readings with Dexcom.
Lilly Insulin Value Program:


     















Lilly insulins are available for $35/month regardless of whether a patient has commercial insurance or no insurance. Lilly's unbranded insulin (Lilly Insulin Lispro Injection 100 U/mL) tends to be the least-costly option for cash-payers (including insured patients with deductibles to satisfy before pharmacy coverage kicks in) instead of branded Humalog (even though it is the exact same insulin) when a manufacturer coupon is submitted to the pharmacy with the patient payment by bypassing their healthcare insurance, hence Lilly Insulin Value Program coupons may be used without insurance.

Sanofi ValYou Insulins Savings Program:


       


My readers may recall that in 2022, Sanofi very quietly introduced an unbranded version of Lantus via the company's Winthrop US business unit over two years after rivals Lilly and Novo Nordisk did the same (I blogged about it HERE), and I suspect the reason was because Lantus was dumped from Express Scripts' formularies in favor of the interchangeable biosimilar known as Biocon's Semglee in 2022. Regardless, the Sanofi Insulins ValYou savings program is not insurance and is not valid for prescriptions covered by or submitted for reimbursement, in whole or in part, under commercial/private insurance, Medicare, Medicaid, VA, DOD, TRICARE, similar federal or state programs, including any state pharmaceutical programs. Eligible cash-paying patients will pay $35 per 30-day supply with a ValYou savings coupon presented to a pharmacy when filling your prescriptions. To pay $35 per 30-day supply, patients must fill all Sanofi insulin prescriptions at the same time, together each month and using the ValYou savings coupon at the time of payment. The Sanofi Insulins ValYou savings program applies to the cost of medication. Sanofi reserves the right to rescind, revoke, terminate, or amend this offer, eligibility, and terms of use at any time without notice. Sanofi Insulins ValYou savings coupons may be used without insurance.
NovoCare Manufacturer Discount Coupons:






       












Novo Nordisk offers unbranded biologics (also sometimes referred to as "authorized biologics" or "authorized generics") which are identical to the branded NDC's of insulins made by the same organization, but are sold under the generic drug names as Novo Nordisk-branded analogue insulins which are sold at a significantly reduced list price in the U.S. from Novo Nordisk Pharma, Inc. (NNPI) unit, which is a Novo Nordisk A/S company. The company copied exactly what Lilly did recognizing it was a good idea given its own contribution to the PBM rebate-driven affordability problem it was perpetuating. Insulin Degludec Injection 100 U/mL, 200 U/mL, and Insulin Aspart Injection 100 U/mL are among the versions of branded insulins sold as unbranded products designed to bypass list price inflation caused by the rebate-contracting model of the large Pharmacy Benefit Managers in the U.S. With availability of unbranded biologic versions of its insulin analogues, Novo Nordisk is providing this affordability option as part of its broader community commitment. NovoCare coupons may be used without insurance.

Xeris Gvoke Hypopen Manufacturer Coupon:



 








Eligible commercially insured patients may pay as little as $25 with a manufacturer copay card. Note: the Gvoke manufacturer copay card does NOT currently apply to cash-payers, it must be used WITH health insurance (hence, they call it a "copay card" not a coupon).
Zealand Pharma (via Novo Nordisk) Zegalogue Savings Offer:










If you have commercial insurance, such as insurance you receive through an employer, depending on your insurance coverage and out-of-pocket responsibility, you may pay $35 or $99 for each one-pack prescription for up to 48 months from date of Savings Offer activation. Call 1-833-992-3299 to request a Zegalogue Savings Offer from NovoCare. NovoCare coupons may be used without insurance.

Wednesday, December 13, 2023

Abbott Gets Real About "Formulary Exclusions" Bankrolled by Rival Dexcom in the U.S.

My followers may recall that I've written not-so-kind blog posts about how Dexcom is paying legally-exempted rebate kickbacks (see https://blog.sstrumello.com/2023/06/dexcom-pays-pbms-kickbacks-to-exclude.html for one such blog post) to major Pharmacy Benefit Managers (PBMs) contingent upon "formulary exclusions" of less costly rival continuous glucose monitoring (CGM) systems such as Abbott Freestyle Libre. 






