The Inflation Reduction Act: Reducing Drug Prices and Maybe Future Biosimilar Development

The Law of Unintended Consequences is an axiom of legislating proved over and over again by the US Congress. In major legislation, there are always issues that (1) were not fully considered in writing the bill or (2) are a direct, unexpected consequence of the law’s implementation.

The reconciliation route used to create and pass the Inflation Reduction Act on August 16 meets both criteria. And it could be harmful to the biosimilar industry, assuming modifications are not made to the new law.

The basic healthcare-related impetus of the Act (I hesitate to use the acronym IRA, because it applies to much else, including my retirement program, and I’m easily confused) is to lower drug expenditures for the government and for patients. It will allow the Center for Medicare and Medicaid Services (CMS) to negotiate prices for a set of high-cost drugs used to treat Medicare eligibles in the fee-for-service and limited-income subsidy program. Let’s assume the term “high-cost drugs” refers to the vast supply of complex biologics. The Act clarifies that this term is based on total Medicare annual costs, not the single-unit price of a drug.

High-Cost Drugs and the Biosimilar Special Rule

The one major provision that we’ll highlight is this: The Act requires Medicare to begin to use its leverage to lower the costs it pays manufacturers. It begins in 2026 with a set of 10 part D drugs, applies to a further 15 part D drugs in 2027, 15 more part D and part B drugs in 2028, and then 20 additional part D and part B drugs for each subsequent year.

At this past week’s Biosimilars 2022 meeting of the Drug Information Association (DIA), effects of the Inflation Reduction Act were a highlight of panels and informal discussions. Eva Temkin, JD, Partner, FDA and Life Sciences, at King & Spalding, LLP, noted that by 2029, we can have 60 drugs on the target listed. Being that biosimilar manufacturers often determine which reference products might make enticing investments based on current sales figures, many of these pipeline drugs will likely be affected. Judging by the timeline for developing a biosimilar today, this may already be the case.

Eva Temkin, JD

It is noteworthy that the original Medicare part D legislation passed in 2003 prohibited the federal government from actively negotiating for the drugs (Medicare Advantage plans and private part D plans were not prohibited). For buy-and-bill pharmaceuticals (covered under part B), Medicare generally reimbursed 106% of the average sales price of the drug.

There are several significant exceptions to pharmaceuticals that will be subject to mandatory Medicare negotiation:

  • Those in active competition with a generic or biosimilar drug
  • Medications that have received FDA approval less than 13 years ago for biologics and 9 years for small-molecule agents
  • Plasma-derived products (e.g., blood factors, CAR-T therapies)
  • Drugs whose sole indication is for the treatment of a designated orphan disease or condition

The challenge is easy to see: The provisions pertaining to biosimilars, the Biosimilar Special Rule, vastly complicate both the decision to move forward with a biosimilar development program and the ability to predict future revenues and opportunity costs. It was devised to actually help biosimilar manufacturers, but it falls well short of the mark, according to most panelists.

To Develop or not to Develop: Timelines and the Guessing Game

Chad Pettit, MBA, Executive Director, Marketing, Global Biosimilars Commercial Lead at Amgen stated in his presentation, “It puts government price controls on the reference product and limits the [financial] opportunity for the biosimilar manufacturer.” He also pointed out that “a big question is the misalignment in the timeline for developing the biosimilar versus the timeline in the legislation.” Ms. Temkin concurred on the timeline issue: “By the time price negotiation by CMS will occur, it will be late in the lifecycle of the biologic. Biosimilar manufacturing development [for that biologic] will be well underway at this point.”

Chad Pettit, MBA

Under the provision, a biosimilar manufacturer expecting to compete in the future with one of the high-cost biologics can file for a delay request, which would prevent CMS from targeting that drug for price negotiation for one year. This would be granted only if “there is a ‘high likelihood’ that the biosimilar will be licensed by the FDA and marketed within 2 years of the selected drug publication date for the relevant initial price applicability year.” A further one-year delay can be requested by the biosimilar maker, again if they can show “high likelihood” of licensure and launch, by offering clear and convincing evidence that the biosimilar “has made a significant amount of progress” towards both licensure and marketing. Nine months after the biosimilar has been launched, the reference drug is removed from the target list (as it now meets the provision for having biosimilar competition).

