Data from Alex Keen - Curated by EPG Health - Last updated 11 June 2018

The European League Against Rheumatism’s Annual European Congress of Rheumatology is being held from 13–16 June 2018 in Amsterdam, The Netherlands. EULAR’s aim is to reduce the burden of rheumatic disease through the promotion of excellence in education and research. These ideals form the basis of their annual congress, encouraging innovation and collaboration across all aspects of rheumatology research and clinical practice, something that is particularly well illustrated by biologics, a truly innovative approach that has revolutionised the treatment of many rheumatic diseases since their introduction two decades ago. But as their patents begin to expire, could cheaper biosimilars unlock the door to accessible, life-changing treatment for millions more?

What are biosimilars?

Biologics are medicines derived from biological sources, such as living cells or organisms. They are typically much larger, more complex and variable than small molecule drugs which makes them difficult to characterise. Biosimilars are biological medicines that are a highly similar and clinically equivalent copy of a previously licensed product, or reference biologic, for which the patent has expired (NHS, 2015). Unlike small molecule generics, the complexity and heterogeneity of biosimilars means that analytical processes are unable to confirm the absolute identity of all aspects of the molecule (Riley, 2017). They do, however, have to demonstrate that there are no clinically significant differences between the reference biologic and biosimilar (NHS, 2015).

Example of variability between a biosimilar and the reference biologic.

Example of variability between a biosimilar and the reference biologic. The blue triangles represent glycosylation of the amino acid chain, represented by the circles. Variability, shown by the purple shadow, can be allowed, however, the amino acid sequence must stay the same (EMA, 2017).

Humira (adalimumab) is one of the best selling drugs of all time, generating over $16 billion in worldwide sales in 2016 for AbbVie, the current licensee (Koons, 2017). Its European patent will expire in the last quarter of 2018, opening the door to competition from other companies that want to manufacture and market biosimilars. Four adalimumab biosimilars have now been approved in Europe which have the potential to substantially eat into AbbVie’s market share (Campbell, 2018; GaBi, 2018a).

As biosimilars become more and more commonplace in clinical practice, particularly for many rheumatic diseases, how big of an impact could they have and what challenges do they face?

How could biosimilars improve care?

The major direct benefit of biosimilars over biologics is affordability and, therefore, improved patient access. This is achieved through greatly reduced research and development costs, particularly as there is less need for extensive and expensive clinical studies (Isaacs, 2017). Increased competition between biosimilars and the reference biologic, and between biosimilars themselves, will also help to drive down prices with saving estimates from increased competition of more than €10 billion from 2016–20 in the EU5 alone (IMS, 2016).

Overall, as much as €98 billion could be saved by 2020 in the EU5 and US if eight key biosimilar products offer a 40% price reduction in comparison to the reference biologic (IMS, 2016). This extra cash will help free up funding in health systems, many of which are facing huge budget black holes, to facilitate greater treatment access or to relieve the strain in other areas. It’s worth noting that price differences between the reference biologic and biosimilar are unlikely to be as great as those between branded small molecule drugs and their generics due to the substantial complexity, and therefore cost, of the manufacturing process and product itself (Mortimer et al., 2017).

Potential cumulative savings from 2016–20 in the EU5 and US is eight key biosimilars offer 20, 30 and 40% price reductions (IMS, 2016).

Potential cumulative savings from 2016–20 in the EU5 and US is eight key biosimilars offer 20, 30 and 40% price reductions (IMS, 2016).

Biosimilars are expected to drive innovation in the industry with the US Federal Trade Commission arguing that the substantial costs involved in obtaining regulatory approval, concerns about safety and efficacy, and the relatively modest price difference between biosimilars and the reference biologic will allow pharma companies to retain a large enough market share to continue to research and develop new biologics. The free-market principle that the more products there are the greater the level of competition and, therefore, the more companies are forced to innovate to stay ahead of the game (Buffery, 2010). Balance is key here to ensure that the market is competitive enough so that the consumer has enough choice at a reasonable price whilst preventing market oversaturation that could slash revenues for companies like AbbVie, disincentivising research into new biologics.

This added choice and competitive pricing stands to benefit all aspects of the health system. Physicians have increased choice due to improved competition and innovation; patients have greater access to biologics with a wider variety of cheaper medicines coming to market; and the payer has a more competitive market from which to select their medicine of choice (Buffery, 2010; IMS, 2016).

What challenges do biosimilars face?

However, as it often is with innovative advancements in medicine, there are a number of challenges to overcome. First and foremost, due to the unique nature of biosimilar products and their manufacture, specific regulations had to be drawn up and implemented to facilitate their development. Introduced in 2001, the EU was the first region in the world to develop a legal framework for the regulation of biosimilars, with Omnitrope (somatotropin) gaining approval in 2006. Since then, Europe has established itself as a leader in biosimilar adoption with approval granted for 41 products as of February 2018, compared to just 10 in the US where legislation wasn’t introduced until 2010 (GaBi, 2018a; GaBi, 2018b).

Lawmakers faced a huge challenge to ensure that the reference biologic and biosimilar demonstrate high similarity to allow for the previously proven safety and efficacy data for each indication to be applied to the biosimilar, a process known as extrapolation. This is further complicated through the use of substitution, interchangeability and switching, terms that describe the various practices of prescribing one medicine instead of another and which differ from country to country (Schiestl et al., 2017).

