Biosimilar Step Therapy for Medicare Part B: Does This Make Sense?

The Centers for Medicare and Medicaid Services (CMS) has decided drugs covered under Medicare part B may be subject to step therapy, if so desired by Medicare Advantage plans. UnitedHealthcare has become the first to publicly implement step therapy policies for these drugs. However, biosimilar step therapy is not the typical utilization management tool that industry executives are used to seeing.

biosimilar step therapyTraditional step therapy or step edits for prior authorization policies are typically used to require the use of an effective, low-cost drug class before trying a more-expensive treatment. For example, a plan might have a step in place before a patient can receive Humira®, such as requiring documented failure on other disease-modifying anti-rheumatic drugs, like azathioprine or methotrexate. This makes very good sense when supported by practice guidelines or treatment pathways, based on solid supportive evidence.

For biosimilar manufacturers, the perspective on the revised CMS policy, seems to imply trying the biosimilar before receiving the branded originator product. This biosimilar step therapy would make very little sense. A doctor would not be practicing evidence-based medicine if he or she prescribed Remicade® to a patient after failure of Renflexis®. There is no evidence to show that the biosimilar will work in a patient who did not receive adequate clinical benefit from the reference product (and vice versa). Similarly, there is no information to show that a patient who has an adverse effect while taking Remicade will not have that adverse effect after injecting with Renflexis (or vice versa). In other words, after failing one, a new mechanism of action should be tried, not a product with a very similar structure. This may be a different argument, if a subcutaneous form of infliximab was introduced, and this might be reason to step the infusible form through this drug.

In United’s announcement, they are clearly seeking to increase biosimilar utilization, as designated preferred part B agents, at the expense of Remicade use, the nonpreferred agent. Therefore, it may make more sense that new patients will have to use a biosimilar before being prescribed the reference product. Step therapy in this case is almost an aside.

Ironically, the Department of Health and Human Services has also expressed its desire to move part B agents like self-administered injectables to part D. This may not apply to infliximab, as it is given as an in-office infusion. Should this be the case, plans will have many pharmacy tools at their disposal beyond biosimilar step therapy.

In other biosimilar news…Fresenius Kabi has signed an agreement with Abbvie to delay its adalimumab biosimilar market entry in the US until 2023. The manufacturer is currently trying to secure European approval for the product. A 351(k) application has not yet been filed by Fresenius in the US.

Pfizer’s Anticompetitive Suit: A Slippery Slope to Competitive Bidding?

When Pfizer first announced its lawsuit against Janssen’s parent Johnson & Johnson in September 2017, it pointed to exclusionary contracting, “anticompetitive” behavior of Remicade®’s maker as the reason for its very limited market access.

The lawsuit claimed that Janssen has withheld or threatened to withhold rebates if payers do not keep Remicade in an exclusive preferred position. The degree to which health plans knuckled under to these demands may only be inferred from the 3% marketshare Pfizer’s Inflectra® now holds. For these drugs, which are still typically covered under the medical benefit, “nonpreferred positioning” usually means no coverage. For drugs covered under the pharmacy benefit, this is not the case.

In August, the Eastern Court of Pennsylvania ruled against J&J in its request that the lawsuit be dismissed. While discovery in the case may be ongoing, we could not find mention of a resolution date for the suit.exclusionary contracting

For the sake of argument, let’s say that the Eastern Court of Pennsylvania rules in favor of Janssen. In other words, exclusionary contracting was not an anticompetitive behavior. That means the status quo is intact, but some factors may affect this situation going forward. These include the Center for Medicare and Medicaid Services’ desire to move part B drugs (the medical benefit) to part D (the pharmacy benefit) for Medicare beneficiaries.

The scrutiny on rebate contracting coming from several sectors, and lack of transparency, may also independently influence future use of these pharmaceutical company tactics. I helped conduct a market research project recently on a nonspecialty drug. As part of these interviews, we were asked by the client to inquire about the range of rebates they were receiving from competitor manufacturers. Their responses were requested as a range (e.g., 20% to 30%), not specific contract details, and we had no intention of providing reports of individual payer deals, only anonymous, aggregate information. We expected little to no response to that query, and that is exclusionary contractingexactly what we received.

