Headlines alleging manipulations of the drug market feed the public perception of big, bad pharma, but they do little to tell the whole story of the challenges of launching a biosimilar.

A read between the lines reveals that the biosimilars market, especially in these early days in the U.S., may prove much more forbidding than many companies expected. Drug sponsors like Pfizer Inc. are finding that it takes a lot more than a 15 percent discount to challenge the dynasties of blockbuster biologics that have had nearly two decades to establish themselves on payer formularies and to build their reputation as the go-to choice for the doctors that administer them.

Ten months ago, Pfizer, of New York, launched Inflectra as the first biosimilar to Johnson & Johnson's (J&J) Remicade (infliximab) on the U.S. market. In the first half of this year, Inflectra seized slightly more than 5 percent of the U.S. infliximab market – less than what either Pfizer or J&J had expected. Pfizer blamed the slow growth on J&J, filing a lawsuit this week that claimed the New Brunswick, N.J.-based company used exclusionary contracts and other anticompetitive activities to protect its Remicade monopoly. (See BioWorld, Sept. 21, 2017.)

While it will be up to the courts to decide whether J&J's actions violate antitrust laws, the case serves as a warning to other drug companies hoping to cash in on the lucrative U.S. biologics market through biosimilars. The first lesson is that this is not a generics market, at least not yet. That means a lot more education, and steeper discounts, will be needed to get market buy-in to the biosimilar concept.

Since biologics like Remicade have to be administered in a health care setting and there's no automatic substitution in the U.S., sponsors must market their biosimilars to payers, as well as doctors who have built up years of experience with the reference biologic.

Unlike the small-molecule drug world in which the brand manufacturer may concede the market to generics awhile after its patents and exclusivities expire, biologics companies may have too much of their bottom line riding on a blockbuster drug to give up market share that readily.

Part of the reason monoclonal antibodies (MAbs) like Remicade generate so much revenue is that they're approved for multiple indications, which means they've been evaluated, at considerable sponsor expense, for each of those diseases and conditions. While the trial data support the expanded label, they also give doctors confidence in using the biologic for a specific indication.

Biosimilars, on the other hand, are generally tested in one or two indications to demonstrate similarity to the reference biologic, and then all the other indications may be extrapolated. Getting doctors on board with biosimilars, especially for extrapolated indications that can be challenging to treat, is going to take time, savings and more experience with biosimilars.

Grappling with extrapolation

Pfizer had forewarning of that challenge at last year's advisory committee meeting on Inflectra. While the FDA's Arthritis Advisory Committee (AAC) voted overwhelmingly to recommend approval of the biosimilar developed in partnership with South Korea's Celltrion Inc., some of the panel members initially were uncomfortable with extrapolating the biosimilar's clinical data for rheumatoid arthritis and ankylosing spondylitis to other Remicade indications, especially inflammatory bowel diseases such as ulcerative colitis and Crohn's.

Despite extensive FDA explanations and assurances, a few doctors on the committee wondered how they could prescribe the biosimilar without clinical data about how it performed in a given condition. (See BioWorld Today, Feb. 10, 2016.)

Several months later, the AAC was still struggling with extrapolation when it considered Amgen Inc.'s biosimilar to Humira (adalimumab, Abbvie Inc.). Like Remicade, Humira is a TNF-alpha inhibitor approved for multiple autoimmune conditions ranging from arthritis to Crohn's. Throughout that meeting, several committee members grappled with the concept of extrapolation, biosimilarity and the stepwise approach to developing the follow-ons. (See BioWorld Today, July 13, 2016.)

Summing up the discussion as the acting chairman for the meeting, David Solomon, a professor at Harvard Medical School, said, "The FDA team attempted – I'm not sure they succeeded – to educate the rest of us about the analytics" that are the foundation to establishing biosimilarity.

Noting how difficult it was for them as experts to get their heads around the concept even with FDA officials sitting there to answer their questions, the AAC panelists voiced concern about the disconnect patients and doctors may have with biosimilars. That disconnect was evident throughout the comments made during the adcom's lengthy public hearing.

