2014 in review – Biosimilars: steady, if unspectacular, progress

If 2013 was a standout year for the biosimilars sector – the high point being approval of Celltrion and Hospira's biosimilar infliximab (Remicade) in Europe – then 2014 has witnessed something of a return to 'normality,' characterised by steady progress in some areas, but disappointment and delay in others.

Last year's approval of biosimilar infliximab in Europe was notable for a number of reasons, representing both the first approval of a biosimilar monoclonal antibody in the region and the European Medicines Agency's willingness to utilise indication extrapolation to full effect.

However, with Celltrion and Hospira's product having only launched in a number of the region's smaller markets to date (due to IP issues), judging the commercial opportunity for biosimilar MAb products in Europe remains difficult.

Norway has led the European charge in seeking to drive biosimilar uptake, but branded players in the anti-TNF market have largely downplayed any impact on their sales to date (ViewPoints: Has Norway's NOR-SWITCH study slowed down the adoption of biosimilar infliximab?). Potential launch of Celltrion and Hospira's product in the region's five largest markets from February 2015 should, however, provide further clarity on how this competitive dynamic will play out.

Encouragingly, the subsequent approval of biosimilar infliximab in Canada was one of 12 global biosimilar approvals in 2014, but illustrating a lack of uniformity in the sector after Canadian regulators chose not to approve the drug across all indications as the EMA has. This raises an all important question as to how the FDA will deal with indication extrapolation.

The FDA did accept a biologic license application (BLA) from Novartis' Sandoz unit for a biosimilar version of Amgen's Neupogen (filgrastim) in July, making it the first disclosed biosimilar submission to be reviewed by the agency. Furthermore, the FDA has recently confirmed its Oncologic Drugs Advisory Committee (ODAC) will meet in early January to discuss the filing.

However, the FDA has yet to release it much vaunted guidelines on interchangeability (as it had suggested it would in 2014), which are expected to play a key role in determining the US commercial opportunity for biosimilar products, MAbs in particular (ViewPoints: Money for nothing? – Indication extrapolation remains key issue for biosimilar developers).

As analysts at Sanford C. Bernstein note "it is tough to determine what would separate interchangeable biosimilar from a 'plain' biosimilar as the agency will never approve a biosimilar that does not adhere to the highest standard."

They add "there are two possible ways to address this, neither is perfect. An interchangeable biosimilar could be required to have no analytical differences from the originator, while a plain biosimilar could have clinically insignificant differences. Instead, an interchangeable biosimilar could simply be required to do more specific clinical trials."

In Europe, the EMA does not have the authority to designate biosimilars as interchangeable. However, France became the first country in February to allow substitution of biosimilars at the pharmacy level.

Simultaneously, the EMA should not be viewed as a walkover in comparison to its regulatory peers in other countries; failure of Celltrion to file its biosimilar Herceptin product (CT-P6) this year suggests the Korean player has been required to undertake additional clinical testing. That said, supporting its status as a proactive biosimilar regulator, the EMA did approve Eli Lilly's biosimilar version of Lantus in September.

Tied to the issue of interchangeability, the debate over naming conventions for biosimilars has continued to evolve over the course of 2014, with efforts by the World Health Organization to bring some uniformity to proceedings met with limited support. European and US regulators are backing different approaches, as are those manufacturers developing biosimilars and those who developed originator brands (see ViewPoints: The 'INNs' and outs of biosimilar naming and Physician Views: At least some similarity needed in biosimilar naming conventions, say majority of physicians, but caveats remain).

While such challenges persist in the regulatory and policy arenas, the number of Phase III studies initiated for biosimilar products in 2014 – with a particular focus on MAbs – has been more encouraging, argues Duncan Emerton, Senior Director of FirstView syndicated insights & analysis (ViewPoints: Amgen becomes first Big Pharma to unveil Phase III biosimilar antibody data). As has been the increasingly visibility of biosimilar development at major medical meetings and conferences. Data for MAb, insulin, EPO-alpha and filgrastim biosimilars were presented at conferences such as EULAR, ASH, ADA, EASD, ASCO, ESMO, SABCS and ACR.

As momentum grows on the development front, the past 12 months has seen further evidence of branded players looking to mobilise their defence strategies. Both Johnson & Johnson and Roche/Amgen have prevailed in the US courts against Sandoz and Celltrion, respectively. "A key reason for heading to the courts is to avoid the 'patent dance' in the 351(k) pathway and this looks to be only way that patents will be sorted in the US," says Emerton. Analysts at Goldman Sachs note "coupled with potential upcoming court rulings, we believe prolonged litigation on longer dated patents could delay the launch of biosimilars (most likely antibodies) for several years after patent expiration, unless biosimilar companies elect to launch at-risk."

While the number of biosimilar-themed collaborations has continued to decline over the past few years, there were 15 deals and alliances forged in 2014, many of which are focused on the emerging markets, which continue to be talked about has providing significant opportunity for biosimilar manufacturers (ViewPoints: New FirstWord report finds that biosimilar developers see emerging markets as holding significant potential, but challenges loom). Chinese regulators notably unveiled draft biosimilar guidance this year, with the Biotechnology Industry Organization noting that it is broadly consistent with guidance published by WHO, the EMA and FDA.

Next year is poised to be an important one. It will potentially witness the aforementioned launch of biosimilar Remicade in the EU5, while analysts at Sanford C. Bernstein argue that the FDA will "reasonably begin" to approve biosimilars over the next 12 months with most of the regulatory requirements now in place.

However, they argue that introduction will be slow, submissions will be dealt with on a case-by case basis, internal debate regarding biosimilars will continue within the FDA and it is likely to be 10 years until biosimilars are a "standard feature" of medicine.

Emerton concurs: "A key barrier is the physician and there are still lots of concerns about the safety and efficacy of biosimilars. Concepts of biosimilarity are also not well understood at key stakeholder levels meaning that more needs to be done in 2015" (see Physician Views Poll Results: Rheumatologists cautious towards FDA biosimilar regulatory guidance; oncologists less so) and Physician Views Poll Results – A Tale of Two Continents; US and EU physicians paint contrasting picture of biosimilar educational space).

To read more IAV Other articles, click here.