Handbook for health care professionals on biosimilar biologic drugs: Case studies
On this page
- Kanjinti, a biosimilar to Herceptin
- Inflectra (infliximab) for Crohn's disease and ulcerative colitis
Kanjinti, a biosimilar to Herceptin
Introduction
A new drug submission (NDS) for the biosimilar Kanjinti was filed by Amgen Canada Inc. on August 21, 2017, and was authorized by Health Canada on February 27, 2020. The reference biologic drug was Herceptin (medicinal ingredient trastuzumab), marketed by Hoffmann-La Roche Ltd.
Herceptin is authorized in Canada for several indications relating to early breast cancer, metastatic breast cancer and metastatic gastric cancer. The NDS for Kanjinti requested authorization for all but 1 of the indications authorized for Herceptin. The indication in combination with Perjeta (pertuzumab) and docetaxel for untreated HER2-positive metastatic breast cancer was not requested for Kanjinti with this NDS.
Data submitted
The sponsor submitted data from comparative quality studies:
- 1 comparative pharmacokinetic study in healthy male subjects
- 1 comparative clinical efficacy and safety study in patients with HER2-positive early breast cancer
The efficacy and safety study included a run-in chemotherapy phase, a neoadjuvant phase and an adjuvant phase.
In the neoadjuvant phase, patients were randomized to receive either:
- Kanjinti or Herceptin along with paclitaxel every 3 weeks, for 4 cycles of treatment or
- paclitaxel, administered once weekly for 12 cycles of treatment
- an alternative dosage regimen for paclitaxel, administered once weekly for 12 cycles of treatment, was permitted in regions where it is the local standard of care
Surgery, with sentinel or axillary lymph node dissection, was completed 3 to 7 weeks after the last dose of the investigational product in the neoadjuvant phase was administered.
In the adjuvant phase, patients received a dose of the assigned drug every 3 weeks, for up to 1 year from the first day of study drug administration in the neoadjuvant phase. Pathologic complete response (pCR) was defined as the absence of invasive tumour cells in the breast tissue and axillary lymph nodes. Supportive pharmacokinetic data were also obtained through the efficacy and safety study.
Review
The structure and functions of Kanjinti and Herceptin were compared side-by-side via numerous laboratory tests using state-of-the-art methods. No significant differences were observed. Comparable pharmacokinetics were demonstrated in the pharmacokinetic study.
Although no differences in efficacy, safety and immunogenicity between Kanjinti and Herceptin were observed in the comparative safety and efficacy study, several major concerns were identified during the review of the study relating to efficacy and safety parameters, data management, analyses and reported outcomes.
The review team concluded that equivalence between Kanjinti and Herceptin was not demonstrated.
Decision made
Due to the concerns identified, the request for market authorization was not granted. A notice of non-compliance (NON) was issued on August 9, 2018.
Follow-up
Kanjinti was subsequently authorized on February 27, 2020, following the filing of a response to the NON by the manufacturer. The response addressed the identified concerns and confirmed equivalency of response in the treatment arms. Kanjinti was authorized for use in patients with early breast cancer, metastatic breast cancer and metastatic gastric cancer.
Although patients with early breast cancer in the neoadjuvant setting is recognized as a sensitive model for demonstrating comparative efficacy and safety, it did not correspond to an indication authorized in Canada for Herceptin. To avoid implying that Kanjinti is indicated in the neoadjuvant setting, the following statement was added to the product monograph:
"The treatment of early breast cancer patients with trastuzumab in the neoadjuvant setting is a model for assessing comparative clinical safety and efficacy. However, it is not an authorized indication in Canada."
For full details of the review, decision-making and authorized indications, please refer to:
Inflectra (infliximab) for Crohn's disease and ulcerative colitis
Introduction
An NDS for the biosimilar Inflectra was filed by Celltrion Healthcare Co. Ltd on November 14, 2011. The reference biologic drug was Remicade (medicinal ingredient infliximab) and marketed by Janssen Inc. It was authorized to treat the following conditions:
- rheumatoid arthritis
- ankylosing spondylitis
- psoriatic arthritis
- plaque psoriasis
- Crohn's disease
- ulcerative colitis
- for pediatric use in Crohn's disease and ulcerative colitis
The manufacturer requested authorization, for Inflectra, for all of the indications authorized for Remicade.
Data submitted
The sponsor submitted data from comparative quality studies:
- 1 clinical safety and efficacy study in patients with active rheumatoid arthritis
- 1 pivotal pharmacokinetic study in patients with active ankylosing spondylitis
No clinical studies were conducted in patients with the other indications. Therefore, authorization of the remaining indications would require a robust demonstration of biosimilarity, such that the authorization could rely on the known safety and effectiveness of the reference biologic drug.
Review
The structure, physicochemical properties and functions of Inflectra and Remicade were compared side-by-side via numerous laboratory tests using state-of-the-art methods. No differences were observed that would likely impact safety and efficacy for the indications (rheumatic diseases) evaluated in the supporting clinical trials.
In the clinical studies, treatment with Inflectra or Remicade resulted in comparable rates of response in patients. The review of secondary endpoints or an analysis of joint damage progression did not identify any concerning differences.
The comparative PK study also compared the efficacy and safety of Inflectra with Remicade in patients with active ankylosing spondylitis (secondary to the assessment of pharmacokinetics). No clinically meaningful differences were identified and the level of responses to both products aligned with what had been reported previously for patients receiving Remicade. Assessment of other secondary endpoints supported the comparability of both products in eliciting improvements in clinical response.
Extensive rationales were provided by the manufacturer to support the authorization of the remaining indications. However, due to observed differences in some in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) assays, as well as other differences, the review team concluded that differences in the ability of the 2 products to induce ADCC could not be ruled out.
The sponsor provided a rationale to support their position that ADCC is not an important mediator of the efficacy of their product (or of Remicade). However, after reviewing the literature on this mechanism of action, the team concluded that ADCC could not be ruled out as a mechanism of action in inflammatory bowel diseases (IBD). It was also noted that pathophysiological differences exist between the rheumatic diseases and the IBDs, making it challenging to extrapolate between the 2 products without clinical or PK/PD bridging data.
Decision made
Authorization of the IBD indications was not acceptable without further evidence to demonstrate biosimilarity in ADCC for the following reasons:
- differences in ADCC were observed between Inflectra and Remicade
- ADCC may be an active mechanism of action for infliximab in IBD, but not rheumatic disease
Inflectra was authorized on January 15, 2014, for use in patients with moderately to severely active rheumatoid arthritis, active ankylosing spondylitis, psoriatic arthritis and chronic moderate to severe plaque psoriasis.
Follow-up
Inflectra was authorized on June 10, 2016, for use in patients with Crohn's disease, fistulising Crohn's disease and ulcerative colitis, after the manufacturer filed a supplemental NDS with supporting physicochemical, biological and clinical data.
For full details of the review and authorization, please refer to:
Page details
- Date modified: