Extrapolation of indications by the Food and Drug
Administration (FDA) has been widely accepted by providers, payers, and most patient
groups. Yet how to address the approval of a narrow indication list (or skinny
label) seems less settled.
The four FDA-approved adalimumab biosimilars received the
agency’s endorsement for a large set of Humira®’s 10 indications. Amjevita®
and its brethren were approved for the treatment of moderate-to-severe
rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, moderate-to-severe
Crohn’s disease in adults, plaque psoriasis, moderate-to-severe polyarticular
juvenile idiopathic arthritis, and moderate-to-severe ulcerative colitis. Missing
are indications to treat pediatric Crohn’s disease, hidradenitis suppurativa,
and noninfectious uveitis (regardless of severity). When payers are asked whether
these missing indications (especially involving other autoimmune disorders) are
important for coverage decision making, they will likely agree that it makes
little difference to them.
In perhaps the more important biosimilar example, rituximab,
the indications are split between cancer treatment (e.g., non-Hodgkin’s
lymphoma and chronic lymphocytic leukemia) and autoimmune therapy (e.g., rheumatoid
arthritis, polyangiitis, pemphigus vulgaris). Although the dosing rate (50
mg/hr) is the same, Rituxan is given as part of a cytotoxic chemotherapy regimen
for patients with non-Hodgkin’s cancer versus methotrexate and methylprednisone
for autoimmune treatment. The two rituximab biosimilars (Truxima®
and Ruxience®) approved by the FDA do not have the rheumatoid arthritis
indication, although Ruxience has received approval for polyangiitis.
The reasons their manufacturers sought the skinny labels could
be many, including avoidance of patent infringement, quicker path to FDA
approval, or simply limited resources. However, Pfizer did complete a phase 3
trial in RA for Ruxience. Currently, Amgen/Allergan have completed phase 3
trials for both non-Hodgkin’s
lymphoma and rheumatoid
arthritis for their investigational biosimilar ABP 798. It is possible that
the partners could submit a 351(k) biologic license application at the end of Q4
2019 or Q1 2020.
For payers, the presence of skinny labels for biosimilars versus
approval for the entire set of indications matters little. In several market research
projects we have conducted with managed care medical directors and pharmacy
directors, their answers have been consistent: If the biosimilar is approved by
the FDA and is covered by the health plan or insurer, then the payer will be
far less concerned how the biosimilar is used. The reasons are simple: Payers are
gaining comfort with biosimilar use. If the reference product and biosimilar
have been demonstrated to be sufficiently equivalent to produce equivalent outcomes,
and the biosimilar is less expensive, why overmanage its use?
Further support for this view was published this month in BioDrugs.
These South Korean authors evaluated 11 head-to-head randomized, control trials
of rituximab biosimilars for use either non-Hodgkins lymphoma or RA. A total of
3,163 patients were included in the meta-analysis. Response rates in the trials
for lymphoma and RA were consistently equivalent, and no significant
differences were revealed in the formation of antidrug antibodies.
Perhaps the best opportunity for managed care organizations to restrict
the use of a biosimilar (or biologic) outside of step therapy is the ubiquitous
prior authorization (PA). Today, there is little, if no, reason for PA criteria
to be different for a reference biologic or its biosimilar(s), other than price
preference. In that case, the skinny label has little effect on a payer’s coverage.
In May 2016, I interviewed Steven Avey, Vice President, Specialty Pharmacy, MedImpact, for the Center for Biosimilars. That conversation speculated on the potential for biosimilars, having only recently experienced the launch of the first biosimilar in the United States, filgrastim-sndz. At the Academy of Managed Care Pharmacy’s 2019 annual meeting last week, I sat down with Steve once again to gain his perspectives on changes in the biosimilar environment.
& Report: Congratulations on winning the Academy of Managed Care
Pharmacy Foundation’s Steven G. Avey Award! This is sort of a double honor,
first having the award initially named after you, and then many years later,
winning it yourself!