The unique nature of biosimilar research and development, and the way in which regulations have continually been evolving alongside biosimilars, has caused many healthcare professionals to question whether enough assurances are being made to guarantee the high similarity required for safe biosimilar use. Extrapolating the indications from the reference biologic to the biosimilar has caused unease in the medical community, for example, CT-P13, a biosimilar version of infliximab, has been approved in Europe across all six indications previously given for the reference biologic. However, as it only underwent clinical testing for one of these indications leading Health Canada withheld approval (Müller, 2014). The lack of head-to-head trial data and mismatched approaches from different regulatory agencies has contributed to safety concerns among prescribers, discouraging the uptake of biosimilars.

Another significant obstacle is the aggressive protectionist strategies of the biologic patent holder that hinder biosimilar development and production. It’s not uncommon for drug companies to obtain over 100 patents protecting their biologics and many of the production processes, from what the drug is made of to its dosages, making it hard for competitors to manufacture a biosimilar without encroachment. Protracted legal battles between patent holders and their competitors slow the development of biosimilars, helping maintain their monopoly. This hostile approach to patenting is particularly effective for biologics as the complex manufacturing process provides the ideal opportunity for extensive and punitive patent applications, with the huge amount of money these drugs make (Humira makes up more than 60% of AbbVie’s sales) heavily incentivising pharma to protect these cash cows (Koons, 2017, Reuters, 2017).

Biosimilars have already started to facilitate real change in people’s lives worldwide, making these cutting-edge medicines more affordable and accessible. As a greater number of patents expire for blockbuster drugs like Humira, it will be interesting to see how the regulations evolve and the industry adapts to the disruptive potential of biosimilars.

Join Yvonne van Eijk-Hustings, Dieter Wiek and a number of other experts at the ‘New drugs - new perspectives: clinical and regulatory issues concerning biosimilars’ session at EULAR 2018, alongside a number of poster presentations and sessions discussing biologics in general. The full programme can be viewed here.

Find out more about biosimilars at the Biosimilars in Oncology Knowledge Centre

References

Buffery D. Competition from Biosimilars an Incentive for Innovation. Am Health Drug Benefits. 2010;3:27–28.

Campbell T. Will Biosimilars in Europe Deliver a Big Blow to AbbVie In 2018? The Motley Fool. 2018. Available from: https://www.fool.com/investing/2018/04/06/will-biosimilars-in-europe-deliver-a-big-blow-to-a.aspx (accessed 4th June 2018).

EMA. Biosimilars in the EU: Information guide for healthcare professionals. 2017. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Leaflet/2017/05/WC500226648.pdf (accessed 7th June 2018).

GaBi. Biosimilars approved in Europe. GaBi Online. 2018a. Available from: http://www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe (accessed 4th June 2018).

GaBi. Biosimilars approved in the US. GaBi Online. 2018b. Available from: http://www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-the-US (accessed 4th June 2018).

IMS. Delivering on the Potential of Biosimilar Medicines. 2016. Available from: https://www.iqvia.com/-/media/iqvia/pdfs/institute-reports/delivering-on-the-potential-of-biosimilar-medicines.pdf?la=en&hash=03018A6A86DED8F901DDF305BAA536FF0E86F9B4&_=1528127625267 (accessed 4th June 2018).

Issacs J, Gonçalves J,  Castañeda-Hernández G, et al. The biosimilar approval process: how different is it? Considerations in Medicine. 2017;1.

Koons C. This Shield of Patents Protects the World’s Best-Selling Drug. Bloomberg. 2017. Available from: https://www.bloomberg.com/news/articles/2017-09-07/this-shield-of-patents-protects-the-world-s-best-selling-drug (accessed 4th June 2018).

Mortimer R, White A, Frois C. Will “Biosimilar” Medications Reduce the Cost of Biologic Drugs? Scientific American. 2017. Available from: https://blogs.scientificamerican.com/guest-blog/will-ldquo-biosimilar-rdquo-medications-reduce-the-cost-of-biologic-drugs/ (accessed 7th June 2018).

Müller R, Renner C, Gabay C, et al. The advent of biosimilars: challenges and risks. Swiss Med Wkly. 2014;144:w13980.

NHS. What is a Biosimilar Medicine. NHS England. 2015. Available from: https://www.england.nhs.uk/wp-content/uploads/2015/09/biosimilar-guide.pdf (accessed 4th June 2018).

Reuters. AbbVie, Amgen settlement sets Humira U.S. biosimilar launch for 2023. Reuters. 2017. Available from: https://www.reuters.com/article/us-abbvie-amgen-humira/abbvie-amgen-settlement-sets-humira-u-s-biosimilar-launch-for-2023-idUSKCN1C32G5 (accessed 7th June 2018).

Riley S. Biosimilars have the same clinical effect as a generic but are only as similar to the original branded drug as validation technologies can confirm. Pharmaceutical Processing. 2017. Available from: https://www.pharmpro.com/article/2017/05/generics-vs-biosimilars-similar-different-advantages (accessed 5th June 2018).

Schiestl M, Zabransky M, Sörgel F. Ten years of biosimilars in Europe: development and evolution of the regulatory pathways. Drug Design, Development and Therapy. 2017;11:1509–1515.

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