Biosimilars—A New Frontier: Is the US Market Ready?


This post has been updated based on FDA approval of Celltrion’s Inflectra™, a biosimilar Remicade® (infliximab) for treating arthritis and other inflammatory diseases, on April 5, 2016. Inflextra is the second biosimilar approved by the FDA and the first to be granted multiple indications. This is an important milestone for biosimilars in the United States.

Since the first FDA approval of a biosimilar in March 2015, biosimilars have quickly become one of the hottest topics in the US pharmaceutical industry. Why is this such a big deal, and is the US market ready?

Biosimilars are alternatives to innovative biologic therapies (known as “originator” products) such as Humira® (adalimumab) and Enbrel® (etanercept) for treating rheumatoid arthritis (RA) and psoriasis, or Herceptin® (trastuzumab) and Avastin® (bevacizumab) for treating cancer.

Biosimilars promise to increase access to these life-changing biologic therapies by reducing costs, analogous to the cost savings of generic drugs over brand-named drugs. In fact, biosimilars could save American consumers about $250 billion over the next 10 years.1

However, until the Affordable Care Act was passed in 2010, there was no regulatory pathway for the approval of biosimilars in the United States. The challenge was devising regulatory standards for the analytical tests needed to prove that these complex biologic molecules are highly similar to the originator product and clinical studies to show that there are no clinically meaningful differences in terms of safety and effectiveness.

In March 2015, Zarxio® (filgrastim-sndz, Novartis/Sandoz) became the first biosimilar approved for the US market. Zarxio is a biosimilar version of Amgen’s Neupogen® (filgrastim), which is used to boost white blood cell counts in cancer patients and help them fight infections.2 But that is just the tip of the iceberg. Dozens of companies are lining up to get their biosimilar products approved. On February 9, 2016, Celltrion’s Inflectra™ (CT-P13), a biosimilar version of Remicade® (infliximab) received a positive vote from an FDA advisory committee, and the FDA approved it for 6 indications on April 5th.3 Biosimilar versions of Humira®, Enbrel®, Herceptin®, Avastin®, Rituxan® (rituximab), Procrit® (epoetin alfa), and Neulasta® (pegfilgrastim) are all in development, and several are currently being reviewed by the FDA. The driving force behind this tidal wave of biosimilar products is the estimated $67 billion in global sales from many blockbuster originator products whose patents will expire by 2020.4

But gaining regulatory approval is just the first step. Biosimilars have been available in Europe since 2006 and initially experienced slow acceptance in many markets, depending on local regulations.5 However, there is evidence that biosimilars are expanding access to treatment in Europe. For example, since Sandoz introduced a biosimilar filgrastim to the European market in September 2008, use of filgrastim has increased by 30%,[IMS data] and a study in Sweden showed reduced costs and improved adherence to treatment guidelines.6 So what are the hurdles to adoption of biosimilars here in the US?

One of the biggest hurdles, surprisingly, is the attitude of treating physicians who are somewhat dubious about the idea of using biosimilars. We conducted interviews with practicing physicians to better understand their opinions about this rapidly evolving field of medicine.

What we learned is that some physicians have reservations about the efficacy and safety of biosimilars, and there is little consensus on many of the critical issues such as indication extrapolation and interchangability.

A wide range of opinions were expressed with regard to: (1) what tests should be required to demonstrate that a biosimilar product is highly similar to the originator product; (2) what clinical data should be required for approval; (3) whether a biosimilar should be approved for all the indications of the originator product without data in every indication (a concept known as “indication extrapolation”); (4) whether biosimilars should be allowed to be used interchangeably with the originator product; and (5) how biosimilars should be named and post-marketing safety data tracked. Of note, the FDA issued a Draft Guidance on nonproprietary naming of biosimilars in August 2015 and has invited comment.7

Many physicians are uncomfortable with indication extrapolation.

