The FDA answered a long-standing question Tuesday of what happens to proteins such as insulin and somatropin that were approved on the 505(b)(2) path when those proteins are deemed biologics March 23, 2020.

They will be 351(a) biologics – not biosimilars.

The answer came in the agency's second draft guidance on the deeming process. When the FDA released the first draft guidance more than two years ago, it raised the question of what to do about the 505(b)(2) proteins, but it said it would deal with the issue in a future guidance. (See BioWorld Today, March 15, 2016.)

The future arrived Tuesday, along with a finalized version of the 2016 draft. Together, the new draft and the final guidance should help sponsors prepare for the transformation of their approved new drug applications (NDAs) to approved 351(a) biologic license applications (BLAs).

Under the proposed guidance, products like Eli Lilly and Co. Inc.'s Basaglar, which was approved by the FDA in 2015 as a 505(b)(2) drug referencing Sanofi SA's Lantus (insulin glargine), will be deemed a "stand-alone" biologic in the U.S., as will Lantus. But in the EU where it's marketed as Abasaglar, and in other parts of the world, the Lilly follow-on is a biosimilar.

The same is true of Sandoz Inc.'s Omnitrope (somatropin), which became the world's first official biosimilar when it was approved by the EMA in 2006. Approved by the FDA that same year as a 505(b)(2) drug, Omnitrope will be deemed a stand-alone biologic in the U.S., as will its reference drug, Pfizer Inc.'s Genotropin. (See BioWorld Today, June 1, 2006.)

Once such drugs are deemed biologics in the U.S., other sponsors can list them or the innovator as a reference product for biosimilars or interchangeables. However, Lilly, Sandoz and makers of other 505(b)(2) drugs that will be deemed biologics can seek a determination of biosimilarity or interchangeability, the FDA said. They would need to work with the agency to address scientific or regulatory issues that could arise and provide additional procedural information.

The FDA explained its reasoning for not deeming 505(b)(2) drugs as biosimilars by pointing out the differences in the statutory standards for the two types of drugs. While a 505(b)(2) drug to some extent relies on data from a reference product, the NDA must include a full report on the drug's safety and effectiveness. A 505(b)(2) drug also may be intended to differ from the reference drug in certain respects.

But a biosimilar must be the same as its reference biologic in terms of strength, dose, route of administration and conditions of use. While it must demonstrate biosimilarity to the innovator, it doesn't have to independently demonstrate safety and effectiveness.

Required changes

The transition itself, mandated by the 2010 Biologic Price Competition and Innovation Act (BPCIA), will be automatic, but sponsors will have to make some changes to meet labeling and chemistry, manufacturing and control requirements, because of differences in the Federal Food, Drug & Cosmetics Act that governs NDAs and the Public Health Service (PHS) Act that applies to BLAs.

For instance, the PHS requires each "package" of a biological product to be plainly marked with the proper name of the biologic and the name, address and license number of the manufacturer. Even though the deeming date is 15 months off, sponsors won't be able to make the labeling changes before then, as the FDA will have to assign a proper name for each deemed BLA (presumably one with a unique but meaningless suffix) and a biologics license number to the manufacturer.

Given the time involved in making labeling changes and getting them approved, the FDA said it intends to give sponsors of deemed biologics a five-year grace period to comply with the PHS labeling requirements. However, it encourages companies not to wait until the last minute. A prior approval supplement with proposed revised product labeling should be submitted by March 23, 2022. The agency also plans to provide more guidance on the proper names for the deemed BLAs before the transition kicks in.

Biosimilar guidance

In addition to the deeming guidances, the FDA Tuesday issued a revision of its final question-and-answer guidance on biosimilar development and the BPCIA, as well as new and revised questions and answers in a draft guidance on biosimilars. One of the development hurdles the draft addresses is when innovators use their risk evaluation and mitigation strategies (REMS) to delay biosimilar competition.

"Too many branded products are still misusing these programs as rhetorical smokescreens to hide anticompetitive behavior," FDA Commissioner Scott Gottlieb said. "We're not going to be partners to these deceptions."

To help end the deceptions, Gottlieb said the FDA, upon request, will review biosimilar study protocols to assess whether they contain comparable safety protections to those in the REMS for the reference product. If they do, the agency will issue a letter to the reference product holder informing it that providing the biosimilar sponsor with a sufficient quantity of the reference product to perform the testing necessary to support a biosimilar application will not violate the REMS.

"This is just a start," Gottlieb said. "We're going to be monitoring these markets. And we'll be taking additional actions. We're actively evaluating how we can make it easier for biosimilar manufacturers to use reference products from outside the U.S. where prices may be cheaper and reference products more accessible."