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.
In a significant coverage move, UnitedHealthcare
(UHC) has signaled that its commercial and Medicaid medical policies on infliximab
and pegfilgrastim have changed direction in favor of the reference drugs.
Effective July 1, 2019, approximately 22.5 million
commercial and 6 million Medicaid UHC members will not be able to access these
biosimilars without trying the reference agents first (virtually eliminating biosimilar
use). Both infliximab and pegfilgrastim are covered generally under the medical
benefit as office-based infusions, and preferring Remicade® and
Neulasta® (including OnPro®).
This move is important for a few reasons. First, it reverses
UHC’s previous position, which preferred the biosimilars over the two
Second, it promotes a prior
authorization practice that makes little
sense—since the biosimilar and reference products are expected to work in
the same way and produce similar outcomes, why would a patient who fails Remicade
then be given Renflexis® instead of a different biologic medicine
like adalimumab, ustekinumab, or others?
Third, it implies that both manufacturers have further
reduced the net cost of these drugs to UHC and its customers, undercutting the
current deals offered by the biosimilar manufacturers. If accurate, this is a
positive development in that infliximab and pegfilgrastim prices are continuing
to come down due to competition. It would also indicate that Amgen, maker of
the pegfilgrastim originator Neulasta, is beginning to defend its prefilled
syringe market more aggressively. This is significant, because Amgen had been
more focused on defending the marketshare of its on-body injector (Onpro), which
is dominant. Alternatively, Amgen may be bundling its filgrastim and
pegfilgrastim products more effectively. Coherus
and Mylan had previously announced pricing that would be one-third less
than the list price of Neulasta. Coherus had specifically indicated that it
would be seeking targeted
deals with payers to ensure at least parity position for its prefilled
syringe product Udenyca®. It did not, however, mention UHC as one of
Fourth, this move puts a further dent into the
sustainability of the US biosimilar market. Obviously, preferring the
originators will make access to their biosimilars considerably more expensive
for patients. It can only promote greater price cuts by the competing brands
and thus reduce profit margins for the biosimilar manufacturers. In the US, biosimilar
makers need a little encouragement to stay in the market, as very
few have had positive experiences to date (e.g., Pfizer,
to name a few).
No one denies the benefits of the increased competition
meaning a halt to price increases and significantly lower net costs, but those
benefits need to be extended across other biologic categories. Without a viable
biosimilar industry, access to lower-cost biologics can only happen through
One of the persistent themes at the Association for Accessible Medicines’ first GRx+Biosims meeting was an existential one. Authorities such as Gillian Woollett, PhD; Hillel Cohen, PhD; and several industry experts worried that without a change in mindset and intervention by government, payers, and the industry itself, the US biosimilar industry may not survive its infancy. And failure to attain US biosimilar market success would have grave consequences for the global biosimilars industry.
In her session, Avalere Health’s Senior Vice President Gillian Woollett, discussed the three mountains that biosimilar manufacturers had to climb in order to be successful. These were, in sequence, Mount FDA Approval, Mount Exclusivity and Intellectual Property, and Mount Commercialization. Indeed, it seems that FDA approval in many ways may be the easiest hill to summit.
Twelve biosimilars have been approved by FDA, but this is a far cry from attaining biosimilar market success. The eight drugs that are approved but have not yet reached the market are testament to this problem. Most have fallen victim to the lengthy delays associated with the exclusivity and intellectual property difficulties, none more so than the adalimumab biosimilars. For US biosimilar makers, each year that Humira® (and etanercept [Enbrel®] which will likely be introduced before 2020) face no market competition represents billions of dollars in unrecoverable revenue, as well as tens of billions of lost savings to the health system. Of course, it also means billions of additional revenues to the reference drug makers and their shareholders, which is substantially why these delays occur in the first place.
Don’t Look to the US, not Yet
Dr. Woollett asked, “Can there be a sustainable multisource specialty market in the US? I don’t think this is a foregone conclusion in the US.” She explained that the US is 50% of the market by dollar volume, yet it is home to only 5% of the world’s population. With aggressive tenders in many EU member countries, manufacturers are looking toward the US market to ensure long-term profitability. “Can the US carry the return on investment for biosimilars for the rest of world? I’m not convinced,” asserted Dr. Woollett.
Dr. Woollett pointed to another potential limiting factor in the commercialization of biosimilars. No interchangeable version of a biosimilar has yet been approved by FDA. However, switching matters greatly to the anti-inflammatory biosimilar drug maker, because it determines the size of the initial market opportunity. She explained, “If it applies to entire anti-TNF market, that’s $30.4 billion for infliximab. If you consider only treatment-naïve patients, that market is much, much smaller. If it is restricted to treatment-naïve patients, then no, these biosimilars will not be viable.” Switching is not a formidable issue for cancer biosimilars, as these are used as chronic treatments; nearly all patients are new to treatment.