Let’s discuss the other potential outcome, in which the Court rules in favor of Pfizer. That implies that this exclusionary contracting practice is indeed anticompetitive. If this is the case, we may be on a very slippery slope. What is the difference between payers and pharma companies engaging in a “1 of 1” contract when there are multiple potential products and a “1 of 2” contract? In both cases, drug makers are committing payers to anticompetitive behavior (as perhaps defined by the Court’s new precedent).

The preferred drug tier (whether preferred generics, preferred brands or whatever) is supposed to be for products with proven clinical, patient care, or economic advantages. Truthfully, payers rarely place medications in the preferred tier for reasons other than net costs or rebate contracting, which is based on marketshare.

Now add in the potential effects of the Administration’s desired shift to part D, where pharmacy benefit rules can be applied. That exposes injectable products that were shielded under Medicare part B to commonly applied formulary placement practices.

To be complete, Janssen’s strategy was not solely based on Remicade. It may be found to have bundled Remicade with other agents in deals to exclude Pfizer’s products. The Court may also react specifically to Janssen’s contract stipulation that threatens to withhold rebates connected to future use of the product, to increase its leverage.

However, if the Court determines that 1 of 1 or exclusionary contracting with rebates are the root of the anticompetitive behavior, why should 1 of 2 or even 1 of 3 contracts in a drug category with 5 similar agents be less so? This is the slippery slope that could undo rebate contracting, and push us towards a system that more resembles a competitive bidding process like in Europe. Alternatively, it could accelerate the move towards outcomes- and value-based contracting. The result could be a system-wide revamping of the drug formulary and the pharmacy–drug maker relationship.

In other biosimilar news…Sandoz has signed a licensing agreement with Abbvie, allowing it to market its biosimilar version of Humira in 2023. The agreement, as with Abbvie’s settlements with other biosimilar makers, halts all patent litigation with Sandoz in exchange for a licensing royalty paid to Abbvie.

Biosimilars and Drug Rebates: A Foot in the Door to Access?

At the September 5–7, 2018 GRx+Biosims meeting, I had the opportunity to moderate a session with three highly experienced biosimilar industry executives. They included Gary Deeb, Senior Vice President, Global Licensing and Business Development, Lupin Pharmaceuticals; Chrys Kokino, MBA, Head Global Biologics— Commercial, Mylan; and Mike Woolcock, MBA, Senior Vice President, Commercial Operations, Apobiologix. In the hour-long session, we covered a range of sticky topics. This post sums up some of the information gained on one aspect—the question of price transparency, recent FDA action to address drug rebates, and whether deemphasizing drug rebates will help biosimilars gain access.

One issue that is getting an awful lot of attention lately is the question of price transparency. This has been highlighted by the difficulties that Pfizer has had in gaining traction for its infliximab biosimilar, resulting in claims of exclusionary contracting by Janssen to protect the latter’s marketshare. One of the principal tools used by the reference biologic manufacturer is its power to rebate. When a drug has the lion’s share of utilization, rebates become very potent inducements to payers to provide or maintain preferred or exclusionary status on formulary. Therefore, the issue of biosimilars and reference drug rebates can be an important one for the industry.

biosimilars and rebatesIn response to the challenges of biosimilars gaining uptake in the US, Health and Human Services Secretary Alex Azar has been investigating whether safe harbor laws that currently protect drug rebates from anticompetitive lawsuits can be changed. This move can affect revenues for both pharmacy benefit managers (PBMs) and payers who share in the rebate monies. It raises a related question, however: Would biosimilar manufacturers be better off competing on list pricing (i.e., wholesale acquisition cost) alone? And does the issue of biosimlars and rebates really matter?

In the backstage green room, this topic generated much discussion among our panelists. And quite frankly, the answer to this question is not yet in.

