Angelo DePalma Ph.D. Writer GEN

Production, yields, characterization, economics, and safety top the list.

In a 2012 presentation Annelie Sköld, Ph.D., program manager for biosimilars at GE Healthcare, identified five drivers for biosimilars development. The three “positive” factors were regulatory framework, treatment costs, and the entry of many large pharmaceutical and biopharmaceutical players. Contra-trends were delays resulting from legal and intellectual property activity, and lack of prescribing interchangeability between biosimilars and originator molecules.

According to early European Medicines Agency guidances and current worldwide practice, manufacturing processes for biosimilars stand on their own and need not duplicate the originator’s production methods. “Instead, the focus is on extended characterization efforts to show that the biosimilar is ‘highly similar’ to the reference medicine. That can really cut clinical efforts and save developers a lot of money,” says Fredrik Sundberg, Ph.D., global director of strategic market development, GE Healthcare Life Sciences.

It also presents opportunities for greater process economy through improved production technology as, for example, through the implementation of single-use equipment, more rigorous process monitoring, process intensification, and other improvements.

Characterization and Quality

Regulators have been encouraging the use of sophisticated analytical tools, particularly as biosimilars have picked up steam. FDA’s guidance, Quality Considerations for Biosimilar Products (Feb. 2012), mentions surface plasmon resonance, microcalorimetry, and classical Scatchard analysis to provide information on binding kinetics and thermodynamics. “Such information can be related to the functional activity and characterization of the proposed biosimilar product’s higher order structure,” according to the guidance.

“These data, as well as immunogenicity as measured by anti-drug antibodies, are key regulatory and technical challenges for biosimilars and other novel drugs,” adds Dr. Sundberg.

Characterization and quality control may be significantly improved with state-of-the-art analytics that provide more data, more rapidly or in real time, provided this occurs during early development. Companies should apply the same methodology for selecting the best clones, assessing higher-order structure, and evaluating function and physicochemical attributes as they would for any well-characterized biological product, says Dr. Sundberg.

“One hurdle for smaller players may be access to several batches of the reference medicine, which are required to establish a threshold for the originator’s process variation—which can sometimes be greater than its dissimilarity with the biosimilars,” he points out.

U.S. Lagging Behind?

Biosimilars have been available in Europe for more than six years, but have not yet been approved for the U.S. market. Lisa Skeens, Ph.D., corporate vp, global regulatory affairs, at Hospira, attributes the late U.S. entry to the fact that many U.S. patents for key biologics don’t expire till mid-decade.

This past July Sandoz reported that the FDA accepted its Biologics License Application for filgrastim, which was filed under the new biosimilar pathway created in the Biologics Price Competition and Innovation Act of 2009. The company was the first to file for approval via the BPCIA process.

Hospira, which expects to file initial applications for biosimilars with the FDA within the coming year, is the only U.S. company already marketing biosimilars in Europe and Australia. “Our experience suggests that once physicians become aware of the safety and efficacy, including from post-marketing studies, they will gain confidence in prescribing biosimilars,” Dr. Skeens tells GEN.

Hospira believes that biosimilars will lower the cost of expensive biologics and expand access. “The U.S. market will be more knowledgeable when biosimilars debut here,” Dr. Skeens says. “U.S. physicians and payors in the United States have had the advantage of observing European experience, and there is a multitude of studies supporting biosimilars.”

It Comes Down to Economics

As noted in a 2011 IMS report, Shaping the Biosimilars Opportunity, biosimilars are expected to increase their market share within biopharmaceuticals from 1% in 2014 to 10% by 2020, representing a market value increase from $1.9 billion to as much as $25 billion.

Because the European Union enjoyed a five to seven-year head start on issuing guidance related to biosimilar development, virtually all sales of biosimilars today occur in Europe. The comparison between European and U.S. approvals resembles a lopsided football score: EMEA 21, FDA 0.

IMS Health attributed the slow uptake of biosimilars in the U.S. to legislation allowing originator companies to delay approval of new biosimilars. Once products begin breaking through these legal and regulatory barriers, however, the U.S. is expected to be a major market for biosimilars.
Another IMS study, commissioned by the Generic Pharmaceutical Association in 2011, calculated that generic drugs saved the U.S. health system more than $150 billion in 2010 alone, and $931 billion during the preceding decade. IMS estimated that biosimilars could save as much as $108 billion over their first decade of U.S. availability.

Analysis by the German asset management firm DVFA indicates that biosimilar development will require approximately half the number of patients and just 60% of the time to market compared with originator biologics. Even more attractive: development costs are just 15% to 20% of those for biologics, with a probability of success that is ten times higher (50% vs. 5%).

Similar numbers no doubt emboldened Hartmann Willner, an FDA regulatory affairs consulting firm, to predict, in 2007, that biosimilar sales would reach $16 billion by 2011. Actual sales that year were about $600 million. Gabriel Morelli, Spain Country Manager at IMS Health, recently wondered if industry analysts were not “expecting too much” at that early point but if the time for optimism has indeed returned. Morelli concludes that biosimilars “are approaching a turning point…but still much has to change.”

On the plus side, biologics sales have doubled since 2006, and growth has been two to three times as rapid as that for all pharmaceuticals. Global sales increases of 14% in 2012 for biologics suggest significant pent-up demand, even as health systems look to cut costs. Yet growth in biosimilars is expected to be strongest in advanced economies, particularly the U.S., Europe, and Japan, while the most rapid growth (based on extremely modest baseline sales) will occur in emerging nations like Brazil, Mexico, and China.

Conversely, the economics of biosimilars are by no means cut-and-dry. Small molecule generics lose approximately 90% of their value compared with the innovator medicine, and their introduction does not increase utilization. Cost reduction estimates for biosimilars may vary from 10% to as much as 60%. Prices will differ by large factors between established economies and developing ones, complicating cross-border sales efforts. Add to this the uncertainties of a huge number of entrants and regulatory disharmony outside of advanced countries, and market predictions become reckless, even parlous.

All in all, Morelli believes that factors positively and negatively affecting biosimilars, including IP and legal challenges, will turn increasingly positive, re-affirming his company’s prediction of $25 billion in sales by 2020.


Nathan Wei, M.D., director of the Frederick, MD-based Arthritis Treatment Center, predicts that biosimilars will be priced about 30% lower than originator drugs. Dr. Wei, who has participated in biosimilar studies for rheumatoid arthritis, is cautious about utilization predictions. “Insurance companies will probably mandate the use of biosimilars ahead of brand name products,” he says, “but as with other generics, some people will be leery about taking them. I know endocrinologists who will only use branded Synthroid, for example, instead of the generic.”

Dr. Wei believes that skepticism will be higher for biosimilars than for generics because “biologics are more difficult to manufacture.” Moreover the lower prices will not likely lead to greater utilization. “Insurance companies will still stonewall, and docs who aren’t prescribing biologics now still won’t,” he predicts.

The price drop for biosimilars in Europe relative to innovator molecules has been 20%–30%, and most experts expect a similar discount in the U.S. Because the U.S. is the world’s largest market for biologics, pharmacy benefits manager Express Scripts has estimated that once biosimilars hit the U.S. market the healthcare system could realize savings of up to $250 billion in the first decade of availability. “The overriding need to bring down healthcare costs will drive lower prices,” emphasized Hospira’s Dr. Skeens, “particularly once physicians become comfortable with these drugs.”  

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