Unless the pharmaceutical rebate is applied at the time patient cost sharing is calculated, there may be no patient incentive to ask for a biosimilar. It’s all in the timing of the drug rebate.
Consider the scenario in which a patient with inflammatory bowel disease is prescribed infliximab by the doctor. Let’s use Health Affairs figures from 2019: The list price or wholesale acquisition cost (WAC) of Remicade® was around $1,175 per 100 mg vial in Q1 2019. The net cost to plans and insurers was approximately $500 after discounts and rebates. It is well known that the average sales price of Remicade is higher than that of the biosimilars. The difference is primarily made up through rebates from Janssen Biotech.
The drug rebate monies are traditionally transferred after utilization of the product, on a periodic basis (e.g., monthly or quarterly), well after the patient has had to pay the cost share. In the case of a drug covered under the medical benefit, this rebate is somewhat more difficult to apply at the time of cost share billing compared with at a pharmacy counter. When the bill comes, the patient is charged a cost share (10% or 20%, for instance) based on whatever the WAC or simple discounts off the list price has been agreed to by the patient’s plan or insurer. That is, further price reductions resulting from the rebate are not considered in the cost sharing amount.
For the sake of argument, let’s use the following figures:
Remicade WAC cost per 100 mg vial: $1,175
Price to plan after simple 20% discount: $940
Price to plan after additional 40% rebate: $564
The patient who uses only one vial of Remicade will be billed a cost share of $188 ($940 × 20%). If the rebate was applied to the patient’s 20% co-insurance, the out-of-pocket cost would be reduced to $113. Now, multiply that by 3, because an average patient will require 3 vials per infusion. That will likely send the patient over the plan’s maximum cost-sharing threshold, which might be $200. Otherwise, the cost difference between cost sharing with rebate versus without rebate considered would be $225 per administration in our example.
However, rebates are not the only factor detrimental to encouraging patient choice of a biosimilar. As discussed in October 2019, the ease of accessibility of patient copay coupons from the manufacturer can erase the likelihood that a patient will ask for a biosimilar over a reference product. These coupons are available from biosimilar makers and reference drug manufacturers alike. They knock down out-of-pocket costs to nominal amounts (often $5 or less per infusion) compared with full co-insurance.
One answer is instituting a biosimilar tier with far lower patient cost-sharing. Otherwise, pharmaceutical rebates will continue to conflict with a patient’s request for a less-expensive alternative to the reference product.
A study was recently published in the Journal of Managed Care and Specialty Pharmacy that evaluated the clinical results and economic benefits of a switch to biosimilar infliximab (specifically Inflectra) compared with the reference product Remicade® in adult patients with inflammatory bowel disease (IBD).
The savings accrued from the widespread use of biosimilars has been valued at tens of billions of dollars over several years. Estimates of savings generally are made from the perspective of system-wide savings.
Conducted at Boston Medical Center, the study authors calculated cost savings attained with transitions to biosimilar infliximab from March 2018 to June 2019. The outcomes of these patients were also evaluated, using a variety of clinical indicators.
To optimize patient conversion to the biosimilar, medical center physicians worked with the pharmacy department to devise the following criteria: Switches were performed in patients who were already taking Remicade for at least 6 months, the physician approved the switch, the biosimilar was approved for coverage by the patient’s insurer, and the infliximab infusions were performed in the medical center’s outpatient infusion facility.
During this period, 146 patients (97%) of the total IBD patient population who were taking Remicade were successfully converted to biosimilar use. Evaluating a subgroup of patients who had certain clinical or disease rating scores available before the switch took place (40 patients), the researchers reported that 90% maintained their remission. Interestingly, C-reactive protein levels fell after patients moved to the biosimilar (but this difference, 11.2 ± 22.0 mg/L vs. 4.1 ± 4.8 mg/L fell short of statistical significance [P = .09]). By the end of the study period, 89% of patients taking the biosimilar continued with this therapy.
Based on these figures, the medical center estimates that it saved $500,000 per year when transitioning this patient cohort to biosimilar infliximab. The study authors stated, “These findings reinforce that certain barriers to biosimilar uptake can be successfully addressed to implement a robust biosimilar adoption program.” They concluded that not only is the transition feasible, but “no significant clinical differences were noted in adult patients with IBD who transitioned from [Remicade to Inflectra].”
On Monday, March 23, biologic products formerly evaluated for approval under section 505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) are now approvable only under section 351 of the Public Health Service Act (PHS Act). That means many categories of drugs will now be considered eligible for biosimilar competition.
The transition date was set under the Biologics Price Competition and Innovation Act. Under the European Medicines Agency (EMA), several of these drug categories, including insulin, were already subject to biosimilar approval (in fact, somatostatin was among the first biosimilars to be approved in Europe in 2006). The Table lists all agents affected by the transition. Insulins are the largest (and most significant category) affected by the transition.
to a statement
released by the FDA on March 23, “Today is a milestone for the future of
insulin and other important treatments—potentially a new era of proposed
biosimilar and interchangeable insulin products. We expect this regulatory
transition to enable a vibrant competitive market for transitioning products,
ultimately empowering patients by increasing choices and potentially lowering
prices of safe, effective, high-quality medications.”
