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Biosimilars - the same, but different?

As more products reach European markets, US regulations are catching up with science

Biosimilars paper men

In retrospect, 2015 could very well mark a turning point in the evolution of biosimilars, with the industry already able to chalk up several milestone events.

These were led by the launch in February of the first biosimilar versions of Remicade (infliximab). This first infliximab biosimilar was developed and manufactured by Celltrion and is marketed by various partners, notably Hospira under the brand name Inflectra and Mundipharma as Remsima. Versions of biologics have been on the market in Europe for a number of years now, but Remicade is the world's second-best selling medicine, and its fellow anti-TNF drugs Humira (adalimumab) and Enbrel (etanercept) - last year's first and third best selling drugs respectively - are also in the biosimilar firing line.

Laurent Chanroux, research director at Research Partnership who leads the company's autoimmune real-world data portfolio with access to more than 175,000 biologic patient records, sees some interesting market dynamics at play when it comes to these blockbuster autoimmune brands. “Although they're now approaching some maturity, none of them have ever seen any kind of competition from biosimilar agents. A lot of biologic manufacturers hoped that the complexity of demonstrating bioequivalence would mean that these would be relatively safe markets for a long time.”

Chanroux says this means that a drug like AbbVie's Humira, whose sales last year rose 17% to $13bn - 11 years after it was first launched in the US, now faces a new unknown risk. “The biosimilars under development by companies such as Sandoz, Amgen and Boehringer-Ingelheim may not be an immediate threat but together they have the potential to severely impact the company's revenue streams in the longer-term.”

Meanwhile, as Europe focuses on the market debuts of Inflectra and Remsima, over in the US regulators are also making some headway in the area. Having long lagged behind its European counterparts, the FDA approved in March its first ever biosimilar in the form of Sandoz's Zarxio - a version of Amgen's white cell stimulator Neupogen (filgrastim). Granted, it took less than two months for Amgen to secure an injunction on sales of Zarxio, but this has subsequently been overturned and Zarxio launched last week. The FDA's approval was a clear signal of intent and the regulator followed up on Zarxio's approval with the release in May of a flurry of guidance to firm up its policy approach.

Having more approved biosimilars is good for public health - Leah Christl, FDA

Biosimilar challenges and dynamics
One of the difficulties with biosimilars - legal manoeuvres aside - seems to be the level of uncertainty about how the market will evolve. There are no benchmarks for sales and the companies moving into this area are up against the likes of AbbVie, Merck & Co and Pfizer, and facing strong, established marketing teams with more than a decade's worth of clinical practice data to draw on.

The key differentiator for biosimilars, certainly at the moment, will be price - with European health systems expected to save around $11bn by 2020 according to one estimate. Certainly when it comes to early experiences of the new infliximab biosimilars their price point looms large, according to Laurent Chanroux, associate director at Research Partnership.

He explains: “In some of the eastern European and Scandinavian markets in which these drugs have been launched for some time we have seen uptake primarily driven by the discounts offered which have been very substantial. Before the launch of Remsima we were expecting maybe a 30% discount. But in Norway, it was recently announced that price regulators have been offered a discount of 72% for biosimilar infliximab in the country's latest tender for drugs.

But if it's price that companies are looking to, they also have a significant job to do in terms of educating physicians about these still-new types of treatments. Chanroux says his company's research among rheumatologists found they didn't think they had yet been given enough information to make an informed decision about how and when to use biosimilar versions of the autoimmune drugs.

Companies have a significant job to do in terms of educating physicians

Emerging regulatory clarity
Beyond pricing policies, regulatory changes should help more biosimilars reach the market, at least, that's what the FDA hopes. The new Questions and Answers document it released last month - its fourth in as many weeks - provided additional guidance on how it plans to regulate the emerging product category.

The latest Q&A document provides further details on how drug developers can demonstrate biosimilarity and - for the first time - the agency now indicates that it is possible for a biosimilar to be interchangeable with a reference product, in other words is so alike that it could be substituted for the reference drug even if the original brand is specified in a prescription. However, the FDA goes on to say that “at this time, it would be difficult as a scientific matter for a prospective biosimilar applicant to establish interchangeability,” adding that it is still trying to determine what information it would need to make such a ruling. Earlier guidance has covered analytical methods to demonstrate biosimilarity and a Q&A document on the product development and marketing application process.

The FDA's efforts to provide the finer details of guidance can only help to drive out uncertainty from biosimilar development and regulation and encourage the development of a market that - according to the FDA's associate director for biosimilars Leah Christl - “can provide more treatment options for patients, and possibly lower treatment costs.”

“Having more approved biosimilars is good for public health [and] FDA looks forward to continuing to help manufacturers develop these important products,” Christl wrote in a blog post.

After regulatory clarity, the focus will certainly move to health technology assessment bodies, such as Germany's IQWiG and the UK's NICE, if biosimilars' place in clinical practice is to be cemented. For its part IQWiG has yet to assess any biosimilar products. In fact, its biologic assessments have so far been restricted to just nine products for rheumatoid arthritis in a single piece of guidance released back in 2013 and a spokesperson told PME that it currently has no other commissions from the G-BA to assess other biologic products.

There has been more movement in England, where NICE began the year by updating its position on appraising biosimilars and explicitly acknowledging their availability and use is likely to become more widespread over the next few years. The first months of 2015 also saw it approve Remsima and Inflectra for use on the NHS to treat moderately to severely active ulcerative colitis after the failure of conventional therapy. The two infliximab biosimilars are also included in the cost-effectiveness watchdog's ongoing appraisals of TNF-alpha inhibitors for ankylosing spondylitis and its review of Humira, Enbrel, Remicade, Cimzia, Simponi, Orencia and Actemra for rheumatoid arthritis.

Having sought governmental advice on the issue, NICE said the Department of Health has confirmed NICE can apply the same remit, and the resulting guidance, to relevant licensed biosimilar products. Its positioning statement also noted: “Evidence summaries will use the brand names of the medicines because substitutability and interchangeability cannot be assumed. Evidence summaries do not make recommendations hence the decision regarding the choice of biosimilar or originator biologic for an individual patient rests with the responsible clinician in consultation with the patient.”

As regulatory and HTA positions towards biosimilars gradually solidify in Europe and the US, the challenge for those marketing the products will be how to move beyond competing solely on price and how to create their own distinct biologic brands.

Article by
Dominic Tyer

PMGroup's editorial director

7th September 2015

Article by
Dominic Tyer

PMGroup's editorial director

7th September 2015

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