2020 guidance offers foresight for transition from NDA to BLA

A proposed guidance intended to help sponsors of proteins see their way forward as the FDA transitions the drugs from the 505 path of small-molecule products to 351 biologics license applications (BLAs) could trip up a lot of development plans and open newer drugs to competition much earlier than expected.

The guidance would implement a provision of the Biologics Price Competition and Innovation Act (BPCIA) that requires proteins such as insulin products and human growth hormones that have been approved under section 505 of the Federal Food, Drug and Cosmetics Act (FDCA) to be regulated as biologics under the Public Health Services (PHS) Act as of March 23, 2020. (See BioWorld Today, July 26, 2011.)

To make the transition, the FDA proposes to "deem" proteins approved via new drug applications (NDAs) and abbreviated new drug applications (ANDAs) as licensed biologics on March 23, 2020. Although sponsors would still be responsible for satisfying post-approval requirements and commitments, including pediatric assessments, the drugs would lose most of their unexpired NDA exclusivities, including pediatric exclusivity, and get nothing in return.

The orphan drug exclusivity is the only one that would carry over, as it is the same on both paths, according to the guidance, which was published in Monday's Federal Register.

While new BLAs enjoy 12 years of exclusivity, that exclusivity wouldn't apply to the transitioned proteins, regardless of how recently they were approved. Nothing in the BPCIA suggests Congress intended to grant these proteins, "some of which were approved decades ago, a period of exclusivity upon being deemed to have a [BLA] that would impede biosimilar or interchangeable product competition in several product classes until the year 2032," the FDA said.

In the past, some follow-ons approved in other countries as biosimilars were marketed in the U.S. as 505(b)(2) drugs because their reference drug had been approved as an NDA. Thus, Sandoz Inc.'s Omnitrope (somatropin), the world's first official biosimilar, was approved in the U.S. on the 505(b)(2) path – four years before Congress granted the FDA the authority to create the abbreviated 351 path for biosimilars. (SeeBioWorld Today, June 1, 2006.)

The draft guidance isn't clear on how the FDA would determine whether to deem a protein approved as a 505(b)(2) drug a new biologic or a biosimilar, as the 351 path has no equivalent to 505(b)(2), which partially relies on safety and effectiveness data for a listed drug. The agency said it would leave that discussion for future guidances.

Nevertheless, once it's finalized, the guidance could increase the development of U.S. biosimilars since sponsors wouldn't have to wait for the 2020 transition to begin developing a biosimilar to a protein that's been approved as an NDA.

LOOK AHEAD

The FDA is encouraging sponsors to start down the 351 path now, recognizing that its interpretation and implementation of the BPCIA could have a significant impact on the development plan for proposed protein products intended for 505 submissions that don't receive final approval by March 23, 2020.

After that date, the NDA route will be closed to proteins – even if their applications are pending at the time. The FDA also won't approve pending or tentatively approved 505(b)(2) applications listing an approved NDA once it's deemed to be a BLA, according to the guidance.

If they still want to file for an NDA/ANDA, sponsors should evaluate whether their development schedule allows adequate time for approval before the cutoff date. They need to consider whether the submission may require a second cycle of review and whether unexpired patents or exclusivity could delay final approval.

It might be more advisable to go the BLA path for a new product rather than risk running out of time with the NDA, the FDA said. And once a highly similar protein has been approved as a BLA, a sponsor may have to go that route.

Sponsors eyeing 505(b)(2) development have more factors to consider, as they will have to modify their program to fit either the 351(a) or 351(k) path.

If their proposed product will differ from the reference protein in terms of dosage form, route of administration, strength or conditions of use, they will have to submit a 351(a) for a new biologic. To rely on information from a listed drug, they may have to obtain a right of reference from the NDA holder. Otherwise, they'll have to conduct their own studies to support the BLA approval.

If the follow-on could qualify as a biosimilar, the sponsor can submit the required comparative data referencing a drug approved as an NDA so long as it will be deemed to be licensed under the PHS Act come 2020.

The transition will place all proteins – meaning any alpha amino acid polymer with a specific defined sequence greater than 40 amino acids – under the PHS. However, unless they otherwise meet the statutory definition of a "biological product," chemically synthesized polypeptides will continue to be regulated under the FDCA. (Alpha amino acid polymers that are made entirely by chemical synthesis and are less than 100 amino acids in size are considered "chemically synthesized polypeptides.")

Proteins that will be deemed licensed biologics include chorionic gonadotropin, desirudin, hyaluronidase, insulin and insulin analog products, pancrelipase, pegvisomant, somatropin and thyrotropin.

Comments on the draft guidance are due by May 13.

COST OF BIOSIMILARS

In related news, the FDA released a final report Monday showing that its cost of developing and maintaining the biosimilars program from fiscal 2013 through 2015 exceeded $82 million. About 40 percent of that cost, $32.7 million, was spent in 2015 when the biosimilars program ramped up and the FDA approved Sandoz' Zarxio (filgrastim) as the first U.S. biosimilar.

More than 58 percent of the cost was for labor, with other expenses reflecting operating costs and overhead, according to the report, required under the BPCIA.

The largest chunk of the total cost, 43 percent, was attributed to biosimilar development activities, with 15 percent to policy and regulation, 13 percent to 351(k) reviews, 12 percent to science and research, and 11 percent to training. Another 5 percent funded regular biosimilar-related meetings, and 1 percent was spent on continuing education and focus groups.

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