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Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Kalydeco is located below.
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorisation information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
The following table describes post-authorization activity for Kalydeco, a product which contains the medicinal ingredient ivacaftor. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
Drug Identification Number (DIN):
DIN 02397412 - 150 mg ivacaftor, tablet, oral
|Activity/Submission Type, Control Number||Date Submitted||Decision
|Summary of Activities|
|(the most recent activities are listed first)|
|SNDS #179589||2014/11/14||Issued NOC 2015/06/12||Regulatory Decision Summary published.|
|NC # 180410||2014/12/08||Issued No Objection Letter 2015/03/17||Submission filed as a Level II (90 day) Notifiable Change (Safety Change) to update the Warnings and Precautions section and the Part III: Consumer Information section of the Kalydeco Product Monograph, with regard to non congenital cataracts. The submission was reviewed and considered acceptable. A No Objection Letter was issued.|
|SNDS # 177199||2014/08/12||Issued NOC 2015/03/13||The submission was filed as a Level I - Supplement, and reviewed under the Priority Review of Drug Submissions Policy, for an expanded indication for Kalydeco. The submission included data from a Phase III, randomized, double blind, placebo controlled, parallel group, 24 week study, involving 69 patients with cystic fibrosis (CF), 6 years of age and older with an R117H mutation in the Cystic Fibrosis Transmembrane conductance Regulator gene. In patients 18 years of age and older, improvements in lung function persisted for the whole study duration (24 weeks). There were no new safety concerns. The benefit/risk profile of Kalydeco was considered favourable and a Notice of Compliance was issued for an expanded indication of the treatment of CF in patients ages 18 years and older who have an R117H mutation in the Cystic Fibrosis Transmembrane conductance Regulator gene.|
|NC # 177651||2014/09/02||Issued No Objection Letter 2015/01/09||Submission filed as a Level II (120 day) Notifiable Change (Safety Change) to update the Drug Interactions section of the Product Monograph. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.|
|NC # 177224||2014/08/12||Issued No Objection Letter 2014/12/23||Submission filed as a Level II (120 day) Notifiable Change (Safety Change) to modify the Adverse Reactions and Action and Clinical Pharmacology sections of the Product Monograph. The submission was reviewed and a No Objection Letter was issued.|
|SNDS # 177216||2014/08/21||Issued NOC 2014/11/07||Submission filed as a Level I - Supplement (labelling only) for a redesigned blister pack configuration. Revisions to the Product Monograph Part III: Consumer Information were submitted, to provide the consumer with information related to the use of the blister packs. The changes were reviewed and considered acceptable, and a Notice of Compliance was issued.|
|SNDS # 170267||2013/11/25||Issued NOC 2014/06/06||The submission was filed as a Level I - Supplement, and reviewed under the Priority Review of Drug Submissions Policy, for an expanded indication for Kalydeco. The submission included data from a Phase III, randomized, double-blind, placebo-controlled, 8-week long crossover study, involving 39 patients with cystic fibrosis (CF) with at least one of the following 9 non-G551D gating mutations: G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R or G970R. Kalydeco showed clinical efficacy: lung function improvement was seen after two weeks and persisted for the whole study duration. There were no new safety concerns. The benefit/risk profile of Kalydeco is considered favourable and a Notice of Compliance was issued for an expanded indication of the treatment of CF in patients ages 6 and older who have one of the nine additional mutations listed above.|
|Drug product (DIN 02397412) market notification||Not applicable||Date of first sale: 2012/11/27||The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.|
|NDS # 155318||2012/04/30||Issued NOC 2012/11/26||Notice of Compliance issued for New Drug Submission.|
Date SBD Issued: 2012/11/24
The following information relates to the original authorization of the new drug submission for Kalydeco.
150 mg tablet, oral
Drug Identification Number (DIN): 02397412
Vertex Pharmaceuticals (Canada) Incorporated
New Drug Submission Control Number: 155318
On November 26, 2012, Health Canada issued a Notice of Compliance to Vertex Pharmaceuticals (Canada) Incorporated for the drug product Kalydeco.