One bold move in the legislation applies to the biosimilar that has not launched after the delays were granted and expired: The manufacturer of the reference would have to pay a rebate to CMS to compensate for the savings lost to the government had price negotiation occurred without the granted delay. The one-year delay requests are not allowed when applied to biologics that have had long monopolies (≥ 16 yr) or for those with launch agreements presently in place between reference manufacturers and biosimilar competitors. Finally, the issue of skinny labels was not addressed in the Inflation Reduction Act: If a biosimilar manufacturer is seeking only one or a portion of the reference product’s indications, the Act applies as if all indications were sought.

How Will We Get Clarity for Biosimilar Development?

Rachel Turow, JD, MPH

The ambiguous terminology (who decides what represents a high likelihood of approval or launch?) and the separation of FDA licensure and launch date raises a host of patent litigation and settlement issues. Does Congress expect CMS to estimate when and if a patent settlement may be reached to allow launch? Rachel Turow, JD, MPH, Associate General Counsel, Regulatory Law and Policy and Head of US Regulatory Policy for Teva, advised, “A biosimilar manufacturer may need to disclose these patent negotiations to CMS if they are filing for the extension. I would think that they would need as much information as possible.”

Amanda Major, JD

Granted, this is an immense problem to grasp. At DIA’s meeting, Amanda Major, JD, Director of Government Affairs and Policy, Coherus Biosciences, said the Act “is more of an outline,” than a proscribed piece of legislation, partly due to the reconciliation process. She believes that Congress “thought to tie the biosimilar industry to the generic industry,” without understanding the timelines and cost differences in developing these two categories of pharmaceuticals. “Congress just doesn’t understand the development of biosimilars,” she added. However, according to Ms. Major, “it was huge that legislators wanted to do something for the biosimilar industry.” She emphasized that the industry members can talk to their Congressional representatives and make their concerns clear.

So, the law attempts to finally enact a method to address high pharmaceutical pricing and the burden on consumers. However, the unintended consequence may be a declining interest by companies to bring new biosimilars to market—which are effective at reducing biologic drug pricing.

Can Biosimilar Development Costs Be “Genericized”?

The argument has been raging for many years: What is the actual cost to bring a novel drug to market? The oft-cited figure from the 2014 Tufts Center for the Study of Drug Development of $2.6 billion seemed bloated. Several others have countered that the figure is actually far lower, perhaps a mean of $1.3 billion (median, $985 million; range, $0.3–2.8 billion). Of note, these figures include the cost of failed drug development, not just of developing the one product that achieves FDA approval. If the latter calculation were ever done, the estimate would be considerably lower.

biosimilar market

The high costs of drug development are directly related to the necessity for clinical trials. The Tufts Center claimed the average cost of a phase 3 study was $255 million. A 2020 estimate found a median cost of a pivotal clinical trial to be $48 million, with an interquartile range of up to $102 million. This also varied considerably by therapeutic area (hematologic drug trials cost a median of $311,000 per patient enrolled, compared with dermatology drug trials, which cost a median of $25,000 per patient).

According to McKinsey and Company, biosimilars cost between $100 million and $300 million to bring to market. I suspect that this number is ranging downward, as some recently approved biosimilars have not been required to do phase 3 trials. McKinsey’s analysis assumed up to 70% of these costs were associated with clinical trials. With biosimilar drug development, one does not have to generally consider the cost of failed clinical trial efforts: failure at this stage is very rare and should be, since the goal of the trial is equivalence (or at least noninferiority) to a biologic molecule that has already been proven to work.

The Basis for Lowering Biosimilar Development Costs

In comparison, the cost for small-molecule generic drug development may be less than $5 million, on average, partly because generic drug manufacturers simply have to prove molecular equivalence to the branded product. In other words, no clinical trials are needed.

