Ready for Prime Time?

February 20, 2012

By Jianfeng Hang, PhD, MRA, RAC


In the past thirty years, FDA approved more than 150 therapeutic biologics including recombinant monoclonal antibodies (mAbs) and genetically engineered proteins.1 These products fulfilled the unmet medical needs and provided patients with valuable treatment opportunities. Often these biologics are the only options for various medical conditions such as hepatitis B, rheumatoid arthritis, hereditary emphysema and some types of cancer. Many originator biologics are very expensive. For example, annual cost for Herceptin, a HER2-positive breast cancer biologic, is $37,000, and that for Gaucher disease drug Cerezyme is $200,000.2 High costs of biologics limit their availability to broader patient populations, particularly to those in need in less-developed countries. One pragmatic solution to improving the accessibility of the costly originator biologics is to develop their subsequent versions, or biosimilars. Once the patents of the originator biologics expire, the market competition naturally drives the price down. This exercise has proven to be very successful in lowering the prices of small molecule brand-name drugs by the introduction of their generic copies.

More than 12 originator biologics with combined global sales of more than $ 67 billion came off patent at the end of 2012.3 Patents of blockbuster biologics Humira (2012 sales: $9.3 billion, US patent expires in 2016), Remicade (2012 sales: $8.2 billion, EU patent expires in 2015), Enbrel (2012 sales: $8.0 billion, EU patent expires in 2015) and Rituxan (2012 sales: $7.4 billion, EU patent expires in 2015) will all expire in US and EU in the period between 2013 and 2019.4

Sales of biosimilars only contribute a small fraction of the entire biologics market. In 2012, their sales in highly regulated markets for the first time reached 1 billion. Nonetheless, according to a study by IMS Health, a market research firm, this number will increase significantly in the coming years. It IMS health predicts sales of biosimilars will exceed $4 billion by 2016 and $11 billion by 2020.

Many investors, including biotech innovator giants such as Biogen Idec and Amgen, are eager to grasp the opportunity presented by biosimilars.5

We will discuss the current regulatory scenario of biosimilars in EU and US, the two most regulated markets. The insights from the discussion will help us understand some investment considerations specific to biosimilars.

Current Regulatory Scenario of Biosimilars in EU and US

A. European Experience

The Europe Union (EU) is the pioneer in building legal framework for biosimilars. EU outlined the regulatory pathway to gain a biosimilar medicinal product approval in European Directives 2003/63/EC,

Annex I, Part II, section4,6 differentiated “generic medicinal products” from “similar biological medicinal products” in European Directives 2004/27/EC.7 The European Commission and the European Medicines Agency (EMA) are the agencies for the implementation of these Directives. The EMA’s Committee for Medicinal Products for Human Use (CHMP) is responsible for issuing general and productspecific guidelines to help the industry for biosimilar application.

In April 2006, the first two biosimilar products were approved by the European Commission. They are human growth hormone (somatropin) products: Omnitrope8 from Sandoz in Austria and Valtropin9 from Biopartners in Germany. The two approvals were based on comprehensive comparisons against their reference products which resulted in different label claims from those on the originator biologics.10 On September 10, 2013, the same agency approved the first biosimilar antibody Inflectra, a copycat version of Johnson & Johnson and Merck & Co's Remicade.11 The short history of the pioneering biosimilar development and application in Europe taught us some valuable lessons that need to be addressed in the future guidelines:13 1) Some differences between a biosimilar and its reference product are acceptable, such as glycoprofile, being expressed from different cell species; but often time they need to be justified, especially for the impurity profile. 2)

Comparative trials need to be conducted in a sensitive population with the consideration of batch-to-batch variability in the reference product. 3) Extrapolation from one usage to another is not a given. 4)

It is not always necessary to demonstrate efficacy in patients. For example, a biosimilar Filgrastim was approved based on its repeat dose studies in healthy volunteers and non-comparative safety studies sponsored by Apotex.

B. US Experience

To control the surging health care spending, the US government is trying to slow down the rising drug expenditures associated with brand-name drugs. According to the congressional budget office’s estimate, biosimilars could save the government 1314 to 25 billion dollars over the next 10 years.15 In 2009, Congress passed the Biologics Price Competition and Innovation Act (BPCI Act of 2009), an amendment to the Public Health Service Act (PHS Act), as a start to improve the affordability and accessibility of biologics. The act created an abbreviated approval pathway for biosimilars demonstrated to be highly similar (biosimilar) to a FDA approved originator biologic [section 351(k) of the PHS Act]. It was signed into law by President Barack Obama on March 23, 2010 under the Patient Protection and Affordable Care Act (PPAC Act).

FDA’s Draft Biosimilars Guidance Documents

14 of the 16 biosimilars approved by the EU to date share only three reference products: Filgrastim, Epoetin, and Somatropin. At least four products have failed the EU approval process (three withdrawals of insulin and one negative opinion on interferon alpha). Even for some biosimilars that did gain approval, their journeys have been bumpy. For example, the clinical trials of two approved epoetins involved more than 600 human subjects with half of them tested on the biosimilar epoetin for at least 24 weeks.