The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (safety and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Kalydeco is favourable for the treatment of cystic fibrosis (CF) in patients age 6 years and older who have a G551D mutation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Kalydeco is not effective in patients with CF who are homozygous for the delta-F508 (F508del) mutation in the CFTR gene. It is not known if Kalydeco is safe and effective in children under 6 years of age or patients with other CFTR mutations.
Kalydeco, a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) potentiator, was authorized for the treatment of cystic fibrosis (CF) in patients age 6 years and older who have a G551D mutation in the CFTR gene. Kalydeco is not effective in patients with CF who are homozygous for the F508del mutation in the CFTR gene. The efficacy and safety of Kalydeco in patients younger than age 6 years and patients 65 years or older have not been evaluated.
Kalydeco is contraindicated for patients who are hypersensitive to the active substance or to any ingredient in the formulation or component of the container. Kalydeco was approved for use under the conditions stated in the Kalydeco Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Kalydeco (150 mg ivacaftor) is presented as a tablet. In addition to the medicinal ingredient, ivacaftor, the tablet contains microcrystalline cellulose, lactose monohydrate, hypromellose acetate succinate, croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, indigo carmine aluminum lake, and carnauba wax. The printing ink contains shellac, iron oxide black, propylene glycol, and ammonium hydroxide.
Additional information may be found in the Kalydeco Product Monograph, approved by Health Canada and available through the Drug Product Database.
Health Canada considers that the benefit/risk profile of Kalydeco is favourable for the treatment of cystic fibrosis (CF) in patients age 6 years and older who have a G551D mutation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene.
Cystic fibrosis is a debilitating and life threatening disease affecting over 70,000 people worldwide. Autosomal recessive mutations in the gene that codes for the CFTR protein are responsible for the disease, and over 1,800 mutations in CFTR have been identified. Dysfunction of CFTR leads to multi-organ CF manifestations, including pulmonary disease, gastrointestinal abnormalities, hepatic dysfunction, pancreatic disease, and reproductive abnormalities. At present, there is no cure for CF. Typical treatment requires numerous chronic medications which help to ameliorate symptoms but do not address the basic defect of the disease that is CFTR dysfunction. Despite currently available therapies, patients with CF have accelerated lung function decline with age. The predicted median age of survival of individuals born today with CF is between 34.4 and 46.7 years, while the actual median age at death reported in Canada is 26 years.
Kalydeco (ivacaftor) represents a novel direction in CF drug development. The primary defect caused by the G551D mutation on the CFTR gene is low CFTR channel opening. In vitro studies showed that ivacaftor was a selective potentiator of the CFTR chloride channel with the G551D gating mutation increasing the channel open probability of the G551D-mutated CFTR protein.
Kalydeco has been shown to be efficacious in two pivotal Phase III placebo-controlled studies in patients with CF who have a G551D mutation in the CFTR gene. The primary efficacy endpoint in both studies was improvement in lung function as determined by the mean absolute change from baseline in percent predicted pre-dose forced expiratory volume in one-second (FEV1) through 24 weeks of treatment. Both studies showed a positive response for the primary endpoint that was sustained at 48 weeks. The trend was similar for the key secondary endpoints. These variables included absolute change in sweat chloride, absolute change in pooled (adult and child versions) Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score, absolute change in body weight, and time to first pulmonary exacerbation.
A Phase II clinical study showed a lack of efficacy in patients with two copies of the most frequent mutation, F508del. In order to manage potential off-label use in that population, a limitation of use was added to the indication, stating that Kalydeco is not effective in patients with CF who are homozygous for the F508del mutation in the CFTR gene.
In all of the clinical studies, Kalydeco was generally well-tolerated. Adverse drug reactions included upper respiratory tract infections, nasal congestion, pharyngeal erythema, oropharyngeal pain, rhinitis, sinus congestion, nasopharyngitis, dizziness, rash, headache, bacterial sputum colonization, diarrhea, and abdominal pain. Most events were non-serious and self-resolved. No fatalities were reported.
