Regulatory Focus™ > News Articles > Updated: The 505(b)(2) Pathway and Why Some Follow-on Insulins Aren’t Yet Biosimilars in the US

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Posted 11 December 2017 | By Zachary Brennan 

Updated: The 505(b)(2) Pathway and Why Some Follow-on Insulins Aren’t Yet Biosimilars in the US


Why has the European Medicines Agency (EMA) approved follow-on insulin products as biosimilars while the US Food and Drug Administration (FDA) has not? A look at several recent examples shows what is happening and what will change in the US over the next several years.

In September, FDA granted tentative approval for Sanofi’s Admelog (insulin lispro injection), a rapid-acting human insulin analog. On 11 December, Admelog received full approval from FDA. In the EU, however, this same product is considered a biosimilar.

Similarly, in July, Merck and Samsung Bioepis won tentative FDA approval for its follow-on to Sanofi’s Lantus (insulin glargine injection), and again, in the EU, this same product (known as Lusduna) is a biosimilar. And back in December 2015, FDA approved Eli Lilly’s 505(b)(2) application for Basaglar (insulin glargine injection), which is also a biosimilar in the EU (and known as Abasaglar).

505(b)(2) Pathway

One of the reasons for these differences (the EU and US also differ on what they consider biosimilar interchangeability to mean) is that in the US, applications for these insulin products are being submitted via the 505(b)(2) pathway (rather than as biosimilar biologics license applications (BLAs)). Under this pathway, FDA can approve these new drug applications (NDAs) based, at least in part, on data not developed by the applicant, according to FDA draft guidance.

And these follow-on products are being granted tentative and not full approvals (except for Admelog and Basaglar) because FDA’s final OK is subject to the resolution of patent infringement lawsuits. Such litigation triggers a stay on final FDA approval for up to 30 months, unless a court rules in favor of the companies winning the tentative approvals.


'Deemed to be a License'

And that 30-month period is key because, according to FDA draft guidance known as "Implementation of the ‘Deemed to be a License’ Provision of the Biologics Price Competition and Innovation Act of 2009," if products approved under the 505(b)2 pathway do not receive full approval before 23 March 2020, the companies may have to re-submit them as BLAs.

Scott Lassman, a partner in Goodwin Procter's technology and life sciences group, told Focus: "If a company submitting an NDA or 505(b)(2) application for an insulin product does not receive final approval before the specified 2020 date, FDA has indicated in draft guidance that they will need to re-submit as a BLA. I think AAM [the generic drug lobby] and others made some pretty strong arguments in comments that FDA’s position is inconsistent with the relevant statutory language, and I thus think there could be grounds for a lawsuit challenging FDA’s position, but right now that is FDA’s expressed position."

And if the products do obtain FDA approval prior to the 2020 date, then FDA will transition them to BLAs, although for 505(b)(2) applications, Lassman said, it’s currently not clear whether that will be a full BLA or a biosimilar.

But part of the reason why the biosimilar route is not open yet for insulin products, he added, is because "there are no full BLAs approved that could be used as reference products. Thus, the (b)(2) pathway allows companies to avoid conducting the full safety and efficacy studies that would be needed for a full BLA."  

The confusing situation is also a result of a provision in the Biologics Price and Competition and Innovation Act of 2009 (BPCIA), which set up the pathway for FDA to approve biosimilars.

In the draft guidance mentioned by Lassman, FDA says it interprets this "deemed to be a license" provision in the BPCIA "to mean that on March 23, 2020, applications for biological products that have been approved under section 505 of the FD&C Act will no longer exist as New Drug Applications (NDAs) (or, as applicable, Abbreviated New Drug Applications (ANDAs)) and will be replaced by approved Biologics License Applications (BLAs) under section 351(a) or 351(k) of the PHS Act, as appropriate."

But the draft also notes that under the BPCIA, Congress did not provide an approval pathway that "precisely corresponds to section 505(b)(2) of the FD&C Act."

Therefore, the agency advises that if a planned 505(b)(2) application may not receive final approval on or before 23 March 2020, the sponsor should consider:

  • "Modifying the development program to support submission of an application under section 351(a) of the PHS Act (i.e., a ‘stand-alone’ BLA) before or after March 23, 2020. This may involve, for example, obtaining a right of reference from the application holder for the listed drug on which the proposed 505(b)(2) application would have relied or conducting studies with the proposed product to provide the scientific data that otherwise would have been relied upon to support approval.
  • Modifying the development program to support submission of a 351(k) BLA for a proposed biosimilar product or a proposed interchangeable product at such time as there is a biological product licensed under section 351(a) of the PHS Act that could be a reference product."

But until then, and depending on the intellectual property, companies may continue to submit follow-on insulins not as biosimilars but as NDAs under the 505(b)(2) pathway.

Updated on 9/5/17 with comment from Lassman. Updated 12/11/17 with information on Admelog's full FDA approval.


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