The retail prices for both CGM sensor brands are remarkably close (ranging from $57.33/sensor to $61.28/sensor). However, the cost computation is not based on the cost per sensor, but must be computed on a cost per day of each sensor being worn. Abbott Libre 3 sensors can be worn for 14 days, whereas Dexcom sensors can be worn for only 10 days. (More frequent sensor replacement costs patients more money unless their insurance picks up some portion of the cost; some such as my plan now pick up about 40% of the cost to keep the rebate cash flowing to Caremark). Anyway, using the per sensor CGM costs derived from Costco's Member Prescription Program https://www.costco.com/cmpp this summer, then I computed a cost per day of wearing CGM sensors (if you are paying cash) which is as follows:

  • Dexcom G6 Sensors $6.13 per day of usage
  • Dexcom G7 Sensors $5.73 per day of usage
  • Abbott Freestyle Libre 3 Sensors $4.23 per day of usage

Now, as noted, earlier in 2023, my own insurance company (Aetna) PBM Caremark started covering about 40% of the cost of my CGM purchases pre-deductible which they did not do the previous year, which means my cost per day is $3.88. I recall thinking: "OK, that's even better for me!" and I did not think anything of it at the time. But then it occurred to me: they want to keep the rebate kickbacks flowing to them, and they know that if patients now have other options, they would do the math (as I did) and might choose the (35.5%) less costly rival CGM but they'd get zero rebates in that case. As I told the FTC in my letter to them, the CVS Health/Aetna/Caremark decision to cover part of the cost of the CGM sensors was executed with near-surgical precision.

Specifically, Dexcom is paying what are effectively bribes (kickbacks) to Aetna/CVS Caremark and United Healthcare's OptumRx to keep less costly CGMs "off-formulary". I documented Caremark's published list of formulary exclusions at https://www.caremark.com/portal/asset/Formulary_Exclusion_Drug_List.pdf -- see page 9 of 21 for the language of exclusion, as well as to United Healthcare/OptumRx (see that company's "standard" formulary exclusion list at https://professionals.optumrx.com/content/dam/optum3/professional-optumrx/resources/pdfs/Premium_Standard_Abridged_PDF_13188_v98_09072022.pdf and its "premium" formulary exclusion list at https://hr.nd.edu/assets/491518/jan_2023_b2b_cycle_premium_formulary_exclusion_list.pdf for the nitty-gritty details).

We know with absolute certainty these kickbacks are happening. 

For its part, Dexcom is aware that its migration to the pharmacy (as opposed to the DME or Durable Medical Equipment) distribution channel causes its product prices to be artificially inflated. As a result, Dexcom now offers manufacturer discount coupons which are conveniently distributed via GoodRx and on the manufacturer's own website enabling patients to "Save $200 per 30-day supply of sensors and an additional $200 on each 3-month transmitter" which are available at https://www.dexcom.com/en-us/savings-center-cgm-without-insurance/. As  far as I can tell, these coupons also have no expiration dates, they are part of Dexcom's ongoing marketing expenses - they are not "limited-time" offers.

My readers may recall that I had the luxury of "test driving" the new Abbott Freestyle Libre 3 CGM for six weeks. I extended that for another 2 weeks with a sample which Abbott gives to anyone. I wrote about my "test drive" at https://blog.sstrumello.com/2022/12/my-trial-of-new-abbott-freestyle-libre-3.html. However, while Dexcom dominates what Automated Insulin Delivery (AID) systems are on the market currently, its newest product (the G7 model) is not universally loved; in fact, it gets very mixed reviews such as people loving the half-hour warm-up time, but really disliking other aspects of the new Dexcom, such as repeated signal losses several times a day and not-at-all-accurate first day numbers (see https://diabetesstories.com/2023/07/21/im-sorry-to-say-im-not-loving-dexcoms-g7/ for one such review).

However, because I'm not on Medicare as my friend Riva Greenberg is, and also because Dexcom pays my insurance PBM Caremark kickbacks to prevent me from having access to non-Dexcom CGMs, I was unaware of any program offered by Abbott for Freestyle Libre until I read an interview with Abbott Diabetes Care CMO Mahmood Kazemi in MedTechDive (see the article at https://www.medtechdive.com/news/abbott-diabetes-mahmood-kazemi-cgm-access/700015/ for the article) and in that interview, the following Q&A came up:

Q: What about cash-pay programs? 

A: We do have a program for the U.S. where if someone is not able to get coverage for that through their commercial insurance, or if they just have no insurance at all, and they need to pay cash, no one has to pay more than $75 per month for their two sensors (note that the Costco Pharmacy price for a box of 2 Libre 3 sensors was $118.51).

