Changing the landscape of biologics, biosimilars entered the market in the U.S. in 2015 after an FDA advisory panel decided unanimously that Sandoz’s replacement biosimilar of Amgen Inc.’s Neupogen (filgrastim) should be accepted.
For the past decade, the EU has been evaluating and approving biosimilars, while the U.S. until very recently has avoided biosimilar applications—with Sandoz’s Zarxio being accepted in 2014 and later approved in early 2015.
Unlike generic drugs, biosimilars are inexact copies and are therefore required to undergo more testing prior to approval.
Biologics, large protein molecules produced by genetically-engineered organisms, are exceedingly complex, as compared to typical drugs which are small molecules made through biochemical processes. The living cells that constitute a given biologic may chemically modify the proteins they make. The conditions when cells are grown can “alter the pattern of these modifications, and thus the molecule’s structure and behavior. The result is a drug so complex that it is difficult—if not impossible—to fully characterize.”1
The FDA defines a biosimilar as follows:
“A biosimilar product is a biological product that is approved based on a showing that it is highly similar to an already-approved biological product, known as a reference product. The biosimilar also must show it has no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products.”
Despite this monumental—and rather overdue—breakthrough in the U.S., there are many questions that have yet to be addressed for biosimilars, such as:
- Regulatory requirements
Michael Kouchakdjian, Ph.D., President and Co-Founder of Blue Stream Labs, a biosimilar company founded in 2006 and located in Woburn, MA, participated in an exclusive Q&A about the biosimilar market.
Q: What is involved in your analytical characterization and comparison between biosimilars and originator molecules?
Kouchakdjian: Every comparability program is tailored to evaluate the unique attributes of the specific molecules. In many cases, a well-designed analytical program will evaluate the confirmation of the amino acid sequence, determine post-translational modifications, including both N- and O-linked glycosylation, along with the structural analysis of the glycan moieties and the degree of sialic acid occupancy, if present. Additional elements of structural characterization may include the mapping and quantification of disulfides and any free cysteines, the integrity of the N- and C-termini, and other modifications including deamidation, oxidation, potential glycation, etc. Characterization including secondary and tertiary structural characteristics can be assessed by means of various biophysical techniques, including circular dichroism, fourier-transform infrared spectroscopy, intrinsic fluorescence, and differential scanning calorimetry to determine parameters for protein folding.
Q: What are some of the guidelines for analytical testing of a biosimilar?
Kouchakdjian: Initial FDA draft guidelines were published in 2012. These guidelines provided a roadmap for assessing comparability and encouraged engagement with the agency early in the process. Final guidance on biosimilar products was released by the FDA in 2015 which further clarified and refined the scientific and regulatory parameters for assessing biosimilar and for guiding development programs. The EMA issued guidelines for biosimilars in 2005. These guidelines were updated in 2013.
Q: What are some of the challenges you see companies facing with regards to biosimilar development?
Kouchakdjian: The greatest challenges involve clinical development of biosimilars. Assuming that data from preclinical and early clinical assessments—pharmacokinetic (PK), pharmacodynamics (PD), and immunogenicity—support advanced clinical stage development, companies will need to demonstrate comparability in the realm of safety and efficacy. Pivotal Phase III trials will need to reinforce and extend earlier work and provide a level of confidence that allows for agency approval. Other challenges in developing biosimilars include identifying critical quality attributes, obtaining sufficient lots of innovator product to establish product variability, and the need, in some cases, for deformulation which may affect product quality.
Q: What are some of the areas that companies often have room for improvement?
Kouchakdjian: The process for developing biosimilars is complex and costly. Success will depend of many factors in the collaboration between clients and CROs. From the very start of a comparability program, communication and project management are critically important. Open and efficient communications will result in the real-time sharing of crucial information, joint troubleshooting, and subsequent achievement of timeline and cost targets. This is an area in which Blue Stream excels.
Q: Are there certain areas that companies creating biosimilars are often very strong in?
Kouchakdjian: Many companies are good at selecting biosimilar candidates to challenge innovator products. Many of the larger companies excel in clinical phase studies to determine safety and efficacy and are very experienced in interacting with the regulatory agencies, which will ultimately approve their biosimilar candidates. In the early phases of biosimilar development, many companies are effective in finding more productive cell lines with more efficient purification processes, which result in lower production costs.
Q: What are some of the trends you see developing with regards to biosimilars?
Kouchakdjian: Due to the evolution over time of guidelines—beginning in 2005 in Europe and continuing in 2012 in the U.S.—from the various regulatory agencies throughout the world, we see the intensity of biosimilar development ramping from region to region. Blue Stream also observes the increasing number of companies worldwide competing against one another in the race for introducing biosimilar candidates to replace the same innovator products. There are multiple biosimilar candidates to replace each reference product. One wonders how the market will be able to absorb all of these products while providing reasonable return to the biosimilar developers.
Q: What do you foresee for biosimilars in the coming year in the U.S., as compared to other countries?
Kouchakdjian: Although up to now, the targets for biosimilar developers have been markets outside to U.S., very quickly the large and relatively rich market in the U.S. will rise in prominence. Blue Stream sees overseas biosimilar developers initially targeting their local markets. However, many of their studies are being conducted with FDA-approval in mind, thus allowing for eventual registration and market rollout in the U.S. Therefore, for many overseas developers, the initial market target for rollout is local, with the longer-term aim being the U.S.
Q: What do you anticipate for the biosimilars market in 2016?
Kouchakdjian: Between 2015 and the end of 2019, many biologics with combined U.S. sales of tens of billions of dollars will lose their marketing exclusivity. It is anticipated that this number will include Humira, Remicade, and Rituxan—all serving huge markets and all for which Blue Stream has conducted biosimilar comparability studies.
- Ledford, Heidi. “First biosimilar drug set to enter US market.” Nature. 2015. http://www.nature.com/news/first-biosimilar-drug-set-to-enter-us-market-1.16709.