This article is an updated version of what previously appeared in the 2014 Nov/Dec issue of Contract Pharma.

2014 has been a notable year for activities in the biosimilars arena. Even the summer months, which are traditionally been viewed as “quiet”, being vacation season, this year were busy with advances, particularly in the United States. This article will examine a few of these more recent developments.

Regulatory Background

The first generation of biotechnology-produced pharmaceuticals has already reached, or is close to, patent expiry. This includes many monoclonal antibody products that are successful blockbuster drugs, and command premium prices for courses of treatment. Within the past decade a pharma sector driven by the need for more affordable medicines has emerged. In many countries, biosimilars are marketed as legally approved versions of existing patent-expired, branded biologics. They are granted marketing approval on the basis of analytical, pre-clinical and clinical data that show they are highly similar to the original drug.

The European Union (EU) established the first legal regulatory guidelines for “similar biological medicinal products” i.e. biosimilars, in 2005. These require the demonstration of similarity by performing side-by-side comparison against the originator product. In addition to general, called overarching, guidelines, product-specific annexes were also published for a variety of molecules including monoclonal antibodies. Several of the original guidelines have been, or are in the process of being, revised. All guidelines plus current revision concept papers and drafts are available on the European Medicines Agency (EMA) Multidisciplinary: Biosimilars website1.

The first biosimilar molecule approved in Europe, in April 2006, was Omnitrope, a version of somatropin. To date, the EU has approved 21 applications2, and is continually updating its guidelines, both general and product-specific, in the light of experience. Initially, the biosimilars approved were simple proteins such as somatropin, epoetin and filgrastim. More complex, larger molecules such as monoclonal antibody products move the challenge of establishing biosimilarity to another level. The first biosimilar mAbs were approved in Europe in June 2013. These two versions of infliximab, Celltrion’s Remsima™ and Hospira’s Inflectra™, pave the way for more widespread access to biological treatments with these complex biomolecules. It is known that Celltrion, Sandoz and several other leading drug developers have more biosimilar mAbs currently in late-stage clinical trials, and these can be expected to be submitted for approval shortly.

Meanwhile, in the US, the Biologics Price Competition and Innovation Act (BPCIA), enacted in 2009, provides a new regulatory approval pathway for biosimilars – the 351(k) route of the Public Health Service (PHS) Act. This pathway also requires the comparison of a biosimilar molecule to a single reference product which has been approved under the normal 351(a) route, with reference to prior findings on safety, purity and potency. One aspect of the legislation unique to the US is the provision for two levels of product – ‘Biosimilar’ and ‘Interchangeable Biosimilar’. An interchangeable biological product is one that may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product. Therefore, more data, including clinical switching studies are required if a product is to be labelled as interchangeable. However, no biosimilar products have thus far been approved following this 351(k) route.

In February 2012, the US Food and Drug Administration (FDA) published three draft guidance documents to assist biosimilar developers: ‘Scientific Considerations in Demonstrating Biosimilarity to a Reference Product’3, ‘Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product’4 and ‘Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009’5. In April 2013, a fourth guidance, dealing with scientific meetings, was issued6, and a fifth draft guidance released in May 2014 (see below).

Both the European and US regulatory pathways and, indeed, those in many other countries, depend on the ability to demonstrate biosimilarity involving rigorous comparison against batches of originator product, initially at the physicochemical level, then in a step-wise manner in appropriate comparative safety and efficacy tests.

Recent Regulatory Developments

As mentioned above, the FDA published their 5th Draft Guidance for Industry document on biosimilars in May 2014, entitled ‘Clinical Pharmacology Data to support a Demonstration of Biosimilarity to a Reference Product’7. Although this guidance mainly deals with the design and use of clinical pharmacology studies to support the demonstration of biosimilarity, it also reinforces some general concepts that FDA has been outlining in public presentations. One aspect which is emphasised is the importance of the step-wise development approach to the demonstration of biosimilarity, beginning with ‘extensive and robust comparative structural and functional studies’.

It states, ‘It may be useful to compare the quality attributes of the proposed biosimilar product with those of the reference product using a meaningful fingerprint-like analysis algorithm that covers a large number of product attributes and their combinations with high sensitivity using orthogonal methods. Such a strategy can further quantify the overall similarity between two products and may provide a basis for a more selective and targeted approach to subsequent animal and/or clinical studies.’

It contends that the results of the comparative characterization may lead to one of four specific assessments:

Not similar: Certain differences in the results of the analytical characterization may lead to an assessment of “not similar” and further development through the 351(k) regulatory pathway is not recommended unless, for example, modifications are made to the manufacturing process for the proposed biosimilar product that is likely to lead to a highly similar biological product.

Similar: Further information is needed to determine if the product is highly similar to the reference product. Additional analytical data or other studies are necessary to determine if observed differences are within an acceptable range to consider the proposed biosimilar product to be highly similar to the reference product. As an example, glycosylation plays an important role in the PK of certain protein products. Manufacturing process conditions may impact glycosylation. Comparative PK and PD studies of the proposed biosimilar product and the reference product help resolve that some differences in glycosylation identified in the analytical studies would be within an acceptable range to consider the proposed biosimilar product to be highly similar to the reference product.

Highly similar: The proposed biosimilar product meets the statutory standard for analytical similarity. The results of the comparative analytical characterization permit high confidence in the analytical similarity of the proposed biosimilar and the reference product, and it would be appropriate for the sponsor to conduct targeted and selective animal and/or clinical studies to resolve residual uncertainty, and support a demonstration of biosimilarity.

Highly similar with fingerprint-like similarity: The proposed biosimilar product meets the statutory standard for analytical similarity based on integrated, multi-parameter approaches that are extremely sensitive in identifying analytical differences. The results of these fingerprint-like analyses permit a very high level of confidence in the analytical similarity of the proposed biosimilar and the reference product, and it would be appropriate for the sponsor to use a more targeted and selective approach to conducting animal and/or clinical studies to resolve residual uncertainty and support a demonstration of biosimilarity.”7

Comments were invited on this draft for a 90 day period ending 12 August, and were received from 24 companies and organisations. Trade groups such as the Pharmaceutical Research and Manufacturers of America (PhRMA), Biotechnology Industry Organization (BIO) and European Biosimilars Group of the European Generic Medicines Association (EGA), were among those who responded. They, and others such as Genentech, were concerned that the four categories of similarity were vague and confusing, and did not lead to clear understanding of what was required to fulfil each of the criteria. In a general comment, BIO also suggested that the introduction of product-specific guidance might be appropriate, based on the European experience. Undoubtedly, there will be continued discussion on these issues within industry.

More recently (4 August), FDA published another draft guidance for comment, entitled ‘Reference Product Exclusivity for Biological Products Filed under Section 351(a) of the PHS Act’8. This is a procedural document, rather than a specific biosimilar guidance; however, the contents are important for consideration during biosimilar development. The stated aim of the draft guidance is ‘to assist sponsors who are developing biological products, sponsors of biologics license applications (BLAs), and other interested parties in providing information that will help the Agency determine the date of first licensure for a reference product under 351(k)7(C) of the Public Health Service Act’ (PHS Act), as added by the Biologics Price Competition and Innovation Act of 2009 (BPCI Act)8.

The BPCIA established a twelve year period of exclusivity from date of first licensure during which a biosimilar or interchangeable product may not be licenced under 351(K). This includes a four year period when an application may not be reviewed by the FDA. The recent draft guideline8 outlines the specific information which the FDA requires sponsors to provide in order to enable it to determine the exact date of first licensure. Comments were to be received on this guideline by October 6.

In relation to this, FDA have just launched (September 9) what they call the “Purple Book”. This is a list of “Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations”9. It is designed to be referred-to by the nickname “Purple Book” in the same way as they reference the “Orange Book” which lists approved drug products with therapeutic equivalence evaluations. The Purple Book will contain lists of biological products licensed under section 351(a) of the PHS act, including date of licensure and exclusivity expiry date, cross referenced with biosimilar or interchangeable products licensed under 351(k). There are separate lists for products regulated by Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) and these will be updated periodically.

In Europe, the regulators were also busy throughout the summer months. In May, the Committee for Medicinal Products for Human Use (CHMP) of the EMA adopted the revision of the overarching guideline on ‘Similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues’ (EMA/CHMP/BMWP/247713/2012). This is the first revision of one of EMA’s General Guidances. The original was effective in June 2006, and this revision will come into effect on December 1, 2014.

In addition, CHMP is also currently working on revisions of other overarching guidelines. Drafts of the updated ‘Similar biological medicinal products’ and ‘Similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues’ had deadlines for comments in October and November respectively last year. Subsequently, in October 2014, the main overarching guideline (CHMP/437/04 Rev.1) was adopted and published . It will become effective 30 April 2015, although it states that applicants may “apply some of the provisions of the guideline immediately”. This is an important point as one of the major developments is in the acceptance of data from non-EU/EEA comparator products. The revision allows for an applicant to conduct certain clinical studies and in-vivo non-clinical studies using a comparator reference product from a country with a similar scientific and regulatory standard to those of the EMA. It is the aim of the EMA to avoid unnecessary repetition of clinical trials. Nevertheless, the applicant wil have to establish that the “foreign” product is representative of an EEA reference.

In addition to revisions of overarching guidelines, one of the product specific guides- on recombinant human insulin and insulin analogues revised for the second time. Deadline for comments was July 31, 2014.

First Biosimilar Insulin

Meanwhile, developments were taking place on both sides of the Atlantic, not just concerning guidance documents, but in actual authorisations of biosimilar products. At the June meeting of the CHMP (23-26 June), a positive opinion for marketing authorisation was given to Eli Lilly for its long-acting insulin glargine product, Abasria, for the treatment of diabetes mellitus. This was a development by Lilly and Boehringer Ingelheim, and was submitted via the biosimilar pathway for approval. This is a biosimilar of Sanofi’s Lantus, whose patent expires next year (Feb in US and May in Europe). It is the first biosimilar insulin to be approved by the EMA in the EU.

In contrast, in the US, the same product has been submitted not via the 351(K) Biosimilar pathway, but through the 505(b)2 route of the Federal Food, Drug and Cosmetic Act (FD&C Act). This means it will not be considered as a biosimilar or an interchangeable biosimilar. Sanofi, in a bid to protect its US sales, launched a court action against Lilly in July for patent infringement on seven patents related to insulin and devices used to deliver it. However, the FDA granted Lilly a tentative approval to the same drug product (LY2963016), named Basaglar in the US, on 18 August. Because of the ongoing litigation, FDA has imposed an automatic stay order of up to 30 months before final approval could be granted, unless the court finds in favour of Lilly prior to this.

First Biosimilars Accepted for Review by US FDA

On July 24, 2014, nearly five years after Congress passed a law enabling an approval pathway for biosimilar biological products under BPCIA, Sandoz (the generics arm of Swiss multinational Novartis) became the first company to announce that FDA has received and is reviewing an application under the 351(k) pathway. The application is for a biosimilar of the anti-infective filgrastim, which is commonly used in treating cancer patients receiving myelosuppresive anticancer drugs to counteract decreased white blood cell counts. The original drug, Neupogen, is licensed by Amgen. The Sandoz biosimilar was approved in Europe in 2008 and is at present marketed as Zarzio in more than 40 countries outside the US.

However, Sandoz reluctance to follow the exact “legal and patent” disclosure prescribed by BPCIA ( the so-called “Patent Dance”) has led to Amgen issuing lawsuits against them in October and also petitioning the FDA .

Following closely behind this first application, on August 8, Celltrion announced it had filed an application to the FDA for its product Remsima, a biosimilar version of Janssen Biotech’s Remicade (infliximab). This will be the first biosimilar monoclonal antibody to follow the 351(k) route. Celltrion made history with this product back in 2012 when it was the first biosimilar monoclonal antibody product to be approved anywhere in the world, by the South Korean regulatory authority. Since then, it has continued to make impressive milestones. In June 2013, the CHMP gave it a positive opinion for six indications: ankylosing spondylitis, rheumatoid arthritis, Crohn’s disease, ulcerative colitis, psoriasis and psoriatic arthritis. Market authorization approval was granted in all 27 member countries, alongside a second infliximab biosimilar, Inflectra, from Hospira. These were the first biosimilar mAbs to be approved by the EMA in Europe. Subsequently, the Japanese PDMA and Health Canada gave approval to Celltrion’s product, although not for all the indications. It now has approval in more than 50 countries.

The Celltrion website explains:

“After prior consultation with the US FDA, Celltrion conducted additional clinical trials (starting on October 2013 and lasting 6 months) to determine the bioequivalency of the originator products with Remsima®. Specifically, Celltrion tested for Pharmacokinetic/Pharmacodynamic (PK/PD) equivalency and safety equivalency for the three distinct products, the originator products sold in the US, the originator products sold in Europe, and Remsima®. These additional clinical trial data, along with Celltrion’s established global clinical trial data, were submitted to the US FDA by Celltrion as part of its application10.”

It is interesting to note that both these biosimilar products submitted to the FDA have already undergone significant regulatory oversight in other countries. These two initial filings will involve FDA clinical reviewers applying the principles described in their recent guidelines. They will also start the clock on a complex procedure to provide information to the originator companies (Amgen and Janssen) on the exchange of patent information. Indeed, in the case of Remsima, the patent on the drug held by Janssen does not expire until the end of 2018. Celltrion had already launched a legal challenge in the federal court of Massachusetts to have the remaining patents declared invalid and unenforceable, but subsequently voluntarily dismissed it’s action against Janssen ( Oct 23rd).

Will these pioneering applications promote further development? Already Hospira has announced that it proposes to file an application with the FDA for a biosimilar EPO later this year or early 2015.

Biosimilar drugs are now available in many highly regulated markets and, in some countries, market share for specific products is already overtaking that of the originator. While there are still many questions left to be answered, such as the extrapolation of indications, interchangeability and naming, the legal and regulatory basis for authorisation of biosimilars is built on strong scientific and quality foundations, coupled with appropriate safety and clinical studies. In the US, legal disputes such as Sandoz/Amgen may help to clarify the BPCIA issues for the future. It will certainly be interesting to see what additional developments occur during the remainder of 2014 and whether this momentum is continued into 2015.


Fiona Greer
Global Director, BioPharma Services Development
SGS Life Science Services


1 European Medicines Agency (EMA) Multidisciplinary: Biosimilars

2 Generics and Biosimilars Initiative (GaBI): Biosimilars Approved in Europe

3 US Food and Drug Administration (FDA): Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product

4 US Food and Drug Administration (FDA): Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

5 US Food and Drug Administration (FDA): Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009

6 US Food and Drug Administration (FDA): Guidance for Industry Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants

7 US Food and Drug Administration (FDA): Guidance for Industry Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product

8 US Food and Drug Administration (FDA): Reference Product Exclusivity for Biological Products Filed under Section 351(a) of the PHS Act

9 US Food and Drug Administration (FDA): Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations

10 Celltrion