Reliable, high-quality products require innovative analytics and production.
By Jill Wechsler
As more biosimilars gain market approval in the United States, and manufacturers launch additional programs to develop competitive biotech therapies, regulatory authorities and industry are recognizing the importance of implementing high-tech strategies and sound oversight policies to overcome concerns about product safety and effectiveness. FDA officials are emphasizing how advanced analytical methods can document product performance similar to a reference drug, and that cutting-edge technology can ensure reliable production of high-quality therapies. FDA had approved four biosimilars for market as of Oct. 1, 2016, and more are on the way: six companies had announced the submission of at least nine biosimilar applications as of the end of July 2016, and the agency is assisting with more than 60 biosimilar development programs.
These efforts will be supported by a new agreement on policies for renewing the Biosimilar User Fee Act (BsUFA II), with provisions to streamline the biosimilar development and approval process (1). The agreement expands communication between FDA reviewers and manufacturers to provide more advice on biosimilar protocols and development programs to reduce multiple review cycles on new applications. BsUFA also sets timeframes for FDA to issue important guidance documents on biosimilar naming and labeling. And new guidance documents are scheduled on standards for achieving product interchangeability, statistical analytical approaches for documenting product similarity, and managing post-approval manufacturing changes.
As new biosimilars emerge for patients, Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), is emphasizing the importance of building public trust in biosimilar safety and performance. She observed at a September 2016 conference, held in North Bethesda, MD and sponsored by the Biosimilars Council, that gaining broad acceptance of these products, especially when patients are being asked to switch from a life-sustaining medicine that is working well, requires extensive analytics and testing under FDA’s “totality of evidence” framework. FDA’s regulation of biosimilars is “under the microscope” in Washington, she noted, but “great science” and “fit-for-purpose, innovative regulation” will support patient access to these more affordable medicines.
Woodcock also urged manufacturers to adopt modern manufacturing methods to produce these critical medicines efficiently and economically. “Advanced bioprocessing is beginning to take off,” she observed, acknowledging that innovator firms largely are taking the lead in this area. But she believes that the demand for affordable alternative therapies makes such innovation critical for biosimilars.
Momenta Pharmaceuticals CEO Craig Wheeler agreed that advances in biotechnology manufacturing and efficient plant utilization will be key over the long term for biosimilars to provide an expected 30-40% cost advantage over reference products. Such manufacturing innovation has been slow to come because providing less costly products has been less important for innovator products, he commented. But efficient plant utilization and adoption of next-generation technologies matter more for biosimilars.
Payers and consumers are looking for reliability in production systems to meet the demands of the larger US market, added Sandoz US President Peter Goldschmidt. He and other leaders in the biosimilars field are looking for partnerships and alliances to help secure the best technology for providing large quantities of these follow-on therapies.
Manufacturing systems for any biological product normally entail multiple revisions and improvements throughout the product lifecycle, and biosimilars are expected to follow this pattern. The regulatory issues for these products, though, are tricky, as seen in discussions about whether a changed biosimilar should be compared to the original reference product or to the initial biosimilar, explained Pfenex Chief Medical Officer Hubert Chen. With 20 or 30 manufacturing changes common over a product’s lifetime, biosimilar developers want to avoid repeated safety and efficacy studies with every alteration. Instead, they want to rely on comparability studies, noted Hillel Cohen, Sandoz executive director for scientific affairs. And after 10 or 20 years, he noted, a reference product may not be available for further comparative testing.
FDA officials say they are aware of concerns about what evidence will be required to manage post-approval changes and plan to address the issue further. Under the BsUFA II plan, FDA has committed to publishing draft guidance that describes processes and considerations related to post-approval manufacturing changes for biosimilars. An initial draft, however, is not scheduled until March 2019--after FDA deals with the hot topics of biosimilar interchangeability and naming.
CDER’s Office of Biotechnology Products (OBP) also aims to issue a draft guidance on statistical approaches to evaluation of analytical similarity. OBP Director Steve Kozlowski explained at the Biosimilars Council conference that extensive structural and functional characterization that identifies critical quality attributes, plus adequate clinical pharmacokinetic studies and pharmacodynamic studies, may suffice to assess immunogenicity with minimal clinical studies. The key question, he added, is “how close is close enough?.”
Developing a sufficient analytical data package for a biosimilar is a “long, hard marathon,” commented Marjorie Shapiro of OBP’s Division of Monoclonal Antibodies at the FDA/PDA regulatory conference in September. Analytical data packages that show differences to the reference product often suffer from poor clone selection, inadequate process development, or testing an insufficient number of product lots for the biosimilar and/or the reference product. “Winning the marathon,” Shapiro continued, starts with analyzing several lots of the reference product over a broad time span. The manufacturer also has to carefully develop analytical methods and the expression system for the construct and host cell. These activities can help refine the manufacturing process, where incorporation of advanced techniques and quality-by-design approaches may facilitate “fingerprint”-like analysis of a biosimilar seeking to achieve interchangeable status.
While such advances can build confidence in the ability of a firm to produce biosimilars equally safe and effective as reference products, there is concern that pressure from Congress and from payers to move biosimilars to market more quickly could jeopardize efforts by FDA and manufacturers to dispel charges about biosimilar immunogenicity and similarity. Woodcock emphasized that extensive testing and quality production are critical to avoiding any political barriers that could block patient access to these critical therapies.
Despite such qualms, insurers and pharmacy benefit managers (PBMs) appear enthusiastic about steering patients to these less costly therapies. CVS Health recently announced that it would add Sandoz’ Zarxio (filgrastim-sndz) biosimilar to its formulary, with preference over the Janssen reference drug Neupogen, and UnitedHealth took similar action (2). The Ohio Public Employees Retirement System reported at the conference that its drug program formulary has added a tier for biosimilars and generic specialty drugs, with a maximum $100 copay for the less costly therapies.
Sanford C. Bernstein financial analyst Ronny Gal predicted at the Biosimilars Council conference that biosimilars will experience strong market growth during the next few years, as regulatory issues related to product naming, labeling, and interchangeability are resolved, and extrapolation becomes more firmly established. Concerns about adverse events have diminished as biosimilar use has expanded in Europe. As more competitors enter biosimilar markets, Gal expects discounts will rise from the 30% range to more than 75% off the innovator pre-biosimilar prices. And, in the end, biosimilars may emerge as safer and more effective therapies than the innovator product due to the utilization of more advanced analytics and more efficient production systems.
1. FDA, Biosimilar Biological Product Authorization Performance Goals and Procedures Fiscal Years 2013 Through 2017, FDA.gov.
2. D. Mangan, “CVS Health to Replace Higher-Cost Drugs on Covered Medication List for 2017," CNBC.com.