As reported previously in BR&R, the transition has been a long time in coming and had to address several hurdles. Whereas the FDA is hopeful that opening biologics like insulin to biosimilar competition will help lower prices and widen availability, few manufacturers have publicly stepped up to the plate and announced their plans to develop insulin biosimilars.
TABLE: DRUGS AFFECTED BY THE TRANSITION TO 351(K) BIOLOGIC STATUS
Initial Date(s) of Approval
Bayer HealthCare Pharmaceuticals Inc.
Valeant Pharmaceuticals North America LLC
fibrinolysin and desoxyribonuclease combined [bovine], with chloramphenicol
Gonal-F Gonal-F RFF Gonal-F RFF Redi-Ject
EMD Serono, Inc.
09/29/1997, 03/25/2004, 05/25/2004
follitropin beta and follicle-stimulating hormone
Follistim, Follistim AQ
Organon USA Inc, a subsidiary of Merck & Co
Amphastar Pharmaceuticals, Inc.
Halozyme Therapeutics, Inc.
Bausch & Lomb Incorporated
Novo Nordisk Inc.
insulin aspart protamine and insulin aspart
Novolog Mix 50/50, Novolog Mix 70/30
Novo Nordisk Inc.
Novo Nordisk Inc.
insulin degludec and insulin aspart
Novo Nordisk Inc.
insulin degludec and liraglutide
Novo Nordisk Inc.
Novo Nordisk Inc.
06/16/2005 and 10/19/2005
Eli Lilly and Company
Sanofi-Aventis US LLC
insulin glargine and lixisenatide
Sanofi-Aventis US LLC
Sanofi-Aventis US LLC
Humulin R U-500 and U-100
Eli Lilly and Company
Celerity Pharmaceuticals LLC
human insulin isophane
Eli Lilly and Company
human insulin isophane and human insulin
Eli Lilly and Company
NPH, human insulin isophane
Novo Nordisk Inc.
NPH, human insulin isophane and regular, human insulin
Novo Nordisk Inc.
regular, human insulin
Novo Nordisk Inc.
Eli Lilly and Company
06/14/1996 and 05/26/2015
Sanofi-Aventis US LLC
insulin lispro protamine and insulin lispro
Humalog Mix 50/50, Humalog Mix 75/25
Eli Lilly and Company
iodinated 1-125 albumin
Iso Tex Diagnostics Inc
albumin chromated CR-51 serum
Iso Tex Diagnostics Inc
kit for the preparation of technetium tc-99m albumin aggregated
radiolabeled albumin technetium tc-99m albumin colloid kit
Sanofi-Aventis US LLC
Ipsen Biopharmaceuticals, Inc.
Organon USA Inc, a subsidiary of Merck & Co
Ferring Pharmaceuticals Inc,
EMD Serono, Inc.
Leadiant Biosciences, Inc.
Pharmacia & Upjohn Company
Chiesi USA, Inc.
QOL Medical, LLC
Ferring Pharmaceuticals Inc.
Microbix Biosystems Inc.
Shire Human Genetic Therapies, Inc.
NDA = New drug approval. Source: Food and Drug Administration.
We had the opportunity
to speak with Christine Simmon, the public face of an organization that has
long championed the biosimilar industry. Our conversation covered topics from
the worst-case scenario in the State of Texas v. USA to oncology biosimilar uptake
and AAM’s current priorities.
Biosimilars Review & Report: What’s the one thing about the
biosimilar industry today that surprises you?
That’s a great question. I would say that it’s really heartening to see the
level of determination and engagement of the industry with policymakers and
stakeholders to advance patient access to biosimilars. Initially, most of the
engagement was on the regulatory side, which is understandable. It took a while
for the agency to come out with guidances that were important for those seeking
biosimilar approval. I recall going to many conferences where much of the focus
of our work was on the regulatory side.
Biosimilar manufacturers have shown great savvy in the
current climate of concern around prescription drug prices. They’ve capitalized
on that by demonstrating the value proposition of biosimilars and educating a
wide range of stakeholders about their critical role driving down prescription
drug costs and overall health care costs, and delivering patient access. That
was sort of a surprise and a very pleasant one.
BR&R: We seem to have reached a point today where new biologic
patent litigation has plateaued—settlements with manufacturers are being
reached faster than new lawsuits against biosimilar makers are being filed. Do
you believe the biosimilar manufacturers have attained a good handle today on
the patent questions and challenges they can expect and whether to participate
in the patent dance?
biosimilar manufacturers have learned much over time about patent litigation
and the patent dance; at the same time, both of these have evolved. I would
never underestimate the endless creativity of patent lawyers seeking to protect
their clients’ monopolies and exclusionary periods.