Long-time biosimilar veteran Sarfaraz Niazi, PhD, stated in August that this testing is unnecessary, from a scientific basis. The clinical efficacy studies of biosimilars do not have sufficient sensitivity to detect significant differences in outcomes from those of the comparator reference products. The FDA has now approved several hematologic biosimilars without having clinical efficacy data. Even phase 1 pharmacokinetic and pharmacodynamics studies provide limited additional information above what in vitro investigations supply. In other words, the “sensitive analytical methods to characterize the molecular structure, correlate binding properties with structure, and establish a robust similarity of the critical quality attributes are of greatest significance in evaluating the safety and efficacy of biosimilars,” according to Dr. Niazi.

Late-stage clinical trials have not picked up important differences in these products, and have accounted for a large portion of their development costs. We’ve reported in the past that certain providers may feel uncomfortable prescribing biosimilars that have not been subjected to randomized, controlled clinical studies. Should we continue to cater to the confidence of these providers when there is ample evidence to decide whether a biosimilar will perform as intended based on the analytical data? This represents an opportunity to significantly lower the bar to entry for more prospective biosimilar manufacturers. Proving comparability and pharmacokinetic/pharmacodynamic equivalence, as in the generic drug industry, seems to render clinical trials unnecessary for biosimilars.

FDA Approves Fresenius Kabi’s Pegfilgrastim Biosimilar Stimufend

On September 6, Fresenius Kabi announced that it had received FDA approval for Stimufend® (pegfilgrastim-fpgk). This agent will be marketed in 2023, according to the company.

The first US biosimilar approval for Fresenius Kabi, Stimufend is indicated for use in patients with non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with clinically significant incidence of febrile neutropenia.

According to Michael Schönhofen, Fresenius Kabi’s Chief Operating Officer, “The FDA approval of our pegfilgrastim biosimilar is an important step to better support the treatment experience and clinical outcomes of cancer patients in the United States.”

Stimufend enters a crowded pegfilgrastim biosimilar category, as the sixth entry. The company intends to launch the prefilled syringe formulation early next year, and did not mention any pricing. Interestingly, the press release announcing the approval did mention that Fresenius Kabi is developing an on-body injector to compete with Neulasta OnPro®.   

Alvotech’s Adalimumab BLA Tripped Up by FDA

Alvotech and Teva plan to launch ATV02, their high-concentration, citrate-free, interchangeable biosimilar version of Humira® in July 2023. However, the US Food and Drug Administration (FDA) issued the company a complete response letter this week, citing Alvotech’s manufacturing issues, which could delay those plans.

The FDA has been catching up on facility inspections (see also Biocon’s issue, below), after COVID-19 related delays.  According to Alvotech, its manufacturing facility in Reykjavik, Iceland, was visited in March 2022 by inspectors, and the review “noted certain deficiencies.” The complete response letter does not seem to cite any clinical issues with study data or comparability between AVT02 and the reference drug.

According to a company press release, Mark Levick, Chief Executive Officer of Alvotech, stated, “Alvotech looks forward to addressing the deficiencies outlined in the post-application action letter and continuing to work with the FDA to close out the facility inspection. We aim to satisfactorily address the issues before the [BsUFA] goal date for the interchangeable biosimilar BLA in December.”

Receiving an initial complete response letter (considered akin to a rejection letter) from the FDA is not unusual for biosimilar manufacturers. However, they are rarely resolved within a couple of months and can cause significant delays in obtaining FDA approval. In this case, the launch date is still 10 months away, which gives Alvotech a bit of a buffer. Mr. Levick stated that despite Alvotech’s manufacturing issues, the company anticipates being “ready by our expected launch date in the US of July 1, 2023.”

Biocon’s FDA Inspection Issues

Biocon Biologics has had its own issues with the FDA’s inspections. On August 31, the company was cited for manufacturing issues at two plants in Bengaluru, India, and one at Johor, Malaysia, where it would produce a biosimilar forms of bevacizumab, trastuzumab, and two insulins. The company was issued citations for a total of 22 problems in the Indian facilities and six deficiencies in the Malaysian plant.

