Regulatory Decision Summary for Rayaldee
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.
Type of submission:
What was the purpose of this submission?
This New Drug Submission (new active substance) was filed to seek market authorization for Rayaldee (calcifediol modified-release capsules, 30 mcg), a vitamin D3 analogue, for the treatment of secondary hyperparathyroidism in adults with Stage 3 or 4 chronic kidney disease and low serum 25-hydroxyvitamin D levels (less than 75 nmol/L [30 ng/mL] at initiation).
Why was the decision issued?
The primary source of data supporting the proposed indication for Rayaldee (calcifediol modified release capsules, 30 mcg) is two multicentre, randomized, double-blind, placebo-controlled Phase 3 studies, conducted in adult subjects with secondary hyperparathyroidism (SHPT), Stage 3 or 4 chronic kidney disease (CKD) and vitamin D insufficiency (total 25-hydroxyvitamin D levels less than 30 ng/mL or 75 nmol/L). These studies are considered to be adequate and well-controlled for the purposes of this submission.
A total of 429 subjects stratified by CKD stage were randomized in a 2:1 ratio to receive a daily 30 mcg oral dose of Rayaldee or matching placebo for 12 weeks at bedtime followed by an additional 14 weeks of treatment with daily doses of either 30 or 60 mcg of Rayaldee (or placebo).
The primary efficacy end-point was the number of subjects who attained a mean decrease in plasma intact parathyroid hormone levels (iPTH) of ≥30% from pre-treatment baseline in the efficacy assessment phase (EAP), which encompassed weeks 20 through 26. The secondary efficacy endpoints were the number of subjects who attained a mean 30% decrease in plasma iPTH from pre-treatment baseline in the EAP, and the number of subjects with adequate serum total 25-hydroxyvitamin D (≥30 ng/mL or 75 nmol/L) in the EAP.A larger proportion of patients randomized to Rayaldee experienced an at least 30% reduction in iPTH from baseline compared to placebo in both trials (33% versus 8% in the first trial (P<0.001) and 34% versus 7% in the second trial [P<0.001]). Serum total 25-hydroxyvitamin D levels increased to at least 75 nmol/L in 80% and 83% of subjects treated with Rayaldee vs. 3% and 7% of subjects treated with placebo (P<0.001) in the two studies, respectively. These results indicate that Rayaldee effectively treats SHPT as soon as 12 weeks after initiation of treatment.
Safety data were obtained from the two pivotal Phase 3 studies, and from an open-label extension of these studies in which all subjects received Rayaldee at 30 mcg or 60 mcg. A total of 324 subjects were treated with Rayaldee for >6 months and 169 subjects were treated with Rayaldee for >12 months. Safety issues were consistent with exaggerated pharmacology and with expected class specific side effects (for example, hypercalcemia, hyperphosphatemia and suppressed PTH). Serious adverse events (AEs) of chronic heart failure and increase in serum creatinine were more frequent in patients randomized to Rayaldee. They were found unlikely to be related to the study drug and resolved while continuing treatment; however, they are considered uncertainties. The Product Monograph is the primary risk management strategy to manage the possible harms and uncertainties associated with Rayaldee. It provides warnings pertaining to the significant adverse events reported in clinical trials, and recommendations to the prescriber regarding treatment monitoring and dose modifications that may be required to manage AEs.
The Prescription Drug Status Committee has recommended the addition of calcifediol to the Prescription Drug List.
The recommended dose for Rayaldee is 30 mcg once daily, in the evening, for approximately 3 months, and maintaining or increasing the dose (if necessary) to 60 mcg once daily at bedtime. Rayaldee requires regular monitoring of serum calcium, phosphorus, and plasma intact parathyroid hormone (iPTH) levels.
Overall, the submitted studies demonstrate evidence that the benefit of Rayaldee (calcifediol modified-release capsules, 30 mcg), a vitamin D3 analogue, for the treatment of secondary hyperparathyroidism in adults with Stage 3 or 4 chronic kidney disease and serum total 25-hydroxyvitamin D levels less than 30 ng/mL (75 nmol/L) outweighs the risks.
For more information on Health Canadas decision, please view the Summary Basis of Decision.
Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.