Steve, you’re considered one of the real thought leaders in
managed care pharmacy. What do you consider to be the main challenges facing your
Steven Avey, PharmD: Thank
you. There are many real challenges today. First of all, we have the potential
for drug rebates to go away. It’s clear that something is going to be done (and
we don’t know what that is), and it could apply not
only to Medicare Part D, but possibly Medicaid and commercial. We will need to
wait and see.
Another challenge relates to the Administration’s emphasis
on reducing list prices for drugs. This will not only influence the industry,
but managed care pharmacy as well.
That challenge is part of the ongoing concern about the cost
of specialty medications (and continuing price increases), and the greater call
from payers for a better understanding of the value that they’re getting from
these medications. Are the people who are taking specialty medications actually
getting real benefit?
addition to payers, employer purchasers and others have been requesting a
better understanding of the value of specialty medications. This has been
sought for 10 years or more. Are we any closer today in getting a grip on this?
Avey: I think we
are. Many PBMs are getting more involved in data management regarding these
medications. The better we get at analyzing the medical and pharmacy data
together, the closer we will get to understanding the value of these specialty
To give you an example, a PBM today is basically reviewed
and assessed on what its financial picture looks like—are you able to bend that
specialty cost trend? But if you don’t know what these specialty agents are really
doing for the patient population, how can you tell if covering them is the
right thing to do? In order for us to know that, we have to evaluate the
medical and pharmacy data together and focus on the total cost of care of that
individual member. Over time, you can say that our costs are either going down
or not. Then, we can ask the question, am I using the right agent or should we
be using those very expensive drugs for these patients?
Given the lack of the medical and pharmacy data, we just
don’t know. That’s one of my greatest frustrations.
switch to biosimilars. Do you believe that if the rebate safe harbor is removed
for Medicare, payers will also stop seeking them?
Avey: Yes. It
will definitely trickle into the commercial side. I can see a day in the not
too distant future where we don’t rely at all on rebates. It will be a new
world focused almost solely on list price reductions.
that give biosimilar manufacturers an edge?
Avey: It will be
a boon for biosimilar makers! When the rebate goes away, then all that remains
is the list price. That will be a huge advantage for biosimilars.
if I’m a reference biologic maker, whose R&D costs were paid off a decade
ago and whose profit margin is extremely high, I can still lower my WAC price
considerably to compete with the biosimilars, right?
Avey: They can,
but they will have to compete with three or even five biosimilars who do not
have to spend millions of dollars on advertising or promotions like the
innovators do to keep their brand’s exposure and visibility high. The innovator
drug maker will do everything possible to avoid losing that high market share.
Now, I haven’t seen much of this in print, but payers are
angry—they’re angry at these 10% to 20% increases in costs each year from the
innovator drug manufacturers. As a payer, if a biosimilar is available, why would
I want to support that innovator maker, who has
dramatically raised costs for the last 10 years? That gives biosimilar
manufacturers the advantage: “Hey, I’m the new guy helping you to reduce costs.
How about supporting me instead?” I think many payers will act on this message.
BR&R: In our
conversation in April 2016, that was the gist of what you said.
Avey: And I
haven’t changed my mind.
asked, how soon are you going to drop the AbbVie contracts (when there was some
expectation that biosimilars would be available before 2020), and you said, “As
soon as humanly possible.” And you weren’t the only one who said this.
And now the timeline has been extended to 2023. This just made us all the more
angry, because this is because AbbVie filed 100 patents on Humira®,
which overwhelmed what the BPCIA was intended to address. The result is that AbbVie
is going to make $16 billion a year (and more each year) for 4 more years
before we’ll be able to see some competition for their market.
Genentech (Roche) is coming out with subcutaneous forms of Herceptin®
and Avastin®. Will these introductions change the way you position the
biosimilars for these two cancer agents, when they are finally launched?
