Tag: biosimilar switching

Biosimilar-to-Biosimilar Switching: The Data Say Its Fine

The question of interchangeability for biosimilars has haunted the US Food and Drug Administration since the promulgation of the Biologics Price Competition and Innovation Act of 2010. The FDA’s draft guidelines on interchangeability evolved very slowly, and the biosimilar industry had to work to (1) keep up with the guidelines as they gained clarity, (2) tirelessly wage war on misinformation as to what an interchangeable biosimilar actually represented, and (3) grasp the value of interchangeability as a for-profit enterprise and whether to charge forward with the necessary clinical trials.

In this column, we have often addressed the interchangeability designation, and how it may be perceived. Leaders in the industry, like Hillel P. Cohen, PhD, Executive Director, Scientific Affairs, Sandoz, have hammered home strong arguments that interchangeable biosimilars are not “better drugs” than their noninterchangeable brethren. They are simply subject to additional switching studies to confirm their clinical similarity to the reference product. That does not mean they are more similar to the reference product than a standard biosimilar.

At the 2021 DIA Biosimilars conference held virtually this week, Dr. Cohen restated logic that may be obvious but less often discussed: if two biosimilars are deemed highly similar to the same reference product, those two biosimilars, through the Law of Transitivity, should be highly similar to each other.

Though logical, the concept of biosimilar-to-biosimilar interchangeability is not acknowledged on a regulatory basis. However, the potential for biosimilar-to-biosimilar switching is undeniably real.

Biosimilar-to-Biosimilar Switching Likely to Occur

A large proportion of patients receiving chronic therapy with biologics will no doubt change health plans or insurers over time. This happens voluntarily (e.g., they may choose a lower-price plan from year to year) or involuntarily (i.e., their employer changes the plan offering from one year to the next). These plans utilize their own drug formularies. Considering the launch of perhaps eight adalimumab biosimilars in 2023, health plans will likely prefer different preferred adalimumab products, based on the contracting offers they receive or the characteristics of the biosimilar (e.g., citrate free, high-dose formulation, interchangeable). The same can be said for insulin products, infliximab, ranibizumab, and even chronically used oncology agents. Assuming that is the case, biosimilar-to-biosimilar switching may be somewhat common in 2025.

Is that an issue? Likely not, said Dr. Cohen. He believes that any immunogenicity concern is a hypothetical argument, “and no empiric evidence exists to support the concern. Furthermore, no data has been published to support immunogenicity on a mechanistic basis.” The biosimilar is highly similar not only in efficacy and safety but also with regard to immunogenicity.

What the Data Say

Most of the available data on biosimilar switching comes from Europe, where biosimilars have accumulated over 2 billion patient treatment-days of exposure. Countries adopt whichever biosimilar has the lowest price, based on tendering systems. This may mean that more than one biosimilar is accepted, and these tenders can change from year to year. The regulatory concept of interchangeability does not exist in the EU, and switching may occur in both infusible as well as injectable agents.

Dr. Cohen pointed out that published studies of biosimilar-to-biosimilar switching, based on the European experience, amount to 12 trials, all of which used observational data. Two trials involved adalimumab, eight infliximab, one etanercept, and one involved rituximab. These totaled 1,223 patients. Additionally, 8 studies were reported as meeting abstracts, six of evaluated infliximab biosimilars, and one each for adalimumab and etanercept. Those trials totaled 1,295 patients. Although the studies varied in terms of their limitations and design rigor, they were consistent in finding no differences in patient clinical outcomes, immunogenicity, or pharmacokinetics and pharmacodynamics.

“From a scientific matter, we can trust biosimilar-to-biosimilar switching,” stated Dr. Cohen. “There have been no safety issues, and we’ll very likely have more (observational) data in upcoming years.” If the data continue to show no significant issues, “it would be reasonable to conclude that biosimilar to biosimilar switching does not have any clinical impact.”

Observational data will have to do here, as no biosimilar manufacturer would reasonably spend the money to conduct a randomized, controlled head-to-head trial with another biosimilar.