In previous market research and access projects performed for pharma and their agencies, it has been clear that health plan medical directors and pharmacy directors would prefer competition based on discounted WAC, whereas PBMs prefer to retain their rebate revenue. However, the plans do share in drug rebate revenue to varying extents, which they are quick to point out are helpful in holding down premium increases or funding other projects beneficial to members and patient care. Hence, they are stuck in the rebate trap as well. They are not generally eager to add a new preferred drug even if the manufacturer is offering powerful discount WAC plus competitive rebate; they realize that the rebate revenue is based mostly on how much marketshare the drug maker can gain (and how quickly it can amass marketshare).

The biosimilar industry representatives at our panel discussion were similarly reticent. Does it represent an opportunity to break the exclusionary contracting hold of companies like Janssen? Without high rebates to cement a reference drug’s place as a preferred or the only covered biologic, other manufacturers can get their foot in the door and compete for marketshare based on price alone. This does not mean that prices would necessarily be more transparent, however. One would expect that discounted prices negotiated (from one plan to another or one PBM to another) would differ and remain confidential in nature. In other words, Kaiser Permanente Southern California could still only guess what Blue Shield of California was paying for infliximab and vice versa.

If the average sales price (ASP) methodology were unchanged, one would expect the ASP, which reflects discounts and rebates, to be closer to the WAC price by the amount no longer rebated. But the wild card in this scenario would be the pharmaceutical and PBM industries’ reaction. Is there a way to reclassify rebates as some other payment, like “administrative fees”? Our panelists believe that the PBMs, for example, will not easily forfeit a revenue line representing pure profit, regardless of its size. One would need to anticipate some attempt to retain this revenue.

The issue of biosimilars and drug rebates may only be shifted, in the end. Payers would still want to see the lowest net cost for any product. In 2018, they don’t care too greatly about how this is achieved, through rebates, discounts, portfolio contracts, or other means. If pharmaceutical rebates were deemphasized, my own guess is that at least biosimilar manufacturers would not be disadvantaged once approved, simply because they don’t have any existing marketshare. And it would also test a payer’s fortitude in foregoing its own drug rebate revenue.

Infliximab Biosimilars Savings Could Exceed $400 Million Dollars Annually

Everyone with an opinion believes that biosimilar drug use will save the health system considerable money. Calculations for biosimilar savings have been hampered by several factors. For example, previous high estimates have not been based on real-life scenarios. Only 3 biosimilars have been launched and utilized in the US; so little experience has been gained on which to base calculations.

Yet, isolating the savings associated with a single approved biosimilar does put their potential into perspective. It also demonstrates the promise of cumulative biosimilar savings with their launch and uptake. Based on current infliximab average sales prices (ASPs), wBiosimilar Savingshich considers discounts and rebates, one organization believes that a 50% marketshare for biosimilar infliximab could result in well over $400 million in annual savings system wide.

The analysis, conducted by Wayne H. Winegarden, PhD, Senior Fellow in Business and Economics, Pacific Research Institute, accrued the lion’s share of the annual savings to employer-sponsored health plans ($262 million to $315 million, compared with no sales of infliximab biosimilars). Medicare accounted for up to $150 million savings annually.

Dr. Winegarden tested several scenarios. The calculation considered the cost of the infliximab regimen based its various indications. He calculated biosimilar savings using different add-on percentages to ASP (including the current ASP + 4.3% payment and up to ASP + 20%), as well as different marketshares of the biosimilars (from 10% to 90%).

The current marketshare of the two available infliximab biosimilars—Inflectra® and Renflexis®is below 5%, based on data from the first quarter of this year. This is partly because of Janssen’s tactics in matching the net costs of biosimilars with additional rebates on Remicade. This raises two important points: Dr. Winegarden’s analysis reveals savings accruing to the health care system (not necessarily to the payer). Also, the very existence of infliximab biosimilars has resulted in significant net savings compared with the price increases seen prior to their introduction.