Some of the potential cost savings associated with biosimilars stem from the regulatory provision for indication extrapolation. That simply means that a biosimilar can be approved for multiple indications―consistent with the labeled indications of the originator product―without conducting clinical trials in each indication. So, for example, a biosimilar infliximab could be studied only in RA and then granted every approved indication of the originator product (Remicade), which includes RA, psoriatic arthritis, plaque psoriasis, ankylosing spondylitis (AS), ulcerative colitis, and Crohn’s disease. Extrapolation of efficacy and safety data across different patient populations is an entirely new concept for US physicians. Celltrion’s Inflectra was the first true test of extrapolation in the US. It was studied only in RA and AS, and yet it was approved for every indication that has been granted to Remicade.3 Although the advisory committee members and the FDA have embraced extrapolation, the real question is whether skeptical physicians will use Inflectra to treat diseases for which there are no clinical data.

Many physicians are uncomfortable with the idea of switching a patient from an originator product to a biosimilar.

If biosimilars are going to improve access and reduce costs, physicians and pharmacists need to start using them in place of the more expensive originator products, just like they do with generic drugs. That can happen in one of two ways: either the physician prescribes a biosimilar instead of the originator product, or the physician prescribes the originator product, and the pharmacist gives the patient a biosimilar instead. The latter is called “interchangeability.” For that to happen, the FDA must first determine that the biosimilar is interchangeable with the originator product. The standards for interchangeability are quite high, and involve demonstrating that patients can be treated sequentially with the originator product followed by the biosimilar and vice versa without any increase in the immune reaction to either drug (ie, immunogenicity).

But here’s the dilemma―many physicians are not comfortable “switching” a patient who is doing well on an originator product to a biosimilar, often because of safety concerns. And the physicians we interviewed are terrified of the idea that a pharmacist could substitute the originator product with an interchangeable biosimilar without their consent. To add to the dilemma, the terms “switching” and “interchangeability” are often confused, and the whole concept is a source of considerable angst. In fact, AbbVie recently filed a citizens’ petition challenging the current FDA regulations that would allow interchangability.8

Despite these reservations, biosimilars are coming to the US market and will soon be an important part of the treatment landscape, and patient advocacy groups are actively supporting the development, approval, and adoption of biosimilars. It will be interesting to see how the availability of biosimilars will shape the US treatment landscape and the opinions of the medical community over the next few years.


blog_byline_frame_MCMissy Callahan, PhD, RAC, is a certified regulatory affairs professional, but she will always be an immunologist at heart. Missy has more than 10 years of experience in the medical and regulatory communication field and provides clients with strategic and tactical guidance for FDA and global regulatory authority interactions. Connect with Missy on LinkedIn.

jeff_blog_v8Jeff Riegel, PhD, combines his scientific expertise in molecular biology with 20 years of global healthcare agency experience to guide medical and regulatory communication strategies for biopharma companies large and small. Jeff has developed strategies, messages, and presentations for multiple FDA Advisory Committee meetings. He also directs publications planning and execution in oncology and other therapeutic areas. Connect with Jeff on LinkedIn.



  1. Novartis wins landmark approval for a biosimilar of Amgen’s Neupogen. FierceBiotech.
  2. FDA Approves first biosimilar product Zarxio.
  3. FDA approves Inflectra, a biosimilar to Remicade.
  4. US$67 billion worth of biosimilar patents expiring before 2020.
  5. Young KE, et al. Boosting biosimilars uptake in European countries. ISPOR 17th Annual European Congress, Amsterdam, The Netherlands, 8-12 November, 2014. Poster PHP23.
  6. Gascon P, et al. Clinical experience with Zarzio® in Europe: what have we learned? Support Care Cancer. 2013;21:2925-32.
  7. Draft guidance for industry: Nonproprietary Naming of Biological Products. August 2015.
  8. What Constitutes Interchangeability? AbbVie Submits Citizen Petition to Suggest Requirements.