A Risk Management Plan (RMP) for Kalydeco was submitted by the sponsor to Health Canada. The RMP describes known and potential safety issues, presents the monitoring scheme, and describes measures that will put in place to minimize risks associated with the product. Upon review, the RMP was considered to be acceptable.
Overall, the therapeutic benefits seen in the pivotal studies are promising and the benefits of Kalydeco therapy seem to outweigh the risks. Kalydeco has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling. Appropriate warnings and precautions are in place in the Kalydeco Product Monograph to address the identified safety concerns.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
The drug submission for Kalydeco was reviewed under the Priority Review Policy. Kalydeco represents a novel direction in cystic fibrosis drug development. The drug is used for the treatment of a serious life-threatening disease and demonstrated a significant increase in efficacy compared to actual treatment available in Canada. The overall benefit/risk profile was improved over existing therapies by drugs marketed in Canada.
|Request for priority status|
|Approval issued by Director, Bureau of Cardiology, Allergy, and Neurological Sciences:||2012/03/22|
|Screening Acceptance Letter issued:||2012/05/31|
|Biopharmaceutics Evaluation complete:||2012/08/30|
|Quality Evaluation complete:||2012/11/19|
|Clinical Evaluation complete:||2012/11/23|
|Labelling Review complete:||2012/11/16|
|Notice of Complianceá issued by Director General:||2012/11/26|
The Canadian regulatory decision on the non-clinical and clinical review of Kalydeco was based on a critical assessment of the Canadian data package. The foreign reviews completed by the European Union's centralised procedure European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as an added reference.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
Summary Basis of Decisions (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorisation information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.
The PAAT for Kalydeco is found above.
For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.
Up to date information on drug products can be found at the following links:
Cystic fibrosis (CF) is a multi-system disease, primarily affecting the lungs and digestive system. It is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene that result in absent or deficient function of the CFTR protein at the cell surface. The CFTR protein is an epithelial chloride channel responsible for aiding in the regulation of salt and water absorption and secretion. Kalydeco (ivacaftor) is a selective potentiator of the CFTR protein. Ivacaftor increases chloride transport by potentiating (increasing) the channel open probability (or gating) of the G551D-mutated CFTR protein. As chloride anions flow out of the channel, positively charged sodium ions follow and maintain electrical balance resulting in the movement of water out of the cell.
The clinical pharmacology program included human pharmacodynamic and pharmacokinetic studies. The study reports included sweat chloride evaluations (a measurement of the amount of chloride in sweat) and data from the pulmonary function test, forced expiratory volume in one-second (FEV1), which support the activity of ivacaftor as a CFTR potentiator.
The pharmacokinetics of ivacaftor was similar between healthy adult volunteers and patients with CF. The exposure of ivacaftor increased 2- to 4-fold when administered with food containing fat. Therefore, Kalydeco should be administered with fat-containing food in order to ensure optimal absorption and exposure.
Ivacaftor is a sensitive cytochrome P450 (CYP) 3A (CYP3A) enzyme substrate. Medicinal products that modify CYP3A activity may impact the pharmacokinetics of ivacaftor. Co-administration with CYP3A inhibitors or inducers tend to increase or decrease ivacaftor exposure respectively. Ivacaftor is also a weak inhibitor of CYP3A. Administration of ivacaftor may alter systemic exposure to medicinal products that share the CYP3A metabolic pathway, which could change their therapeutic effect and/or produce adverse reactions.
Together the clinical and pharmacological data support the use of Kalydeco for the indication.
For further details, please refer to the Kalydeco Product Monograph, approved by Health Canada and available through the Drug Product Database.
The clinical efficacy of Kalydeco in patients with cystic fibrosis (CF) who have a G551D mutation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene was evaluated in two Phase III, randomized, double-blind, placebo-controlled clinical studies (Study 1 and Study 2). In both studies, 109 patients received Kalydeco 150 mg and 104 patients received placebo, twice daily with food containing fat for 48 weeks in addition to their prescribed CF therapies. Study 1 evaluated 161 patients with CF who were 12 years of age or older (mean age 26 years) with a baseline forced expiratory volume in one-second (FEV1) between 40-90% predicted. Study 2 evaluated 52 patients who were 6 to 11 years of age (mean age 9 years) with a baseline FEV1 between 40-105% predicted.