The latter part of the Abbott coupon on Libre was news to me, and I consider myself pretty well-informed on these matters. If I wasn't aware of it, I likely would have completely missed the following language on Abbott's web page for Freestyle Libre (see https://www.freestyle.abbott/us-en/private-insurance.html for more) under the tab for "Cost & Coverage", it says:

Under the section entitled "How much will it cost?", Abbott says "If you are commercially insured and asked to pay over $75 for two sensors, please contact our customer care team to get an eSavings voucher and start saving immediately on your sensors. You may also contact our customer care team if you have any additional cost and coverage questions."

Abbott's Customer Care Team can be reached by telephone at 1-855-632-8658 (Available Monday to Friday from 8AM - 8PM ET). You must call, provide them with some basic information, and ask them for the eSavings voucher so you can get two Libre sensors for no more than $75. That applies to anyone with or without insurance.

So, I called Abbott customer care team and asked them to send me an eSavings voucher. Voila: about 24 hours later and I had a coupon to buy Libre sensors for $37.50 each compared to $61.28 for Dexcom G6. The cost per day of wearing a Libre 3 sensor with the new, manufacturer coupon is $2.68 (compared to $3.88 if I used my insurance pre-deductible)! As for "upgrading" to G7; on that, I plan to wait until Dexcom stops selling the G6. But with a coupon from Abbott for Libre 3, I am no longer forced to use Dexcom. 



















It's nice to have options, and not be FORCED by a rebate-collecting PBM based on whomever pays them the most in rebate kickbacks. With Abbott's eSavings voucher for Freestyle Libre, that could be an option which did not exist before the Abbott manufacturer coupon emerged.

Author P.S., December 19, 2023: Abbott has informed me that its eSavings vouchers expire at the end of each calendar year. They informed me patients will therefore need to call the toll-free telephone number and request a new voucher in January for a new coupon which expires a year later. Just beware on the timing and expiration date of the eSavings voucher you may receive.

Wednesday, November 29, 2023

Novo Nordisk to Discontinue Levemir in 2024

Upgrade to Patent-Protected Tresiba — or else!

On Wednesday, November 8, 2023, Novo Nordisk announced that it would discontinue its long-acting insulin Levemir (insulin detemir injection) in the United States, citing manufacturing constraints, reduced patient access and available alternatives. The company's official statement (see https://www.novomedlink.com/diabetes/products/treatments/levemir.html) said: 


"We will continue to provide Levemir FlexPen and Levemir vials to wholesalers while supplies last, up to the discontinuation dates, but supply disruptions should be expected."

It added further: "Levemir FlexPen, the injection pen version of insulin detemir, will likely face supply disruption starting in mid-January 2024, lasting up until the FlexPen's discontinuation on April 1. Levemir in vial form will no longer be available after Dec. 31, 2024." 

The company also warned of imminent supply chain issues. 

"Discontinuing Levemir was the result of thoughtful deliberation", according to the statement. 

That line of bullshit I've heard previously from Novo Nordisk.

What it "deliberated" was to ask whether can it deploy an old tactic of forced upgrades following discontinuation of a product? The answer to that may not be yes as of 2023. I recall when Novo Nordisk originally discontinued Novolin L(ente). The good news for me was that at the time, Lilly still made that product for about a year or two after Novo pulled the plug on it, so I just switched without issue until Lilly stopped making it. As of 2023, Lilly doesn't even have a proprietary basal insulin of its own, only a biosimilar of Lantus (Rezvoglar, known generically as insulin glargine-aglr) and a follow-on version of Lantus (branded Basaglar, which was approved when Lantus was still governed as a drug rather than a biologic, hence it was approved under a different FDA approval process).

For its part, Novo Nordisk introduced a newer, still patent-protected basal insulin branded as Tresiba (insulin degludec injection) in 2015 which has been its primary marketing focus on basal insulins, especially since Levemir lost all U.S. patent exclusivity in April 2021. Tresiba and the unbranded version have been in short supply for some time. Payers, on the other hand, were not willing to pay a premium price for Tresiba or even the unbranded version of it. Right now there are already several biosimilars of Sanofi's Lantus on the market, and at least five more are anticipated to be considered by FDA in 2024 and another from Meitheal Pharmaceuticals (assuming its biosimilar is FDA approved) a few years after. Once again, while Tresiba may be superior (it was only Novo Nordisk's second attempt at a "Lantus killer") as a basal insulin (flatter curve of action, longer-lasting in the bloodstream), but when rebates on insulin go away starting in 2024, the market dynamic could change for Novo Nordisk's newest Lantus killer.