It is a bit more difficult to pinpoint the system savings resulting from the use of the first biosimilar approved in the US, filgrastim-sndz (Zarxio®). The other branded product, tbo-filgrastim (Granix®), was launched a couple of years earlier and gained its own marketshare from the reference brand Neupogen®. No doubt, Zarxio contributed to some level of cost savings. In other words, the infliximab example is an easier calculation with a cleaner result.

With eight biosimilars for six reference products awaiting their turn to hit the market, and drugs like adalimumab and etanercept among them, it is easy to see how biosimilars savings can easily exceed $10 billion. Just not yet.

Is Celltrion Paving a New Road for Biosimilars? A New Route of Administration Being Tested for Infliximab

When payers, patients, or physicians discuss biosimilars, they assume that the biosimilar works just like the reference product. They also assume that the biosimilar is administered in the same way as the originator biologic. Celltrion is actively researching a new subcutaneous infliximab. This could result in a first for the biosimilar industry.

Sponsored by Celltrion and conducted in multiple sites, the research results were announced at the annual meeting of the European Congress of Rheumatology in June. The investigators presented outcomes data on the use of a subcutaneous (SC) form of infliximab-dyyb. Currently, infliximab is only available as an intravenous (IV) infusion at the physician’s office that takes at least 2 hours. Subcutaneous infliximab was given on a biweekly basis.

subcutaneous infliximabThe researchers studied 48 patients with rheumatoid arthritis, finding that outcomes were not clinically different through 30 weeks of follow-up. Three dosages were tested, and in this small study, no ACR20 differences were reported in any subgroup receiving infliximab infusions or SC injections.

Hypersensitivity reactions did occur in one patient each receiving the lowest dose (90 mg) SC and the middle dose (120 mg). None were seen in the group receiving the highest infliximab SC dose (180 mg). Injection site reactions occurred in two patients apiece in the 90 mg and 180 mg dose cohorts. receiving subcutaneous infliximab. The formation of antidrug antibodies was detected in nine patients receiving the standard infusion, but less than half that number in each of the subcutaneous groups.

Currently, infliximab treatment requires a lengthy office visit for each infusion (every 8 wk in the maintenance phase). It is one of the key limiting factors to its use. A self-injectable formulation should result in lower administration costs, and the potential for covering the agent through the pharmacy benefit.

A phase 1, open-label trial of subcutaneous infliximab has already been conducted by Celltrion in patients with Crohn’s disease. That trial found similar outcomes between the SC and IV formulations. Another phase 1 trial is wrapping up, this one evaluating safety and pharmacokinetics in healthy volunteers. Celltrion is also sponsoring a phase 3 trial of more than 300 patients with rheumatoid arthritis. Preliminary results will not be available until December 2018.

It is not yet clear, however, what type of data the Food and Drug Administration would require for approval of a new formulation of a biosimilar. The regulatory agency may decide to treat this as it would a new route of administration for any approved product, which would focus on pharmacokinetic and pharmacology factors. Celltrion seems to be covering all of its bases.

Celltrion Bounces Back, Resubmits for FDA Approval of Rituximab Biosimilar

Anticipating that its issues with the Incheon, South Korea, manufacturing plant will be resolved, Celltrion has resubmitted its biologic license application for a rituximab biosimilCelltrion rituximab biosimilarar (CT-P10).

In the April 2018 complete response letters sent by the Food and Drug Administration (FDA) on CT-P10 and the trastuzumab biosimilar CT-P6, FDA cited aseptic practices at the manufacturing plant that it announced in January. The resubmission should mean that a decision will come within six months of the application date, keeping it in the race for the first rituximab biosimilar.

Celltrion, in its announcement, also affirmed that it intends to resubmit its application for its trastuzumab biosimilar in June. In its press release, Celltrion stated, “Celltrion has made progress addressing the concerns raised by the FDA in the warning letter and is committed to working with the Agency to fully resolve all outstanding issues with the highest priority and urgency.”

This marks the quickest turnaround seen yet for reapplication following an FDA rejection of a biosimilar. Truxima® is the brand name of Celltrion’s rituxumab biosimilar that is approved in Europe.

