The Biosimilars Market / by TI

Biosimilars have increasingly become an important and somewhat controversial topic in the healthcare space. Depending on who one speaks to, the opinion on biosimilars changes. However, there are certain truths that all stakeholders should keep in mind. Specialty pharmaceuticals are growing in proportion of total pharmaceutical spend in the United States as well as in cost to the patient and healthcare system at an unsustainable rate.

The Biologics Price Competition and Innovation Act (BPCIA) of 2009 was enacted as part of the Patient Protection and Affordable Care Act on March 23, 2010, to alleviate some of those pressures. It amended the Public Health Services Act to include an abbreviated pathway in section 351(k) for biological products shown to be biosimilar to or interchangeable with an FDA licensed reference product. The BPCIA opened the door for biosimilar versions of already approved biologics where “generic” competition didn’t exist prior. Two years after the enactment of the BPCIA, the FDA issued its first draft guidance on biosimilars in February 2012, which laid out a framework for approval, providing direction for biosimilar development.

More FDA Clarity
The FDA continues to clarify biosimilar guidelines. The most recent draft guidance providing additional details was published on May 2014 and included three very interesting clarifications. First, the FDA stated the usefulness of a pharmacokinetics (PK) and pharmacodynamics (PD) study done in healthy subjects for certain molecules. In some cases, a study completed in healthy volunteers is more informative and sensitive than in patients. Second, the FDA acknowledged that a non-US licensed product may be used for comparison in a PK and, if applicable, PD study as long as adequate data are presented to scientifically justify that use along with an acceptable bridge to the US licensed reference product. Third, the FDA established four levels of similarity with the need for additional, phase III type data diminished as a higher level of similarity is achieved.

The FDA’s approval of enoxaparin, a complex, low-molecular weight heparin (LMWH), in July 2010 demonstrates its evolving thinking in terms of the body of data needed to determine similarity across molecules. While not a biologic, enoxaparin is complex enough in structure that the European Medicines Agency (EMA) requires clinical trials for generic approval. The FDA took a robust approach weighted on scientific analysis of the molecule. In a Q&A about generic enoxaparin the FDA stated that there is no scientific need to perform additional clinical studies to demonstrate equivalence of clinical effectiveness and safety of generic enoxaparin to Lovenox. Although the EMA Guideline requires clinical studies to demonstrate comparable effectiveness to a similar LMWH, FDA notes that its approach is more sensitive to differences between two enoxaparin products than the clinical studies recommended in the EMA guideline. The same may hold true for a biosimilar depending on the data package and level of similarity as laid out in Exhibit B.The FDA also created the purple book in September this year. The purple book will contain lists of all licensed biosimilar and interchangeable biological products and will act as a reference once approvals are made in the US. While these initial guidances provide a solid framework for development, there are still numerous questions that remain unanswered, including the naming structure, specifics around coding in the buy-and-bill space as well as clinical data requirements for interchangeability. The FDA is expected to continue to release updated guidances to address these and other issues in the coming year.


The World Health Organization (WHO) has put a proposal together to address one of these controversial topics, naming. WHO is responsible for ensuring there is a single name acceptable worldwide for each approved active pharmaceutical substance, known as an international nonproprietary name (INN). The July proposal includes a voluntary global naming scheme for all biologics including biosimilars that would involve a 4 letter code attached to the INN known as a biological qualifier.

While the US is moving towards a more concrete pathway to biosimilar approval and usage, biosimilars are not new to most of the world. In less regulated markets “similar biologics” have been in use for years. The highly regulated markets of the EU, Australia, Japan and Canada have had biosimilar guidelines in place since 2005, 2008, 2009 and 2010 respectively. The EU currently has 16 authorized biosimilars including the first monoclonal antibody approval for a biosimilar infliximab. There are 9 authorized biosimilars in Australia. Japan has 6 authorized biosimilars including a mAb and Canada has 3 authorized biosimilars including a mAb. With the passing of the BPCIA, the doors have opened in the US. 

