Biosimilars have been sold in the U.S. for years but haven't managed to gain much traction. One reason? Unlike generics of small molecules, biosimilars can't be automatically substituted at the pharmacy unless clinical data prove interchangeability with their reference products.
Now, to “help promote competition in the biologic market,” the FDA has finalized a road map for how to do just that.
The new guidance (PDF) is “very reasonable” and seems “rather friendly to biosimilar developers,” Bernstein analyst Ronny Gal said in a Friday note to investors. He expects it to help with biosimilar adoption, and he pointed out that the market has been undervaluing the risk for legacy antibodies such as Johnson & Johnson’s Remicade.
“We expect that with this final guidance we will start seeing efforts to develop interchangeable products coming to the front,” he wrote. “In fact, it seems like unacceptable business risk not to develop interchangeable biosimilars (when your competitor does).”
Currently, under the revised Public Health Service Act, an interchangeable biosimilar should demonstrate the same clinical result as the comparator “in any given patient.” For their interpretation, innovators like AbbVie argue that switching data should be required for each approved indication. But the FDA doesn’t seem to think so.
While the agency recommends that copycat developers seek green lights in all of a reference product's indications—and adds that it expects to see data and information in all those indications—it also says the “data and information […] will likely not involve additional clinical studies other than those necessary to support other elements of demonstrating interchangeability.”
As Gal sees it, “these requirements seem very similar to requirements for extrapolations of non-interchangeable biosimilars.” It means that biosimilar sponsors could choose a condition to study and then just provide scientific justification such as mechanism of action for extrapolating data for other indications without more clinical trials.
However, in what Gal called “the core of the additional need to prove interchangeability,” the agency does carry over the requirement for “switching studies” from its draft guidance unveiled in 2017. For these extra studies, the FDA envisions two arms. In one arm, patients stay on the reference drug, and those in the other start with the originator and switch back and forth twice between the two products before landing on the biosim.
Notably, by recommendation of the FDA, the primary endpoints in these studies look at pharmacokinetic and/or pharmacodynamic markers rather than clinical efficacy, as the agency considers efficacy endpoints less sensitive to detect changes in switching. “This will materially lower costs of doing these trials,” Gal said.
Other “lenient” measures, according to Gal, include allowing drugs approved outside of the U.S. as comparators and combining of biosimilarity and interchangeability into one registration trial.
The FDA has so far greenlighted 19 biosimilars, but only Boehringer Ingelheim is known to have started an interchangeability study for its biosimilar to AbbVie’s Humira. For those already approved, adoption has been slow, and some still haven't reached the market long after approval.
Ex-FDA chief Scott Gottlieb has publicly criticized reference drugmakers of using tactics such as litigation, rebates or behind-the-door settlements to stall the entry of cheaper copies. Under Gottlieb, the FDA unveiled plans to reclassify insulin as a biologic starting from March 2020.
“An interchangeable insulin product may be substituted at the pharmacy, potentially leading to increased access and lower costs for patients,” acting FDA Commissioner Ned Sharpless, M.D., said in a statement on Friday.
The new guidance will certainly enable such biosimilars to insulin, which has a low molecular weight, single target, clear pharmacodynamic marker and low immunogenicity, Gal said. However, as uptake picks up, prices might come down, and Gal said he’s not certain whether the balance will be positive for insulin knockoffs.