If the biosimilar market is to take off in the U.S., the FDA needs to figure out how to better communicate the follow-ons with the public, Jennifer Horonjeff, a research fellow and patient advocate at Columbia University Medical Center, said during the hearing.

The wariness among U.S. physicians toward biosimilars also was borne out last year in a survey conducted by the Biosimilars Forum. The survey of 1,201 specialty doctors – those most likely to use biologics in their practice – revealed that only 12 percent of respondents said they were completely comfortable with the concept of extrapolation.

In light of such wariness, panelists at the Inflectra advisory committee warned Celltrion and Pfizer that a steeper discount would be needed to persuade doctors to try the biosimilar. Committee Chairman Liron Caplan, associate professor of medicine at the University of Colorado, reminded the sponsors that biosimilars are not a new treatment option; their only reason for being is to improve access and lower costs. He added that he would not prescribe a biosimilar unless it significantly reduced the cost of treatment.

Other AAC members agreed, with one saying he would be angry and frustrated if, after the committee discussion, Inflectra came to market at a price just slightly lower than Remicade.

Attitudes toward biosimilars will change, but it will take more than a few months and a 15 percent discount, according to Clarivate Analytics new report Biosimilars: Opportunities and Challenges in the EU, U.S. and Russia.

Time and money

The European experience with biosimilars, which began in 2006, shows that attitudes change over years, not months. In 2013, the year the EMA approved Remsima – Celltrion's brand name for the infliximab biosimilar – as its first biosimilar MAb, only about 28 percent of the members of the European Crohn's Colitis Organization responding to a survey said they believed biosimilars were interchangeable with or could be switched with their reference biologics, said Ho-Ung Kim, division head of marketing, public relations and medical affairs at Celltrion. Three years later, nearly 72 percent of the members agreed that biosimilars are interchangeable with or could be switched with the innovator.

A similar shift in attitude occurred with the British Society of Gastroenterology. In 2014, the society said patients already on a biologic shouldn't be switched to a biosimilar, or vice versa, until more safety data were available. The group also stressed that any apparent cost advantage of a biosimilar must be balanced against the "uncertain efficacy and unknown risk" from the biosimilar, Kim said. By 2016, the society was saying there was sufficient evidence to switch stable patients from the innovator to the infliximab biosimilar.

Remsima, which wasn't launched in the major European markets until February 2015 due to a pediatric patent extension granted to Remicade, saw its market share expand as attitudes changed. In the first quarter of 2015, the biosimilar, marketed by Celltrion and various partners, had only 4 percent of the EU infliximab market. A year later, it had claimed nearly a quarter of the market, Kim said.

However, the growth in market share wasn't evenly distributed across the EU, Kim noted, as early European adapters of Celltrion's biosimilar were countries that purchase drugs through competitive government tenders. In the first quarter of 2016, Celltrion's biosimilar claimed only 14 percent of the infliximab market in France and 17 percent in Germany, but it had the entire Bulgarian market and 92 percent of the market in Norway and Poland.

Much of that adoption, and attitudinal change, was in response to pricing. Norway switched to the infliximab biosimilar in 2015 when a bidding war between two Celltrion partners, Hospira Inc. (now part of Pfizer) and the Orion Group, gave the country a 69 percent discount with Remsima in a government tender. Within weeks of Espoo, Finland-based Orion winning the bid, more than half the Norwegian patients on infliximab were switched to the follow-on, even though doctors could still prescribe Remicade. (See BioWorld Today, May 4, 2015.)

As a result of the strong relationship between price and market adoption, biosimilar discounts in the EU have averaged about 30 percent, with steeper discounts occurring in some tender markets and when multiple biosimilars compete. That lesson hasn't translated to the U.S., where the discounts for the first few biosimilars to come to market have been limited to 15 percent.

Yet biosimilar developers see the U.S. as a crucial market due to its size and usage of biologics. Kim pointed out that the U.S. alone accounts for 59 percent of the global infliximab market. The next largest share is Canada with 8.4 percent.

Editor's note: For an in-depth look at regulatory and competitive issues facing biosimilars, download Clarivate Analytics' report Biosimilars: Opportunities and Challenges in the EU, U.S. and Russia.

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