Regulatory Decision Summary for Defitelio

Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), occurs most often following haematopoietic stem cell transplantation (HSCT) due to the myeloablative regimens that are used. The condition is the result of damage to sinusoidal endothelial cells which results in the obstruction of hepatic sinusoids and typically is seen within 30 days post HSCT. The clinical presentation of severe forms of hepatic VOD is usually accompanied by multi-organ dysfunction and, if left untreated, is associated with a mortality rate greater than 80%. There are no currently approved therapies to treat VOD in Canada. Defitelio has been available in Canada for prevention and treatment of hepatic VOD through SAP (Special Access Program) since 2010.

The benefit of Defitelio was supported by the results from one pivotal study (Study 2005-01) and three supportive studies (Study 99-118, Study 2006-05, and a Registry Study CIBMTR). Taken together, the Day+100 post-HSCT survival rates across all four studies ranged from 38% to 45% and were higher than the survival rates in the historical control arm, the CIBMTR registry supportive care arm, and from the literature (<20%).This result shows the clinical meaningful benefit of Defitelio in the target patient population. This conclusion takes into account the totality of all data provided in the submission and is in agreement with those of other major regulatory agencies.

These clinical benefits of Defitelio were weighed against inconclusive statistical findings based on limitations in pivotal study design and methodologies for data analysis. The clinical benefits were also considered in light of the severity and rareness of the disease. Veno-occlusive disease (VOD) with associated multi-organ dysfunction is a rare and frequently fatal complication of HSCT and is associated with a mortality rate greater than 80%. There are currently no approved therapies for the treatment of VOD with multi-organ failure.

There is a high rate of adverse reactions in patients being treated for hepatic VOD with multi-organ dysfunction using the proposed dose-schedule of Defitelio. Hemorrhage, hypersensitivity and pharmacologic interaction with anticoagulants and fibrinolytic therapies are the main safety concerns.

The Risk Management Plan was reviewed by MHPD (Marked Health Products Directorate). The issues regarding the pediatric safety data and a long term safety monitoring were addressed and the responses from the sponsor are deemed satisfactory.

Overall, based on the available safety and effectiveness data, the lack of alternative treatment, and the high mortality, the potential toxicities and risks are outweighed by the benefit of treatment with Defitelio in this patient population.

In order to ensure that the benefit continues to outweigh any risks after authorization, Health Canada has required post-approval activities to be carried out.

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