Lilly, Novo Nordisk Fight Insulin Biosimilars With Tweaks to FDA Draft Guidance

Regulatory NewsRegulatory News
| 11 February 2020 | By Zachary Brennan 

As Americans with diabetes continue to die because they cannot afford their insulin, two of the three insulin manufacturers in the US are doing their best to try to alter US Food and Drug Administration (FDA) draft guidance that seeks to bring more insulin competition to market.

The draft guidance, unveiled last November, explains how insulin biosimilar developers may not need to conduct comparative clinical immunogenicity studies under certain circumstances.

As part of FDA’s reasoning behind its scientific thinking on a “lack of clinical impact of immunogenicity with insulin,” the draft cites a revised guideline from the European Medicines Agency in 2015, which said that it no longer recommends a clinical immunogenicity study to support a biosimilar marketing application in some cases.

FDA also points to “decades of clinical experience with approved insulin products, including the lack of a correlation between immunogenicity and safety or effectiveness as reflected in approved product labeling for insulin products.”

But in comments submitted 28 January, Novo Nordisk and Eli Lilly do their best to try to maintain the status quo and delay competition from coming to market.

Novo, for instance, said it “experienced a circumstance of unexpected immunogenicity in response to a new insulin analog which was encountered during its clinical development.”

The company also said that its experience “exemplifies the unpredictable nature of immunogenic reactions in response to insulin formulations. As such, we believe caution needs to be applied regarding the broad assumption” in the draft guidance that says that “if a comparative analytical assessment based on state-of-the-art technology supports a demonstration of ‘highly similar’ for a proposed biosimilar or interchangeable insulin product, there would be little or no residual uncertainty regarding immunogenicity.”

Lilly, meanwhile, said that FDA should revise the guidance to explain which biosimilar applications this immunogenicity testing policy applies to.  

“Should FDA intend to apply the Draft Guidance to insulin products which were not approved under a section 505(b)(2) application, Lilly believes that good science dictates some amount of clinical immunogencity data should be required in order to understand the impact of potential differences in immunogenicity profiles on clinical outcomes,” Lilly said.

The company also wants FDA to revise the guidance to note that it does not address issues with respect to product biosimilarity and interchangeability of delivery devices and presentations, including connected systems.

And Lilly laid out its case for why insulin biosimilars may have a hard time being approved as interchangeable products.

“Although presentation considerations are important for biosimilarity assessments, FDA should pay particular attention to the insulin products presentations in the interchangeability context. There, by virtue of automatic substitution based on an interchangeability designation, a patient could be confronted with an unfamiliar presentation without the benefit of prescriber oversight or additional training,” Lilly added.

A Lilly spokesperson added in an emailed comment to Focus: "We support the introduction of biosimilar insulins. We think interchangeable insulins can be introduced prior to such guidance. But having that guidance would help sponsors of interchangeable insulins to know how the testing requirements vary based on the product presentation." 

The other insulin manufacturer serving the US, Sanofi, did not submit a comment on the draft guidance, according to the docket.

All three have raised their prices significantly over the past decade. For instance, in 2012, a vial of Lilly’s Humalog insulin was priced at $130, and by 2016, the same vial was priced at $255.

Both Lilly and Novo have launched authorized generics versions of their insulin products at reduced prices in preparation for biosimilar competition. But an investigation from Sens. Elizabeth Warren (D-MA) and Richard Blumenthal (D-CT) found that Lilly’s authorized generic was widely unavailable in pharmacies.


Editor's note: Article updated on 2/13/20 with additional comment from Lilly.


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