FDA News

FDA declines proposed Rituxan, Herceptin biosimilars from Celltrion

The FDA has rejected approval of Celltrion’s biologics license applications for Truxima, a proposed rituximab biosimilar, and Herzuma, a proposed trastuzumab biosimilar, issuing Complete Response Letters for both products.

“We are committed to working with the regulatory agency to fully resolve all outstanding issues with an aim to receive approval this year,” Celltrion said in a statement.

Although both Celltrion biosimilars have received marketing authorization from the European Commission, observations of “multiple poor aseptic practices” during an inspection of a manufacturing facility in Incheon, South Korea prompted the FDA to issue a Form 483 in September 2017.

In a January 28 warning letter from Francis Godwin, acting director of the Office of Compliance and the Office of Manufacturing Quality at the FDA’s Center for Drug Evaluation and Research, to Celltrion CEO Woo Sung Kee, the FDA charged that the facility exhibited “significant violations of current good manufacturing practice regulations for finished pharmaceuticals.”

Celltrion has taken steps to comply with the FDA’s letter, according to a statement the company issued in response: “The letter raises issues related to certain manufacturing process at the facility. We are making progress addressing these concerns, and we are committed to working with the agency to fully resolve all outstanding issues with highest priority. Celltrion remains confident in the safety and efficacy of its products manufactured at the site.”

Allan Gibofsky

In an interview with Healio Rheumatology, Allan Gibofsky, MD, JD, professor of medicine and public health at Weill Cornell Medicine and attending rheumatologist at the Hospital for Special Surgery, noted that this rejection demonstrates the careful scrutiny that the FDA applies to both the manufacturing process and quality control of biologic products.

“The action taken is not a surprise, as Celltrion received several previous communications from the FDA about problems with their processes, and it is not clear they have adequately responded to the FDA’s concerns,” Gibofsky said. “While I don’t think this rejection will ‘shake’ consumer or prescriber confidence in biosimilars, I do think it will make both stakeholders look carefully at the reputation of the manufacturer and, where appropriate, any manufacturing partner they may have.”

Although Celltrion has maintained an optimistic 2018 timeline for FDA approval of their biosimilars, their commercial partner, Teva Pharmaceuticals, noted in its fourth-quarter financial results report that “it is likely that the remediation by Celltrion of the issues addressed in the warning letter will result in a delayed approval of the biosimilar products by the FDA.”

Leonard H. Calabrese

Furthermore, Celltrion has stated that the FDA warning letter would not affect their ability to manufacture Inflectra (infliximab-dyyb, Celltrion/Pfizer) from the Incheon facility, yet has not addressed whether these actions would impact production and supply of Truxima.

“The FDA rejection of these biosimilars demonstrates to me that the agency is displaying an abundance of caution,” Leonard H. Calabrese, DO, professor of medicine at the Cleveland Clinic and Chief Medical Editor of Healio Rheumatology, said in an interview. “Concerns that have previously been expressed about technical and manufacturing issues may belie this response. While I do not believe this has broader implications, this is a serious blow to Celltrion. In the meantime, we await further details.”

The FDA has rejected approval of Celltrion’s biologics license applications for Truxima, a proposed rituximab biosimilar, and Herzuma, a proposed trastuzumab biosimilar, issuing Complete Response Letters for both products.

“We are committed to working with the regulatory agency to fully resolve all outstanding issues with an aim to receive approval this year,” Celltrion said in a statement.

Although both Celltrion biosimilars have received marketing authorization from the European Commission, observations of “multiple poor aseptic practices” during an inspection of a manufacturing facility in Incheon, South Korea prompted the FDA to issue a Form 483 in September 2017.

In a January 28 warning letter from Francis Godwin, acting director of the Office of Compliance and the Office of Manufacturing Quality at the FDA’s Center for Drug Evaluation and Research, to Celltrion CEO Woo Sung Kee, the FDA charged that the facility exhibited “significant violations of current good manufacturing practice regulations for finished pharmaceuticals.”

Celltrion has taken steps to comply with the FDA’s letter, according to a statement the company issued in response: “The letter raises issues related to certain manufacturing process at the facility. We are making progress addressing these concerns, and we are committed to working with the agency to fully resolve all outstanding issues with highest priority. Celltrion remains confident in the safety and efficacy of its products manufactured at the site.”

Allan Gibofsky

In an interview with Healio Rheumatology, Allan Gibofsky, MD, JD, professor of medicine and public health at Weill Cornell Medicine and attending rheumatologist at the Hospital for Special Surgery, noted that this rejection demonstrates the careful scrutiny that the FDA applies to both the manufacturing process and quality control of biologic products.

“The action taken is not a surprise, as Celltrion received several previous communications from the FDA about problems with their processes, and it is not clear they have adequately responded to the FDA’s concerns,” Gibofsky said. “While I don’t think this rejection will ‘shake’ consumer or prescriber confidence in biosimilars, I do think it will make both stakeholders look carefully at the reputation of the manufacturer and, where appropriate, any manufacturing partner they may have.”

Although Celltrion has maintained an optimistic 2018 timeline for FDA approval of their biosimilars, their commercial partner, Teva Pharmaceuticals, noted in its fourth-quarter financial results report that “it is likely that the remediation by Celltrion of the issues addressed in the warning letter will result in a delayed approval of the biosimilar products by the FDA.”

Leonard H. Calabrese

Furthermore, Celltrion has stated that the FDA warning letter would not affect their ability to manufacture Inflectra (infliximab-dyyb, Celltrion/Pfizer) from the Incheon facility, yet has not addressed whether these actions would impact production and supply of Truxima.

“The FDA rejection of these biosimilars demonstrates to me that the agency is displaying an abundance of caution,” Leonard H. Calabrese, DO, professor of medicine at the Cleveland Clinic and Chief Medical Editor of Healio Rheumatology, said in an interview. “Concerns that have previously been expressed about technical and manufacturing issues may belie this response. While I do not believe this has broader implications, this is a serious blow to Celltrion. In the meantime, we await further details.”

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