She also noted a decline in the number of biosimilar development programs registered with FDA, which may be a signal of problems in the perception of manufacturers regarding their market opportunity.
Limited Reference Biologics Targeted
“Interest in biosimilar development only occurs for successful originator biologics,” Dr. Woollett pointed out. When filtering out biologics that are also not nearing patent expiration, it leaves a limited set of very expensive reference medications.
In making the business decision whether to develop a biosimilar, drug makers consider a number of questions, including the ease and cost of obtaining samples for evaluation, potential need for expensive clinical studies, and finally, what expense and time may be required for commercialization (including patent litigation). If a company plans on making the biosimilar available in a number of countries, it may be required to prove its molecule is adequately similar to samples obtained from each country or region. This could mean the need to purchase over 100 lots from the manufacturer, which is often not willing to sell to potential competitors. This is the reason for legislation like CREATES Act, which attempt to make this easier for potential biosimilar manufacturers.
Lowering Costs Through Harmonization of Comparators
However, Dr. Woollett and her colleagues in the biosimilars industry threw their support behind a different approach in 2017. Theirs is an initiative to establish “global reference comparators.” Under this approach, a manufacturer would only have to prove biosimilarity with a single licensed version of the reference product. “If the reference product is the same worldwide, then oughtn’t the biosimilar be able to be, too?” she asked. “Requirements for different datasets cannot be justified,” said Dr. Woollett. “Biologics been around for a very long time.
Once approved, complexity is no longer a relevant argument.” This would eliminate the need for biosimilar makers to confirm equivalence in bridging studies between their molecule and the licensed standard approved by each jurisdiction.
This approach reflects a growing understanding that the lot-to-lot variations seen in usual manufacturing of biologics (and over time) do not generally represent a risk to patients in terms of clinical effectiveness or safety. This, Hillel Cohen, PhD, Executive Director, Scientific Affairs, Sandoz, has just not shown to be an issue over 20-odd years of biologic production (outside of the Eprex® incident in 1998). In essence, today’s biologics are biosimilars to the original product approved by the FDA or EMA decades ago, without adverse effect on efficacy or safety. He pointed out that bridging studies that have been required add time and complexity to biosimilar development. Global comparators would help resolve this, and it can be applied to both biosimilarity and interchangeability comparisons as well. Dr. Cohen noted that “the FDA’s draft interchangeability guidelines still require comparison with US-licensed reference products only.”
Interchangeability not a Guarantee of Biosimilar Market Success
Dr. Cohen said that when a biosimilar product is so extensively studied as to its comparability with the reference product, “I cannot imagine scientifically why we thought switching would be a problem. In the opinion of the EU, these agents are substitutable, under proper supervision, with clinical monitoring. Indeed, the concept of interchangeability is unique to US regulations. However, even this designation may not hold the key to biosimilar market success.
Leah Christl, PhD, FDA, agrees with EMA that biosimilars in theory are interchangeable with their reference for the purpose of MD prescribing (meaning they are substitutable). This helps address the question of whether a noninterchangeable biosimilar is somehow a lower quality or less equivalent to a reference product than an interchangeable biosimilar might be. In fact, Dr. Cohen pointed out, “There is no definition of a ‘noninterchangeable biosimilar’ in the BPCIA.”
The cost of development of biosimilars, which may be in the hundreds of millions of dollars, is very high, considering that only four have been launched in the US. Dr. Woollett thinks that something will have to change in order for biosimilar manufacturers to maintain their interest in this sector. Yet, in view of the limited options available in the US to remedy the situation, Dr. Woollett remains pessimistic. “These investments in biosimlars of up to $500 million will be reconsidered,” she concluded.
At the GRx+Biosims meeting, Secretary Azar’s assistant Daniel Best restated the administration’s desire to preserve the biosimilar industry for the benefit of lowering prices and greater competition. He said, “We absolutely have to find a market for biosimilars. We can’t allow it be be eradicated through the perverse incentives in the marketplace.”
In fact, the only biosimilar market success story to date, Zarxio®, may be as much the result of a certain set of preconditions as that of Sandoz’s marketing efforts. First, another branded product, tbo-filgrastim (Granix®), was already available and was eroding the share of Amgen’s reference product. Second, this agent, though not technically a biosimilar by the regulatory approval pathway, cleared away some of the patent issues for Sandoz in its development of Zarxio. Third, Amgen eventually yielded the top position to Sandoz (at around 40% of marketshare). This set of circumstances is a bit unlikely for the introduction of other biosimilar drugs. Many will be looking to Mylan and its commercialization of pegfilgrastim as the next test of biosimilar market success.