Biologics, such as the TNF-alpha inhibitors adalimumab and infliximab, have transformed the management of inflammatory bowel disease (IBD), significantly brightening the outlook for the global population affected by this debilitating chronic condition. The high cost of biologics is increasingly putting them beyond the reach of many eligible patients worldwide – but, as some frontline biologics approach patent expiry, other companies are able to begin developing less costly versions known as biosimilars. For regulatory approval in their first indication, biosimilars need to demonstrate comparable safety and efficacy to the originator biologic in a head-to-head clinical trial to show that their mechanism of action matches that of the originator.
Inflammatory bowel disease – encompassing Crohn’s disease (CD) and ulcerative colitis (UC) – is a chronic, incurable, disabling condition that typically strikes in early adulthood, significantly impairing quality of life, impeding career aspirations, and limiting productivity. Although the causes and risk factors are not well understood, IBD is strongly associated with Western lifestyles and industrialization. It has evolved into a global disease with escalating prevalence in every continent.1 As of 2015, approximately 1 million people in the United States and 2.5 million in Europe have IBD1 and its incidence is rising sharply in the newly industrialized nations of Asia, Latin America and the Middle East.1–4 Some authors describe the surge in IBD worldwide as a ‘global epidemic.’5
"Biologics, especially the anti-TNF agents, have basically revolutionized the way we treat patients with IBD. We now have effective therapies, hospitalization-reducing, surgery-reducing,
However, the reality is that many patients with IBD are not able to reap the considerable benefits of biologics. The reason, of course, is cost. With a price tag of USD $25,000– 50,000 per year,1,8 TNF-alpha inhibitors are currently the main drivers of cost in many IBD units.9 A recent study suggests that TNF-alpha inhibitors account for as much as 64% and 31% of total healthcare costs in CD and UC, respectively.10 Although their use results in lower follow-up costs (for surgery and/or hospitalization), these savings are often not sufficient to offset the cost of the drugs.10,11 The need for long-term maintenance therapy is a significant contributor.
"[TNF-alpha inhibitors] are very, very costly, to the point where insurance companies are balking at approving them without a very good indication."8
In the past decade, the Western world has largely tolerated the cost of biologic agents for IBD. However, in the next decade the sustainability of managing patients with IBD will become increasingly strained as the global prevalence of the disease climbs steadily.1 Reports from several Asian countries indicate that patient access to TNF-alpha inhibitors for IBD is already restricted12,13 and the same seems to be true of some parts of Eastern Europe.4 In general, healthcare systems that administer equitable healthcare will struggle more than systems that can shift drug cost to private insurers; however, in these markets, those who can pay will have greater access to biologic therapy.
Consequently, the expense of biologic agents will divide the global IBD community into ‘have’ and ‘have-not’ countries and lead to disparity of care within countries based on socioeconomic status. Even wealthy countries that can afford to pay for biologic agents will eventually reach a tipping point whereby the cost of treatment becomes unsustainable.1
The costs of modern IBD biologics reflect the scientific innovation and the investment required to support biotechnological research and development. But it puts the treatments beyond the reach of many people. Pursuit of innovative new drugs – like the gut-selective monoclonal antibody vedolizumab – is clearly of great importance, but so is broadening patient access to established existing treatments. There’s no quick-fix solution – but, as some frontline IBD biologics start to approach patent expiry, the opportunity arises for other companies to develop less costly versions, which are most commonly known as biosimilars.* Biosimilar versions of infliximab have already been approved in several highly regulated markets including the EU, US, Australia, Canada, and Japan.
*Also known as follow-on biologics, subsequent-entry biologics, and biocomparables, among others.