In other biosimilar news…The European Commission announced a proposal that would enable biosimilar manufacturers to produce and export their products before EU full intellectual property rights terminate. This would obviate Special Protection Certificates, which were created in 1992. Under these certificates, intellectual property rights continue for 5 years after EU patent expiration. The announced change would be implemented by end of this year. It will mark the end of special compensation to pharmaceutical industry for the extended period required for research, development, and regulatory approval.

Sandoz biosimilars

Sandoz’s biosimilar version of infliximab has been approved by the European Medicines Agency. Dubbed Zessly™ this agent was the fourth infliximab biosimilar approved in Europe.

More Clinical Study Evidence That Biosimilar Switching Carries a Low Risk

A literature review published this past weekend in Drugs reaffirms what most parties interested in biosimilars suspect—that switching from a reference product to biosimilar is not a significant clinical concern. Biosimilar switching was not generally associated with poorer outcomes.

The study evaluated the results of 90 clinical studies comprising more than 14,000 patients with 14 diseases or conditions. The authors from Novartis (and its Sandoz subsidiary), the Oregon Medical Research Center, Rocky Mountain Cancer Centers, IBD Center of Humanitas Clinical and Research Hospital (Milan), and Avalere Health stated that “the great majority of the publications did not report differences in immunogenicity, safety, or efficacy [as a result of biosimilar switching]. The nature and intensity of safety signals reported after switching from reference medicines to biosimilars were the same as those already known from continued use of the reference medicines alone.” In addition, they reported, “Three large multiple switch studies with different biosimilars did not show differences in efficacy or safety after multiple switches between reference medicine and biosimilar.”

In this evaluation, the biosimilars tested included those for infliximab, epoetin, filgrastim, growth hormone (which has not been considered a biosimilar in the Ubiosimilar switchingS), etanercept, and adalimumab. Infliximab was the subject of the majority of the clinical studies.

Of the 90 studies, two were outliers, suggesting potential safety issues associated with biosimilar switching. One was described as a 2016 retrospective study of a claims database from Turkey, which found a much higher discontinuation rate with the infliximab biosimilar compared with originator product in patients with rheumatoid arthritis.

The authors correctly note that the vast majority of the studies reviewed involved a single biosimilar switch, and that multiple switches may result in additional safety signals. However, they also point out that “patients have already been exposed to de facto multiple switches for many originator biologics when product quality attributes changed after one or more manufacturing process modifications were introduced.”

The question arises as to whether multiple switch studies are truly necessary outside of the requirement to prove interchangeability between a biosimilar and a reference product. There is a practical reason for doing so—the possibility (actually, the likelihood) of a patient enrolling in a new health plan one year, which covers the biosimilar but not the reference product. If the patient’s health plan changes once again one or two years later, that person may well be required to switch back to the reference product or yet another biosimilar.

This will heighten the importance of collecting real-world evidence and accumulating more experience outside of the clinical trial environment in terms of switching. Efforts such as those at the Biologics and Biosimilars Collective Intelligence Consortium should fill this gap over the next several years.

 

Pfizer US Biosimilar Revenues Growing Slowly, Better News Internationally

According to an article posted on the Market Realist website, Pfizer’s US and global biosimilars revenues are growing, but its sales of Inflectra® remainPfizer Headquarters stunted.

In the fourth-quarter of 2017, the New York–based company posted US biosimilar revenues of $44 million—all attributable to its infliximab biosimilar. The product was launched in Q4 2016 (and gained only $4 million in revenues), but the revenue was reported to be somewhat higher than in Q3 2017. Total 2017 Inflectra revenue was $118 million.

Internationally, where Pfizer not only markets Inflectra, but its Retacrit® form of epoetin alpha and its Nivestim® brand of filgrastim, biosimilars contributed $531 million to the bottom line in 2017, an increase of 37% compared to the previous year.

There is little doubt that Pfizer’s US Inflectra revenues will continue to increase, but competition from Samsung/Merck’s Renflexis® and Janssen Biotech’s continuing heavy rebates on Remicade® should prove challenging to Pfizer. Merck has not yet reported its Q3 or Q4 sales of Renflexis, which was only launched in July 2017.

