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Extrapolation is at the heart of biosimilar pathway and patient concern


By Mari Serebrov
Regulatory Editor

After grappling with the limited clinical data the FDA uses to determine biosimilarity and what that might mean in the real world, at the end of the day Tuesday the agency's Arthritis Advisory Committee (AAC) got it.

The committee voted 21-3 that the totality of the evidence – which included results from two clinical studies in rheumatoid arthritis (RA) and ankylosing spondylitis (AS) – supported licensure of Celltrion Inc.'s infliximab biosimilar for all nine indications of the reference biologic, Janssen Biotech Inc.'s Remicade.

"Given that this would be the first biosimilar monoclonal antibody [MAb] to be approved in the U.S., this advisory committee meeting is an essential step in increasing acceptance of these critical medicines and increasing access for every patient who needs these treatments," Celltrion CEO HyoungKi Kim said following the meeting.

Not only is CT-P13 the first MAb biosimilar to be considered by the FDA, it was the first biosimilar to come before the AAC. In considering it, some of the panel members initially seemed uncomfortable with extrapolating the RA and AS data to the other indications, especially inflammatory bowel disease (IBD) such as ulcerative colitis and Crohn's. A few doctors on the panel wondered how they could prescribe the drug without clinical data about how it performed in a specific condition.

Extrapolation of indications is the key concept behind the abbreviated biologics pathway, but it isn't a given, the FDA's Leah Christl said as she explained the biosimilars path to the committee.

Steven Kozlowski, director of the FDA's Office of Biotechnology Products, pointed out that if a sponsor needed clinical data for every indication, the biosimilar path would be much more cumbersome than starting fresh with a new biologic. In developing a biosimilar, the sponsor is "filling in and confirming" the data – not reproving it, he said.

Panelist Jogarao Gobburu, a professor at the University of Maryland School of Pharmacy, suggested the FDA use a word other than extrapolation. "Extrapolation implies no data. That is not the case," he said. "We have data." Once a follow-on establishes that it is highly similar to the reference product, it shouldn't have to prove safety and efficacy over and over again for all the indications, he added.

Committee Chairman Liron Caplan, associate professor of medicine at the University of Colorado, noted that biosimilars are not another treatment option for patients. They are biosimilars to existing drugs. Their only reason for being is to improve access and reduce cost, he said. In a challenge to Celltrion, of Incheon, South Korea, and other biosimilar makers, he added that he would not prescribe a biosimilar unless it significantly reduces the cost of treatment.

Other panel members agreed, with one saying he would be angry and frustrated if, after the committee discussion, Celltrion's biosimilar comes to market at a price just slightly lower than Remicade. That decision won't be made by Celltrion. If the biosimilar is approved by the FDA, Pfizer Inc., of New York, will assume commercialization rights in the U.S, under the proposed brand name Inflectra. Pfizer gained those rights when it acquired Hospira Inc., which had a partnership with Celltrion.

Unless Pfizer chances an at-risk launch, it could be awhile before the biosimilar hits the U.S. market. In August, Janssen, a unit of Johnson & Johnson, of New Brunswick, N.J., sued Celltrion for patent infringement and has repeatedly vowed that it will robustly defend its remaining U.S. patent on Remicade. That patent won't expire until September 2018 – the same time the MAb loses its orphan exclusivity for pediatric ulcerative colitis (UC). The two companies are still hashing out the patent litigation. (See BioWorld Today, Feb. 8, 2016.)

The FDA is expected to make an approval decision in April. If the agency approves the biosiimilar, it would withhold the pediatric UC indication until the exclusivity ends, Christl said.


During the public hearing at the AAC meeting, the National Organization for Rare Disorders took the agency to task for putting the pediatric indication before the committee before Remicade's exclusivity ends. By discussing it prematurely, the FDA could weaken incentives for developing drugs for orphan diseases and it showed less than a 100 percent commitment to the Orphan Drugs Act, the organization said.

Several patients and doctors also spoke up in the hearing about safety and efficacy issues, spotlighting the difficulties sponsors and the FDA face in creating a market for biosimilars. Reminding the committee that patients are the stakeholders with the most at risk, many of those testifying offered suggestions to make the path more palatable.

For instance, one rheumatologist group called for new pharmacovigilance measures for biosimilars, steps to discourage nonmedical switching of the drugs, required notification if the drug dispensed isn't what was prescribed, labeling that specifies if a drug is a biosimilar and changes to the Medicare Part B payment plan.


Despite those concerns, the FDA seemed predisposed to approve CT-P13 with the extrapolated label. It would not be the first regulatory agency to do so. In 2013, a year after the drug, marketed as Remsima, gained approval in South Korea as the first biosimilar MAb in the world, EU officials gave the nod based on clinical data in RA and psoriasis and extrapolation to IBD. (See BioWorld Today, July 1, 2013.)

Remsima did not, however, gain extrapolation to IBD in Canada when it was approved there in April 2014, as the Canadian health authority cited differences in glycosylation between it and Remicade. Despite legal challenges in several countries, the biosimilar continued its march across the world, including approvals in Latin America and Australia. It has now been approved in more than 60 countries. (See BioWorld Today, April 3, 2014.)

Although Celltrion's drug may be the first Remicade biosimilar to make it to market, it won't be the last, as several others are already in development. Boston-based Epirus Biopharmaceuticals Inc. this week initiated a global registration study for BOW015, its infliximab follow-on, in active rheumatoid arthritis patients. The UNIFORM study will enroll more than 500 patients at sites in Europe, North America and Latin America.