Regulatory Decision Summary for Folotyn

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):


Therapeutic area:

Antineoplastic agents

Type of submission:

New Drug Submission (New Active Substance)

Control number:

What was the purpose of this submission?


This New Drug Submission (NDS) was filed to obtain market authorization for Folotyn (pralatrexate injection) for the following new indication:

"Folotyn (pralatrexate injection) is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL)."


Why was the decision issued?


Peripheral T-cell Lymphoma (PTCL) is a life-threatening, incurable disease, with limited effective treatment options. The efficacy of Folotyn was supported by a Phase II, single arm, multi-centre study (PDX-008) that enrolled patients with relapsed/refractory PTCL. The overall response rate (ORR), as determined by an Independent Review Committee, was the primary efficacy endpoint of this study. The ORR was 27% (95% CI: 19, 36) with a corresponding median duration of response of 287 days (range: 1-503). The complete response rate was 8%. Five of the patients who responded to pralatrexate did not have evidence of response to any prior therapy. Fourteen patients who responded to pralatrexate did not have evidence of response to their most recent prior therapy. Four patients who had a response went on to transplant as their initial subsequent therapy after discontinuing treatment with Folotyn.

The Bureau of Metabolism, Oncology and Reproductive Sciences (BMORS) considered the demonstrated anti-tumor activity of Folotyn to be meaningfully promising evidence of clinical benefit. However, the submitted data package lacked robust evidence of a survival benefit, or of a quality of life benefit. This remains an uncertainty associated with Folotyn as a therapeutic option for PTCL patients. BMORS recommended that Folotyn be granted market authorization under the Notice of Compliance with Conditions (NOC/c) policy. In a Letter of Undertaking dated October 4, 2018, Servier Canada Inc. committed to submit to Health Canada the final results of the Phase III pivotal study SPI-BEL-301, in order to confirm the biological activity and the clinical benefit of Folotyn treatment.

The most common toxicities associated with Folotyn were mucosal inflammation and bone marrow suppression (mostly thrombocytopenia and neutropenia). In PDX-008, serious adverse events were reported in 44% of patients, most commonly (>3%) pyrexia, mucosal inflammation, sepsis, herpes zoster, pneumonia, neutropenia, febrile neutropenia, dehydration, dyspnea, and thrombocytopenia. Mucosal inflammation, thrombocytopenia and neutropenia were generally manageable through dose omissions and reductions, with relatively few discontinuations. Treatment discontinuation occurred in 23% of patients, and was most frequently due to mucosal inflammation (6.3%) and thrombocytopenia (4.5%) . Eight patients (7%) died while they were still on treatment with Folotyn, or within 30 days of their last dose of Folotyn. Seven of these patients died due to disease progression. The post-marketing safety profile was mostly consistent with what was identified in clinical trials, with dermatologic (including toxic epidermal necrolysis), pulmonary, renal, and hepatic toxicities identified as new significant adverse reactions.

Folotyn was not studied in pregnant women; however, non-clinical reproductive studies indicated a risk of fetal harm and loss. These safety findings, as well as monitoring and management recommendations are adequately described in the Folotyn Product Monograph. While there are significant toxicities associated with Folotyn, they are consistent with other agents of the anti-folate class, they are generally tolerated, and they are manageable through dose omissions, reductions, and appropriate labeling. Overall, the safety profile of Folotyn is considered acceptable for the proposed indication.

A Risk Management Plan containing pharmacovigilance measures was submitted by Servier Canada Inc. and was considered acceptable by the Marketed Health Products Directorate. Servier Canada Inc. has committed to submit to Health Canada the annual Periodic Safety Update Reports or Periodic Benefit Risk Evaluation Reports, to analyse significant safety findings and to ensure a positive benefit-risk profile of Folotyn in the post-market setting.

Health Canada considers the documentation provided in this Response to Qualifying Notice to be sufficient to recommend Folotyn (pralatrexate injection) for approval under the NOC/c policy for the treatment of patients with relapsed or refractory PTCL.

Overall, Folotyn demonstrated clinically significant anti-tumor activity in patients with relapsed or refractory PTCL. In the context of this life-threatening, incurable disease that is not adequately managed by available therapies in Canada, the potential clinical benefit of Folotyn is considered to outweigh the associated risks.

For more information on Health Canadas decision, please view the Summary Basis of Decision.


Decision issued

Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.