The Declining Value of Interchangeability Over Time

The inevitability of this discussion has a noteworthy effect: It lowers the value of an interchangeable designation over time. Consider the adalimumab situation, which is similar to one we posed a few years ago: A health plan decides to prefer biosimilar C, which is designed by FDA to be interchangeable to Humira®, around mid-2023. In doing so, the plan places an NDC block on the reference product, and moves to convert as many patients as possible to interchangeable biosimilar C. It achieves more than 80% conversion through substitution at the pharmacy or specialty pharmacy. However, the plan is offered a far better price in 2024 on biosimilar F, a noninterchangeable drug. Biosimilar C no longer has an interchangeability advantage. All of the patients who were converted from Humira were already converted. And biosimilar C is not considered interchangeable (by the FDA) with any approved biosimilar. Payers, however, will likely consider these agents freely switchable with each other, depending on how much weight the payer gives to citrate status and dose concentration characteristics of the products.

What does interchangeability mean in the realm of insulin products? We’ll delve into that rabbit hole in the next post.

How Confusing Is Biologic and Biosimilar Substitution?

Evidence is mounting, especially from Europe that biosimilars to a single reference product result in the same clinical outcomes, with no appreciable safety issues. Evidence of this type from America will take time to accumulate, because competition in categories with multiple biosimilar options has been much more limited.

British Columbia biosimilar uptake

The recent announcement in British Columbia of the province’s decision to switch patients with inflammatory bowel disease from Remicade® to biosimilars has once again inflamed some passions. This is part of a broader effort by the Canadian province to increase utilization of biosimilars to gain economic savings. The Canadian GI Society, an advocacy group, published a letter firmly against the plan. They believe only the physician and patient should decide whether a biosimilar switch should occur. The British Columbia government, on the other hand, will pay for either Renflexis® or Inflectra® but not Remicade® after March 5, 2020. Even if patients have been taking the reference product, they will have to switch to one biosimilar or the other.

The Biosimilar Switching Argument

With medical experience supporting the case for switching, the argument by this Canadian advocacy group is less than solid. There may be the need for a medical exception for the infrequent patient taking infliximab, but these drugs can be effectively switched: there is no meaningful difference in effectiveness and safety outcomes on a population-wide basis among infliximab choices.

That said, here is where the supporting arguments get somewhat messy. The Food and Drug Administration (FDA) approves a biosimilar based on its equivalence to a reference product (not to other biosimilars). At the implementation of the Biologics Price Competition and Innovation Act, a biosimilar manufacturer has been required to show that its biosimilar was comparable in physiochemical, pharmacokinetic, and clinical studies to a designated reference product (i.e., US-licensed version of the originator). That required some manufacturers to first prove the equivalence of the US-licensed version to the EU-approved originator in a “bridging study.” This requirement was borne from the understanding that the US- and EU-licensed originator biologics make not be exactly the same either—biosimilars of each other. With more experience, the FDA has backed away from this requirement, understanding that the clinical outcomes differences between two licensed originator products are negligible.

The Laws of Transitivity and Biosimilar Switching

However, the FDA has not revised its opinion on whether two drugs proved to be biosimilar to one reference product are biosimilar to each other. Nor whether an interchangeable biosimilar might be considered interchangeable with other biosimilars. The answer remains: The evaluation process does not require such testing to gain basic biosimilar approval. In other words, the evidence did not yet exist.

This all relates to the basic premise of so-called “nonmedical substitution.” The issue is whether a payer-initiated change with a noninterchangeable biosimilar is considered to be more like therapeutic or generic substitution. Therapeutic interchange or substitution takes place when a drug is switched for another in the same category (e.g., switching Lipitor for a different statin rather than the generic atorvastatin).

Therapeutic Interchange vs. Biologic Substitution

A payer would be hard pressed to justify an unauthorized switch of adalimumab for infliximab. They are very different TNF-inhibitors. Patient outcomes would likely be affected in some way. Are Inflectra and Renflexis—different infliximab biosimilars—to be considered wholly different biologics? Because the FDA does not endorse that Inflectra and Renflexis are biosimilar to each other, it does imply (whether wrongly or rightly) that they are different biologic brands. If this was considered in the traditional sense, switching might be construed as an example of therapeutic interchange.

Framing the argument in this manner can drive patient and provider resistance to biosimilar uptake. Misinformation? Rather, I believe that this is an embodiment of the ambiguity of our regulatory policies. Certainly, payers don’t subscribe to it; they cover one versus another based more on net costs—certainly not on clinical outcome differences. For payers, it is more black and white; for certain other groups, much remains gray, especially when people believe more decision-making authority is being challenged. Only greater biosimilar clinical utilization, proof of savings, and better dissemination of education about this experience will change advocacy’s perspective .