I don’t believe that biosimilar manufacturers and their legal teams can ever really rest on their laurels. More likely, litigation will ebb and flow based on which biologics become more widely available through biosimilar launches and which ones have patents that are ripening for challenges. I certainly wouldn’t recommend being complacent around the litigation landscape. It’s always evolving, it’s always a challenge, and it’s always expensive. And it’s still a critical barrier to biosimilar access.
BR&R: Do you think we reached a point where average time to market after FDA approval will start to decrease?
Simmon: It depends. It is product specific and very specific to the patent thicket situation for that product. Some manufacturers have and may continue to invest in biosimilar product portfolios and others may never pursue their proposed products because of the patent landscape, patent thickets, and the litigation costs associated with that. It will depend on the company’s level of financial resources they can devote to continuing that slog through patent litigation and also potentially their ability to reach pro-competitive settlements with the reference biologic manufacturer. As we have seen with biosimilar adalimumabs for Abbvie’s blockbuster Humira—which will enter the market 11 years earlier than the expiration of the brand’s patent—settlements can accelerate biosimilar competition and access for patients.
BR&R:With that in mind, what are AAM’s top priorities
today in terms of biosimilar advocacy?
Simmon: Our top
priority continues to be strengthening patient, provider, and payer incentives
to increase biosimilar utilization. That includes several of the pending pieces
of legislation as well as actions the administration can take (particularly
around shared savings).
We remain, of course, committed to education of all stakeholders
and to our anti–patent abuse platform, which pertains particularly to
biosimilars. There’s no shortage of priorities. Overall, increasing biosimilar
utilization is really priority number 1.
BR&R:Let’s talk a bit about the shared savings question.
Do you actually have to be in an ACO or other alternative care model
environment to benefit from the differential reimbursements that the federal
government is trying to implement? The reason I ask that is most organizations
are not in shared savings context right now. Will the increased ASP-plus
reimbursement move the needle on biosimilar utilization in those medical
Simmon: Well, the
current proposal is to raise the provider reimbursement from ASP + 6% to ASP +
8%, even though we recognize that with financial sequestration, this is really
only ASP + 4.3%. It’s helpful, but at best it’s a Band-Aid. It will not move
the needle longer-term.
That said, we do support the legislation to increase the
provider reimbursement. We do appreciate that bipartisan policy makers are
engaged and supportive of this.
It helps further the conversation and the education
platform. In terms of significantly increasing uptake and utilization, shared
savings is likely to be more effective and for a longer term, as we have seen
in the European Union and Canada.
BIOSIMILAR UPTAKE ON PREVIOUS EXPERIENCE
BR&R: Do you anticipate that the uptake of cancer treating
biosimilars like trastuzumab and bevacizumab will be faster than that of other
Simmon: I do think the oncology class in particular is poised to really breakthrough in terms of biosimilar uptake. The cancer community more than most has been very supportive of biosimilars, based on the savings and access they bring to patients with cancer. Stakeholder groups like the American Cancer Society Cancer Action Network, CancerCare, and Oncology Nursing Society Cancer Care Network have been extremely engaged with us and have been powerful education and advocacy partners. Their providers are well educated. Their patient advocacy groups are well educated. They seem very eager to embrace biosimilars. Uptake of this class is likely to be faster, because there’s such a strong foundation in the oncology community.
Their providers are well educated. Their patient advocacy groups
are well educated. They seem very eager to embrace biosimilars. Uptake of this
class is likely to be faster, because there’s such a strong foundation in the
BR&R: Is the experience they’ve already had with the supportive
oncology medications like filgrastim one reason?
Simmon: Yes, and the utility of these products is
supported by real-world evidence. Oncologists have been using these biosimilars
in their practices. That’s very helpful. Not to mention, having a spokesperson
like Dr. Sameer Awsare from Kaiser Permanente—who is a highly visible leader on
not only oncology biosimilars, but biosimilars generally—has been particularly
helpful with education of medical professionals.
BR&R: In a way, the granulocyte
colony-stimulating factors were almost an entry level type of therapy for the
hematologists and oncologists, to help them gain that comfort level with
biosimilars. Unfortunately, that is not the case for the autoimmune category.
The rheumatologists, dermatologists, and gastroenterologists cannot “get their
feet wet” to help them understand the nature of biosimilar infliximab,
etanercept, or adalimumab.
CAN WE QUICKLY PASS
BPCIA AGAIN, IF NECESSARY?
BR&R: Does State of
Texas v. USA keep you up at night?
Simmon: The BPCIA
is a small part of the Affordable Care Act (ACA). That said, this is not the
first challenge to the ACA. There have been many. The most recent Supreme Court
decision was in King v. Burwell
(2015), which involved the validity of the individual mandate. I still have the
faded headline clipped on my bulletin board. Even at that time, concern about
the BPCIA was not widespread, because conventional wisdom was that in a
negative decision, the BPCIA would be resuscitated immediately by the Senate
and the House. That’s likely the same scenario today.
I don’t believe there’s any intent in any of the ACA
challenges to derail biosimilars or roll back the 351(k) approval pathway. So,
no, it really doesn’t keep me up at night.