According to Biocon, “The observations primarily relate to the need for improving strategies for microbial control, enhancing quality oversight, augmenting the use of software applications & computerized tools to aid risk assessment & investigations and other procedural & facility upgrades.”

The FDA was conducting preapproval inspections for Biocon’s insulins and bevacizumab (MYL-1402O), and for an expansion of biosimilar trastuzumab (Ogivri®) production.

Samsung Bioepis and Organon Score Citrate-Free, High-Concentration Dose Approval

On August 17, the Food and Drug Administration granted approval to partners’ Samsung Bioepis and Organon for its new formulation of Hadlima™. This adalimumab biosimilar is now approved for use in a citrate-free, high-concentration formulation, in addition to its low-concentration, non–citrate free version that was approved in July 2019.

In its press release, Samsung Bioepis’ Vice President and Regulatory Affairs Team Leader Byoungin Jung stated, “With this approval, we now have both a low- and high-concentration adalimumab biosimilar approved by the FDA, marking an important step towards expanding treatment options for patients suffering from certain chronic, autoimmune diseases.” She added, “By leveraging our development expertise, manufacturing excellence and supply chain reliability, we will continue our work to ensure healthcare systems have more affordable treatment options available.

Organon will launch Hadlima in the US in early July 2023. At present, only Fresenius Kabi and Sandoz do not have a citrate-free version of their biosimilar at this time, although Fresenius, Alvotech, and Celltrion are still awaiting FDA approval on their original 351(k) applications. It is also important to note that for the manufacturers who have received approval for citrate-free versions, the approval is specific to its high- or low-dose formulation (i.e., the low-concentration version may have been approved as non—citrate free, but the high-concentration dose was not).

In Other Biosimilar News

Formycon AG announced that its ustekinumab biosimilar passed its Phase 3 test, with preliminary results demonstrating itself to be noninferior to the reference product Stelara® in patients with moderate-to-severe plaque psoriasis. This could put the product on pace for a 2024 launch, and to compete with Amgen’s and Celltrion’s candidates for first approved ustekinumab biosimilar.

Tocilizumab Biosimilars Approaching: Developments on Three Fronts

This IL-6 is approved for treating several autoimmune diseases, including rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, and systemic juvenile idiopathic arthritis. Roche’s reference product Actemra® was also the subject of an Emergency Use Approval for the treatment of COVID-19.

In 2021 Roche’s U.S. sales of Actemra totaled $1.9 billion. In a second-quarter conference call, Roche disclosed that sales increased substantially because of the drug’s utilization in patients hospitalized with COVID-19.

The principal patent for the reference agent’s rheumatoid arthritis indication was said to expire as early as 2015, and there appears to be several secondary patents in play. There is little public clarity on this point. As a result, tocilizumab may be another poster child for skinny label approvals, where approval is limited to indications that are off-patent (and certainly not COVID-19 related indications). Of course, the EUA will likely not come into play here, as it is certainly subject to a patent that will expire many years from today. Once the EUA expires, there is no guarantee that the FDA will grant a traditional approval for this indication.

With this level of revenue, and expired patents, one might think there were several competitors vying for a piece of this market. We could identify only three who have included tocilizumab in their active pipelines.

Fresenius Kabi’s MSB11456

Fresenius Kabi announced August 1 that FDA accepted its application for the Actemra biosimilar. A decision is expected during the second quarter of 2023. If the path to approval goes well, Fresenius Kabi will be positioned for a third-quarter 2023 launch of the first tocilizumab biosimilar.

One interesting aspect of this biosimilar is that Roche first introduced Actemra in 2010 as an intravenously administered biologic. The subcutaneous (SC) form was introduced in 2013; yet clinical testing of MSB11456 has been with the SC formulation. Roche is moving patients to the SC drug, which means that Fresenius Kabi is placed well if it obtains approval. The company is seeking biosimilar approval for both the intravenous and SC forms of the reference drug.