Unlike the generics of the chemical drug world, biosimilars are not exact copies of originator biologics, as it is not possible for a new manufacturer to precisely replicate the highly complex and sophisticated production processes. However, extensive regulatory requirements are designed to ensure that candidate biosimilars are rigorously compared with their originators both analytically and clinically, to establish that quality, efficacy, and safety are all a very close match. By January 2016, 22 biosimilars in a range of therapy areas had been launched in Europe with no adverse clinical consequences compared with their originators14,15 – and have resulted in significant cost savings.16 In Germany, for instance, the use of biosimilar erythropoietin between 2007 and 2011 led to more than €600 million in savings.17 Other markets are starting to follow Europe’s example.
The extent of the clinical testing required means that biosimilars can’t be as heavily discounted as chemical generics. The average savings are projected to be approximately 30%,18 but they could well be higher. For TNF-alpha inhibitors, these savings are highly worthwhile, especially as some patients with IBD may require treatment for decades. In addition, the introduction of competition may prompt the manufacturers of originator biologics to reduce their prices and to consider investing in innovative new products as they seek new competitive advantages.
The first biosimilars for IBD were approved in Europe in 2013 and came into use the following year. As of March 2016 there are two EMA-approved infliximab biosimilars (Remsima™ and Inflectra™), which – although marketed separately – are identical versions of an original Celltrion product (CT-P13). It is important to note that the EMA approval of CT-P13 was gained on the basis of data from head-to-head analytical similarity studies, in vitro and in vivo non-clinical studies, and clinical studies in rheumatoid arthritis (RA). The regulators considered the data package to be sufficiently robust and convincing to merit what is known as ‘extrapolation’ of the licence to include all the approved indications of the originator Remicade®, including IBD. In April 2016, the FDA came to the same conclusion as the EMA, approving CT-P13 for all of Remicade’s indications via extrapolation.
These regulatory decisions to extrapolate data from RA to IBD have been somewhat controversial. The European Crohn’s and Colitis Organisation (ECCO) has raised concerns, pointing out the different pathophysiologic factors in IBD vs RA and the fact that RA may not be the most sensitive disease model for revealing potential differences between the biosimilar and the originator.19,20 The EMA and FDA in turn have justified their decision, stating that the comprehensive analytical, non-clinical and clinical data all demonstrated high similarity and therefore the ‘totality of evidence’ indicates that regulatory requirements for extrapolation have been fulfilled.
Since the approval of Remsima and Inflectra in Europe, a rapidly growing body of literature has confirmed their safety and efficacy in IBD. This evidence has included at least 10 independent real-world studies involving switching to one of these biosimilars in nearly 600 patients who were stable on Remicade.21 Similarly reassuring switching data in a pediatric IBD population (n=39) was announced in March 2016.22 This post-marketing experience has led to endorsement of infliximab biosimilars for IBD not only by payers but also by academic societies such as the British Society of Gastroenterologists.23 In addition, a survey of delegates at the 2016 ECCO congress reported that 44% considered biosimilar infliximab interchangeable with Remicade – a sharp contrast with the mere 6% who felt that way in 2013.24 A 2015 abstract presented at ECCO reports that using biosimilar infliximab instead of the originator for treating CD alone could lead to savings of between €76 million and €336 million across the UK, Italy and France within the 5 years from 2015 to 2019.25 In a UK study, switching from Remicade to infliximab biosimilars in IBD achieved savings of approximately £300,000 (€400,000) in only 4 months (April to July 2015) with no adverse effects on patient care.26
But despite the clear scientific arguments for the validity of data extrapolation put forward by the EMA and FDA – and despite the post-marketing experience with infliximab biosimilars in IBD – some clinicians understandably remain wary about prescribing a new drug without clinical trial data in their own therapy area.19,20 Principally for this reason, sponsors of biosimilars are now initiating trials specifically in IBD. In particular, generating data on candidate biosimilars of adalimumab is seen as an important goal. While infliximab biosimilars are approved and in use, there are still no approved biosimilars of adalimumab in highly regulated markets.