BR&R: I’ll share what keeps me up at night: Unintended
consequences. I agree completely that it’s very likely that the BPCIA would be
deemed severable. It’s fully encapsulated within the ACA and not part of the
intended function of the larger legislation. Yet, if the ACA is struck down, we
will depend on Capitol Hill to refile and reapprove the legislation in its
entirety, while resisting the urge to attaching some other legislation to it or
making an attempt to “improve” certain aspects of the BPCIA. This could delay
reimplementation and/or cause important, unforeseen effects down the road. Any
significant delay can freeze the marketplace. That’s the kind of thing that
very valid, but it would have worried me more years ago. However, if the
legislation has to be reintroduced and quickly passed, the risk of something
like an increase in marketing exclusivity to 14 years (from 12) or some other
type of provision is slightly lower I believe —not because there aren’t
interests who would certainly push for that, but because the climate on
prescription drug pricing has changed. There is a stronger willingness today to
discount advocacy efforts that will result in higher drug costs.
This administration has certainly done more, at least
rhetorically, acknowledging the value of biosimilar competition. Look at the
passage of the CREATES Act, which targets drug pricing in a helpful way. That
was extremely bipartisan. Many sponsors, strange bedfellows, and stakeholder
alliances worked together to pass that legislation. Also, the successful
adoption of the USMCA without provisions to increase our trading partners’
exclusivity periods for biologics. That was a big victory for biosimilar competition.
BR&R: In 2025, will there be more biosimilar manufacturers as members of AAM or fewer, based on the challenges biosimilars face today and the successes we’ve seen in bringing their products to market.
Approved in 2018, Herzuma®
is hitting the market, announced Teva and Celltrion. Teva, which is marketing
the trastuzumab biosimilar in the US and Canada, will begin offering the
biosimilar at a wholesale acquisition cost (WAC) of 10% below that of the
reference biologic Herceptin®.
In a press
release, Brendan O’Grady, Executive Vice President of Teva’s North
America Commercial operation, stated, “The launch of Herzuma continues our
commitment to help lower healthcare costs and increase price competition
through the availability of biosimilars. Teva is continuing to invest in
biopharmaceuticals as part of our long-term strategy for the future, and to
help patients around the world, and we look forward to additional milestones
for our biosimilar products later this year.”
Celltrion’s Vice Chairman Hyoung-Ki Kim added, “We look
forward to continuing our partnership with Teva to bring biosimilars to as many
patients as possible in the US, as we believe they address an unmet need
in the market.”
Teva announced that the WAC prices for the 150-mg and 420-mg
doses will be $1,402.50 and $3,927, respectively, or 10% below that for
Herceptin. However, net costs to plans and insurers are likely to be
considerably lower due to competition. The partners said in their press
release, “Actual costs to individual patients and providers for Herzuma are
anticipated to be lower than WAC, because WAC does not account for additional
rebates and discounts that may apply.”
Uptake of biosimilar trastuzumab has been brisk since the launch of Kanjinti in July 2019. According to data from Sanford C. Bernstein and Company’s Ronny Gal, biosimilar trastuzumab have penetrated 17% of Herceptin’s market as of January 2020.
At the World
Biosimilars Congress this month, we had the opportunity to sit down with Dr. Leah
Christl, formerly one of the key scientists at the FDA’s Center for Drug
Evaluation and Research. She was “present at the creation” of the FDA’s
biosimilar approval pathway and in 2019 moved into her current position at
Amgen. Our conversation ranged from topics involving biosimilar development and
approval to the future pipeline.
Biosimilars Review & Report: Dr. Christl, you’ve recently
transitioned from working at the Food and Drug Administration (FDA) to the
private sector. Has your view of the biosimilar industry changed at all with
Leah Christl, PhD:
There’s definitely a transition when moving from the FDA into the private
sector, but I don’t think my view of the industry has changed at all. I’ve
worked within the biosimilar space for over 11 years. Although my role at the FDA
included setting up the internal biosimilar review process and working on
policies associated with biosimilars, I had a great deal of external
interaction as well. My job was to make the program work, which required
efforts to reach out externally.
The biosimilar field represents a new industry. Some of the
players are traditional innovative biologics firms, some are traditional
generics manufacturers, and then others were created specifically for this
space. At that time, the agency had to engage with those external stakeholders,
to work with them in this new process.
Folks who are working in the biosimilar space are dedicated
to being here and are really looking for success. Everyone shares that common
goal—to make the biosimilar industry a sustainable success. There are some differences
in opinion about how we might get there though…
BR&R: Looking back at your work in developing and implementing
the analytical and evaluation policies for biosimilar approval, what do you
believe the FDA really got right?
Dr. Christl: In
terms of the analytical similarity assessment, the FDA was always focused on
the science and in really doing a robust analysis. During my time at the FDA, one
of our strengths was in focusing on comparability and then building on it. However,
some folks want that space to just be about comparability, but we’re trying to
show much more: We’re talking about a completely new manufacturing process. At the
FDA, we recognized that. We thought very hard about what that analytical process
should look like.