Bio-Thera’s BAT1806

Guangzhou, China–based Bio-Thera Solutions partnered with Biogen in 2021 for the manufacture and commercialization of its tocilizumab biosimilar. The company’s phase 3 clinical trial is complete, and the partners announced the positive results in June 2022. In this study the intravenous infusion of BAT1806 was tested against the intravenous infusion of Actemra.

This timing would seem to indicate a pending 351(k) application, likely before the end of this year, with perhaps a late 2023 decision and early 2024 launch.

Celltrion’s CT-P47

Celltrion expects initial results for its phase 1 trial of CT-P47 in October 2022. Not wanting to lose further time, its phase 3 trial for CT-P47 was initiated this month, with an estimated primary completion date of August 2023. This double-blind trial also tests the intravenous formulations of tocilizumab, in approximately 450 patients.

With these dates in mind, an FDA filing could be made by December 2023, with a decision in late 2024.   

Appeals Court Says “So What?” to Patent Thickets

AbbVie has successfully defended against a suit that accused the Humira® maker of violating antitrust laws by agreeing to settlements with all of the other biosimilar adalimumab makers and that it impeded competition through its filing of 132 patents on the drug.

U.S. Circuit Court Judge Frank Easterbrook ruled on August 1 that the patent thicket did not constitute a monopoly and that signing settlements such as these “are traditional resolutions of patent litigation” and that AbbVie did not pay any of the other manufacturers to settle. The case, brought by the City of Baltimore and a group of welfare-benefit plans, was originally dismissed in District Court. The affirmation of the appellate court in the Abbvie Patent Case will likely affect the U.S. Senate’s request of the Federal Trade Commission to investigate the anticompetitive effects of these patent thickets.

Judge Easterbrook, while acknowledging that several of the 132 patents held by AbbVie may be “weak” patents, they were patents nonetheless. The fact that the main composition-of-matter patent on Humira expired in 2016, but the existence of the patent thicket delays competition until seven years later, did not sway the jurist.

It is unknown whether the Circuit Court’s ruling will have an effect on the Senate’s current request that the Federal Trade Commission (FTC) investigate patent thickets. If nothing else, the FTC should investigate why Enbrel®’s approved biosimilar competitors are unable to launch until 2029.

Coherus Scores Approval of Cimerli® as Interchangeable Ranibizumab Biosimilar

In a couple of firsts, the U.S. Food and Drug Administration (FDA) approved the second biosimilar ranibizumab on August 2, but the first as an interchangeable ranibizumab agent and the first as an interchangeable that did not require extensive switching studies for approval.

The new biosimilar, named Cimerli (ranibizumab-eqrn), will be marketed in October 2022 by Coherus Biosciences. This agent, the product of a developmental partnership between Coherus and Bioeq (which is a joint venture between Polpharma and Formycon AG), was granted 180 days of exclusivity for its interchangeability designation.

Cimerli is approved and interchangeable for all five of Lucentis’ indications:

  • Neovascular (wet) age-related macular degeneration
  • Macular edema after retinal vein occlusion
  • Diabetic macular edema
  • Diabetic retinopathy
  • Myopic choroidal neovascularization

This approval is notable because the FDA’s approval is based on the usual pharmacokinetic and pharmacodynamic comparability data but only on a head-to-head study against Lucentis, not a switching study between the two. This is a departure for the FDA, which could lower the bar in terms of complexity and cost for other biosimilar makers seeking an interchangeability designation.

However, the interchangeability designation in the case of Cimerli may not be extraordinarily meaningful. Ranibizumab is typically injected intravitreally in a physician’s office. As a result, it is less frequently covered under the pharmacy benefit (though it may be distributed by specialty pharmacies to the clinician’s office, rather than purchased by the physician through a buy-and-bill arrangement). Therefore, it is far less likely to be substituted automatically for the reference brand.

Samsung Bioepis received approval for Byooviz® as the first ranibizumab biosimilar in September 2021 and began marketing this agent in July 2022. The next likely FDA decision in this category will be for Xbrane Biopharma’s biosimilar, which is expected shortly.

