Despite some confusion over what's considered a clinically meaningful difference, the FDA's Oncologic Drugs Advisory Committee (ODAC) voted unanimously Wednesday that Sandoz Inc.'s filgrastim biosimilar should be approved for all the indications of its reference drug, Amgen Inc.'s Neupogen.

The evidence Sandoz presented from trials in healthy volunteers and breast cancer patients clearly showed "that this is filgrastim," said panelist Bernard Cole, a statistics professor at the University of Vermont. To call it anything else would be a misnomer.

Jane Zones, the consumer representative, agreed, adding that it was the easiest vote she's made as a member of ODAC.

Randy Hillard, the patient representative, wrapped up the vote and the meeting, saying he was willing to bet his life on it – an indirect reference to his introduction earlier in the day. Suffering from Stage IV stomach cancer, Hillard introduced himself, saying, "I wake up every morning surprised at how undead I am."

The meeting was unusual in that the FDA went into it fully onboard with Sandoz's proposed Zarxio. Rather than seeking ODAC's advice or support for approval, the agency seemed to be using the meeting to educate the committee on biosimilars and the data needed to demonstrate biosimilarity. (See BioWorld Today, Jan. 6, 2015.)

Although the agency has until early May to approve the follow-on, its confidence in the drug and pressure to finally launch the U.S. biosimilar market could lead to a much earlier approval date.

COGNITIVE DISSONANCE

In opening the historic meeting, the FDA's Janet Woodcock noted the "cognitive dissonance" that regulators, industry and the public must overcome to make the paradigm shift required for this new market. Much of the dissonance stems from the development focus on similarity rather than on efficacy and safety.

With all other drugs, the FDA and adcoms balance risks and benefits. But that's not part of the discussion with biosimilars, Woodcock said. Instead, the agency evaluates the level of similarity between the follow-on and the reference biologic and looks for clinically meaningful differences.

To help prepare the committee for the discussion, the FDA provided a crash course on what data may be necessary to demonstrate biosimilarity.

Despite the tutorial, a bit of dissonance popped up during the committee discussion on whether Sandoz's data revealed any clinically meaningful differences between Zarxio and Neupogen.

A few panelists raised concerns about an unexplained discrepancy in the numbers on two datasets pertaining to patients' recovery of neutrophils. Because of that discrepancy, Scott Waldman, chairman of the pharmacology and experimental therapeutics department at Thomas Jefferson University's Sidney Kimmel Medical College, said he was a little skeptical and wondered how the FDA was defining a clinically meaningful difference.

Albert Diesseroth, the medical team leader of the FDA's division of hematology products, reminded the panel that while it's important to analyze biosimilar trials, the data can't be looked at in terms of safety and efficacy.

PATIENT VOICE

The dissonance was even more apparent during the public hearing session in which several patients and patient groups expressed concerns about the safety of biosimilars and the automatic substitution that could come with interchangeables. Several of them stressed that patients must be part of the discussion in the development and approval of biosimilars. Their concerns were not with Sandoz's product specifically, but with biosimilars in general.

Robert Yapundich, a neurologist speaking on behalf of the Alliance for Patient Access, encouraged the FDA to take this opportunity of reviewing its first biosimilar application to create a solid foundation for patient safety that could be used in approving all biosimilars in the future. He stressed that sponsors should be required to conduct clinical trials for each indication when they are developing a biosimilar of a complex, unpredictable molecule.

Others used the public hearing to push the FDA to adopt policies that would further shape the biosimilar market. Richard Markus, Amgen's vice president of global development, called on the agency to require distinguishable names for every biologic, along with transparent product labeling that would identify a product as a biosimilar or interchangeable and provide clinical trial data.

When appropriate, post-marketing studies also should be required to further assess immunogenicity in the most sensitive populations, especially for extrapolated indications, he said.

Although price is not part of the FDA's approval process, it came up a few times during the ODAC meeting. It is, after all, the "elephant in the room," according to Kimberly Blackwell, an oncologist and Sandoz consultant. It also is driving the demand for biosimilars.

When asked about the price, Sandoz's Mark McCamish responded that he can't say what the price will be given the complexity of drug pricing in the U.S. In some cases, it may be on par with Neupogen. However, in the EU where Sandoz's Zarzio is one of nine filgrastim biosimilars on the market, the follow-ons have led to expanded use of filgrastim and about a 30 percent price reduction, he said.