Why a biologic was still in the Orange Book months after all others were transitioned to BLAs

The Biologics Price Competition and Innovation Act of 2009 (“BPCIA”) contained a provision that would change the NDAs for biological products to BLAs after the tenth anniversary of the BPCIA’s enactment. [See section 7002(e)(4) of the BPCIA]. As I discussed in my last blog posting, the FDA deleted, on schedule, all of the biologic products that were listed in the Electronic Orange Book (“EOB”). Except for Sanofi’s two insulin glargine products, LANTUS and LANTUS SOLOSTAR. 


I sent a message to the Orange Book Staff about their retention of the Sanofi products in the EOB, and they responded by referring me to legislation called the Further Consolidated Appropriations Act, 2020 (“FCAA”) that was passed by Congress just before their holiday recess on December 20, 2019. Three pages of the 715 pages of the FCAA, pp. 594-596 (Sections 605-607) contain amendments to the Public Health Service Act (“PHSA”) and BPCIA provisions that involve biological products.


Through a cursory search I found that the main emphasis by commentators in the blogosphere was on Section 605 of the FCAA that amended the definition of “biological product” in the PHSA (42 USC 262(i)(1)). The original definition of “biological product” included proteins, but with an exception for “any chemically synthesized polypeptide.” So chemically synthesized polypeptides, even if large enough to be thought of as a “protein” were not “biological products” under the PHSA.


The FCAA amendment removed the parenthetical exception for chemically synthesized polypeptides. So anything that would be considered to be a “protein” would be a “biological product” regardless of how it was produced. Not long afterwards, the FDA finalized a rule that defines a “protein” as “any alpha amino acid polymer with a specific, defined sequence that is greater than 40 amino acids in size” [85 Fed. Reg. 10057 (Feb. 21, 2020)]. According to a Goodwin’s “Big Molecule Watch” blog entry dated January 30, 2020, there were three synthetic polypeptide products (ACTHREL, EGRIFTA, and ADLYXIN) that were approved under NDAs and met the FDA’s definition of “protein.” So those products could now be considered to be “biological products” under the PHSA, as amended. As such, those products were now deemed to have been approved under BLAs, and have been deleted from the EOB.


So what about the continued listing in the EOB of Sanofi’s insulin glargine products? There was much less about that in the blogosphere. The same Big Molecule Watch posting that I mentioned above also reported that the FDA had been planning to require 505(b)(2) applicants to refile their application as a BLA if the drug they had referenced in their application was one that was being transitioned to a BLA, and if that 505(b)(2) application was still pending on the March 23, 2020 transition date.


Section 607 of the FCAA, entitled “Streamlining the Transition of Biological Products,” eliminated any need for a 505(b)(2) applicant to go through the process of refiling their NDA as a BLA. The Act amended Sec. 7002(e)(4) of the BPCIA by dividing it into two parts. New Subsection (e)(4)(A) contains the original text of Subsection (e)(4) which recites “deeming” a biological product that was originally approved under an NDA to have been approved under a BLA on the tenth anniversary of the BPCIA.


New Subsection (e)(4)(B) is entitled “Treatment of Certain Applications.” Sub-subsection (B)(i) allows the FDA, as described in the Big Molecule Watch posting mentioned above, to continue reviewing a 505(b)(2) application or ANDA for a biological product (which for simplicity I will refer to collectively as a “competitive biological application”) if the competitive biological application was filed not later than March 23, 2019, and is still pending as of the NDA-to-BLA transition date of March 23, 2020. So that is why any competitive biological application that referenced Sanofi’s insulin glargine products would not need to be refilled as a BLA if it met the stated timing requirements.


However, it is not until we get to Sub-subsection (B)(ii), entitled “Effect on Listed Drugs” that we finally learn why Sanofi’s LANTUS and LANTUS SOLOSTAR insulin glargine products continued to be  listed in the Electronic Orange Book for several months after the March 23 transition date while all the other biological products that had been listed in the EOB were deleted.


In a nutshell, Sub-subsection (B)(ii) says that the drug referenced by the competitive biological application shall remain in the Orange Book until one of the events in Sub-subsection (B)(ii)(I)(aa) or (bb) occurs. The (I)(aa) and (I)(bb) Sub-subsections are actually triggered by one of three possible events: 

  1. the competitive biological application is approved and there are no other such pending applications [Sub-subsection (B)(ii)(III)],
  2. the approval of the referenced drug is withdrawn or suspended, or the referenced drug is withdrawn from sale [FDCA 505(j)(7)(C)], or
  3. the competitive biological application has not been approved by the sunset date of October 1, 2022 [Sub-subsection (B)(vi)].

So, there you have the reason that Sanofi’s LANTUS and LANTUS SOLOSTAR insulin glargine products continued to be listed in the EOB for several months after all the other NDA-approved biological products had been deleted. However, Sanofi’s insulin glargine products are now also deleted. This deletion likely coincided with Mylan’s and Biocon’s June 11, 2020 joint press release announcing that their competitive biological application under 505(b)(2) for SEMGLEE (insulin glargine injection) had been approved by the FDA. That approval would have triggered the first of the three events that I listed, above.


The final step occurred sometime between Friday June 12, and Monday June 15. On June 12,  I saw that LANTUS was still listed in the Drugs@FDA database as having been approved under an NDA. On June 15, I found that the Drugs@FDA record had been changed to “BLA.”


You might ask if there are any other NDA-approved biological products that are still listed in the EOB. I originally selected products at random from the FDA’s “Revised Final List of Approved NDAs for Biological Products That Were Deemed to be BLAs on March 23 2020 (CORRECTED)” file (“Revised Final List”), and searched for them in the EOB. Every product I tried came back empty. 


But then I thought “write some code”! So I extracted all of the trademarks from the FDA’s “Revised Final List,” and recursively searched for them in the FDA’s Volume 40, Supplement 4 “products.txt” raw data file. That  “products.txt” file should only contain biological products from the Revised Final List if they were being retained in the EOB under the FCAA provisions. Sure enough, my code only found Sanofi’s LANTUS and LANTUS SOLOSTAR.


Therefore, as far as I can tell, the EOB is now completely devoid of biological products that are eligible to be transitioned to a BLA. If you know of any that I might have missed, please let me know in the comments.


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