A Conversation With Sonia T. Oskouei, PharmD, Vice President of Biosimilars, Cardinal Health: Part 2

In the second part and conclusion of our conversation, Dr. Oskouei and I discuss several other interesting aspects of switching among products within a drug category, including biosimilars and follow-on agents, the potential barriers to switching in the ophthalmology category, and how to collect data on biosimilar switching.

Stanton Mehr, Content Director, BR&R: We can learn several lessons about biosimilar switching from the insulin category, related to the topic at hand. For several years, we’ve had follow-on products like Basaglar® and Toujeo® for glargine, and Admelog® for lispro. That’s not even counting Semglee®, which was a follow-on glargine before being designated a biosimilar (and interchangeable at that). With the exception of Semglee, these are not biosimilars, but for all practical purposes, they are really treated like biosimilars. We talk about switching data among biosimilars. How about among the follow-on products? We could also point to the two primary branded rapid-acting insulins (Humalog® [aspart] and Novolog® [lispro]). Switching between these two is also a possibility. Do we have any relevant real-world data?

Sonia Oskouei, PharmD: I believe the need for switching data and the discussion about switching will vary based on therapeutic area and product type. To your point, the insulin category is incredible! We now have six insulin glargines approved—with each one coming with a certain regulatory “labels”—including originator biologic (Lantus®), follow-on biologic (Basaglar®), biosimilar (Rezvoglar®, which is approved but not commercially available yet), and interchangeable biosimilar (Semglee). This dynamic is essentially the result of approval timing and the transition of insulins to be regulated as biologics (in March 2020).

Compared with insulin molecules, monoclonal antibodies are so much larger and represent a whole different level of complexity. There’s a reason why Semglee was the first interchangeable biosimilar approved in the U.S. The FDA’s updated guidance specifically for insulins states that switching studies may not be necessary to gain interchangeable designation, which is appropriate given the relatively simple nature of insulins as biologic molecules and the vast number of years of experience with these products.

BR&R: OK, do we have the need to monitor biosimilar-to-biosimilar switching data and outcomes? If so, who should be doing it?

Oskouei: I am a big advocate for any organization that can act proactively and collect this data. This discussion will happen more and more, and it is where we are heading in immunology. We want to make sure the infrastructure is in place for these data to be captured.

To your point, though, we still struggle a bit in this country with giving the appropriate credibility and weight to the accumulated international data. We really need to leverage as much as we can.

BR&R: Once the adalimumab biosimilars are added to formularies, we will begin to gain a lot of data. Whether we are in a position to capture may be a question for the BBCIC. [Note: In a separate conversation, Dr. Cate Lockhart, Executive Director of the Biologic and Biosimilar Collective Intelligence Consortium, told us that the organization has begun investigating the descriptive factors necessary to collect biosimilar-to-biosimilar switching information from the Consortium members’ claims databases. She noted that there may be a data lag of perhaps 18 months between the time the first adalimumab biosimilar is launched and enough data are collected and analyzed.] This might then, using U.S.-derived data, completely put the issues of safety and efficacy to rest. 

In any case, I do believe that some segments of the health care system—payers at least—already accept it as this is a fait accompli. And payers will be the major force behind the demand for switching.

Oskouei: To your point, it’s already happening. The payer landscape is a strong driver of switching. We saw that happen even earlier this year when one key regional payer went from preferring one particular infliximab biosimilar, to then preferring both a different infliximab biosimilar and the originator product. Of note, the new infliximab biosimilar that was being preferred (at parity with the originator) had the lowest market share at the time, too. So in this scenario, patients could be in the position to switch to another biosimilar or even back to the originator product. This is just an example of how the managed care landscape can, and does, influence adoption patterns.

Biosimilar-to-Biosimilar Switching and One Touchy Subject

BR&R: Among these individual drug categories, do you think one stands out that might be more risky than others in terms of biosimilar-to-biosimilar switching?

Oskouei: The ophthalmologic agents injected intravitreally stand out. There may be less clinical confidence there than in some other drug categories and perhaps some overall hesitation with biosimilar switching.

