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When biosimilars go bad
MOUNTAIN VIEW, Calif.—Noting that Teva and Lonza have recently terminated their 2009 joint venture agreement to co-develop biosimilars based upon the realization that the development costs and time to market were beyond initial estimations, Frost & Sullivan Senior Industry Analyst Deborah Toscano observes: "When biosimilars were first a hot topic, it was a common perception that the scenario would parallel producing generic copies of conventional small-molecule drugs, which can typically steal up to 90 percent of the originator drug's sales with miniscule development costs, by comparison. When you combine this erosion potential with the high price tags of biologic drugs, you get a seemingly easy path to billion dollar revenues. However, as many companies are realizing, copying a biologic drug close enough to pass regulatory standards is proving to be more technologically and economically challenging than originally thought."
Case in point: In Europe, where biosimilars are marketed, they have garnered a meager 11-percent market share. Toscano notes that many U.S. companies are still awaiting final U.S. Food and Drug Administration (FDA) guidance. She cites a case where a patient died after taking a biosimilar.
"There are many issues at stake, most importantly patient safety," she says. "One amino acid can throw the immune system off. Successful biosimilars will not only have to pass regulatory muster, but will also have to earn the confidence of the prescribing physicians who will rely on strong clinical data and not necessarily only on FDA approval, since they will not be, by definition, identical to the originator biologic drug."
Safety issues are of sufficient concern that Genentech has issued a formal statement, which says in part that switching between an innovator biologic and a biosimilar "should only be done following demonstration through clinical studies that switching back and forth … causes no greater harm than using the innovator alone." The statement adds another cautionary note by stating that "each claimed indication for a biosimilar should be established by indication specific clinical trials, unless there is a solid scientific rationale to justify extrapolation of the clinical safety and efficacy data from one indication to another."
If this sort of scenario prevails, the required costs and expertise behind the advanced technology, clinical trials, regulatory negotiations and marketing efforts may be beyond the capabilities of many would-be biosimilar players. Additionally, as Toscano points out, others may decide that application through the full Biologics License Application (BLA) pathway or development of biobetters rather than biosimilars makes better financial sense because the overall development costs may not be significantly different in the long run—and a BLA provides 12-year patent protection.
In Europe, two companies have recently been granted marketing authorization for a biosimilar monoclonal antibody: Celltrion for Remsina, and Hospira for Inflectra. Both are biosimilar versions of Remicade (infliximab) marketed by Merck and Johnson & Johnson. While some are exiting the playing field, other larger, more experienced companies such as Sandoz (Novartis), Hospira and Pfizer are forging ahead.
"Sandoz and Hospira already have vast experience launching biosimilars in Europe and elsewhere, giving them a significant advantage over less experienced players," Toscano says. "Sandoz is running several late-stage clinical trials ahead of the FDA's final guidance, and Pfizer has initiated several early-stage clinical trials for their versions of blockbuster monoclonal antibodies such as Herceptin, Rituxan, Remicade and Humira. Likewise, Eli Lilly, no stranger to insulin therapy for diabetes, has initiated two late-stage trials of their version of Lantus, the blockbuster long-acting insulin from Sanofi."
As of June, the FDA had received no applications, but has received requests to meet with various biosimilar developers, stressing the need to meet early and often. The agency has still not ruled out dealing with biosimilar issues on a case-by-case basis and continues to emphasize that they will weigh analytical data very highly and maybe back off on the requirements for clinical trials to some extent. Yet another unknown: once biosimilars are introduced, will third-party payers in effect force physicians to prescribe them?