The decision to pull the plug on Levemir was unexpected. Earlier this year, in March 2023, Novo Nordisk announced that effective beginning January 1, 2024, Levemir would be listed at $107.85 per vial (or $161.77 per FlexPen) which was 65% lower than that product had been priced at previously. However, recall that in September 2022, Novo Nordisk introduced two "unbranded" versions of Tresiba (U-100 and U-300 for the severely insulin-resistant Type 2 diabetes patient market, which I covered HERE) designed to bypass PBM list price inflation caused by ever-higher legally-exempted rebate kickbacks demanded by PBMs to secure formulary placement. 

When Lilly slashed its insulin list prices in March 2023, Novo Nordisk and Sanofi followed suit almost immediately (both were pretty much forced to do so; although they had likely been considering doing so anyway), and to pay for those cuts, they would simply disintermediate the Pharmacy Benefit Managers (PBMs) and voila: it costs the manufacturers almost NO money, and patients win.

Nevertheless, the discontinuation of older, patent-expired insulins is hardly a new development for Novo Nordisk (or Lilly, for that matter). The company has routinely operated from a mindset of forcing patients and their doctors to "upgrade" them to newer, more-expensive and still-patent protected insulin varieties because they were given no choice. 

But those all happened prior to the advent of biosimilar insulins.

Biosimilars opens the prospect that the innovator company may stop making a product, but copycat biosimilars could theoretically emerge selling a version of the same product made by a different company available. So far, that has not happened, but it remains a possibility on a patent-expired basal insulin such as Levemir.

diaTribe news reported (see https://diatribe.org/levemir-long-acting-insulin-be-discontinued-novo-nordisk): 

"Levemir represents a sizable portion of the basal insulin market (it generated $649 million in revenue in 2022 alone)." With Levemir being taken off the market, theoretically the advent of FDA-approved biosimilar insulins which means that potentially, a biosimilar company could potentially step in to manufacture Levemir and then sell it, although perhaps not timely-enough to be available when Novo Nordisk's branded Levemir is no longer available on the U.S. market. Theoretically, however, one could emerge which is an interesting possibility.

In spite of their vastly lower prices, biosimilars have been very slow to take-off in the United States. As I have written in the past, in the U.S., costly but heavily-rebated products are much more likely to secure formulary placement. The artificially-inflated list prices are driven by legally-exempted rebate kickbacks paid to PBMs to secure formulary placement. But in 2022, the Federal Trade Commission (FTC) unanimously announced it would undertake a comprehensive 6(b) study of PBM business practices. The prospect of that, combined with the passage of the American Rescue Plan Act of 2021 which capped Medicaid rebates at 100% of the Average Manufacturer Price (AMP), may force biopharmaceutical companies to take further action to reduce prices. Companies with biopharmaceuticals with high list prices and significant rebates (e.g., older branded medicines such as insulin) may have been forced to pay Medicaid to cover those drugs. Let that sink in; companies would have to pay Medicaid instead of getting paid by Medicaid for having their medicine on the list of covered medications. The only remedy for such companies is to lower their prices drastically to avoid negative pricing consequences.

Anyway, no doubt Novo Nordisk in 2024 hopes to replicate its previous "upgrade because we're not making the older product you once relied upon anymore" has a number of unknowns this time around. 

For one thing, there is nothing stopping a biosimilar manufacturer stepping in to sell biosimilar versions of Levemir. Or, Lilly and/or Sanofi could potentially make ones, too. Either are now possibilities which simply did not exist until 2019.

Personally, I like the idea of biosimilars, although I'm not certain we'll see any for Levemir, although it remains a theoretical possibility. Also a possibility is that a big insulin-maker with a miniscule share of the basal insulin market such as Lilly might decide to make it (after all, $649 million in revenue in 2022 would be there for the taking if it could move quickly enough).  Levemir is viewed as an older, dying product and every one of the biosimilar companies to my knowledge plan on launching Lantus biosimilars in 2024, combined with Sanofi's branded and unbranded versions as well as 6 or 7 biosimilars does not make Novo Nordisk's Tresiba a guaranteed success story (why there are market shortages is a different question; as I understand it, Novo Nordisk does not manufacture that product in the U.S., rather it imports it from Denmark). Much depends on timing. The short notice Novo Nordisk is giving aim to make the prospect of copies more difficult.