This indicates the complexity of demonstrating biosimilarity in practice. Regulators and sponsors are gaining more experience and learning with each application.

The groundbreaking work on the modern system of generic drugs is the “Hatch-Waxman Act”16 - the Drug Price Competition and Patent Term Restoration Act. This 1984 United States federal law established the Abbreviated New Drug Application (ANDA) process in section 505(j), founded legal ground for faster approval pathway for small molecule generic drugs. Thousands of less expensive generic drugs were approved ever since and affordability of many drugs was improved dramatically.17 The United Sates’ contribution to bringing biosimilars into the market cannot yet match their landmark work on the introduction of generic drugs. The US regulatory framework and practice on biosimilars lag significantly behind Europe and even some Asian countries. The BPCI Act of 2009 is six years behind European Directives 2003/63/EC.

As of February 2012, FDA only held 21 Pre-IND meetings, received 9 INDs18 and no BLAs under 351(k) biosimilars pathway (no 351(k) application is submitted yet to this date). These low numbers reflected some serious concerns from the sponsors and the potential biosimilars investors - the lack of clarity in regulations was discouraging the development and commercialization of biosimilars in the US. Providing the interested parties with certain predictability and more detailed guidance was imminent for FDA.

On February 09, 2012, FDA issued three long-awaited biosimilar draft guidance documents that are designed to help the industry to develop biosimilars and to compete with originator biologics. The agency released the fourth guidance outlining how sponsors should plan to use formal meetings to interact with the agency before and during the application process on April 01, 2013.19 The first three guidance addressed scientific, quality considerations of biosimilars and clarified some issues regarding the implementation of the BPCI Act of 2009. The pivotal document of the three is the “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product.”20

Draft Guidance on Scientific Considerations of Biosimilars

The guidance focuses on addressing the issue: how similar is enough to be biosimilar? At the beginning, FDA uses most common protein products as examples to discuss the complexities of biological products in detail and to show the difficulty of proving biosimilarity.

It is pointed out that primary amino acid sequence, higher order (secondary, tertiary and quaternary) structures and enzymatic modifications including glycosylations can all make proteins different and lead to heterogeneity. In addition, many factors such as temperature, moisture, light, and even packaging or delivery materials can affect protein modifications and change their higher order structure.

Limited by resolution, detection limit, and processing speed of current analytical technologies, in most cases it is very challenging, if not impossible, to determine structural and functional differences between two proteins from slightly different manufacturing sources.

Considering the presence of impurities generated during the processes, added formulation agents and excipients in the biological products, the degree of certainty of using structural analysis and functional assays to determine the biosimilarity of two proteins is not high at all.

Despite the advances in the state-of-the-art analytical technologies for biological products, the agency is fully aware of their limitations.

A “stepwise approach to developing the data and information needed to support a demonstration of biosimilarity” is hence recommended. The sponsors can start with extensive analytical, physiochemical and biological characterization of the proposed product to show the degree of similarity to the reference product.

FDA then evaluates the information and suggests necessary animal and human tests accordingly to the sponsor to further demonstrate biosimilarity of the two products. The agency will consider the product’s complexity, stability, formulation, manufacturing process and clinical data in comparison with the reference product, and then determine the extent and scope of these tests on a case-by-case basis.21 FDA will use a Totality-of-the-Evidence approach to evaluate all data and information submitted in support of demonstrating biosimilarity, including “structural and functional characterization, nonclinical evaluation, human PK and PD data, clinical immunogenicity data, and clinical safety and effectiveness data.”22 FDA will allow the sponsors to skip repeating studies that are not necessary to address residual uncertainty, therefore speeding up the application process and saving costs for the sponsors.

By definition under the PPAC Act, a biosimilar is “a biologic product that is highly similar to a reference biologic product notwithstanding minor differences in clinically inactive components, and it has no clinically meaningful differences from the corresponding reference product in terms of the safety, purity, and potency.”23 It is clear that minor differences are allowed in clinically inactive components.

Currently, biologic products are process-dependent. Different manufacturing processes can possibly change a protein product in four ways: (1) protein sequence; (2) protein composition by different enzymatic glycosylations or phosphorylations; (3) higher order structure; (4) impurities, formulation reagents, excipients, etc. Any subtle changes may alter the efficacy and the safety profiles of the product. Immunogenicity is also a critical issue; even small amount of impurities may stimulate immune responses. Unfortunately, current analytical and functional assays cannot detect subtle protein structural changes and impurities. Based on these facts, the guidance suggests that the sponsors at least run one human clinical studies, either immunogenicity or PK/PD if applicable. If residual uncertainty exists, comparative safety and effectiveness may be needed for the determination of biosimilarity.

It is apparent that many suggestions in this draft guidance document are designed to address the issues raised from European experiences.

Draft Guidance on Quality Considerations of Biosimilars The draft guidance document titled “Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product”24 has some overlap with the scientific considerations draft guideline, and it focuses on analytical studies necessary to assess biosimilarity. The discussion on the importance of extensive analytical, physiochemical and biological characterization is repeated in this guidance.