Pfizer’s second US biosimilar approval was also for an infliximab biosimilar (a legacy product from its Hospira acquisition). This agent, infliximab-qbtx, dubbed Ixifi™, was approved in December 2017 and will apparently not be launched in the US.

 

Its next big splash into the US biosimilars market may not occur in 2018. Its rituximab biosimilar (PF-05280586) met its primary outcomes measures in a phase 3 trial, as announced in January, but no target date has been yet reported for its 351(k) application to the Food and Drug Administration (FDA). However, this product may face stiff competition from Celltrion and Sandoz for their rituximab biosimilars currently being reviewed by the FDA. Celltrion is partnered with Mylan (not Pfizer) in the commercialization of its rituximab biosimilar.

A Pre-Holiday Gift for Pfizer—a Second Infliximab Biosimilar Approval. Now What?

On December 14, Pfizer got an early Christmas present, the approval by the Food and Drug Administration (FDA) of the second infliximab biosimilar in which it has a stake. First came Inflectra® in 2016, and here comes Ixifi™ (infliximab-qbtx). Unlike Inflectra, which Pfizer markets for Celltrion, Ixifi is Pfizer’s alone—Web image for headera product that was under development at the time of the acquisition.

This of course puts Pfizer in an interesting position. Ixifi would be the third infliximab biosimilar to reach the market, after Inflectra and Samsung/Merck’s Renflexis™. True, Inflectra has limited marketshare in the US, and competition from more heavily discounted Renflexis could compound the situation.

It seems that Ixifi is not intended to reach the US market at all, and may be marketed in other countries where the Celltrion agreement does not hold sway. However, this begs the question: Why did Pfizer decide to go apply for a 351(k) application for FDA approval? That is unclear at this time. Perhaps they will use this biosimilar as insurance if Inflectra does not perform as promised. On the other hand, Pfizer could license it to another manufacturer and collect additional royalties from its sales in the US and overseas.

For those of you who guessed the last choice, congratulations! Under a deal signed in early 2016, Sandoz obtained the rights to market this agent in the European Economic Area. This would enable Pfizer to earn cash rewards and other prizes from two biologics in the same biosimilar category.

A Health System Biosimilar Survey’s Implications

When asked about potential cost savings with the infliximab biosimilar, nearly one-quarter of health system respondents did not believe that it represented a cost savings opportunity for their organization, according to a newly published survey in the Journal of Managed Care and Specialty Pharmacy.

Conducted by Premier, Inc., a group purchasing organization, 57 US health systems responded to its questionnaire in April and May 2017 (before the launch of Merck/Samsung Bioepis’ Renflexis® biosimilar). All of the health systems currently used infliximab at their facilities.

The greatest barrier to adoption cited by the health systems was the reimbursement from payers (28%), with actual cost of the biosimilar being a lesser concern (10%). According to the survey, about one-third of the respondents had had communications by that time with payers regarding the latter’s approach to biosimilar coverage.

Interestingly, 62% of those systems represented by the survey respondents had not reviewed Pfizer’s Inflectra® in their Pharmacy and Therapeutics Committees. In large part, thiBR&R Logo Transparent1.5-21-2017s was a continuation of a “wait-and-see” approach, particularly in view of the relatively small discounts offered by Pfizer. Others responded that they were awaiting Merck’s entry into the marketplace, to review both biosimilars at the same time.

“For sites of care that approved formulary addition of the infliximab biosimilar, implementation strategies ranged from full product conversion to ‘new patients’ only,” wrote the author, Sonia T. Oskouei, PharmD, Director of Pharmacy Program Development-Biosimilars at Premier. “Some sites added it to their formularies as a preferred product but only when payer coverage supported it.”

Seventy-six percent of respondents perceived that there was a cost savings opportunity for biosimilars compared with the reference product. What are the expectations of the remaining health system executives? If they don’t believe biosimilars do not save the system money, why not?