The committee voted 17-0 Thursday for Amgen Inc. and Allergan plc's ABP-215, referencing Avastin (bevacizumab) and 16-0 a few hours later for Mylan NV and Biocon Ltd.'s Herceptin (trastuzumab) biosimilar.
Throughout the two half-day meetings, FDA reviewers made it clear that they considered both antibodies to be highly similar to their reference biologics and that extrapolation of indications would be scientifically justified in both instances.
However, the FDA support, coupled with the strong ODAC vote, doesn't guarantee a passing grade for the biosimilars by their BSUFA dates. After getting a 14-1 ODAC vote in May and positive FDA briefing documents, Pfizer Inc., of New York, was handed a second complete response letter (CRL) last month for its Retacrit, an Epogen (epoetin, Amgen) biosimilar that has been on the market for several years in the EU. The CRL cited manufacturing problems at Pfizer's McPherson, Kan., plant that had been identified as the potential manufacturing site for the follow-on. (See BioWorld Today, May 26, 2017.)
Although manufacturing issues weren't raised at Thursday's meeting, they've already caused a regulatory hiccup for the Mylan/Biocon biosimilar in Europe, due to concerns cited by French regulators following a pre-approval inspection of a Biocon manufacturing plant in Bangalore, India. Biocon revealed Sunday that a follow-up inspection will be needed to verify that the plant has implemented a proposed corrective and preventive action plan before the biosimilar will be approved in the EU. The companies are working with French and EU officials to address the issue with the goal of getting the re-inspection scheduled as soon as possible. (See BioWorld Today, July 11, 2017.)
The Herceptin biosimilar is the first to be submitted in the U.S. and EU from the collaboration between Canonsburg, Pa.-based Mylan and Biocon, of Bangalore. It's one of six biologic products being co-developed by the partners. Under their agreement, Mylan has exclusive commercialization rights for the Herceptin biosimilar in Australia, Canada, Europe, Japan, New Zealand and the U.S., while Biocon has co-exclusive commercialization rights with Mylan in the rest of the world.
Extrapolation and exclusivity
In an effort to speed the biosimilar to market, Mylan reached a patent settlement with Roche earlier this year, clearing the way for an immediate U.S. launch once the Herceptin biosimilar is approved. Should the follow-on be approved before Oct. 20, it would be labeled for use only in HER2-positive breast cancer, as Herceptin has a few more months remaining of its exclusivity for a second indication, gastric cancer. After some discussion, ODAC members told FDA officials they would be comfortable with extrapolating that indication for the biosimilar, which was tested in breast cancer.
Extrapolation was more of a discussion with Amgen and Allergan's ABP-215. The biosimilar candidate was tested in nonsquamous, non-small-cell lung cancer (NSCLC), but Amgen, of Thousand Oaks, Calif., is seeking six indications, five of which would be extrapolated – first- or second-line treatment in metastatic colorectal cancer, second-line treatment for metastatic colorectal cancer in patients who have progressed on a first-line Avastin-containing regimen, glioblastoma, metastatic renal cell carcinoma and cervical cancer.
The FDA also has approved Avastin to treat platinum-resistant ovarian cancer and metastatic renal cell carcinoma, but those two indications are still protected by exclusivities. The FDA's Leah Christl told the advisory committee that, once the exclusivities end, Amgen would have to present a data package to support adding the two remaining indications to the label of its biosimilar.
The same would be true of new indications granted to a reference biologic after a biosimilar is approved, she said. The FDA will work with sponsors to determine what the data package should include on a case-by-case basis.
Some of the ODAC members struggled with extrapolating the glioblastoma indication for ABP-215, citing concerns about the blood-brain barrier and questions about whether the VEGF inhibitor has antitumor as well as vascular activity. But panelist Deborah Armstrong, a professor at the Johns Hopkins Kimmel Cancer Center shrugged the concerns off, saying, "We make extrapolations in the clinic all the time."
ABP-215 is the first of four biosimilar cancer antibodies being developed via Amgen's partnership with Dublin-based Allergan (formerly Watson Pharmaceuticals). Under the 2011 agreement, Amgen assumed the primary responsibility for developing, manufacturing and initially commercializing the follow-ons. (See BioWorld Today, Dec. 21, 2011.)
The FDA seemed to be using Thursday's meetings more to school ODAC on biosimilars than to seek advice from the committee. Part of the learning curve was the makeup of the study populations. Cynthia Chauhan, the patient representative for the Amgen hearing, criticized the sponsor for testing ABP-215 primarily in older white men. "The population of the United States is not male Caucasian," she said.
Amgen officials explained that the purpose of clinical trials in biosimilar development is to demonstrate similarity to the reference product. Diversity in the study population isn't necessary, because gender and racial differences are already known for the reference biologic.
For Mylan's biosimilar, committee members raised concerns that it hadn't been tested in conjunction with Perjeta (pertuzumab, Roche), which is used in combination with Herceptin. Mylan officials stressed that Herceptin has been tested with pertuzumab, so there was no need to repeat that testing for the biosimilar.
The FDA and sponsors weren't the only ones doing the teaching. Some of the speakers in the public hearings that always accompany adcom meetings did a bit of lecturing themselves and tried to give the agency homework assignments. Dennis Cryer, of the Biologics Prescribers Collaborative, called on the FDA to finalize its biosimilar guidances and refine its existing guidance for the follow-ons. He also stressed the need for transparent labeling that has a clear statement indicating that a biosimilar is not interchangeable with the reference biologic.
In addition, biosimilar labeling should include a summary of, or a link to, the full clinical data the sponsor submitted for approval, so doctors will know if an indication was extrapolated. Labeling is a "critical tool for physicians," he said.
Thair Phillips, CEO and president of Retire Safe, also spoke out on interchangeability, noting that the lines are being erased between biosimilars, which must be prescribed, and interchangeables, which can be substituted automatically at the pharmacy and, thus, require robust switching studies for approval.
The growing payer practice of kicking innovators off formularies and replacing them with biosimilars is making interchangeability moot, Phillips said. Nonmedical switching of biosimilars will eliminate the incentives for sponsors to pursue an interchangeability designation, he warned.