Biosimilar Competition in the US
Competition in the US biosimilars market will be unlike competition in any other segment of the pharmaceuticals for multiple reasons. First, there are high costs associated with the development, approval and commercialization of biosimilars. Second, biosimilars are not automatically substituted yet, which will require biosimilar companies to invest in organization and strategies commonly associated with a brand company. Third, with no biosimilar approved in the US, there is a lack of understanding of these products across all areas of the health care sector. Lastly, the interchangeability designation will disrupt any norms created by a biosimilar-only market. Additionally, many deals have been struck to fill competency gaps among partners, creating interesting competitor profiles.

There are numerous competitors vying for the US market which fall into three categories. First, innovator companies which have diversified into biosimilars like Amgen and Pfizer. Second, traditional generics manufacturers which have expanded into biosimilars like Hospira and Teva. And third, companies created solely to provide better access to patients for complex biologics such as Therapeutic Proteins International. 
In the US, two biosimilar applications have been filed. In addition, the FDA tentatively approved a copy version of Lantus. Because Lantus was not originally filed as a BLA, an NDA/505(b)(2) pathway had to be pursued even though the product was filed as a clinically and analytically equivalent molecule or what would be considered biosimilar.


Sandoz is currently the leading name in biosimilars. The company has three biosimilars marketed in highly regulated markets ex-US and six late stage molecules. In July 2014 Sandoz announced the FDA had accepted its biosimilar application for filgrastim, the first biosimilar application accepted by the FDA.

The second biosimilar application in the US was for a biosimilar infliximab from South Korean company Celltrion. The product received approval from the EMA in October 2013 and is marketed in the EU under the name Remsima. In March, Celltrion filed two declaratory judgment suits against patents related to infliximab, which demonstrates the intellectual property considerations that will be prevalent in this space. 
Boehringer Ingelheim, one of the most established biomanufacturing companies, confirmed plans to develop versions of adalimumab, bevacizumab and rituximab in its annual conference this past April. Currently, the company is running two clinical trials for its biosimilar rituximab (BI 695500), a phase I trial in follicular lymphoma and a phase III trial in rheumatoid arthritis. In addition, Boehringer initiated a phase III study for BI 695501, a version of adalimumab. Boehringer and Lilly partnered to create a copy insulin glargine which was tentatively approved by the FDA.

Other innovator biologics competitors have biosimilar pipelines but have not yet announced any FDA filings. Amgen has products in development on its own and with partner Actavis, including a completed Phase III for adalimumab and Phase III studies in progress for trastuzumab, bevacizumab and rituximab. Pfizer has multiple biosimilar products in development including adalimumab, infliximab and trastuzumab.

Hospira partnered with Celltrion for multiple products including infliximab, which has EU approval under the name Inflectra. Hospira has announced they intend to bring a biosimilar version of Epogen to the US before August of 2015.

Teva received approval for tbo-filgrastim, brand name Granix, through the BLA route and is not considered a biosimilar in the US. The company announced it would withdraw its balugrastim BLA for FDA consideration. Recent moves contrast with Teva’s initial plans for presence in the space including a joint venture with Lonza to develop a biosimilar version of rituximab which was discontinued in July of 2013. 
One untraditional player in the emerging biosimilars market is Samsung, who first entered the market by building a biomanufacturing facility for contract service opportunities. Eventually, the Korean company started the Bioepis unit and entered into partnerships with both Biogen Idec and Merck to bring biosimilar versions of monoclonal antibodies to market. Currently Samsung Bioepis has multiple products in varying stages of clinical development including infliximab (SB2), trastuzumab (SB3), etanercept (SB4) and adalimumab (SB5).

Looking Forward
It is clear to see that the US market will be a highly competitive one with remaining uncertainty on how biosimilars will be treated once approved and launched. The driving factor in the forefront should be expanded access to more affordable options for patients.