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.

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.

 

What Happens When Switching Among Biosimilars?

Late last year, I wrote about a biosimilar challenge that could be on the horizon. With the approval of the second infliximab biosimilar (infliximab-abda by Samsung Bioepis), that horizon is a lot closer. However, we are no closer to understanding how to address the issue.

When Renflexis™ is launched in October (it is unknown whether the US Supreme Court ruling that wiped away the 180-day postapproval waiting period will affect this), 3 noninterchangeable versions of infliximab will be available. Based on patient turnover in health plans, the following scenario will soon occur.

 

Lee 2
Image Copyright 2017 by Lee Fogel

Mr. Jones, a 39-year-old man with Crohn’s disease, works for a large self-funded employer. He has been taking Remicade®, the reference product, for some time. In January 2018, his employer decides to change its plan offerings. His new health plan does not cover Remicade, favoring Inflectra® (infliximab-dyyb) instead. He could seek a medical exception to continue on Remicade, but his new plan actually offers considerable incentives to switch, including significantly lower cost sharing. After discussing the situation with his doctor, he makes the change, and experiences much the same clinical results. In 2019, his employer makes another change in plan. And this plan covers Renflexis on the specialty tier but has Remicade available on the higher-cost nonpreferred specialty tier. He and his physician are unsure of the best move.

Keep in mind that it would be rare and probably makes little sense for a health plan to cover both biosimilars and the reference product. At some point, the plan will seek a contract that leverages marketshare. In the scenario above, at what point does the patient unduly risk the development of neutralizing or antidrug antibodies?

No data have been published on switches among 3 biosimilar products. These agents are not designated as interchangeable—though Pfizer’s Inflectra may be closest to it based on its NOR-SWITCH investigations; therefore, no one is truly confident of what might or might not occur with regard to efficacy or safety. I suspect it may be some time before switches among reference product, biosimilar A, biosimilar B, or even biosimilar C may be considered routine.

Patients receiving biologic products for serious chronic diseases may also be subject to case/care management. This is not a clean transition when changing health plans. The situation described above will likely happen in the near future with infliximab and possibly adalimumab (once the patent litigation is cleared). It would be a good idea for health plans and insurers to start reviewing their options now to ensure both patient safety and cost-effective decision making.

Large European Society Lends Its Support to Switching

In a recent statement published in the Journal of Crohn’s and Colitis, the European Crohn’s and Colitis Organization (ECCO) announced its support for switching from an originator product to a biosimilar in patients with inflammatory bowel disease  (IBD).

In its position statement, ECCO asserts that switching from the originator to a biosimilar in patients with IBD is acceptable if it is in line with national recommendations and has been discussed among the physician, nurse, pharmacist, and patient. This view, which represents a change from ECCO’s previous position, is based on the clinical experience gained from investigational studies and postmarketing trials using the biosimilar version of infliximab.

Lead author and President Elect of ECCO, Silvio Danese, MD, said, “Findings from the 2015 ECCO survey of IBD specialists found that around 80% of specialists are either totally confident, very confident or confident enough in using biosimilars, which is a huge change compared to 39% when a similar survey was conducted back in 2013.”

As for all biologics, traceability should be based on a robust pharmacovigilance system. The authors also noted that several postmarketing studies are ongoing or near publication, which lends further support to the improved confidence in the safety and efficacy of the biosimilar (Celltrion’s Remsima®, which is marketed in the US as Inflectra®).

This marks a significant shift in attitude from the previous ECCO position paper, which advised that switching from an established biologic to a biosimilar was inappropriate and called for more data on the safety and benefit of biosimilars in general.

Dr. Danese and his colleagues concluded, “there have been no reports so far that switching from the reference to the biosimilar infliximab [Remsima] has caused problems, in either adult or pediatric IBD patients. On the contrary, an increasing number of publications have shown that there are no safety or efficacy concerns about switching.”

Largest French Hospital System Decides on Infliximab Substitution

Although Celltrion and Pfizer’s Inflectra® was not approved as an interchangeable product to Remicade®, this will generally not matter to US payers when deciding the coverage of the product in patients who have not had anti-TNF treatment in the past. This is of even less importance to French prescribers, where the European Medicines Agency does not have a mandate to rule on the interchangeability of biosimilars. That means it’s entirely up to the health systems and physicians to decide this matter, including whether to allow substitution or switching.

The basic question is whether the evidence exists this biosimilar monoclonal antibody is close enough therapeutically to the innovator product to justify substitution. In a commentary, French physicians stated that substitution is a foregone conclusion in their country. There is a French law forbidding the practice of automatic therapeutic interchange, preventing systematic institution of the practice.

The biosimilar version of infliximab was approved in 2014, and as governments in the EU have generally not taken a stance on substitution, hospitals and other healthcare systems have addressed this issue, building a consensus based on the experience of the Assistance-Publique Hôpitaux de Paris (AP-HP) (this is the largest public hospital group in Europe, accounting for 22,000 beds and caring for 12 million patients). Unlike in the US, infliximab is administered in the hospital setting in France.assistance-publique-hôpitaux-de-paris-office

However, AP-HP does have its version of the typical US Pharmacy & Therapeutics Committee, called the Committee on Medicinal Products (COMED). This hospital system decided that COMED should decide for itself whether infliximab biosimilars yielded essentially equivalent outcomes and on substitution issues within its hospitals. Last year, it came to the conclusion that the two available biosimilars were substitutable for each other and the originator product.

Furthermore, COMED recommended that (1) “a vigorous post-approval surveillance (full traceability) of these products should be implemented in AP-HP” and (2) “physicians should be encouraged to take part in the registries that will be implemented by the medical disciplines concerned in the AP-HP.”

Back in the US, will payers make their own public statements on switching? This is unlikely, owing to the potential for negative press, but it could ease any concerns prescribers have in using biosimilars. Again, the choice of prescription, without an interchangeability designation, is still in the doctor’s hands. It will be largely up to them to speed adoption.