In Moving Patients to Biosimilars, Transferring Patient Services Is Key

John Q. Smith, a patient of Dr. Kelly’s has been receiving his biologic therapy for rheumatoid arthritis for more than a decade. He has been in contact with the reference manufacturer’s patient services hub for several years, and utilizes it both for payment assistance and for nurse support. He appreciates the co-pay coupon, which can save him hundreds of dollars, especially since his health plan has a high deductible.

The following year, his employer has changed its sponsored plan, and Mr. Smith finds himself in a situation where originator biologic is no longer preferred (or even excluded). Barring a successful medical exception appeal, he will have to start biosimilar therapy. He worries not only about whether the biosimilar will be as effective and safe, but also whether he will have to bear more of the cost of treatment. I might argue that the biosimilar drug maker’s hub services are extremely important to gaining uptake for patients and even some providers.

From a 30,000-foot view, this may not be as widely considered as contracting with payers and health systems. Early on, I assumed that all manufacturers’ patient/provider hub services were as similar as the biosimilarity of the drugs. However, it is one of the ground-level details that optimizes (or undercuts) an opportunity for gaining biosimilar uptake.

Consider if a biosimilar maker’s services program exposed its patient population to significantly greater cost sharing. The collective howl would certainly be heard by their doctors (and probably their plan or insurer). If the physicians’ offices received worse coordination services or administrative assistance from the new hub provider, the push back would be considerable as well.

The bar for patient and provider hub services is pretty high, but it is consistent. For example, Janssen’s CarePath covers the bases for Remicade®. Merck’s Renflexis® Access Program focuses on copay and ongoing financial assistance for patients and on coverage/reimbursement/prior authorization support and answering coding questions for doctors’ offices. Pfizer’s enCompass offers similar support functions.

When biosimilar manufacturers do receive the opportunity for plan coverage, they must ensure a transition of services that feels seamless to the patient and provider. Otherwise, John Q. Smith and his brethren will make their dissatisfaction (and challenges) known to anyone who will listen. Without a smooth transition, biosimilar makers risk not only drug coverage, but their reputation as well.

In Canada, Mandated Biosimilar Switching Again Shines Spotlight on Need for Education

The Canadian province of British Columbia mandated on May 27 that patients receiving public coverage who are using reference insulin glargine, infliximab, and etanercept therapies must be switched to biosimilars in the next 6 months. This has caused a predictable flaring of tempers, and generated some opposition on my Twitter feed.

The article in the (Vancouver) Globe and Mail announcing the decision quoted the province’s health minister: “Biologic drugs continue to be a growing pressure for public drug plans. If we continue to spend more and more of our finite health dollars on biologics, it restricts our ability to provide coverage for existing drugs … not to mention hindering our ability to list any new drugs.” According to the article, British Columbia will save nearly $100 million through 2022 as a result of the policy. This policy does not affect those individuals who receive their drugs through private insurance or employer-sponsored plans (which can act independently of the government).

Like in the US, Janssen’s Remicade® still accounts for 92% of the infliximab utilization in Canada.

On the morning after the decision was announced, opinion on Twitter was divided. One side acknowledged the limited dollars available in the Canadian system. The other side wondering whether this economic decision will result in deleterious outcomes. Here, I breakdown some of the more notable negative responses:

“Specialists prefer the biologic to the biosimilar”

Any physician treating a patient with stable chronic disease would not want to change the drug regimen without good reason. However, the point of the tweet may have been that specialists actually believe the biosimilar to be inferior. In dozens of interviews with specialists, I’ve not found this to be the case. They accept the biosimilar to be safe and effective, as determined by the Food and Drug Administration (FDA), and that the biosimilar should not provide a greater risk to a treatment-naïve patient compared with the originator product. A new French study found that patients with ulcerative colitis taking Inflectra® actually had fewer serious side effects than those taking Remicade. Does this mean the biosimilar is a better medication? No one would claim this is the case. However, it is certainly no less safe.

“For teens hoping to live for decades, are 2-month to 1-year studies adequate?”

It is true that regulatory groups like the FDA do not require biosimilar agents to be subjected to long-term safety evaluations. The FDA has emphasized that it values the physiochemical and pharmacokinetic comparability to be far more important in biosimilar evaluations. In fact, the argument has been made that phase 3 trials are of very limited use in biosimilar testing.

That said, there are at least 2 areas where longer-term evidence does exist and can be generated: (1) the actual experience in Europe, where biosimilar infliximab has been available for use since 2014, (2) and the ongoing efforts of organizations dedicated to studying and monitoring postmarketing use and outcomes. For the former, see the previously cited French study, involving nearly 5,000 patients with ulcerative colitis. For the latter, consider the Biologics and Biosimilars Collective Intelligence Consortium in the US.

“Biosimilars, well, they’re synthetic, not the same at all”

Without regard to how the writer defines “synthetic,” biosimilars are engineered proteins, just as reference biologic are engineered and produced using live cell lines. Of course, no one is arguing that biosimilars are exact copies of biologics. Even manufacturers of interchangeable biosimilars would never infer this.

It has been pointed out repeatedly that the originator drugs introduced years ago are, by our definitions today, biosimilars of themselves, because of manufacturing changes, production modifications, etc. Therefore, making the statement that biosimilars “are not the same at all” is not really true, particularly if we view the similarities in molecular structure, pharmacodynamics and pharmacokinetics, and patient outcomes.

When Biosimilars Are Switched for Each Other

In April, the Center for Biosimilars reported on a study of infliximab switching in patients with psoriasis. The researchers found no differences in safety or effectiveness in 24 patients taking infliximab biosimilars. I had to read the copy twice; it took me a couple of moments to understand the significance of this small study.

Beyond the disease state, the interesting part of this investigation is that the switch was not made between the reference product (Remicade®) and a biosimilar, but between two biosimilars (Inflectra® and Renflexis®). With today’s focus on the interchangeability guidelines and the well-publicized NOR-SWITCH studies, the potential questions around biosimilar to biosimilar switching is often overlooked.

biosimilar to biosimliar switching

As more biosimilars are approved and launched for several disease categories, this concept will prove to be as important as the reference biologic to biosimilar switch (or vice versa). The reason is simple: Coverages among plans will vary, and as patients change plans, they may need to change from one biologic version of the reference product to another. It is easy to visualize the scenario where Big Health Plan covers biosimilar A and City Health Plan covers biosimilar B, and patients changing plans every year or so might need to switch therapies. Then biosimilar to biosimilar switching becomes a common occurrence.

In 2019, this is not yet the new normal. Infliximab coverage is commonly limited to Remicade, and if a plan or insurer decides to cover another version of infliximab, payers usually choose one biosimilar to improve the deal they receive. Therefore, a patient changing insurers at the end of the year will most likely not have switch from one biosimilar to another (e.g., from Inflectra to Renflexis). They might, however, have to change from the innovator product to a preferred biosimilar.

For the other competitive, marketed biosimilar drug categories (filgrastim and pegfilgrastim), therapies are given less on a chronic basis, so the need for mid-regimen switching among biosimilars is pretty small.

When the FDA evaluates a biosimilar, it requires comparative physiochemical and pharmacokinetic analyses between that biologic and its reference agent. The FDA cannot find that two infliximab biosimilars are biosimilar to each other. That only stands to reason and the laws of transitivity. Yet, possible differences in immunogenicity, for instance, may cause some concern for physicians and patient groups. This has not been found to be a concern in Europe, where multiple biosimilars (including infliximab) have gained years of experience. Experience is also accumulating with another immunologic biosimilar, adalimumab, as multiple versions are widely in use since October 2018.

Payers may be less concerned, and for basic reasons: (1) they anticipate that FDA approval is sufficient proof of safety and efficacy, (2) they seek to cover the most cost-effective products, and (3) the scenario has not yet arisen to any degree. In the US, switching between biosimilars is still mainly a hypothetical problem.

The benefits of interchangeability in this case are hypothetical as well. One might expect that two adalimumab agents that are designated interchangeable to an innovator product would likely be associated with fewer fears of safety problems when switched with each other. To use a well worn cliche, we’ll cross that bridge when we come to it.

Managed Care Pharmacists Survey: We’re on Board With Biosimilars, and Maybe Even Switching

Few suspected that payers were doubters of the clinical value of biosimilar agents, and as the first biosimilars were approved (2015-2016) managed care medical and pharmacy executives were somewhat reluctant to embrace them. However, within the past couple of years, managed care pharmacists told me these concerns were dissipating rapidly. (See the recent interview with Steven Avey as an example.)

A new survey on biosimilars released by the Academy of Managed Care Pharmacy (AMCP) confirmed that managed care pharmacists are on-board with biosimilar safety, efficacy, and the potential for switching. Conducted in October 2018, this survey offers solid evidence of the most recent thinking by pharmacy professionals on biosimilar access and promise.

Investigators from the Academy, PRIME Education, and the University of Pennsylvania analyzed the first 300 responses to their broad solicitation of AMCP members and associated professionals. Thirty-eight percent worked within a health plan or insurer setting, 22% in a pharmacy benefit management organization, and 40% in a specialty pharmacy.

The researchers stated, “84% agreed or strongly agreed that FDA-approved biosimilars are safe and effective for patients who switch from a reference biologic.” Although this does not specifically endorse switching to biosimilars from reference products, it does imply that the payers have no problem with the concept. They were still a bit wary of extrapolation of indications, however. A slight majority (54%) agreed or strongly agreed that extrapolation of indications for biosimilars was safe and effective.

The surveyed payers were asked to select the most effective strategies for increasing biosimilar utilization (i.e., overcoming barriers to biosimilar use). The responses rated the following strategies “extremely likely to be effective”:

  1. Clear FDA guidance for substituting reference biologics with lower-cost biosimilars that meet requirements for interchangeability (54%)
  2. Expanded Medicare and Medicaid policies that promote biosimilar use (41%)
  3. Educational programs for prescribers focusing on evidence from studies in which patients switched from reference biologics to biosimilars (39%)
  4. Formulary policies that promote biosimilar use for treatment-naive patients (39%)
  5. Educational programs for prescribers focusing on real-world evidence from postmarketing studies on biosimilars, including European studies (34%)
  6. Reduced cost sharing for patients using biosimilars (34%)
  7. Incentivizing providers by adjusting fee schedules for biosimilars (34%)

It should be noted that of the 16 potential strategies presented, only 2 (see below) did not garner more than 50% of respondents believing that they were at least “likely” to be effective.

In contrast, the strategies least likely to be effective were:

  1. Requiring therapeutic drug monitoring for patients who switch to biosimilars to address concerns about immunogenicity (28%)
  2. Incentivizing providers by using quotas for prescribing biosimilars to treatment-naïve patients (28%)
  3. Educational programs for prescribers focusing on streamlined billing, coding, and reimbursement processes for biosimilars (12%)
  4. Laws that promote greater public transparency on pricing of biosimilars and reference biologics (11%)

This survey does demonstrate that pharmacists’ comfort levels with biosimilars are fairly high. At the time of the study, it is likely that they had significant experience with only filgrastim and infliximab biosimilars (based on launch dates of the other approved agents, including epoetin and pegfilgrastim).

Challenges Extremely Difficult Difficult or Extremely Difficult
Concerns about biosimilar safety and efficacy among prescribers 16% 61%
Pricing and contracting issues 22% 57%
State laws for substitution and interchangeability 17% 53%
Concerns about biosimilar safety and efficacy among patients 13% 49%
Formulary management issues 8% 35%
Concerns about biosimilar safety and effiacy among payers 7% 23%
Data adapted from
https://www.jmcp.org/doi/full/10.18553/jmcp.2019.18412 .

In terms of these pharmacists’ opinions as to the most challenging barriers to biosimilar adoption, they rated as “extremely difficult”: pricing and contracting issues (22%), state substitution and interchangeability laws (17%), and prescriber concerns about efficacy and safety of biosimilars (16%).

When asked what biosimilar manufacturers can do, their responses emphasized pricing: Use contracting “to overcome the current [biologic reference] products’ substantial rebated dollars” and “come to market with more aggressive discounts off [average wholesale price].”

A Blueprint for Successful Infliximab Biosimilar Switching

Payers have not been quick to add biosimilar infliximab to their drug coverage. Yet, biosimilar switching is the objective for most health plans and insurers who are thinking about long-term savings. Even if they do not exclude the reference product Remicade® from coverage, some health plans, like Kaiser, have been moving forward in this effort.