There may have been some missteps around the application of
a statistical analysis, how rigorous that should be, and what was reasonable with
regard to the variability of biotechnology manufacturing.
BR&R: As you mentioned this morning during your remarks, the
FDA’s initial work built upon the European Medicine Agency’s (EMA’s) original
work. Did the EMA do an adequate job of considering biosimilar manufacturing variability
when developing its own pathway? How long ago did we fully understand the
nature of variability in biologic production and its implications?
Dr. Christl: While
I was at the FDA and the agency entered this space, we looked at it a little
bit more robustly, a little bit differently. But one could say that there
wasn’t really a good understanding in how to apply the statistical analysis for
the analytical comparison.
At the FDA, we immediately implemented the “totality of the
evidence” approach, where the foundation is the analytical comparison. We considered
the concept of residual uncertainty, applying an approach of step-wise evidence
development using the analytical underpinnings and expanding to considerations
of what clinical data were needed to demonstrate biosimilarity. The FDA considered
carefully the sensitivity of certain clinical endpoints and the use of
pharmacodynamic evaluations. The EMA’s original approach, which evolved over
time, included expectations of specific clinical studies with traditional hard
On the other hand, the FDA had the ability to consider the
evolution of the regulatory approaches over time. As a result, we had more of a
scientific but flexible standard at the beginning, which has also been implemented
by other regulators in this space. There is good scientific harmony among
stringent regulatory authorities.
BR&R: The flexibility has been a very intriguing aspect of the
evolution of the biosimilar development and process. The FDA has been in constant
contact with the manufacturers through its biosimilar clinical development
program, consulting with them on the analytical, physiochemical, and clinical expectations
for a successful BLA. To an extent though, this creates what appears to be a
moving target. It’s sometimes difficult communicating that evolving expectation
outside of the industry to payers, prescribers, and others. How are the payers specifically
reacting to the requirement around the extent of clinical trials needed for
approval of a specific product?
Dr. Christl: Yes,
it was such a new paradigm. Getting prescribers, patients, and payers to
understand the data that underpin those approvals was a problem earlier in my
tenure at the FDA, and it continues to be a challenge. It can differ for two biosimilars
to the same reference product. Two slightly different submission data packages
could imply different levels of residual uncertainty.
Many payers are used to seeing a certain data set that is
used to approve a product, including two adequate and well-controlled clinical
trials. My thinking has evolved around that concept of comparative clinical
studies. It can involve pharmacokinetic similarity, pharmacodynamic similarity,
all the way up to what they consider a phase 3 study. These are comparative investigations
and are not designed to demonstrate efficacy of the biosimilar independently.
Again, we are seeking to evaluate similarity. People default to the language
that they know and call it a phase 3 study, but it’s not demonstrating the same
We talk a lot about the education needed to help gain the understanding
and acceptance, and uptake of these programs. That continues to be a work in
progress. I do think it’s very important to understand that any of those
studies are assessing similarity and potential differences between the
products. The studies then need to be designed to ferret that out. It’s the
whole intent and purpose of it. Once this is understood, people can grasp why
there’s a difference in the study design and the data package that underpins biosimilar
approvals. And there’s more trust when the agency states, “We’ve looked at these
data, and the biosimilars are safe and effective for those labeled conditions
FROM A PAYER’S PERSPECTIVE
BR&R: As far as payers are concerned, when they see
multiple biosimilars approved for adalimumab, they will treat them as they are
pretty much clinically equivalent to each other (not just to the reference
product). Will it matter that technically, biosimilar A is not biosimilar to B
or C, only to the reference product?
Dr. Christl: I
believe it will matter. As with other abbreviated approval pathways, like for generic
drugs and 505(b)(2) medications, these agents are compared with a reference
drug, not each other. You’re right, those other evaluations haven’t been done.
BR&R: In a specific geographic area, you may have multiple health
plans. Plan A has placed one biosimilar on its formulary, Plan B may cover a
different biosimilar, and Plan C may decide to cover the reference product
only. If a person needs to change plans (or the plan decides to change its
formulary coverage) from year to year, this question becomes potentially relevant.
If the change is from one biosimilar adalimumab to another
biosimilar adalimumab, that’s one thing. If you are changing coverage from one
biosimilar to that interchangeable product, that’s again something else. Is
there a scientific basis for concern in switching coverages like this?
Dr. Christl: I
don’t think that question is answerable yet. We don’t have the data to say that
it is or it isn’t. That may come out as we have more experience with these
products, and more products with multiple competitors to a reference product. We’ll
be able then to establish some real-world evidence, real-world data on that
We should be aware and cautious, and monitor patients. We
need transparency for the prescribers and the patients, so people know when there’s
been a change. We also need transparency in order to collect that information
for monitoring purposes.
THE SPREAD OF GOOD
BR&R: Several manufacturers produce biosimilars in overseas
production facilities. Have we obtained adequate harmonization of the US’s good
manufacturing practices with those in other countries? Can we be confident that
the overseas production is safe?
Dr. Christl: In
the US, we have requirements or standards for good manufacturing practices. The
EMA and Health Canada have similar requirements. When they approve a product,
they inspect those production facilities, looking very carefully at the chemistry,
manufacturing and controls. We have the expectation that the production
facility meets those standards, regardless of where it is located.
That said, I don’t think the standards are the same in the
some of the emerging markets. There is a big push around biosimilars especially
to make sure that we are applying equivalent standards for all biologics,
including biosimilars. We want to have a global definition of biosimilar, in
terms of how it is compared with a reference product. We need to move in that
direction, and make sure that those production standards are elevated globally.
But I do think some work needs to be done in the emerging markets.
THE NEXT GENERATION
BR&R: Amgen obviously has a long history of quality
biologic manufacturing and a quality culture. Amgen has certainly taken the
lead in launching the cancer-treating biosimilars of trastuzumab and
bevacizumab. From a research and development perspective, what does the company
believe will be the next important frontier in biosimilars?
Dr. Christl: Amgen’s
present focus is on oncology, hematology, and the chronic inflammatory
diseases. There is a pretty wide range of products in those spaces. Certainly, conversations
have taken place at Amgen and within the industry as a whole about other
opportunities outside of our standard therapeutic areas.
We need to look at where biological products are used. For
the industry as a whole, those areas could include the orphan and rare
diseases. Is there an opportunity there, not just from a business-case perspective?
Can we say that we have a good platform to provide those products and create
competition in those environments? Also, biologics used to treat neurological diseases,
for example Parkinson disease or multiple sclerosis, may offer interesting
targets. Certainly, in the oncology and the chronic inflammatory diseases, a
wide range of products and diseases are waiting to be tackled.
BR&R: Well, yes, in the autoimmune category, it seems a new
interleukin is introduced every couple of months.
Amgen, of course, is one of the few companies that can
actually look at rare diseases from something other than an economic standpoint.
You might not get a big return on investment on a biosimilar for an orphan drug.
But without biosimilar competition, you risk drying up the supply chain for a
specific drug, even an orphan biologic. Where do you think the biosimilar
industry will be in 2025?
Dr. Christl: In
2025 in the US, we are going to have many more products approved and we are
going to see many more new launches. Hopefully, we will be moving through some
of the intellectual property (IP) issues. We’ve seen a lot of progress in that
space, beginning with the interpretation of the BPCIA and what does it mean.
All the conversations around the patent dance and whether it is mandatory or optional—and
if it’s optional, then what does that mean?
Being a former regulator, I know that folks think that the
regulatory process is slow—and it can be at times—but it’s also a necessary
process. I don’t think that any of the IP issues are different. We need to work
through them to build a foundation with understanding and transparency so that prospective
biosimilar makers have confidence in their expectation of what their programs
need to look like and what they will need to do to reach the market. That is really
important for this industry. There will be more certainty in the regulatory
space overall, and that will help this industry move forward.
Globally, I expect we’ll see in some of those emerging
markets a real drive and desire to align with the stringent regulatory
authorities. There will be movement toward true global development programs and
a global definition of biosimilars.
BR&R: I’ll put you on the spot with this last question: By 2025,
how many biosimilars (not which ones) will Amgen have?
Dr. Christl: We
have four approvals now… we’ll go with eight or nine, I’ll say.
The Canadian provinces have begun to line up behind automatic substitution of biosimilar infliximab for Remicade®, after the announcement of British Columbia’s policy change in May 2019. Ned Pojskic, Leader, Pharmacy & Health Provider Relations, Green Shield Canada, offered some background into the decision on biosimilar switching at the World Biosimilar Congress on March 2 in San Diego.
Canada is a heavy user of biologics, weighing in at 22.5% of total healthcare spending, and rising, said Mr. Pojskic. This is second only to the US.
Green Shield Canada is a private, nonprofit plan. Most pharmaceutical
costs are covered through the private health system (not the provincial health
systems) in Canada, according to Mr. Pojskic.
Currently in Canada, the list price for infliximab biosimilars
is between 47% and 51% below that for the reference product. Throughout the
country, annual Remicade sales are $1 billion, which accounts for an outsized
proportion of total Remicade revenue for Janssen Biotech. But with only 5%
penetration of biosimilar infliximab in Canada, “we were at ground zero,” he
said. “We could achieve around $800 million in savings overall for all launched
biosimilars. But we’re not. This is mostly due to pharma company tactics.
“The ‘Biologic Savings Partnership’ is the name given by Janssen to the opaque pricing discount used to keep Remicade on the formulary,” explained Mr. Pojskic. “If you keep it on the formulary, you get discounts on other Janssen portfolio products. The big question is, how to disentangle yourself?” He pointed out that if other manufacturers lowered their net prices, Janssen would simply unveil new discount deals to preserve Remicade marketshare.
In 2016, Green Shield Canada announced its new pilot policy: All patients who were newly prescribed infliximab (or other available biosimilars) were required to be given the biosimilar. However, patients already receiving treatment with a reference drug had a choice: The plan would pay the cost of the biosimilar only, but patients could pay the difference between that and the cost of the reference brand if they wished. “It was important to give patients the belief that they had a choice,” he said.
The biopharmaceutical industry was not ready to give in to biosimilar switching, however. “Nineteen percent of those on Enbrel® (etanercept) stayed on the reference product,” Mr. Pojskic stated. “We assumed patients were paying the difference, but it turned out that the reference manufacturer was paying the difference for them.” On the other hand, Janssen decided it would not similarly “bridge” patients already taking Remicade. Under the pilot, Green Shield Canada saved approximately $8,500 per member using these biologics.
Plan members understood the change and were receptive to it, and began talking to their physicians about transitioning to the biosimilar agents. The provisional governments began evaluating the program, he explained, and British Columbia decided in 2019 to roll out their own biosimilar switching program. Alberta and Ontario followed. Today, more than 60% of the country participates in a mandatory switch program.
The physician societies have gotten behind the new policies,
as well. Mr. Pojskic said that physicians have preferred to use the originator
drugs, largely because of comfort levels with these biologics. The rheumatology
community has been quicker than the gastroenterology community to embrace the
policy, but “the GIs have been coming around,” he said.
Several weeks ago, the Food and Drug Administration (FDA)
and the Federal Trade Commission (FTC) announced plans to collaborate to manage
and restrict misleading information on biosimilars being disseminated by
reference manufacturers. This messaging, designed solely to place doubt into
the mind of patients, providers, and payers, is considered to be a significant
obstacle to biosimilar adoption. In order to advance its initiatives, the FDA
and FTC organized a public “workshop” on March 9.
Tara Isa Koslov, Esq., Chief of Staff, of the FTC read the
prepared remarks by Chairman Joseph Simons, which pointed to the regulator’s
extensive experience in bringing actions against branded drug manufacturers engaging
in anticompetitive activities against generic manufacturers. “Competition
between reference biologics and biosimilars is just as important as competition
between brand and generic small-molecule drugs,” he said. Mr. Simons noted that
“competition only works when consumers have reliable and truthful information.”
There is little doubt that enforcement will be needed, based
on past experience. Reference manufacturers have tried to malign biosimilar
agents either through outright false statements (e.g., “biosimilars do not
provide the same effectiveness/safety of a reference biologic”) or misleading messages
(e.g., since biosimilars are not exact copies, they are somehow of lower
quality relative to the branded reference drug). Most of the enforcement powers
of the FDA and FTC in this realm come from their ability to issue warning
letters, according to Dominic Cirincione, Regulatory Council, Office of
Prescription Drug Promotion at the FDA.
Ms. Koslov indicated that misleading information would violate
the law by (1) violating consumer protection laws by falsely advertising the
impression that there are “clinically meaningful differences between a
reference biologic and its biosimilar” and (2) creating an antitrust situation
whereby misleading or false information forms “artificial barriers to
entry and creates costs for biosimilar manufacturers.”
Lowell Schiller, Principal Associate Commissioner for Policy
at the FDA, asserted that there is a natural incentive for reference drug makers
to discourage competition, “but it undermines our system.” Those efforts
usually take the form of trying to position competitive products as somehow
inferior, which is not the case for biosimilars.
A product designated as interchangeable, on the other hand, could present a more challenging situation: How can a reference product maker argue that an interchangeable biologic is inferior to its originator drug (although the same should be said with any biosimilar)? Mr. Cirincione noted that the FDA had not yet written any policies for misleading information regarding interchangeable products. It matters little, because the FDA has not provided that designation to any manufacturer’s biologic. An interchangeable designation would not be relevant for a drug covered under the medical benefit, which is the case with all biosimilars launched to date. The reason is that it would not be substitutable at the retail pharmacy.
Hillel Cohen, PhD, Executive Director, Scientific Affairs,
Sandoz, emphasized that misleading information is not limited to statements
that are not factual. Speaking as co-chair of the Education Committee of the
Biosimilars Forum, Dr. Cohen pointed to “negative framing of factual
statements,” where inferiority can easily be inferred, is a real problem. An
example is, “biosimilars are only similar or highly similar, but are not
identical.” He continued, “We’ve seen negative comments about efficacy, safety,
quality, and the regulatory pathway. We’ve also heard that we still don’t have
enough data on switching, implying that we don’t know it’s safe.” Michael A.
Carrier, Distinguished Professor, Rutgers Law School, added, “You can have
deceptive, misleading statements even if they are not completely false.”