Sunday, October 15, 2023

Your Insulin of the Future Could Be "Made in China" if Big PBMs Have a Say in the Matter

Back on June 16, 2022, I published an article on LinkedIn entitled "How the Civica Insulin Announcement May Be Disruptive to the PBM Kickback Scheme" (see the article at https://www.linkedin.com/pulse/how-civica-insulin-announcement-may-disruptive-pbm-scheme-strumello/ if you wish to read it) which predicted that a growing number of insulin biosimilars whose active pharmaceutical ingredients (API's) are cultured in offshore laboratories are forecast to hit the U.S. market in the next few years. According to the FDA and the individual companies whom I also follow on LinkedIn, the U.S. Food and Drug Administration (FDA) typically reviews their various insulin biosimilars Biologics License Applications (BLA's) about 11 months from the date the BLA's are filed, which means we are likely to start seeing the first of them hitting the market sometime in early 2024. 

However, the thesis of my article was that of the five companies (Biocon, Sandoz, Lannett, Amphastar and Civica) now anticipating FDA decisions on insulin biosimilars in the next year or two, only ONE of them was likely to have a truly "disruptive" impact on patients' insulin prices. Because of the very broken U.S. insulin market whereby PBMs are behind-the-scenes, manipulating prices to their own financial benefit while patients and employers alike pay ever-more and insulin manufacturers realized net prices have continued to decline, it really took the presence of a nonprofit drug company to fundamentally shake insulin prices up.

On September 21, 2023, a sixth company known as Meitheal Pharmaceuticals, Inc. announced (see https://blog.sstrumello.com/2023/09/another-three-biosimilar-insulins.html for the news) that it would also pursue bringing biosimilars of insulin glargine, insulin aspart, and insulin lispro to the U.S. market with clinical trials expected to happen starting in 2024. As I covered in my recent post on Meitheal's insulin biosimilars, those will be cultured in a Chinese laboratory owned/operated by Tonghua Dongbao Pharmaceutical Co., Ltd. However, Meitheal's insulin biosimilars will be about six years behind those of many of its rivals (including Biocon, Sandoz, Lannett, Amphastar and Civica) The others are a mixed bag.

Recall that Civica, Inc. is a non-profit generic drug company established in 2018 by some leading U.S. health systems and three philanthropies to respond to acute and chronic shortages of essential medicines used primarily in hospitals and associated price hikes. In 2020, Civica established a business unit known as CivicaScript incorporated as public benefit corporation (PBC) to bring affordable versions of common but high-priced generic medicines to market. 

Until the March 3, 2022 Civica insulin announcement https://www.businesswire.com/news/home/20220303005321/en/Civica-to-Manufacture-and-Distribute-Affordable-Insulin/, many people failed to realize that insulin manufacturer's realized "net" prices had continued to fall (according to University of Southern California research, see https://jamanetwork.com/journals/jama-health-forum/fullarticle/2785932 for more), and yet patient out-of-pocket prices were concurrently rising steadily-upward to unaffordable levels. That is a sign of a market which is being manipulated by PBM middlemen known as Pharmacy Benefit Managers (PBMs), whereby the six largest among them are now being investigated by the Federal Trade Commission (FTC) https://www.ftc.gov/news-events/news/press-releases/2022/06/ftc-launches-inquiry-prescription-drug-middlemen-industry in a comprehensive 6(b) study. FTC is the only government agency with the ability to legally subpoena data without having a specific law-enforcement intent.

In fact, the very first insulin biosimilar made by a company other than Lilly, Sanofi or Novo Nordisk was originally brought to the U.S. market by Viatris, which had a joint-venture with India-based Biocon Biologics Ltd. Viatris had attained FDA approval for two identical copies of the branded reference product known as Sanofi Lantus on July 28, 2021. It had also attained FDA's "interchangeable" designation for those products, meaning it was approved so the products could be substituted for branded Lantus at the pharmacy counter, without the pharmacist needing to first get permission from a prescribing doctor. 

However, more recently, FDA has published a new Draft Guidance document entitled "Labeling for Biosimilar and Interchangeable Biosimilar Products, Guidance for Industry" https://www.fda.gov/regulatory-information/search-fda-guidance-documents/labeling-biosimilar-and-interchangeable-biosimilar-products/ in which "interchangeable" biosimilar products would not be allowed to disclose or explain their interchangeability designations on their products' labels. In effect, the revised guidance reversed FDA's previous stance on disclosing interchangeability in a product's labeling, even though pharmacists would still be enabled to switch the products with the brand-name reference products without permission from the prescribing doctors.

