Regulatory Decision Summary for Idhifa

Review decision

The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.

Product type:


Medicinal Ingredient(s):


Control Number:


Therapeutic Area:

Antineoplastic agents

Type of Submission:

Supplement to a New Drug Submission - Confirmatory

Decision issued:

Authorized; issued a Notice of Compliance in accordance with the Food and Drug Regulations, as per the Notice of Compliance with Conditions Guidance

What was the purpose of this submission?

This Supplement to a New Drug Submission-confirmatory (SNDS-c) was initially submitted to fulfill Commitment #1 of the Letter of Undertaking (LoU) for Idhifa, dated September 4, 2020. As per the LoU, the SNDS-c provided the final report of Study AG-221-AML-004, a Phase 3, multicentre, open-label, randomized study comparing the efficacy and safety of Idhifa versus conventional care regimens (CCRs) in older patients with late-stage Acute Myeloid Leukemia (AML) harbouring an isocitrate dehydrogenase 2 (IDH2) mutation. The confirmatory study failed to confirm the clinical benefit of Idhifa in the indicated patient population, and a Notice of Non-Compliance (NON) was issued. This Response to NON was filed and formally notified the Pharmaceutical Drugs Directorate (PDD) of the Sponsor’s intent to cancel the drug identification number (DIN) and withdraw Idhifa in Canada.

Why was the decision issued?

Idhifa (enasidenib) is a first- and only-in-class selective, oral inhibitor of the isocitrate dehydrogenase 2 (IDH2) mutant enzyme. Idhifa was granted market authorization by Health Canada under the Notice of Compliance with conditions (NOC/c) policy, based primarily on the efficacy and safety demonstrated in the phase 1/2, single arm clinical trial Study AG221-C-001, for the treatment of adult patients with relapsed or refractory (R/R) Acute Myeloid Leukemia (AML) with an IDH-2 mutation. Due to the single-arm study design, which lacked a comparator with which to contextualize the results, a randomized Phase 3 trial (Study AG-221-AML-004) was required as a confirmatory study, as per the Commitment #1 of the Letter of Undertaking (LoU).

The final report of Study AG-221-AML-004, an international, multicentre, open-label, randomized Phase 3 study comparing the efficacy and safety of enasidenib plus best supportive care (BSC) versus conventional care regimens (CCRs) plus BSC in the target patient population, was provided to confirm the benefit of Idhifa. The CCR treatment options included BSC only, azacitidine (AZA) plus BSC, low-dose cytarabine (LDAC) plus BSC, or intermediate dose cytarabine (IDAC) plus BSC.

The primary efficacy endpoint of overall survival (OS) was not met, and a survival benefit was not demonstrated. The enasidenib group had an observed 14% reduced risk compared with subjects in the CCR group; however, the comparison of the 2 survival curves did not meet the pre-defined level of significance based on the log-rank test (HR = 0.86; 95% CI: 0.67, 1.10; stratified p = 0.2288). The median duration of OS was 6.5 months (95% confidence interval [CI]: 5.5 months, 9.5 months) in the enasidenib arm and 6.2 months (95% CI: 4.6 months, 7.7 months) in the CCR arm. A post-hoc, hypothesis-generating OS analysis in patients pre-selected for non-intensive therapy showed a median duration of OS of 6.8 months (95% CI: 5.5 months, 10.7 months) in the Idhifa group compared with 6.2 months (95% CI: 4.6 months, 7.9 months) in the CCR group (HR 0.79, 95% CI: 0.60, 1.04; stratified log-rank test p = 0.0909). While no statistically significant OS benefit was demonstrated, the data reviewed did not suggest a detrimental effect on OS in patients treated with Idhifa. Other efficacy endpoints included overall response rate (ORR), event-free survival (EFS), haematological improvement (HI) and transfusion independence (TI), and generally showed a numerical benefit for the Idhifa group versus the CCR group. However, statistical significance of these results was not demonstrated, and the magnitude of benefit is therefore not known. Further, analyses by the Independent Response Assessment Committee (IRAC) were limited by the substantial number of non-evaluable patients, particularly in the CCR group, and the analyses based on the investigator assessment were prone to biases due to the open-label design of the study. Overall, the available efficacy results from Study AG-221-AML-004 were concluded to have significant limitations and could not be considered to provide substantial evidence of clinical effectiveness. The data therefore did not confirm the promising evidence of efficacy of Idhifa in the indicated patient population, and a positive benefit-harm-uncertainty (BHU) profile for Idhifa was not established. A Notice of Non-Compliance (NON) was issued requesting adequate discussion and/or additional data supporting the clinical effectiveness of Idhifa.

The submitted Response to NON (R-NON) provided a notification by the sponsor of their plans to cancel the Drug Identification Number (DIN) for Idhifa and withdraw the drug from the Canadian market. A draft Health Professional Risk Communication (HPRC) was also provided for review and endorsement by Health Canada. The HPRC, targeting healthcare professionals (HCPs) and community pharmacies currently dispensing Idhifa, communicated that the confirmatory study failed to demonstrate an improvement in OS in patients treated with Idhifa, and, although the safety profile remained unchanged, Idhifa will be withdrawn from the Canadian market. The HPRC also advised HCPs not to initiate Idhifa in new patients and, as there were only 7 patients in Canada currently taking Idhifa, HCPs were recommended to apply to Health Canada’s Special Access Program (SAP) to request Idhifa for those patients who will continue treatment.

Given the DIN cancellation and withdrawal of the drug in Canada, no revisions were made to the Idhifa Product Monograph and Risk Management Plan in the current submission.

A Notice of Compliance with conditions (NOC/c) remained in effect until the cancellation and withdrawal of Idhifa, and a NOC/c was recommended for the disposition of this SNDS-c R-NON.

Date of Decision:


Manufacturer / Sponsor:

Celgene Inc. / Bristol-Myers Squibb

Drug Identification Number(s) Issued:


Prescription status:

Available by prescription only

Date Filed: