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Know All Regarding DIR and GER Fees?

Acronyms….. they seem to be everywhere….. especially in healthcare. 

One acronym that has surfaced in the specialty pharmacy world is MIP

Scratching your head on what that one means? Well, it stands for Medically Integrated Specialty Pharmacy, one of the now hundreds of SPs that are owned and operated by Integrated HealthCare Systems (IHCSs) and hospitals. 

But wait…  there are more acronyms associated with MIPs….! How about DIRs? Yes, Direct and Indirect Remuneration (DIR) fees. Even MIPs are being hit by DIRs

But wait, there is now yet another acronym referencing the type of DIR fees being assessed by PBMs….. a GER which means Generic Effective Rate. Huh?  These new fees are calculated on a drug’s maximum allowable cost, wholesale acquisition cost, or average wholesale price (AWP).

Confused yet?

The article below is well worth a read even for those of us who think we are experts at understanding DIR fees. It covers a lot of ground and offers examples in fairly straightforward English. Any staff member who is less proficient on the topic would benefit from reading this article. 

An excerpt from the article follows…..

  • Between 2010 and 2020, retroactive DIR fees increased by more than 100,000%.  DIR fees are charged by PBMs outside of administration fees and are often collected after the point of sale (POS) and do not reflect the pharmacy’s actual reimbursement at the time of dispensing. Traditionally, DIR fees are based on so-called pharmacy performance metrics.  DIRs have recoupment fees of up to 15% of the adjudicated price paid to the pharmacy for dispensing a prescription. PBMs develop and manage specific criteria used to score the contracted pharmacy. The scoring process varies from insurer to insurer and may include unachievable goals for specialty pharmacies focused on dispensing oncology medications [for example]. Unrealistic goals may include………….

CLICK HERE to read the full article — PBM Fees Put the “GER” in Danger for Specialty Pharmacies


Limited Distribution Deals Announced

Announcements for newly approved specialty drugs often state that the product will be available through specialty pharmacy in limited distribution. However, the press releases rarely specify the specialty pharmacy(ies) selected as the designated partner(s).

Here are several LD deals that have been recently publicly confirmed subsequent to the approvals.

Rezlidhia HUB to be managed by AscellaHealth

December 13, 2022–(BUSINESS WIRE)–Optime Care, a member of the AscellaHealth Family of Companies, announced a contractual partnership with Rigel Pharmaceuticals, Inc., bringing its full suite patient support/HUB service capabilities to support Rezlidhia (olutasidenib), a recent FDA-approved treatment for adult patients with relapse or refractory acute myeloid leukemia (AML). Optime Care’s services for life sciences manufacturers include pre-commercialization and market access expertise, exclusive distribution partnerships, national medication fulfillment and high-touch patient support and HUB services for enhanced patient outcomes.

Rezlidhia now available at Biologics by McKesson

December 21, 2022 — McKesson Corporation recently announced that its independent specialty pharmacy, Biologics by McKesson, has been selected by Rigel Pharmaceuticals as one of two specialty pharmacies in a limited distribution network for Rezlidhia (olutasidenib). Rezlidhia is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test. 

KRAZATI now available at Biologics by McKesson

Dec. 14, 2022 — Biologics by McKesson has been selected by Mirati Therapeutics as one of two specialty pharmacies in a limited distribution network for KRAZATI (adagrasib), indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with KRAS G12C mutation.

KRAZATI now available from Onco360 

December 15, 2022–(BUSINESS WIRE)–Onco360 has been selected by Mirati Therapeutics to be a specialty pharmacy partner for KRAZATI (adagrasib) indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with KRAS G12C mutation.

HEMGENIX: Orsini Specialty Pharmacy Selected as a Limited Distribution Partner

Dec. 20, 2022 /PRNewswire/ — Orsini Specialty Pharmacy was selected by CSL Behring as a limited distribution partner for Hemgenix (etranacogene dezaparvovec-drlb), the first and only one-time gene therapy option for hemophilia B. Hemgenix is indicated for the treatment of adults with hemophilia B who currently use factor IX prophylaxis therapy or have current or historical life-threatening hemorrhage or have repeated, serious spontaneous bleeding episodes.


FDA Approves BLA for MS – Briumvi

The FDA recently approved a biologics license application (BLA) for a new infused therapy, Briumvi from TG Therapeutics, Inc., indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. Briumvi is a novel monoclonal antibody that targets a unique epitope on CD20-expressing B-cells. CD20 using monoclonal antibodies have proven effective in managing autoimmune disorders such as RMS.

Multiple sclerosis is a neurological disease in which the immune system attacks the brain cells causing physical disabilities.  The National Institutes of Health says that MS affects about 400,000 people in the United States.

The label for Briumvi indicates that there is the potential for serious, life-threatening or fatal, bacterial and viral infections in some Briumvi-treated patients. In MS clinical trials, the overall rate of infections was 56% compared to 54% in teriflunomide-treated patients. The rate of serious infections was 5% compared to 3% respectively. There were 3 infection-related deaths in Briumvi-treated patients.

TG Therapeutics did not announce plans for distribution.

Neither did TG Therapeutics confirm pricing at the time of the announcement. Industry analysts differ in their estimates for cost at launch with pricing ranging from a low of $30,000 to as much as $60,000 per patient per year. By comparison, Roche’s Ocrevus, also for MS, has a current list price of about $68,000 annually.

CLICK HERE for prescribing information


FDA Approves Infused Tx for Alzheimer’s – Leqembi

Earlier this month the FDA approved a new infused therapy, Leqembi (lecanemab-irmb) from Eisai R&D Management Co., Ltd., indicated for the treatment of Alzheimer’s disease. Therapy was approved for patients with mild cognitive impairment or mild dementia stage of disease. 

Alzheimer’s is an irreversible, progressive brain disorder affecting more than 6.5 million Americans that slowly destroys memory and thinking skills and, eventually, the ability to carry out simple tasks. Neither Leqembi nor Biogen’s Aduhelm are cures for Alzheimer’s. Neither medication reverses disease progression for those who have already developed symptoms of Alzheimer’s disease or to show clinically significant slowing of cognitive decline, memory loss, or personality and behavior changes.  

It is expected that Leqembi will need to comply with the same barriers as Aduhelm. Currently, Medicare eligible patients must be enrolled in a clinical trial to obtain coverage. Eisai said it doesn’t expect the requirements to be revised or removed in the near term.

Eisai confirmed a launch price of $26,500 year. Biogen cut Aduhelm’s price in the U.S. by about half, effective Jan. 1, 2022. For a 74 kg (163 pounds) patient, the annual cost of Aduhelm dropped to $28,200….. a difference of about $1700 annually vs. Leqembi.

Leqembi is infused every 2 weeks vs. every 4 week infusion schedule for Aduhelm. That burden may prove to be a drag on uptake for Leqembi especially with a requirement for frequent MRIs / PET scans to confirm therapy continuation.

Eisai did not disclose plans for distribution of Leqembi at the time of the announcement. However, a press release dated January 11 confirmed that Soleo Health Specialty Pharmacy has been named as the sole distributor of Leqembi.


FDA Grants Accelerated Approval for Alzheimer’s Disease 

January 06, 2023 — Today, the U.S. Food and Drug Administration approved Leqembi (lecanemab-irmb) via the Accelerated Approval pathway for the treatment of Alzheimer’s disease. Leqembi is the second of a new category of medications approved for Alzheimer’s disease that target the fundamental pathophysiology of the disease. These medications represent an important advancement in the ongoing fight to effectively treat Alzheimer’s disease.

“Alzheimer’s disease immeasurably incapacitates the lives of those who suffer from it and has devastating effects on their loved ones,” said Billy Dunn, M.D., director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research. “This treatment option is the latest therapy to target and affect the underlying disease process of Alzheimer’s, instead of only treating the symptoms of the disease.”

Leqembi was approved using the Accelerated Approval pathway, under which the FDA may approve drugs for serious conditions where there is an unmet medical need and a drug is shown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. The results of a Phase 3 randomized, controlled clinical trial to confirm the drug’s clinical benefit have recently been reported and the agency anticipates receiving the data soon.

Researchers evaluated Leqembi’s efficacy in a double-blind, placebo-controlled, parallel-group, dose-finding study of 856 patients with Alzheimer’s disease. Treatment was initiated in patients with mild cognitive impairment or mild dementia stage of disease and confirmed presence of amyloid beta pathology. Patients receiving the treatment had significant dose- and time-dependent reduction of amyloid beta plaque, with patients receiving the approved dose of lecanemab, 10 milligram/kilogram every two weeks, having a statistically significant reduction in brain amyloid plaque from baseline to Week 79 compared to the placebo arm, which had no reduction of amyloid beta plaque. 

These results support the accelerated approval of Leqembi, which is based on the observed reduction of amyloid beta plaque, a marker of Alzheimer’s disease. Amyloid beta plaque was quantified using positron emission tomography (PET) imaging to estimate the brain levels of amyloid beta plaque in a composite of brain regions expected to be widely affected by Alzheimer’s disease pathology compared to a brain region expected to be spared of such pathology. 

The prescribing information for Leqembi includes a warning for amyloid-related imaging abnormalities (ARIA), which are known to occur with antibodies of this class. ARIA usually does not have symptoms, although serious and life-threatening events rarely may occur. ARIA most commonly presents as temporary swelling in areas of the brain that usually resolves over time and may be accompanied by small spots of bleeding in or on the surface of the brain, though some people may have symptoms such as headache, confusion, dizziness, vision changes, nausea and seizure. Another warning for Leqembi is for a risk of infusion-related reactions, with symptoms such as flu-like symptoms, nausea, vomiting and changes in blood pressure. The most common side effects of Leqembi were infusion-related reactions, headache and ARIA.

As specified in the prescribing information, Leqembi is indicated for the treatment of Alzheimer’s disease. The labeling states that treatment with Leqembi should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was studied in clinical trials. The labeling also states that there are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied.

The FDA granted this application Fast Track, Priority Review and Breakthrough Therapy designations. 

The approval of Leqembi was granted to Eisai R&D Management Co., Ltd.


FDA Approves Gene Therapy for Bladder Cancer – Adstiladrin

The FDA recently approved a novel gene therapy, Adstiladrin (nadofaragene firadenovec-vncg) from Ferring Pharmaceuticals A/S, indicated for the treatment of adult patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors. 

According to the Centers for Disease Control and Prevention, about 57,000 men and 18,000 women are diagnosed with bladder cancer annually, and roughly 12,000 men and 4,700 women die from the disease each year in the United States.

Adstiladrin is administered three times annually via intravesical catheter.

Ferring did confirm that Adstiladrin will be commercially available in the US in the second half of 2023. Ferring did not release pricing information at the time of approval. Industry sources expect the therapy to be priced in the $160k-$260k price range. Given cost and need to track outcomes and patient experience, Ferring will likely distribute this product through SP distribution.

CLICK HERE for prescribing information


FDA Approves First Gene Therapy for the Treatment of High-Risk, Non-Muscle-Invasive Bladder Cancer

December 16, 2022 — Today, the U.S. Food and Drug Administration approved Adstiladrin (nadofaragene firadenovec-vncg), a non-replicating (cannot multiply in human cells) adenoviral vector based gene therapy indicated for the treatment of adult patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors.

“This approval provides healthcare professionals with an innovative treatment option for patients with high-risk non-muscle invasive bladder cancer that is unresponsive to BCG therapy,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research. “Today’s action addresses an area of critical need. The FDA remains committed to facilitating the development and approval of safe and effective cancer treatments.”

Bladder cancer, one of the more common forms of cancer, is a disease in which malignant (cancer) cells form a tumor in the tissues of the bladder. These abnormal cells can invade and destroy normal body tissue. Over time, the abnormal cells can also metastasize (spread) through the body. Most newly diagnosed bladder cancers (75% to 80%) are classified as NMIBC – a type of cancer that has grown through the lining of the bladder but hasn’t yet invaded the muscle layer. This type of cancer is associated with high rates of recurrence (between 30 to 80%) and the risk of progression to invasive and metastatic cancer. 

Treatment and care of patients with high-risk NMIBC, including those with carcinoma in situ, or CIS (abnormal cancer cells found in the place where they first formed and that have not spread to nearby tissue), often involves removing the tumor and the use of BCG to reduce the risk that the cancer will recur. Few effective treatment options exist for patients who develop BCG-unresponsive disease. The failure to achieve a complete response, or the disappearance of all signs of cancer as seen on cystoscopy, biopsied tissue, and urine, is associated with an increased risk of death or a disease-worsening event. Without treatment, the cancer can invade, damage tissues and organs, and spread through the body. 

The safety and effectiveness of Adstiladrin was evaluated in a multicenter clinical study that included 157 patients with high-risk BCG-unresponsive NMIBC, 98 of whom had BCG-unresponsive CIS with or without papillary tumors and could be evaluated for response. Patients received Adstiladrin once every three months for up to 12 months, or until unacceptable toxicity to therapy or recurrent high-grade NMIBC. Overall, 51% of enrolled patients using Adstiladrin therapy achieved a complete response (the disappearance of all signs of cancer as seen on cystoscopy, biopsied tissue, and urine). The median duration of response was 9.7 months. Forty-six percent of responding patients remained in complete response for at least one year.