Since Semglee was approved by the FDA, Viatris has exited the U.S. insulin biosimilars space. On February 28, 2023, its partner Biocon Biologics formally acquired Viatris' half of their joint venture biosimilars assets in an acquisition which was structured as part-cash, part-equity. Viatris received an up-front payment of $2.3 billion, and compulsorily convertible preference shares in Biocon Biologics, which were valued at $1 billion. Viatris agreed to provide commercialization and certain other transition services for an expected two-year period following the closure of the deal intended to ensure business continuity for patients, customers and colleagues.

Biocon had a Biologics License Application (BLA) of Novolog (insulin aspart) pending, but on Jan 7, 2022, the FDA denied the aspart biosimilar. A second denial was procedurally-based, rather than based on scientific matters. The FDA's second Complete Response Letter (CRL) for its denial on its insulin aspart biosimilar product was received in February 2023. The company said that the CRL did not identify any outstanding scientific issues with the product, but it did cite deficiencies at its insulin manufacturing facility in Johor, Malaysia initially observed in August 2022. The company has since told investors the company will respond to the CRL to satisfy the FDA's requests (see https://www.business-standard.com/article/current-affairs/usfda-rejects-biocon-viatris-application-for-insulin-aspart-122010701442_1.html for more). I am not currently aware that Biocon has any biosimilars of Humalog, Apidra or Levemir in development even though patents have expired on all of those insulin analogues (although Biocon could potentially have biosimilars in development for one or more of them).

At the time their Lantus copy was introduced, Viatris/Biocon was forced to launch two identical versions of its insulin glargine-yfgn product including both a branded high-priced/high-rebate version known as Semglee whose target market was PBMs with their rebate-contracting model, and a second unbranded (sold under the generic drug name) lower-priced version of the biosimilar which had a Wholesale Acquisition Cost (WAC) list price which was 65% lower than that of the branded reference product (Sanofi's Lantus). 

In other words, a vial of the high-price/high-rebate version of branded Viatris/Biocon Semglee (insulin glargine-yfgn) had a Wholesale Acquisition Cost (WAC) list price $295.11, while an identical unbranded version called Viatris Insulin Glargine Injection (insulin glargine-yfgn) had a Wholesale Acquisition Cost (WAC) list price of $98.65. The decision to sell both a branded, high-price/high-rebate product and an identical lower-price/low-rebate version was documented by Pembroke Consulting's President Adam J. Fein in his "Drug Channels" blog found at https://www.drugchannels.net/2021/11/why-pbms-and-payers-are-embracing.html which is worth a read.

As I suggested in my LinkedIn article, of the different biosimilar insulins planning to enter the U.S. market, so far, Civica, Inc.'s CivicaScript PBC operating unit will come from GeneSys Biologics, Ltd. which is located in Hyderabad, India. As noted, Biocon Biologics insulin laboratories are located in Johor, Malaysia, and is similar to labs based in India, in that FDA inspectors are free to inspect those facilities on-demand anytime FDA deems appropriate.

By comparison, my assessment is that Chinese laboratories remain somewhat more problematic insofar as FDA inspectors are not free to inspect those laboratories anytime on-demand; inspections in China must be arranged through the Chinese government in advance, which means the Chinese labs could theoretically try to clean-up known noncompliance with Good Manufacturing Protocols (GMP) standards before the FDA inspectors arrive to make it appear as if the laboratory had been compliant all along. However, U.S.-based partners retain free access to Chinese labs anytime in accordance with Chinese contract law. By comparison, India-based and Malaysia-based laboratories can be inspected freely by the U.S. Food and Drug Administration inspectors anytime without advance notice. That risk to the manufacturer of a random FDA inspection makes insulins procured from those sources safer than those procured from Chinese laboratories.

Aside from not knowing what happens behind-the-scenes in Chinese biotech laboratories, another critical reality of having even just a single entity like Civica looking out for the best interests of patients rather than pharma and drug distribution system entities has already had a very disruptive impact on the U.S. insulin market. Consider this:

PBMs' contracts with retail pharmacies do not permit the pharmacies to set cash prices at any amount that would be lower than any PBM would ever reimburse them for the same drugs, and patients with deductibles to satisfy may be charged for insulin at the artificially-inflated cash prices set by those pharmacies, rather than the deeply-discounted prices their insurance companies' PBMs pay for the same drugs. PBMs have been emboldened by the pharmaceutical industry's unhealthy co-dependency on their rebate-contracting commercialization model for most drugs deployed by their insurance company's PBMs (including a number of heavily-rebated drugs like insulin whose patents have already expired). Simply stated, pharma marketers didn't know nor did they wish to explore any other way to sell drugs than by rebating them to PBMs. That's also why disruptors like Mark Cuban Cost Plus Drug Company have been fairly successful in disrupting that kickback scheme.

However, the nonprofit entity I cited in the article was the unique CivicaScript model, which is driven by what the company calls its Unilateral Pricing Policy ("UPP") which sets a Maximum Retail Price (MaxRP) for all CivicaScript products which are printed on the packages of all medicines sold which are clearly visible to patients (see https://civicascript.com/upp/ for more). Pharmacy violations or refusal to participate in CivicaScript's UPP could result in loss of a retailer's ability to purchase CivicaScript products, many of which are vastly cheaper in price than comparable products purchased from drug wholesalers.

On March 3, 2022, Civica, Inc. announced plans to develop biosimilar versions of the three bestselling insulin analogues on the U.S. market: glargine, aspart and lispro. Civica also intends to set a maximum recommended price to the patient of no more than $30 per vial of insulin, and no more than $55 for a box of five prefilled insulin pens (we know those will be the Ypsomed UnoPen device, see https://www.businesswire.com/news/home/20230131005294/en/ for the Ypsomed UnoPen licensing announcement; at least one other biosimilar-maker [specifically Lannett Company, Inc.] has also licensed the Ypsomed UnoPen thus far). I anticipate others may choose Ypsomed's ready-to-use insulin pens as well.

Thanks to disclosures from China-based Gan & Lee (which will manufacture biosimilars of glargine, aspart and lispro for Sandoz) data revealed in the company's 2022 Annual Report (see page 62 of 375 of the report at https://www.ganlee.com/uploads/files/2023/0428/ILHLDWv4RJ5kJaR1AVfVZOMa8FgQrC13lKU6VnGH.pdf for more detail), we know that underlying costs of goods sold for lispro and aspart is less than $8.70 per vial (prices were disclosed in Chinese Yuan). The Civica insulin products will be cultured in Hyderabad, India-based GeneSys Biologics, while Biocon's lab is in Malaysia but all the others are based in China. But we know that unless CivicaScript had not announced its biosimilar insulin plan, the biosimilar industry would likely have instead followed the very dysfunctional path that Biocon Biologics had already pursued, which was to rely primarily on the rebate-contracting model promoted by the largest Pharmacy Benefit Managers (PBMs). That would have otherwise guaranteed that all of the benefit of offshore manufacturing of biosimilar insulins would have gone to insurance company-affiliated PBMs rather than to patients.

Consider this uncomfortable reality: 

On October 20, 2021, Viatris kind of boasted that branded Semglee would become the "preferred" basal insulin (see the press release at https://www.prnewswire.com/news-releases/viatris-first-ever-interchangeable-insulin-biosimilar-preferred-on-express-scripts-largest-formulary-301404843.html for details) on Express Scripts formularies for 2022, and that the branded Semglee product would be on Express Scripts' National Preferred Formulary (NPF). The NPF is Express Scripts' largest commercial formulary, with more than 28 million [covered] lives. Express Scripts also highlighted the exclusion of the Lantus reference product from its NPF. In fact, the unbranded product would be relegated to Express Scripts' National Preferred Flex Formulary, which favors drugs with lower list prices over the high-list/high-rebate versions of these products. The reason PBMs offer multiple formularies is to satisfy demands from some big employer plan sponsor clients. For example, some employer healthcare plan sponsors won't select a PBM formulary that gives preference to expensive but heavily-rebated branded high-price drugs, and instead they demand preference for lower-cost generics. But many smaller, less sophisticated employer plan sponsors buy into the bogus notion that the biggest PBM formularies offering the lowest "net" drug prices will somehow save them money when they receive no proof or evidence validating that presumption. As Adam Fein said it: "Put another way: Viatris had to nearly triple the list price of [branded] Semglee before Express Scripts would add the product to its formulary."