BR&R: I guess it’s a visceral reaction really, when talking about agents that act on the retina.

Oskouei: Following ranibizumab, we have aflibercept, which now is up to about eight candidates in the pipeline. That number isn’t too different than the number of adalimumab biosimilars, which isn’t just a coincidence. In fact, if you look at the top 10 selling pharmaceuticals in 2021, aflibercept is number 9. This is just a fascinating space, because beyond the biosimilars, there continues to be significant advancements in the treatment options for these retinal conditions, competing with both the existing originators and biosimilars. I really do enjoy focusing on it.

Subcutaneous Infliximab: What Does That Mean for Biosimilar Switching?

BR&R: I’d like to get your take on another aspect of the biosimilar-to-biosimilar switching scenario. On the horizon, we have the potential approval of Celltrion’s subcutaneous (SC) injectable form of infliximab. Obviously, this agent is derived from Celltrion’s Inflectra/Remsima infusible biosimilar. However, it requires approval not as a supplemental biosimilar application but as a new brand. It would offer the advantage of a quick self-injection at home versus an hours-long infusion at a provider office or infusion center, should it be approved in the U.S. Do you think there would be significant pushback if payers wanted to move patients to the SC formulation? What will happen in this situation?

Oskouei: That’s a very good crystal-ball question. I’ve tried to understand it by reviewing the performance of the SC version in Europe, where it is already available. There’s not a lot of adoption so far.

BR&R: According to Celltrion’s recent earnings report, the market uptake has been relatively low—in the single digits in certain regions. Now, U.S. payers might be more aggressive, given the right price, and on the pharmacy benefit. That may result in a different cost-sharing scenario for patients (possibly higher out-of-pocket costs).

Oskouei: I’m thinking about a couple of things here. You’re right, the SC form will be considered an originator biologic by the FDA. I also think certain physicians will view patients’ infusion office visits as opportunities for pharmacovigilance or monitoring. It is another opportunity to maintain engagement with the patient. It may not be a fit for all.

The SC formulation will have its place though. This type of product or dosage form expansion will continue to occur, and I view it as another positive that results from a healthy, and successful biosimilars market in the U.S. Innovation is further ignited through enhanced competition, which ultimately brings new innovative treatment options to patients that further improve outcomes. Those innovations may be through novel mechanisms of action, dosage forms, dual-product combinations, or other types of treatment advancements.

A Conversation With Sonia T. Oskouei, PharmD, Vice President of Biosimilars, Cardinal Health

In part 1 of this conversation, Dr. Oskouei and I take a deep dive into biosimilar-to-biosimilar switching, a potentially confusing topic that will grow in importance within the next couple of years. (Note: See also the BR&R post on a new study released this week on the safety of biosimilar-to-biosimilar switching—S.M.)

Stanton Mehr, Content Director, BR&R: Welcome, Sonia! This topic is certainly a favorite of mine, because very few people take the time to consider it fully. You brought it up at a biosimilars meeting in Boston in late June, and I thought this would be a good time to give it some visibility. So, let’s do our best to clearly differentiate, first of all, what we mean by “biosimilar-to-biosimilar switching.” How’s this different from automatic substitution, where we are switching to a biosimilar from a reference product?

Sonia Oskouei, PharmD: When we refer to biosimiliar-to-biosimilar switching, we’re talking about a scenario where multiple biosimilars are available for the same reference product. This is a very real scenario today in several drug categories. The patient may be initially prescribed a reference biologic and is then moved to Biosimilar A, and then the biosimilar-to-biosimilar switch would be to Biosimilar B for that same reference product. On the other hand, a new patient may first be prescribed a biosimilar and then they switch to another biosimilar for the same reference product.

BR&R: Let’s bring this scenario to ground level and consider the case of Mr. Jones. He’s been using the infliximab reference product Remicade® for many years to treat an autoimmune condition. Last year, his health plan decided to cover the biosimilar Inflectra® (and excluded Remicade); his provider did not object to the switch. This year, Mr. Jones changed health plans, but the new plan only covers the newest biosimilar, Avsola®. He will have to switch from one biosimilar to another. This is not an uncommon occurrence.