Adstiladrin is administered once every three months into the bladder via a urinary catheter. The most common adverse reactions associated with Adstiladrin included bladder discharge, fatigue, bladder spasm, urinary urgency, hematuria (presence of blood in urine), chills, fever, and painful urination. Individuals who are immunosuppressed, or immune-deficient should not come into contact with Adstiladrin. 

This application was granted Priority Review, Breakthrough Therapy, and Fast Track designations.

The FDA granted approval of Adstiladrin to Ferring Pharmaceuticals A/S.


FDA Approves Oral & Sub-Q Regimen for HIV – Sunlenca

The FDA recently approved a new antiviral therapy regimen, Sunlenca (lenacapavir) from Gilead Sciences, indicated for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations. Sunlenca is given in combination with other antiretroviral(s). 

Sunlenca is the first of a new class of drugs called capsid inhibitors. Sunlenca blocks the HIV-1 virus’ protein shell (the capsid)interrupting multiple essential steps of the viral lifecycle. 

As noted, Sunlenca is supplied as both an oral and subcutaneous injectable regimen. It comes with two induction schedule options (see below). Startup doses and then followed by maintenance injections every six months.

Recommended dosage:

Initiation with one of two options followed by once every 6-months maintenance dosing.

• Initiation Option 1

   Day 1                927 mg by subcutaneous injection (2 x 1.5 mL injections)

600 mg orally (2 x 300 mg tablets)

   Day 2                600 mg orally (2 x 300 mg tablets)

• Initiation Option 2

   Day 1                600 mg orally (2 x 300 mg tablets)

   Day 2                600 mg orally (2 x 300 mg tablets) 

   Day 8                300 mg orally (1 x 300 mg tablet)

   Day 15              927 mg by subcutaneous injection (2 x 1.5 mL injections)

• Maintenance

927 mg by subcutaneous injection (2 x 1.5 mL injections) every 6

months (26 weeks) from the date of the last injection +/-2 weeks.

Gilead confirmed that Sunlenca injection and tablets are expected to cost $42,250 in the first year of therapy and $39,000 annually after that (maintenance injections only).

Gilead did not provide detail on how Sunlenca would be distributed. Given its benign safety profile, it could be expected that the therapy regimen (oral and sub-q injectable) will be provided by specialty pharmacy in limited distribution. Compliance and persistence are central to therapy success.

CLICK HERE to access prescribing information


FDA Approves Sunlenca – New HIV Drug for Adults with Limited Treatment Options

December 22, 2022 The U.S. Food and Drug Administration approved Sunlenca (lenacapavir), a new type of antiretroviral medication for adult patients living with human immunodeficiency virus type 1 (HIV-1), whose HIV infections cannot be successfully treated with other available treatments due to resistance, intolerance, or safety considerations. After the starting dose is completed, Sunlenca is administered…………………

CLICK HERE to access the full FDA press release


Biologics Are Going Through an Identity Crisis (reprise)

So, can you easily explain the differences between a chemically synthesized drug and a biologic? 

You might be surprised how difficult that has become.

The article below should be thought provoking for those in the specialty pharmacy industry as it goes to the core of what exactly SPs actually sell….. chemically synthesized drugs and biologics. But…. if you were asked to list which column your drugs should be listed you would likely be stumped.

Here’s why….. the Consolidated Appropriations Act of 2020 included new guidance on how drugs can be classified. Specifically, the change states that the purpose of the amendment is to allow for the possibility that a manufacturer may chemically synthesize a biologic product. Huh?? 

Here’s an example…. Vondys 53, a biologic analog made through synthetic chemistry – not by any biologic process – is considered a biologic. The author of the (somewhat ‘tongue in cheek) article below polled pharma colleagues for their opinion as to whether similar drugs – are or aren’t biologic drugs. 

The results: 

41% agreed that these new drugs were biologics, 39% disagreed, 20% responded “Confused” 

….. so am I. 

Non-pharmacists may be a bit intimated by the technical references in the article…. just skip over them as that’s not the point of this Alert. The real purpose is to alert those working in the specialty pharmacy industry that today’s crop of new biologics ‘ain’t your grandfather’s biologics’. If you are going to be selling both chemically synthesized drugs and biologics you should have, at a minimum, a basic understanding of these developments.


What is a Biologic Drug Anyway?

Or, How I Learned to Stop Worrying and Love My Own Definition

January 19, 2020 — Recently I posted on “biologic drugs” which were approved in 2019. All was well in my little scientific universe, until I received this in an email: 

“You recently reported on “14 novel biologic drugs,” referring to ‘novel’ biopharmaceuticals approved through CDER. But, … You also include several synthetic drugs, which are clearly not biopharmaceutical/biologics.”

Wait, what? Synthetic drugs are clearly not biopharmaceutical/biologics? Sure, the siRNA drug, Givlaari, and the antisense oligonucleotide, Vyondis 53, are both technically made by chemical synthesis. But, not considering these RNA-based drugs “biologic drugs” just felt… wrong.

It got me thinking – what is the definition of a biologic drug, anyway? I immediately started my research the way any good, card-carrying scientist does — I punched it into the Google:

GOOGLE:  A biopharmaceutical, also known as a biologic medical product, or biologic, is any pharmaceutical drug product manufactured in, extracted from, or semisynthesized from biological sources. [source] Wikipedia

Though Wikipedia delivers good answers to probably 90% of my questions, I knew this definition was incomplete – nobody considers natural products like penicillin “biologic drugs.” Not wanting to spend the rest of my Sunday night reading FDA guidance documents, I did instead what any good millennial does – I asked social media.

As one comment pointed out, the term “biologic” itself is anachronistic, coming from a time when chemistry and biology were considered distinct (i.e. before chemists started getting upset about Nobel Prizes in Chemistry going to “biologists”). The Biologics Control Act, which first gave the US government control over the processes to make biological products, was passed in 1902 – long before it was clearly established that proteins are polymers of amino acids and that genetic information is stored chemically in nucleobases.

Digging Deeper

Based on the lack of strong consensus, I decided this was a topic worth diving further into.

Readers likely remember that “biologic” became a charged term in the 2000’s, due to expensive biologic products like filgrastim and epoetin alfa, approved under Biologic License Applications (BLAs) rather than New Drug Applications (NDAs). Since the abbreviated generic drug approval process (ANDA) only applied to originals filed under NDAs, there was no way to create a “generic” biological product without repeating expensive and lengthy clinical trials. This loophole led to the creation of the abbreviated follow-on biologicals approval pathway (aBLA) through the 2009 Biologics Price Competition and Innovation Act (BPCI).

So how are the adjectives, “biologic” or “biological,” legally defined in the US Code of Laws after BPCI in 2009? Turns out, they’re not. The term “biological product,” is legally defined only with examples, not properties:

“The term “biological product” means a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.”

42 U.S. Code § 262. Regulation of biological products.

With no basis in the text for determining what an “analogous product” is, no definition of what exactly makes a product “biologic” or “biological,” and with, of all things, arsphenamine (or any other trivalent organic arsenic compound) being the only exemplified exception, no wonder everyone is confused. The FDA and the industry spend an enormous amount of resources deciding new registrants on a case-by-case basis, which was part of the justification for a recent change in the definition. 

A Legal Update on Synthetic Processes

It gets better. The Further Consolidated Appropriations Act, 2020, signed into law in December 2019, amended this definition by removing the phrase “except any chemically synthesized polypeptide”: 

“The term “biological product” means a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (deleted: except any chemically synthesized polypeptide), or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.” 

New legal definition of “biological product” after the Further Consolidated Appropriations Act.

The recent FDA press release on the change states that the purpose of the amendment is to allow for the possibility that a manufacturer may chemically synthesize a biologic product. Under the old definition, if an original biologic product was licensed under a BLA, a new chemically synthesized biologic follow-on could not be licensed through an abbreviated aBLA pathway, since it was made by a synthetic process, but also could not be licensed through an ANDA, since the original was not filed under an NDA.

In the end, what this demonstrates is that there are at least two simultaneous uses of the term “biologic” in the industry – an arbitrary regulatory definition to decide what drugs are licensed under BLAs vs. NDAs, and a scientific colloquialism which most of us use on a day-to-day basis. Neither definition is clear and unambiguous, and no single criterion (e.g. chemical process) universally captures all cases. 

Biolognas, Anybody?

Having both uses at the same time is confusing enough to make you want to give “synthetic biologics” a different name without “biologic” in it. But what would we call them? Biologishes? Biolognas? I guess I have a year to think about it before 2020’s Biologic Drug Approvals post. 

But back to my original question– since oligonucleotide drugs are all filed under NDAs, they’re regulated more like most small molecules than most biologics. But just because they’re filed under NDAs, doesn’t mean we can’t still call them biologics (e.g. insulins are all filed under NDAs). Anyway, all this makes me very glad that we have a lot of brilliant professionals working in our very important Regulatory Affairs departments, though I’m glad it doesn’t include me!

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