Regulatory Decision Summary for Istodax

This Supplemental NDS-Confirmatory (SNDS-c) submission was initially filed in June 2021 to seek removal of the condition through the submission of the confirmatory study data, maintaining the Istodax monotherapy indication for relapsed/refractory peripheral T-cell lymphoma (R/R PTCL). The confirmatory study failed to confirm the clinical benefit of Istodax in combination with CHOP as a first line treatment for PTCL. However, given that the indication for which Istodax was approved under the NOC/c policy was for the monotherapy treatment of R/R PTCL, the benefit-harm-uncertainty profile of Istodax monotherapy remains unconfirmed. A Notice of Non-Compliance (NON) was issued. The sponsor acknowledged receipt of the NON, and noting no additional plan for confirmatory studies, agreed to withdraw Istodax from the Canadian market.

In the present SNDS Response to NON, the sponsor provided details on the withdrawal process of Istodax from the Canadian market. To maintain access to patients who are currently receiving Istodax a sunset plan was proposed. Istodax should not be initiated in new patients, and it will be discontinued on the Canadian market once all current patients have completed treatment with Istodax.

Istodax was authorized for the treatment of patients with relapsed/refractory Peripheral T-Cell Lymphoma (R/R PTCL) who are not eligible for transplant and have received at least one prior systemic therapy under the NOC/c policy. The Ro-CHOP Phase 3 confirmatory study was submitted with the request to convert the NOC/c to NOC for the R/R PTCL indication.

The benefit-harm-uncertainties profile of Istodax as a monotherapy treatment of R/R PTCL remains unconfirmed and a NON was issued. The safety profile of Istodax monotherapy for the treatment of R/R PTCL remains unchanged.

Noting no additional plan for confirmatory studies, the sponsor acknowledged receipt of the NON and agreed to withdraw Istodax from the Canadian market. In the R-NON, the sponsor provided details on the following three commitments to facilitate withdrawal:

A Health Professional Risk Communication (HPRC) was drafted by the sponsor and endorsed by Health Canada. Health Care Professionals (HCP’s) will be informed of the results of the confirmatory Ro-CHOP Phase 3 trial, the restriction of Istodax access to current patients through enrollment in the Restricted Access Program, followed by eventual withdrawal of Istodax from the Canadian Market.

The target audience includes HCP’s specialized in the use of cytotoxic chemotherapy. The HPRC will be disseminated via email, fax, and registered mail. Recipients will be requested to return an acknowledgment of receipt of the communication. HCP’s must complete an order form to receive Istodax access for each patient for each treatment cycle. The HPRC will be further uploaded on the Bureau of Medical Science (BMS) Website, Health Canada Safety and Recalls Website and the NOC/c database Website.

The Indication and Serious Warnings and Precautions sections of the Product Monograph (PM) were revised to include the following key messages:

“a distribution restriction of Istodax to current patients, for whom Istodax access will be provided through enrollment in the Restricted Access Program, and the eventual withdrawal from the Canadian market. The clinical benefit of Istodax in the R/R PTCL setting remains unconfirmed. The Patient Medication Information section aligned with Part I.”

HCP’s treating current patients with Istodax are requested to enroll them in the Restricted Access Program. A database will be generated by the sponsor with enrolled patient IDs. Once a patients' treatment has ceased, they will be removed from the database. The sponsor will update Health Canada’s Pharmaceutical Drugs Directorate (PDD) (after 14 days and every 6 months post-dissemination of the HPRC) with the number of successfully reached HCP’s and the number of patients currently treated with Istodax. Once the last patient has been removed from the database, the Sponsor will submit to Health Canada a Discontinuation of Sale Notification within 30 days. As of 2022, approximately 80 patients received treatment with Istodax in Canada. The sponsor has indicated a willingness to consider making Istodax available through the Special Access Program post-Drug Identification Number (post-DIN) cancellation on a case-by-case basis, should requests be received. Istodax will remain authorized under the NOC/c policy until the last current patient completes treatment with Istodax.

The Ro-CHOP study (RM-PTCL-COOP-0031) design, although accepted as a confirmatory trial, does not provide direct evidence of clinical benefit of romidepsin for the treatment of R/R PTCL. The study did not confirm the clinical benefit of Istodax in combination with CHOP as a first line treatment for PTCL. The benefit-harms-uncertainties assessment for Istodax in combination with CHOP for the first line treatment of PTCL is negative.

A Notice of Compliance with conditions (NOC/c) continues to remain in effect and is recommended for this SNDS-c-RNON.