Dr. Cohen and the Biosimilars Forum believe that all
messaging “should be based on the FDA documents (though not all are easy for
patients to understand) and tailored to their audiences. The Biosimilar Forum
is willing to work with stakeholders to make this happen.” He concluded, “The
FDA and FTC should exercise their authority when possible to ensure this
The real question may not be what constitutes misleading
information or false characterizations that might set off alarms at the FDA and
FTC, but what enforcement teeth the agencies use to discourage and prevent such
In its recent earnings call discussing
fourth-quarter 2019 results, Mylan disclosed that the US Food and Drug
Administration (FDA) accepted its 351(k) application for a potential new bevacizumab
The application was submitted
in the late fourth quarter of last year and was not publicized through Mylan’s
communications department. The agent, MYL-1402O, had been subject to a phase
1 human trial, testing pharmacokinetic and pharmacodynamics similarity to
the reference product with 111 healthy volunteers. A randomized study in
patients with metastatic colorectal cancer was also conducted with an Indian
patient population only, but it is unknown whether this study, which was used
to secure approval in India, was included in the 351(k) submission. According to the company, the submission
package included comprehensive analytical data, which in addition to the clinical
study results, adequately demonstrated biosimilarity with Avastin®.
Another clinical study,
testing the product in patients with stage 4 nonsquamous non–small cell lung
cancer had been registered
in 2016 in Europe, but there is no further information on whether this
investigation was completed.
An FDA decision is expected on or before December 27, 2020. If approved, this agent could be the third or fourth bevacizumab available on the marketplace (depending on the status of Samsung Bioepis’ SB 8, which was filed for approval in November 2019).
In other biosimilar news…In the ongoing patent litigation between Sandoz and Amgen regarding Enbrel®, the case was heard in appeals court on March 4. Sandoz and its parent company Novartis have argued that the remaining patents on Enbrel are “obvious” and should be invalidated by the court, allowing a biosimilar to finally reach the market. In a report by FiercePharma, the majority of judges seem to be less than sympathetic to Sandoz, and this could extend Amgen’s market exclusivity through 2029— giving the reference drug an unprecedented 30 years of marketing protection. Sandoz’s biosimilar agent Erelzi® was approved by the FDA in 2016.
After a flurry of action in December and January, there has
been comparatively little action on the biosimilar news front in the past
couple of weeks. As a result, I was looking forward to refreshing the till with
a visit to the World
Biosimilars Congress 2020 in San Diego this week. And the meeting didn’t
disappoint. Over the next few days, I’ll be gathering my thoughts for specific
posts from the meeting and individual discussions with my colleagues and (new
and old) friends, and what I learned and could retain from experts who know far
more than me.
The sessions themselves provided the opportunity to consider
the current status
of the industry in the US: 26 approved agents, 15 launched biosimilars from
9 reference classes as of today. The 26 approvals is fairly impressive, and the
number of biosimilars passing Food and Drug Administration (FDA) scrutiny over the
past two years alone is impressive. Fifteen launches, however, is a frustrating
number, the well-understood result of a difficult experience on the patent dance
and litigation learning curve. The vast majority of the delays have involved
adalimumab and etanercept—the two biologics that would benefit most from
Nine reference products is perhaps more telling regarding
the future of the industry. According to Sarah Yim at FDA’s CDER,
the FDA is consulting on 74 biosimilar development programs, many of which may
involve biosimilar categories with existing competition. The FDA does not
disclose information on its consulting program, other than total numbers. One
may assume that several of these developmental programs involve insulins that
will be evaluated under the 351(k) pathway after March 22. Comparing the number
of biosimilar approvals based on reference products with that of the European
Medicines Agency (EMA) is flawed. The EMA considered growth hormones, insulins,
and other proteins as biosimilars from the outset, and the FDA is only doing
In the future (near and distant), there will be ample
anti-TNF inhibitors, interleukins, multiple sclerosis agents, checkpoint
inhibitors, VEGF antagonists, and other immunotherapies that may be subject to
biosimilar competition, assuming the industry is sustainable.
At the meeting, the overarching sense was that the industry
is at a crossroads today. I term it using Winston Churchill’s description: “This
is the end of the beginning.” Hopefully, not the opposite. The reason I believe
this is that 10 years after promulgation of the BPCIA, those chosen to play in
the biosimilar field and remain today seem to have a clearer understanding of
where they would like to go and how they will get there. The number of patent
lawsuits being filed today seems to be lower than the number of settlements.
However, as Christine Simmons, Executive Director of the Biosimilars Council
pointed out, we should not underestimate the ingenuity of patent lawyers—this
may only be a trough in a cycle.
Barring a surprising, catastrophic decision in State
of Texas v. USA, the underpinnings of the biosimilar framework may be
getting stronger—in part due to actions at the federal level and bipartisan
sentiment against high drug prices. Yet, this positive take is a bit fragile,
partly because relatively few manufacturers have experienced success on the
marketplace to date. In addition, too few manufacturers are currently among the
active players in the US marketplace.
What does this mean going forward? How will the industry
cross section be characterized in 2025? Will there be more players? Will we
find eight companies selling adalimumab biosimilars or will that number be
winnowed down to three or four? Which biologic reference drugs will be the next
biosimilar success stories? And will anticompetitive behavior by reference
manufacturers be a continuing concern or consigned to the past? I’m getting
more optimistic and hope to be present for the unveiling beyond the crossroads.