Regulatory Decision Summary for Replagal

Evidence was provided that patients diagnosed with Fabry disease can benefit from Replagal therapy. During a period of drug shortages patients expressed concerns about non-availability of Replagal, while those that were able to access Replagal "AF" provided no complaints regarding its use. While the efficacy results from clinical trials are limited and only trend towards substantiating patient comments in the context of Fabry Disease, the value of patient statements is considerable.

Furthermore, there is sufficient information from the small studies available with Replagal "AF" to consider, by any standards and particularly for a rare disease, that the outcomes reported from those studies indicate, at minimum, promising efficacy for a product where the safety profile is known. Clinical data indicate that some patients receiving Replagal "AF" may benefit from this therapy. No controlled studies were conducted with Replagal "AF", and the sample size in the clinical studies conducted so far did not support a robust statistical analysis approach. However, trends in efficacy endpoints tested suggest a positive outcome in these patients. Additional clinical studies are required to validate the efficacy claims for Replagal "AF". The choice of primary endpoints, sample size, statistical analysis methods, dosing regimen, and the timing of therapy initiation may be critical in confirming the efficacy claims for Replagal "AF".

The risks of Replagal are well known. Aside from a minor concern of potentially increased antibody generation with some long-term consequences on efficacy, there is no indication that the safety profile of Replagal would have changed in any substantial way. This is based on post-market observations and a PBRER. Only long term use has the potential to show any safety issues that may be new or novel, and those are usually found after market approval has been granted for a product.

Hence, the efficacy information is promising and the safety profile is established. We can conclude that there is a reasonable balance between benefits and risks for Replagal and that the promising nature of the efficacy should be an important factor when considering whether to grant a NOC to Shire and under what conditions.

The safety profile of Replagal "AF" is consistent with that of previously authorised Replagal "RB" and is considered to be "acceptable". The following important points were considered in drawing the conclusions of this benefit-risk assessment:

1. The indication sought for Replagal "AF" is in patients with a rare disease, and as such, certain limitations and caveats in the clinical development program are expected.
2. The efficacy of Replagal "AF" has been studied and evaluated in small, open-label clinical trials, some of which also recruited patients that received the previously authorised Replagal "RB". Efficacy results suggest potential benefits in at least some of the patients treated.
3. As Replagal "AF" is approved in many international jurisdictions, there is extensive post-marketing clinical data supporting a positive benefit-risk for this therapy.
4. A large percentage of Canadian patients with Fabry disease have been receiving Replagal "AF" for years through the Canadian Fabry Disease Initiative (CFDI). Although not absolute, there is no indication that the safety profile for Replagal has changed when the manufacturing was changed from "RB" to "AF". Because Replagal is a biological product, switching from one biological to another is not advisable due to the potential for development of antibodies, which might bind the drug and counteract its therapeutic benefits.

In conclusion, clinical data obtained in open-label studies with Replagal "AF", and as reported in the CFDI registry, indicate some benefits in the target patient population at the proposed dose. Due to the small sample size in most of these studies, a confirmatory clinical trial with an adequate sample size is desirable and recommended. The safety profile is understood and considered "acceptable" and the apparent benefits of the drug outweigh its risks.

A NOC/c is recommended as there is a clear unmet need for patients with Fabry disease. Fabry disease is progressive and degenerative whereby appropriate treatment for affected patients is essential to support their lives. An option is needed for these patients in the event of lack of supply or intolerability to the currently approved Fabrazyme. Despite the known potential risks of switching biologicals, not having an alternative treatment is a significant and real risk to patients.