The FDA has finally released its guidance on biosimilar interchangeability. Radar on Specialty Pharmacy speaks with Ryan Cox, Precision for Value Vice President, Access Experience team on how the new guidelines reduce administrative hurdles and duplicative clinical trials. However, he notes that reimbursement issues may discourage uptake.

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FDA Unveils Final Interchangeability Guidance for Biosimilars
by Angela Maas
AIS Health

More than two years after publishing draft guidance on biosimilar interchangeability (RSP 2/17, p. 5), the FDA has finalized the document. Released on May 10, the final guidance (84 Fed. Reg. 21342, May 14, 2019) contains much of the same content as the proposal, with a few changes. No biosimilars currently have interchangeability status, which would allow the substitution of that interchangeable biosimilar without a health care provider’s intervention. While this change might pave the way to more use of these products, other challenges to their uptake still exist.

Finalizing this document, contends acting FDA Commissioner Ned Sharpless, M.D., in a statement unveiling it, will help promote competition among biologics. According to Sharpless, “the final interchangeability guidance is informed by the FDA’s cumulative experience providing development-stage advice to sponsors of proposed interchangeable products. The FDA meets regularly with sponsors of proposed interchangeable products through the agency’s Biosimilar Product Development Program. The agency also considered the numerous comments on the draft interchangeability guidance and made changes to provide increased clarity to stakeholders.”

The final guidance comes in at seven pages shorter than the proposed guidance. The FDA still recommends that companies generate data and information through a stepwise approach. The agency says that information demonstrating that the proposed product is biosimilar to the reference product must meet the “highly similar standard,” but did not include the “fingerprint-like characterization” that was in the proposed guidance.

As far as postmarketing data for already approved biosimilars to be used in support of interchangeability, the FDA “will evaluate proposals to include postmarketing data in applications to support demonstrations of interchangeability on a case-by-case basis.” The agency is still recommending switching studies, although it will allow companies to provide justification for why they are not necessary, such as when a product is administered only once.

One change from the proposed guidance is that companies can now use non-U.S.-licensed reference products in these switching studies, provided that the manufacturer of the proposed interchangeable product includes bridging data between the non-U.S.-licensed and the U.S. licensed products and justifies the former’s use.

“The guidelines seem to be reasonable and have several items that appear to reduce administrative hurdles and duplicative clinical trials,” observes Ryan Cox, R.Ph., vice president, access experience team at Precision for Value. He points to the use of ex-U.S. licensed drugs in the studies, as well as the ability to combine “the submission for biosimilarity and interchangeability into one registration trial, rather than sequentially, thereby reducing administrative work and duplicative trials. The guidance also allows for data extrapolation across indications, rather than conducting trials on all of a reference product’s indications.”

However, while this document should encourage biosimilar uptake, rebating and contracting among manufacturers, physicians and payers continue to be a hindrance to these drugs’ use (RSP 3/18, p. 5).

“Generally, payers are going to follow the money — specifically, which product will get them to the lowest net cost,” Cox tells AIS Health, noting that small molecule generics’ uptake “was driven almost exclusively off the significant discounts provided to the brand product. A general rule of thumb [is] that each 1% in generic market share shift would result in about $1 million reduction in drug spend. Similarly, physicians will need to be incented to prescribe and/or administer a biosimilar in lieu of a brand name product. This can be accomplished through medical/pharmacy policy, reimbursement structures and inclusion in their performance measures, or a combination of these. Until the biosimilars can offer this type of savings, the incentive for payers to move will not be there, and, thereby, they will not persuade prescribers to switch.”

Only One Firm Has Disclosed Study

It’s unclear how many companies will seek interchangeable status. When the FDA approved Boehringer Ingelheim Pharmaceuticals, Inc.’s Cyltezo (adalimumab-adbm) in August 2017, a biosimilar to Humira, the company stated that it was conducting an interchangeability study with the drug, but so far it is the only company to disclose existence of such a study. Boehringer Ingelheim had been engaged in patent litigation with Humira manufacturer AbbVie, Inc., but on May 14, Boehringer Ingelheim said it had resolved all intellectual property-related litigation concerning Cyltezo and that the drug’s license period in the United States will begin July 1, 2023. In its press release unveiling the resolution, Boehringer Ingelheim said the interchangeability clinical trial VOLTAIRE-X was ongoing.

“I would speculate that products that have biosimilarity and interchangeability in Europe or Canada would be the next likely candidates,” says Cox. This differs according to the country. Germany, for instance, allows for automatic substitution of multiple bioidentical biosimilars of epoetin alfa, filgrastim, infliximab and interferon beta-1b.

Interchangeable Insulins Are Anticipated

“Additionally, the FDA has noted the need for interchangeable insulins as well,” points out Cox. “Although Lilly has recently launched a lower-cost version of Humalog (insulin lispro), the likelihood of a biosimilar seems high.”

The various insulin products are approved under the Federal Food, Drug, and Cosmetic Act, which has no biosimilar pathway. However, those drugs are among the protein products that will transition over to the Public Health Service Act, which contains the 351(k) biosimilar pathway, on March 23, 2020 (RSP 5/18, p. 1). At that point, those products will be considered biologics, allowing for biosimilar competition.

Sharpless specifically mentioned insulin in his statement unveiling the guidance: “After this [May 23, 2020,] transition, the FDA will be able to license biosimilar and interchangeable insulin products that meet the requirements of the PHS Act, and today’s guidance will, among other things, help developers seek licensure for such products.”

For more information, read the final guidance at Contact Cox through Tess Rollano at