Avey: We’ve dealt
with this 15 years: It’s really no different than what we’ve seen occur with conventional
agents. Consider a sustained-release form of a brand that is approved around the
time the generic for the immediate-acting formulary is launched. You look at
the new product and ask, what does that premium in pricing buy us? Is it a
site-of-care advantage? Maybe, but does it really offset the cost of using that
more expensive agent? We generally decide to cover the lower-priced (albeit it
not as convenient) dosage form. With biologics, the cost differential between
the new agent and the biosimilar is very large, and there is very little
advantage for the new subcutaneous formulation.
BR&R: We are
seeing something similar playing out right now with pegfilgrastim. Most of the
market has moved to the use of Amgen’s on-body injector OnPro®, and
the biosimilars are being launched using prefilled syringes. To the extent that
payers are interested in eroding OnPro’s marketshare, assuming the price
difference is substantial, OnPro does represent a bit more patient convenience.
Some payers may be thinking this way. To the extent that this will happen may
predict some similar effect for the trastuzumab and bevacizumab markets.
Avey: You have to
remember that payers are receiving a lot of criticism that we’re not doing a
good job of supporting the biosimilars. Quite frankly, the biosimilar drugs
that have been approved up until now are really covered under the medical
benefit. We have a little trickle that can be covered under the pharmacy
benefit. Payers have only so much bandwidth. They know that under present
conditions, a new biosimilar has to build market share from scratch. Some have
said, “You know, it’s not worth the effort. We have other fish to fry. We’re
not going to get too excited yet about these products.”
We have an HMO client that did an amazing job moving market share
away from Neupogen® to Granix®. But they own their
prescribers and they can easily analyze the combined medical-pharmacy spend.
They saw a dramatic lowering of expenditures.
BR&R: Are you
expecting biosimilar products for trastuzumab and bevacizumab to be managed
Avey: We see
those drugs under the pharmacy benefit now. Remember that those drugs have a
greater utilization than the other biosimilars that have been launched to date.
I do think that they will attract a lot of attention. And if the rebates do go
away, that takes the market share question right off the table. The biosimilars
will do quite well.
four-letter suffixes: The FDA recently came out with an updated guidance,
saying that the agency will no longer consider adding four-letter suffixes to
previously approved reference agents. However, they will continue to add
suffixes to newly approved biosimilars and interchangeable agents.
is trying to figure out what’s next here. When we look at biosimilars’
pharmacokinetic information, one biosimilar is going to be somewhat different
than another. I don’t think it will be an insurmountable problem, but just a
headache. We’ll just have to be more in synch with our specialty pharmacies to
ensure that they stock and dispense this one biosimilar with this one
we made any progress from an educational standpoint here? Do providers and
patients still think that a product with a four-letter code is not comparable
to the originator brand? What is the level of discomfort today?
watched this carefully over the last year. I don’t think there will be huge
angst from the payer. The prescribers and to some
degree the patients that will need more educating to make them feel more
comfortable. We will need better educational materials and communications for
The situation is really no different than when we started instituting
the generic substitution laws. We heard a lot of claims that docs will never
prescribe generics, patients will never take them. We had to do a lot of
educating to alleviate their fears, and to help prescribers understand that
these drugs work like the brands work. At the end of the day, I don’t think
that this will be a long-term challenge.
It can be fun to go back in time! That’s the case with an old column I wrote for the Center for Biosimilars, just after Zarxio was approved. Here, I reprint a portion of the column, with some additional commentary.
study from 2014 boldly predicted $44.2 billion in savings from
biologic drugs over the 10-year period ending in 2024. The study’s authors
believed that upwards of 20% of the savings would come from the anti-TNF
These savings would salve the wounds of payers and purchasers suffering annual double-digit increases in specialty pharmaceutical costs. It has kept them up at night. Worries about the affordability of medicines have kept patients and their families on edge. All of this light focused through the magnifying glass, refracting to a point, has heated up attention on the first biosimilars in the 351(k) approval process. US health plans, pharmacy benefit managers, and insurer executives have been anticipating the push to biosimilars and their possible savings since the implementation of the Biologic Price Competition and Innovation Act in May 2010.