However, in its technical definition of biosimilarity, the Food and Drug Administration (FDA) does not address the comparability of one biosimilar to another—only to the reference product. Therefore, from a regulatory standpoint, Biosimilar A and Biosimilar B are not biosimilar to each other. What are the implications of this?

Oskouei: You’re spot on from a regulatory standpoint. This gets to the question I asked at the conference. As it stands today, the FDA is not responsible for considering whether one biosimilar is biosimilar to another.

I would say that there is greater demand for data on this topic, particularly in the immunology space—your infliximab example, and next year with adalimumab, and soon after with ustekinumab, tocilizumab, etc.

Oncologists’ Comfort With Biosimilar-to-Biosimilar Switching

Oskouei: We’ve seen this scenario play out from payer-driven initiatives to prefer one drug over another, like you mentioned. This has already occurred in the oncology space, too. Oncologists have a high level of comfort; our latest market research show that the majority feel comfortable even switching between biosimilars.

BR&R: Are oncologists switching patients to a different biosimilar between treatment cycles?

Oskouei: Even within the same treatment cycle. That speaks to the clinical confidence that oncologists have with these agents.

Some practices are even monitoring quarter-to-quarter trends in average sales price in an effort to decide which drug (biosimilar or biologic) makes the most sense to use. That may result in some switching among biosimilars.

If a practice switches between biosimilars for the same reference product, the conversation with patients may be very simple. If the patient asks, “Hey, this name looks different.” The response is, “Oh, it’s the same treatment, just a different manufacturer.”

BR&R: The evidence from Europe in terms of biosimilar switching, even with the adalimumab biosimilars (which were launched in October 2018), has been reassuring. The studies on biosimilar-to-biosimilar switching have not reported significant negative outcomes.

Injector Device Differentiation   

BR&R: There is no reason why these data cannot be extrapolated to the U.S. population. What about any differences in injector devices? Are there significant differences among them that can raise issues for biosimilar-to-biosimilar switching?

Oskouei: The human factors associated with a specific device and the resulting ease of administration—or risk or potential failure to administer—could be worth considering when a patient is self-administering. It will be interesting to see how these perceptions play out in the adalimumab category.

BR&R’s Director of Content

BR&R: Historically, payers have not heavily weighed the device types or patient preference for device types when making coverage decisions, particularly when many choices are available. Sonia, many of your organization’s clients are health systems and providers. Do you see health systems and physician practices putting a lot more weight on the type of administration device?

Sonia Oskouei

Oskouei: Yes, I do believe that they will put greater weight on the device. From current engagements with our health system network, along with my own previous experience practicing within a health system, we know that product characteristics such as device can absolutely influence formulary decisions. We might receive samples of a novel device for insulin, for instance. As part of our assessment, we would check to see how the device and package would fit into the automated dispensing machines to ensure optimal inventory management and pharmacy-nursing operations so that the treatments can be easily accessed for patients located in different hospital units. Ease of use for patient administration is naturally another important factor. These health care stakeholders understand how to evaluate products beyond clinical and financial characteristics. That’s why I believe the device will play a role in formulary decision making, particularly with providers.

BR&R: You mentioned insulin. It’s has been the poster child for device innovation over the years. I participated in some payer market research, more than 15 years ago, on a new insulin autoinjector. This one device was created for use by elderly people with poor vision and who have difficulty handling the small dials on injector pens. The manufacturer made it much easier to see the large numbers on the dosing dial and perform the administration. In that case, the payers were very impressed by the device. Many decided to cover this device for specific populations. However, I’ve never seen another case where payers thought the device made a big difference.

In part 2 of our conversation, which will be posted next week, Dr. Oskouei and I will discuss several other interesting aspects of switching among products within a drug category, including biosimilars and follow-on agents, the potential barriers to switching in the ophthalmology category, and how to collect data on biosimilar switching.