At the Academy of Managed Care Pharmacy’s Nexus 2018 meeting in Orlando this week, two clinical pharmacy specialists from Kaiser Foundation Health Plan of the Northwest described what may be a best practice in converting patients to biosimilar Inflectra®.

RELEVANCE OF BIOSIMILAR SWITCHING AT THE PLAN LEVEL

Kayla Hubrich, PharmD, emphasized the importance of patient education, and patients’ reliance on Google for research. She said, “When patients will turn to Google and type in ‘Should I switch to an infliximab biosimilar?’ the first search result they see is an ad for ‘Finely Tuned,’ a Janssen website.” This, of course, discourages the use of biosimilars.

At Kaiser Foundation Health Plans, coverage decisions are made at a national level for its 12.5 million members and implemented at the regional plan level, according to Lynsey Smith, PharmD. The health plan made Zarxio® its preferred filgrastim product in 2016, and registered 96% of all filgrastim dispensings in self-injected settings, and 100% of all clinical administrations for this biosimilar.

Biosimilar switching
Source: Kaiser Foundation Health Plan

Obtaining that level of use means that not only treatment-naive patients were using Inflectra, but also those using Remicade in the past. Dr. Smith outlined the key steps in this conversion, starting with the providers. “For new starts,” said Dr. Smith, “the tactic was just to have the doctor choose the biosimilar” using tools incorporated into the electronic health record that encouraged them to order the preferred product. Concerning those patients needing to be converted from the reference product, Kaiser asked the prescriber to sign a ‘Therapeutic Equivalency Protocol’ agreement, which authorized the plan to make the switch. The biosimilar switching agreement was voluntary, and virtually all the rheumatologists, dermatologists, and gastroenterologists signed. “One GI out of 20 declined to authorize the switch in patients already receiving Remicade,” she said.

Kaiser emphasized patient notification and education. A letter, signed in their doctor’s name, was sent to each patient at least 2 weeks before the conversion date, explained Dr. Smith. Clinical Pharmacy Services was enlisted to answer patients’ questions via phone and E-mail. Patients were also given informational handouts about the biosimilar switching program at their infusion center.

“During this process, the clinical pharmacists received 30 to 40 calls,” she said. “The patients’ main concerns were whether the product was going to work as well as their old drug and whether they would receive the same copay assistance as before.” Active patient outreach was not conducted after the switch was instituted. Any patients reporting issues or concerns were triaged through Clinical Pharmacy Services.

Dr. Hubrich added that infusion center pharmacists reviewed all patients scheduled for infusions one week ahead of their appointment. The infusion center confirmed that the provider signed a TEP document, that patients were sent the notification letter, and that the infliximab order changed to Inflectra. Kaiser also developed a nurses’ protocol for the biosimilar switch and worked to educate practice staff about the program.

 

INFLIXIMAB SWITCHING PROGRAM RESULTS

The conversation program began on May 1, 2017, with dermatologists and rheumatologists, focusing on patients who were getting their first infliximab treatment. Dr. Hubrich stated that notification letters were sent to 158 patients. Three weeks later, current patients began to be switched from Remicade to Inflectra. The GI conversion began on May 11, 2017 with treatment-naïve patients, and letters were sent to 188 adult patients (as Inflectra did not have the pediatric ulcerative colitis indication). Active therapeutic switching began in September. “The one GI who declined to sign the TEP agreement joined in 2018,” said Dr. Hubrich. This is likely because of the experience of this doctor’s peers.

A total of 22 patients (6.4%) across specialties reported adverse events, with nine being changed back to reference product (2.6%), five changed to a different medication class, four resulted in a dosage increase, one patient decided to discontinue therapy, and three continuing biosimilar infliximab treatment without any change. They did find that 12.8% of patients experienced some “nocebo” effects, despite the fact that “no statistically significant changes in effectiveness and safety were observed after a medican of four infusions in 9 months of study.”

Dr. Smith asserted that communication was critical to the success of the program, with patients and providers. The provider’s agreement to sign the TEP document was a necessary step, and was accepted by all Kaiser’s specialist providers.

It must be emphasized that Kaiser has a different magnitude of leverage over its physicians than a network plan like Aetna or CIGNA. Yet a biosimilar switching program like this could be a blueprint for other integrated health plans to move forward if they desire to move patients quickly and efficiently to biosimilar therapy.

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.