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By Robert g. Bell

Robert BellAs many are aware, the Food and Drug Administration (FDA) approved its first biosimilar using the recently enacted abbreviated licensure pathway under section 351(k) of the Public Health Service Act. In March 2015, Novartis-Sandoz Zarxio (filgrastim-sndz) was approved as biosimilar with the same indications to Amgen Inc.’s Neupogen (filgrastim). The Zarxio approval was based on physical, chemical, biological, preclinical, pharmacokinetic, pharmacodynamic, clinical, safety, and immunogenicity comparisons that demonstrated Zarxio is biosimilar to Neupogen. It is important to note that although Zarxio was approved as biosimilar, it was not approved as an interchangeable or “switchable” product as per 351(k)(4), since the cost savings to health care result not only in use but substitution of the biosimilar for the reference biologic.

This is supported by the Rand Corporation estimates that the use of biosimilars could save the U.S. health care systems $44 Billion in the next 10 years, depending on the regulatory approval and substitution/interchangeability of the biosimilar to the reference product.

Substitution and interchangeability of a biosimilar for a reference biologic require additional studies as well as demonstrating biosimilarity. Some biosimilar companies may not want the burden and costs of the additional biosimilar interchangeability studies for substitution of the reference product, but this may be an issue for them at the state formularies. To date, approximately 23 states considered legislation establishing state standards for substitution of a biosimilar to that of the reference biologic product. Eight states have enacted legislation.

In general, these laws provide requirements for pharmacists on how to dispense and substitute biological products. For instance, the Florida law H365 allows substitution of a biosimilar if FDA has determined substitute biological product is “biosimilar to and interchangeable for prescribed biological product.” The prescribing provider must not “express a preference against substitution,” the pharmacist must notify the patient or person at the counter of the substitution and substitution record retained for two years and requires the state Board of Pharmacy to maintain current list of interchangeable biosimilar products.

However, it is uncertain how many companies will conduct the additional studies required by FDA for interchangeability and substitution to be listed as interchangeable in the Purple Book. If this is not completed, the formularies, physicians, and pharmacists may still be able to substitute a biosimilar for a reference product. The Florida law requires the state Board of Pharmacy to maintain a current list of interchangeable biosimilar products, hopefully one that will mirror the Purple Book. Zarxio is biosimilar to Neupogen but was not approved as an interchangeable product, but state formularies, at their discretion, can establish a list of interchangeable biosimilar products. In addition, in at least 14 states and Puerto Rico have mandatory generic substitution (if available), including biosimilars for the reference biologic. This will set up an interesting battle state by state in the formularies regarding biosimilars use and substitution, similar to the NTI (narrow therapeutic index drugs) substitution battles of the 1990s.

In addition to formulary issues, legal challenges will always exist. Amgen has tried to stop the launch of Zarxio, arguing Sandoz should have provided its Biologic License Application and manufacturing plans within 20 days after the FDA’s acceptance of its application last July and given Amgen six months notice of its plans to market the drug. According to the order from a U.S. District Court, Sandoz had agreed with Amgen to delay its Zarxio launch until April 10 or face a legal judgment in its favor, whichever came first. Sandoz also agreed to give Amgen a five-day warning about its launch. Amgen intends to appeal the decision and why not—Neupogen is a $1.2 billion blockbuster for Amgen.

Besides an arduous regulatory approval, issues with formulary substitution, and patent and legal challenges, biosimilars may also face slow uptake and acceptance from the medical and patient communities. And the price of the biosimilar will be less than the reference biologic, but not by much. But over time, the medical and patient communities and market will come to accept biosimilars as therapeutic equivalents to the reference biologic, as they have come to accept small molecule generic products. Until then, enjoy the fireworks and games between the sponsors of biosimilars and the reference biologics—it promises to be good viewing.

Robert G. Bell, Ph.D., is president and owner of Drug and Biotechnology Development LLC, a consultancy to the pharmaceutical industry and academia for biological, drug, and device development.