On December 7, the Guangzhou, China–based manufacturer Bio-Thera Solutions announced that it had received FDA approval for its bevacizumab biosimilar. Dubbed Avzivi® (bevacizumab-tnjn), the agent will be marketed (globally) by Sandoz.
The drug is indicated for:
Metastatic colorectal cancer in combination with intravenous fluorouracil-based chemotherapy for first- or second-line treatment
Metastatic colorectal cancer, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for second-line treatment in patients who have progressed on a first-line bevacizumab product-containing regimen. (Limitation of Use: not indicated for adjuvant treatment of colon cancer)
Unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer, in combination with carboplatin and paclitaxel for first-line treatment
Recurrent glioblastoma in adults
Metastatic renal cell carcinoma in combination with interferon alfa
Persistent, recurrent, or metastatic cervical cancer, in combination with paclitaxel and cisplatin, or paclitaxel and topotecan
Epithelial ovarian, fallopian tube, or primary peritoneal cancer in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for platinum-resistant recurrent disease who received no more than 2 prior chemotherapy regimens
The biologic licensing application for BAT1706 (the original investigational name for the agent) included the results of a phase 3 comparative trial with Avastin® in patients with nonsquamous, non–small cell lung cancer. The 351(k) application was originally filed in December 2020. Information was not publicly reported as to the cause of the much-delayed decision.
Avzivi will be the fifth bevacizumab biosimilar to enter the market; biosimilars have approximately 85% of the US bevacizumab marketshare, according to the latest figures.
Bio-Thera’s Avzivi approval comes on the heels of its Actemra® biosimilar—Tofidence®—FDA approval on October 2.
In the years since the authorization of the BPCIA in 2010 and the drafting of the US biosimilar pathway in 2012, the Food and Drug Administration has given those in the biosimilar field plenty of complexities and ambiguities to debate. And we, in this column certainly have.
First was the notion of adding four-character suffixes, which were originally to be retroactively applied to all biologics, and then they weren’t, and their practical utility, which was limited at best.
Another area is the apparent need for large phase 3 clinical trials to prove nonsuperiority (or at least no safety issues). This, according to industry experts and the FDA itself, is turning out to be unhelpful. Yet, the majority of manufacturers interested in upcoming biosimilar categories are expending resources in phase 3 studies or study preparation.
Screen capture from a Seinfeld episode classic: Is interchangeability “the old switcheroo?” Copyright by Viacomm.
Now the topic of interchangeability has raised its head again, and this is a topic we’ve tackled repeatedly in BR&R. It sounds simple but it is not: It took several years for the FDA to publish its initial guidance on the topic—what information manufacturers have to supply to obtain the designation as well as what it actually means. It was to be applied to biosimilars for the purposes of automatic substitution at pharmacies only, until it wasn’t. Sarah Yim, MD, the Director of FDA’s Office of Therapeutic Biologics and Biosimilars, suggested that product labelling incorporate a universal “biosimilarity statement,” which specifies that either biosimilars or interchangeable biosimilars can be safely switched in place of a reference product. General confusion over its meaning and the value of the designation has resulted in calls by industry insiders and Congress for dumping the concept. I get the impression over the course of several years that the FDA wouldn’t mind, either!
Finally, in the last month, the FDA added further fuel to the fire. In the original legislative language, the manufacturer to first earn an interchangeable designation would be awarded 12 months of exclusivity. This was a direct parallel to the Waxman–Hatch Act, which allowed the first generic manufacturer to gain approval for a specific branded product 180 days of exclusivity before competition can launch. To the extent that this incentive to drive initial generic competition would transfer to the biosimilar market was unknown—it was difficult enough traversing the patent and regulatory barriers in getting a biosimilar approved.
Can Interchangeability Exclusivity Expire Before Launch?
Apparently it can. Companies have not had a clear idea as to when 12-month exclusivity begins for an interchangeable biosimilar (and the FDA has done a pretty poor job of clarifying it). They had their own opinions: was it from time of approval of the designation? From the time of launch? Some other date based on delayed launches based on patent settlements? Under the terms of the law, the FDA determines that patent exclusivity expires according to the earliest of the following milestones: (1) 12 months after commercial marketing begins, (2) 18 months after a final court decision to clear patents or the dismissal of patent litigation, (3) 42 months after approval of the first interchangeability approval when litigation continues during that period or 18 months after the first interchangeability approval if the applicant has not been sued. Which of these conditions apply? Even lawyers’ opinions will differ, based on the actual dates involved.
An FDA internal memo decreed in mid-November that Boehringer Ingelheim’s interchangeability exclusivity on its existing Cyltezo® 40 mg/0.8 mL formulation expired on April 15, 2023, three months before it was launched. This notice, released in advance of a formal guidance on the matter, supported an October decision by the FDA that Pfizer’s Abrilada® could be approved as an interchangeable adalimumab, and that Cyltezo no longer had exclusivity. This conflicts with the Purple Book listing, indicating that Boehringer’s period of exclusivity had not yet expired. If that was the case, the FDA would have been prohibited from approving the interchangeability designation for Abrilada. Boehringer was first granted interchangeability status on October 15, 2021. Because of its patent settlement with AbbVie, it was unable to launch before July 1, 2023. Pfizer submitted its supplemental 351(k) application for interchangeability on December 14, 2021.
I won’t pretend I understand the basis for the FDA’s decision that Boehringer’s interchangeability exclusivity expired before its launch. I suggest that you read the memorandum yourself. But from a common-sense perspective, this judgment in no way aligns with the intent of the legislation.
With its adalimumab decision, the FDA has undercut the value of first exclusivity for manufacturers in seeking interchangeability. Interestingly, the agency has still not directly addressed another key question: Is a biosimilar interchangeable for both the high-concentration and low-concentration formulations, and what effect does it have, if any, on exclusivity?
The FDA still intends to publish a final guidance on the matter of exclusivity. They need to get this right, or it will be just another reason to jettison the interchangeability designation. And they need to do it quickly: Ustekinumab biosimilars, due to launch in early 2025, may repeat this delayed launch scenario (see below).
In Other Biosimilar News
Samsung Bioepis announced that it has settled its patent litigation with Johnson & Johnson on its biosimilar for ustekinumab (reference product, Stelara®). Samsung Bioepis has been given a launch date of February 22, 2025, and is the fifth biosimilar manufacturer to enter the launch sequence (it will be the third to launch over a 4-month period, so far announced).