QuintilesIMS is actively supporting the development of IBD biosimilars and we invite you to join us as a clinical investigator. The patients you enroll in these studies will all receive active therapy, either with the originator TNF-alpha inhibitor or with a biosimilar candidate at no cost to them or to their insurers.
Our current IBD biosimilar study opportunities are with candidate biosimilars of adalimumab, which will be compared head-to-head with the originator Humira®.
1. Kaplan GG. The global burden of IBD: From 2015 to 2025. Nat Rev Gastroenterol Hepatol (2015) 12: 720–727.
2. Mandel MD, Miheller P, Mullner K et al. Have biologics changed the natural history of Crohn’s disease? Dig Dis (2014) 32:351–359.
3. M’Koma AE. Inflammatory bowel disease: An expanding global health problem. Clin Med Insights: Gastroenterol (2013) 6:33–47.
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8. Cleveland Clinic, 1 February 2016. Biosimilars could change how physicians treat inflammatory bowel disease. https://consultqd.clevelandclinic.org/2016/02/biosimilars-change-physicians-treat-inflammatory-bowel-disease/. Accessed 31 March 2016.
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13. ajbpLive, 10 March 2016. When will biosimilars be available for inflammatory bowel disease? http://www.ajpb.com/articles/when-will-biosimilars-be-available-for-inflammatory-bowel-disease?p=2. Accessed 31 March 2016.
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17. Turner M, Walsh K & Whitehouse J. Economic evaluation of epoetin alfa Hexal/Binocrit compared to darbepoetin alfa (Aranesp) in the treatment of chemotherapy-induced anemia (CIA) in Germany. Poster presented at ISPOR 16th Annual European Conress, Dublin, Ireland, 2–6 November 2013.
18. PharmTech.com, 30 September 2014. New report details players and pipelines in the biosimilar space. http://www.pharmtech.com/pharmtech/News/New-Report-Details-Players-and-Pipelines-in-the-Bi/ArticleStandard/Article/detail/855810. Accessed 31 March 2016.
19. Park DI. Current status of biosimilars in the treatment of inflammatory bowel diseases. Intest Res (2016) 14:15–20.
20. Scheinberg M. Biosimilars in Crohn’s disease (letter to the Editor). J Crohn's Colitis (2014) 8:710.
21. FiercePharma, 18 March 2016. Switching to Remsima®▼ (infliximab) from originator has no negative effect on safety or efficacy in 10 real-world studies. http://www.fiercepharma.com/press-releases/switching-remsima-infliximab-originator-has-no-negative-effect-safety-or-ef. Accessed 31 March 2016.
22. Sieczkowska J, Jarzębicka D, Banaszkiewicz A et al. Switching between infliximab originator and biosimilar in paediatric patients with inflammatory bowel disease: Preliminary observations. J Crohn’s Colitis (2016) 10:127–132.
23. The Pharma Letter, 18 February 2016. New British IBD prescription guidelines issued. http://www.thepharmaletter.com/article/new-ibd-prescription-guidelines-issued. Accessed 31 March 2016.
24. FiercePharma, 18 March 2016. Doctors taking a shine to biosimilars as they get experience with them. http://www.fiercepharma.com/story/doctors-taking-shine-biosimilars-they-get-experience-them/2016-03-18. Accessed 31 March 2016.
25. ECCO. P137 5 year budget impact analysis of CT-P13 (Infliximab) for the treatment of Crohn's disease in UK, Italy and France. https://www.ecco-ibd.eu/index.php/publications/congress-abstract-s/abstracts-2015/item/p137-5-year-budget-impact-analysis-of-ct-p13-infliximab-for-the-treatment-of-crohnaposs-disease-in-uk-italy-and-france.html. Accessed 31 March 2016.
26. Hospital Pharmacy Europe, 28 January 2016. Biosimilar Remicade® – the cost-saving benefits. http://www.hospitalpharmacyeurope.com/featured-articles/biosimilar-remicadeÂ®-â-cost-saving-benefits. Accessed 31 March 2016.