Expectations have pent up that biosimilars will begin to
relieve the pressure building from the annual double-digit specialty drug
trend. If payers are given 20% and 25% lower net prices, they will likely jump
at the opportunity to save millions of dollars, if they can. That means putting
net pricing ahead of clinical data when making coverage decisions (assuming no significant
immunogenicity differences, as payers and providers would consider this a powerful
Payers may presuppose that the Food and Drug Administration (FDA) will do its utmost to evaluate the equivalence in outcomes and pharmacokinetic/ pharmacodynamic characteristics of the agent. The real question is whether payers care enough about the clinical data to make extrapolation a potential issue if the FDA does not. They may well leave that decision to the prescribers, taking a more laisse faire approach, as they did in the very early days of generic drug introductions (before the days of automatic generic substitution).
Well, the verdict seems to be in, both from payers’ and
providers’ perspectives. Payers are leaving it up to the FDA, and in some
cases, without any clinical data in patients (just phase 1 trials in healthy
volunteers), to determine the appropriateness of biosimilars in several disease
Proprietary market research, as well as individual
conversations with payers, support that they have crossed a critical point of
confidence—the safety and effectiveness of using a biosimilar instead of a
reference product is no longer much of an issue. Any question about
extrapolation, similarly, is no longer deemed clinically relevant in approved
biosimilars. This may not be the case with a future product. We must also await
experience involving FDA approvals of products with “skinny labels” or limited
indications. In these cases, we don’t know yet whether plans and insurers will discourage
use of a biosimilar for the reference product’s full slate of applications (privately,
they have told me they wouldn’t discourage this use, assuming similar dosage
However, payers hunger for biosimilar choices. Not necessarily
to add to their formularies, but to force originator manufacturers to halt
further price increases. They want the opportunity to worry less about one
biologic agent for which next year’s expenditures will jump—and by how much
exactly? The few biosimilars approved in the US have forced WAC pricing (and
ASP pricing) down. We are expecting the same for the latest market entrants,
As for RAND’s predictions? Not enough has happened from 2014
until now to make one think that cumulative savings of $44 billion is
realistic. It is possible, however, if one considers the near-term launches of trastuzumab
and bevacizumab biosimilars. The one-year savings from adalimumab biosimilars
may top $8 billion by itself (out of total revenues exceeding $20 billion prior
to the introduction of these biosimilars).
A Shrug of the Shoulders on Savings Payers are becoming increasingly pessimistic that they will be seeing substantial savings with biosimilar products in the near term. The results of several market research projects we’ve conducted point to payers’ assumption that the 15% discounts seen today with Inflectra® and Zarxio® introductions will be mimicked by manufacturers of new biosimilar and follow-on products (assuming they cross the FDA approval and patent litigation barrier). Risking these introductions, the payers assume that makers of the originator products will simply match the offer, enabling the payer to take the path of least resistance and stick with the originator. But this means that the predicted tens of billions in savings to be gained by the biosimilar introductions will remain a mirage, at least until several competitors enter the market for the same originator.
Trastuzumab Biosimilar Data Published The Mylan and Momenta partnership announced that the phase 3 trial data on its biosimilar version of trastuzumab, previously announced at major medical meetings this year, has been published in the Journal of the American Medical Association. The HERITAGE study confirmed the safety and efficacy of MYL-1401O.
Final Guidance Released by FDA The Food and Drug Administration finalized and released its guidance “Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product,” which describes how biosimilar products may be listed as “not similar,” “similar,” “highly similar,” and “highly similar with fingerprint-like similarity.” The latter, it is assumed, will be used as a basis for considering interchangeability designations. The guidance is a belated tool to assist drug makers with proving pharmacologically the similarity of their molecule to the originator.