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
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
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
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.
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
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.
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
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”:
Clear FDA guidance for
substituting reference biologics with lower-cost biosimilars that meet
requirements for interchangeability (54%)
Expanded Medicare and
Medicaid policies that promote biosimilar use (41%)
Educational programs for
prescribers focusing on evidence from studies in which patients switched from
reference biologics to biosimilars (39%)
Formulary policies that
promote biosimilar use for treatment-naive patients (39%)
Educational programs for
prescribers focusing on real-world evidence from postmarketing studies on
biosimilars, including European studies (34%)
Reduced cost sharing for
patients using biosimilars (34%)
Incentivizing providers by
adjusting fee schedules for biosimilars (34%)
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.
contrast, the strategies least likely to be effective were:
therapeutic drug monitoring for patients who switch to biosimilars to address
concerns about immunogenicity (28%)
providers by using quotas for prescribing biosimilars to treatment-naïve
programs for prescribers focusing on streamlined billing, coding, and
reimbursement processes for biosimilars (12%)
promote greater public transparency on pricing of biosimilars and reference
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).
Difficult or Extremely Difficult
Concerns about biosimilar safety and efficacy among prescribers
Pricing and contracting issues
State laws for substitution and interchangeability
Concerns about biosimilar safety and efficacy among patients
Formulary management issues
Concerns about biosimilar safety and effiacy among payers
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
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.
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.
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 US), 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.