While the PBMs have correctly been identified by members of both political parties in Congress as a major problem thanks to their ability (enabled by lawmakers in Congress and Presidential cabinet members who run the Office of Inspector General of the U.S. Department of Health and Human Services who created the widely-abused "safe harbor" exemption to the Federal Antikickback Statute) to collect legally-exempted kickbacks from drug companies which are paid to PBMs to secure a preferred place on commercial healthcare insurance company formularies. 

The PBMs are a very bad element in an industry full of ethically-challenged entities, the reality is that the entity guiltiest of perpetuating the kickback scheme are the insurance companies themselves (CVS Health is a bit of a role-reversal, in that the parent of Caremark in 2017 also acquired the commercial healthcare insurance company Aetna). United Healthcare (parent of PBM OptumRx), CVS Health (parent of (PBM Caremark and insurer Aetna), and Cigna (parent of PBM Express Scripts) have all come to rely on their PBM revenues far more than they rely on insurance premiums anymore. In other words, it is the kickbacks PBMs collect that earns more than any other part of the insurance business. But those corrupt business practices are now under the microscope of the Federal Trade Commission. When the FTC's 6(b) study of PBM business practices wraps-up, we could soon see huge litigation similar to the lawsuit which broke the old telephone monopoly known as the Bell System back in 1982.

Health insurance whistle-blower Wendell Potter has extensively documented (see https://wendellpotter.substack.com/p/big-insurance-2022-revenues-reached for one such article) and has written quarter-after-quarter how United Healthcare, Cigna and Aetna/CVS Caremark have all seen explosive growth in the companies' pharmacy benefit management (PBM) businesses.  The big insurers are now getting far more of their revenues from the pharmaceutical supply chain and from taxpayers via their privately owned and operated Medicare replacement plans they market as Medicare Advantage than they do from traditional insurance premiums. Collectively, their PBM profits increased 438%, from $6.3 billion in 2012 to $27.6 billion in 2022. Cigna now gets far more revenue and profits from its PBM than from its health plans. And CVS gets more revenue from its Caremark PBM business than from either Aetna's health plans or its nearly 10,000 retail stores. That insanity has to stop.

There are some glimmers of more good news.

First, insulin is proving to be an exception, and I believe the nonprofit Civica decision to enter the insulin market is a major reason for that exemption. But in March 2023, in rapid-fire succession, Lilly followed by Novo Nordisk and eventually Sanofi all collectively announced they would all slash their Wholesale Acquisition Cost (WAC) list prices on insulins anywhere from 70% to 78%, and also cap insulin prices starting in 2024. To pay for those price-cuts, big insulin manufacturers will simply disintermediate the PBMs from the transactions.

Beyond that, as I have said in multiple recent posts, the best full explanation of how and why that happened on insulin comes from University of Southern California professor Robert Popovian in an article he co-authored with Erin Delaney (also of USC) and Michael Mandel entitled "Are we on the cusp of a new drug pricing paradigm?" published in the Progressive Policy Institute (see https://progressivepolicyinstitute.medium.com/are-we-on-the-cusp-of-a-new-drug-pricing-paradigm-fdf611c009b3 for the article). 

However, if it weren't for the prospect of at least one of the half-dozen biosimilars of the bestselling insulin analogues to be sold at a price of $30/vial or $55 for a box of five prefilled insulin pens by CivicaScript PBC in the first place, we COULD have seen the type of profound nonsense which we first saw when the Semglee biosimilar was introduced, with the company's focus on the rebate-contracting model while patients were once again, completely forgotten about. Thankfully, Civica had PATIENTS in mind with its own insulin biosimilars (and, while they'll be cultured in labs based offshore, those will be from labs in countries where FDA can freely inspect the laboratories, which is unlike Chinese labs).

There also happens to be legislation in Congress called The Modernizing and Ensuring PBM Accountability Act which would mandate flat-rate charges for PBM services, rather than enabling them to engage in shady practices like "spread pricing" and pocketing the difference for themselves, but there are also other bills including both the PBM Transparency Act and the Patients Before Middleman (PBM) Act, and impressively, many of them seem to have bipartisan support.

As for made-in-China insulins, that will soon be a real thing. The PBMs will take kickbacks from any company that want formulary placement, and the biggest kickbacks win. Now that Lilly, Novo Nordisk and Sanofi want out the kickback-driven mill, we may soon have a situation whereby instead of therapeutic choices being rendered by PBMs rather than doctors with their patients, we could potentially see a choice for patients and their doctors to choose which prandial insulin works best for THEM, rather than whoever is paying their insurance company's PBM the biggest kickbacks.