Patients who had persistent Burkholderia cenocepacia, dolosa, or Mycobacterium abcessus at screening and patients with abnormal liver function defined as three or more liver function tests (alanine transaminase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, total bilirubin) at ≥3 times the upper limit of normal were excluded.
The primary efficacy endpoint in both studies was improvement in lung function as determined by the mean absolute change from baseline in percent predicted pre-dose FEV1 through 24 weeks of treatment.
Secondary efficacy endpoints included absolute change in sweat chloride, absolute change in pooled (adult and child versions) Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score, and absolute change in body weight. Time to first pulmonary exacerbation through Week 48 was also assessed in Study 1. Pulmonary exacerbation was defined as a change in antibiotic therapy as a result of 4 or more of 12 pre-specified sino-pulmonary signs/symptoms.
In both Phase III studies, treatment with Kalydeco resulted in a significant improvement in FEV1 at Week 24 and Week 48. The analysis of the primary endpoint (absolute change of percent predicted FEV1 at 24 weeks) was 10.6% (p<0.0001) in Study 1 and 12.5% (p<0.0001) in Study 2. This treatment effect remained statistically significant at 48 weeks. This trend was similar for the key secondary endpoints.
In Study 1, the sweat test results decreased from a mean value of 100.4 mmol/L to 50.8 mmol/L. Despite being below the diagnostic threshold for CF, this value was above the upper limit of normal, in the indeterminate range. Kalydeco improved CFTR function but did not appear to normalize it.
In the subgroup analyses, CFQ-R respiratory domain scores showed a statistically significant increase for the adolescent/adults or when the adolescent/adults were pooled with children. Treatment effect was 7.59 for adolescent/adults and 8.60 for adolescent/adults pooled with children. Both results were statistically significant. An analysis of the CFQ-R scores for children alone could not be performed as the number of children in Study 1 was too low.
The estimated Week 48 pulmonary exacerbation-free rate was 67% for the Kalydeco group versus 41% in the placebo group. This reduction was statistically significant.
The adjusted mean change in body weight at Week 48 was 3.11 kg for Kalydeco versus 0.4 kg for placebo. The treatment difference was statistically significant (p = 0.001). For the patients <20 years of age (47 patients), weight for age z-scores were calculated and the difference was also statistically significant.
Study 2 confirmed that Kalydeco was effective in patients 6-11 years of age. This study showed a rapid and durable improvement in FEV1 that was statistically significant. Non-pulmonary assessments of CFTR function by change in weight and in sweat chloride values were also statistically significant. Treatment with Kalydeco also resulted in improvement in respiratory symptoms compared to placebo, although the treatment effect was not statistically significant. The improvements in clinical endpoints and CFTR function observed through Week 24 of treatment were maintained through Week 48 of treatment.
A Phase II, 16-week randomized, double-blind, placebo-controlled, parallel-group study was conducted in 140 patients with CF age 12 years and older who were homozygous for the F508del mutation in the CFTR gene and who had FEV1 ≥40% predicted. Efficacy endpoints were similar to the two previous studies. The primary endpoint was improvement in lung function as determined by the mean absolute change from baseline through Week 16 in percent predicted FEV1. This study showed that Kalydeco is not effective in patients homozygous for the F508del CFTR mutation, the most common cause of CF. Treatment with Kalydeco resulted in no improvement in FEV1 relative to placebo. The mean absolute change in FEV1 from baseline through Week 16 was 1.5% and -0.2% for patients in the Kalydeco and placebo groups, respectively (p = 0.15). There were also no meaningful differences between patients treated with Kalydeco compared to placebo for the secondary endpoints (change in CF symptoms, change in weight, or change in sweat chloride). The lack of efficacy in CF patients homozygous for the F508del mutation in the CFTR gene is notable as Kalydeco is the first disease modifying agent developed for CF and therapeutic expectation has to be managed. This fact is clearly stated as part of the indication in the Kalydeco Product Monograph to avoid off-label use and to emphasize the lack of clinical efficacy for patients who are homozygous for the most frequent genetic mutation (F508del mutation in the CFTR gene) causing CF.
