Andrew D. Zelenetz, MD, PhD
The world of biosimilar manufacturing seems laden with sugar and spice. While these “generic” biologics have the potential to create competition and result in healthcare savings, the path to the marketplace has proven complex, and technical issues with the process of making the agents have troubled drug manufacturers.
At the 2016 NCCN Annual Meeting, Andrew D. Zelenetz, MD, PhD, took to the podium to present NCCN’s position on biosimilars—a topic the organization has been mulling for some time, publishing a white paper on the topic in 2011.
“Many of the recommendations from the paper found their way into the FDA guidelines on biosimilars,” noted Zelenetz, a medical oncologist and vice chair of medical informatics at Memorial Sloan Kettering Cancer Center.
“Biologicals are expensive, and the therapeutic spending in oncology dominates all of medicine’s spending,” Zelenetz told his audience. Annual spending on oncology biologicals in 2014 was estimated at $28 billion, and the 10 most-used drugs in 2012 were biologicals, Zelenetz added, many of which used in cancer management.
Zelenetz said that with several biologicals moving toward patent expiration, the industry and other stakeholders are paying closer attention to how biosimilars can replace these expensive biologicals. “The extremely high prices of most biological products have forced us to look for options,” Zelenetz said.
“This is really about competition causing price decrease,” Zelenetz said in an interview at the conference with OncLive.
“Biosimilar rituximab is never going to outdo rituximab—they are biosimilar. They are actually going to do the same thing. Biosimilar filgrastim isn't going to outdo filgrastim.”
“The idea is to create competition in the marketplace…that was actually the motivation for the US Congress to even develop a biosimilar pathway.”
The biological manufacturing process is extremely complex…much more than that of a small molecule, Zelenetz explained. Studies have shown there may be a lot of variation with the innovator products themselves, and analytical evaluation of biological products has uncovered slight changes in the manufacturing process.
“Is this difference acceptable?” Zelenetz asked. Additionally, immunogenicity risks could be heightened with these variations, which ultimately could impact clinical efficacy and raise questions about interchangeability with the reference product, although the United States does not yet have any interchangeable biosimilars.
At the preclinical stage, the structure and function of the biosimilar is important to ensure minimal lot-to-lot variation. Manufacturers also have to be wary of the fingerprint-like identity of biosimilars, including their amino acid sequence and posttranslational modifications, higher-order structure, bioactivity, glycoforms, and impurity profile.
Zelenetz told the audience that educating stakeholders, particularly the prescribing physician, about biosimilars is critical. Physicians need to be educated on safety and efficacy of these products.
“They’re going to be seeing biosimilars in their practices, and they need to understand what they are and how to incorporate them in a way that continues to add value to their patient and provide optimum care,” he said.
What are the implications of biosimilars for the NCCN? Although only one has been FDA-approved so far, biosimilars should be added as an alternative to the originator product, Zelenetz said.
“When we develop the NCCN guidelines, we are asked to develop them in a cost-insensitive way. We're supposed to come up with what we think is the best clinical care. But if the same exact high-quality clinical care can be delivered at a lower cost, it's going to allow for continued innovation and improvement in the marketplace.”
For the first FDA-approved biosimilar, Zarxio (filgrastim-sndz), it was a long road to finally reach the market. The FDA approved the biologic in March 2015; however, it did not reach the market until September 2015, due to various lawsuits. Compared with the reference product Neupogen, Zarxio cost 16% less when it was approved. A savings to be sure but less than was hoped for.
Nevertheless, the approval of Zarxio represented a turning point in the biosimilar story, with several applications submitted for other products, despite the inevitable legal battles. This hurdle has not dampened interest. In fact, by the end of January 2016, the director of the FDA's Center for Drug Evaluation and Research, Janet Woodcock, MD, noted that nearly 60 biosimilars had enrolled in the agency's development program. In many ways, Zarxio represents just the tip of the iceberg.