For more information, refer to the Kalydeco Product Monograph, approved by Health Canada and available through the Drug Product Database.
The overall safety profile of Kalydeco was based on pooled data from the placebo-controlled Phase IIb and Phase III clinical studies conducted in 221 patients who received Kalydeco and 132 patients who received placebo for 16 to 48 weeks. In these studies, the proportion of patients who prematurely discontinued use of the study drug due to adverse events (AEs) was 2% for Kalydeco-treated patients and 5% for placebo-treated patients.
In the Phase III placebo-controlled study, Study 1 (described in Clinical Efficacy), AEs were reported by >95% of the patients in each treatment group. This is not surprising, considering that many of these AEs were part of the CF symptoms spectrum. Serious AEs (SAEs) were much less frequent in the Kalydeco group (24% versus 42% for the placebo group), mostly because of a reduction in the number of CF exacerbations, captured as AEs. However, the incidence of SAEs related to study drug was higher for Kalydeco (7.2% versus 3.8%). Adverse events for which incidence in the Kalydeco group was >5% higher than the placebo group through Week 48 included: dizziness; rash; upper respiratory tract infection; headache; bacteria in sputum; and nasal congestion.
In Study 2 (described in Clinical Efficacy), the number of AEs possibly related to the study drug was higher in the Kalydeco group than the placebo group: 39% versus 23%. However, the incidence of SAEs was similar between the two groups. Patients receiving Kalydeco had a higher incidence of nasopharyngitis, upper respiratory tract infection, otitis media, diarrhea, headache, and oropharyngeal pain. This study demonstrated that the pattern of AEs was similar in patients 6-11 years of age to what was observed in the older population in Study 1. During the clinical studies, most AEs were non-serious and self-resolved. There were no fatalities reported.
Rare cases of increased liver enzymes were reported during the clinical studies although the overall incidence was the same as placebo. Periodic evaluation of liver function is recommended in the Product Monograph for patients treated with Kalydeco.
For more information about the drug product, refer to the Kalydeco Product Monograph, approved by Health Canada and available through the Drug Product Database.
A Risk Management Plan (RMP) for Kalydeco was submitted and reviewed by Health Canada. The RMP describes known and potential safety issues, presents the monitoring scheme, and describes measures that will put in place to minimize risks associated with the product. Upon review, the RMP was considered to be acceptable.
In vitro studies showed that ivacaftor was a selective potentiator of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) chloride channel with the G551D gating mutation. Ivacaftor increased chloride transport by potentiating the channel open probability of the G551D-CFTR protein.
The sponsor performed a comprehensive toxicology program. After oral dosing, ivacaftor was shown to be distributed mainly to the gastrointestinal system as well as the liver, kidney, and to a lesser extent to the lungs, heart, and spleen. The liver was the target organ in 3-month toxicity studies in rats and mice. In the chronic toxicity studies in dogs, the target organs were the gastrointestinal tract and heart with occasional instances of atrioventricular block and supraventricular premature complex runs observed in the 12-month study.
An increased incidence of cataracts was observed in juvenile rats at doses lower than the maximum recommended clinical dose. However, cataracts were not observed in the 3- and 6-month studies in adult rats at higher doses, and therefore the relevance to humans is unknown.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Kalydeco Product Monograph. In view of the intended use of Kalydeco, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Kalydeco Product Monograph, approved by Health Canada and available through the Drug Product Database.
The Chemistry and Manufacturing information submitted for Kalydeco has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of Kalydeco is acceptable.
The proposed limits of drug-related impurities are considered adequately qualified from toxicological studies.
The facility involved in the production is compliant with Good Manufacturing Practices.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.
There are no excipients of human or animal origin used in the manufacture of the drug substance One excipient, lactose monohydrate, used in the manufacture of the Kalydeco tablets is of animal origin; however, the lactose monohydrate is manufactured in compliance with the European Medicines Agency Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Products. Certification letters attesting to these claims were provided by the sponsor.