Summary Basis of Decision for Eucrisa
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Eucrisa is located below.
Recent Activity for Eucrisa
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization 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 decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Post-Authorization Activity Table (PAAT) for Eucrisa
Updated:
The following table describes post-authorization activity for Eucrisa, a product which contains the medicinal ingredient crisaborole. 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 and to the list of abbreviations that are found in PAATs.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
Drug Identification Number (DIN):
- DIN 02476991 - 2% w/w crisaborole, ointment, topical
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| Drug product (DIN 02476991) market notification | Not applicable | Date of first sale:2018-08-29 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 206906 | 2017-06-23 | Issued NOC2018-06-07 | Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Eucrisa
Date SBD issued: 2018-10-18
The following information relates to the new drug submission for Eucrisa.
Crisaborole
2% w/w, ointment, topical
Drug Identification Number (DIN):
- 02476991
Pfizer Canada Inc.
New Drug Submission Control Number: 206906
On June 7, 2018, Health Canada issued a Notice of Compliance to Pfizer Canada Inc. for the drug product Eucrisa.
The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit-harm-uncertainty profile of Eucrisa is favourable for topical treatment of mild to moderate atopic dermatitis in patients 2 years of age and older.
1 What was approved?
Eucrisa, a phosphodiesterase-4 inhibitor, was authorized for topical treatment of mild to moderate atopic dermatitis in patients 2 years of age and older.
Health Canada has not authorized an indication for pediatric patients below the age of 2 years given that currently there are no available data for this age group.
Eucrisa is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
Evidence from clinical trials of Eucrisa did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.
Eucrisa was approved for use under the conditions stated in Eucrisa Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Eucrisa (2% w/w, crisaborole) is presented as an ointment. In addition to the medicinal ingredient crisaborole, the ointment also contains the following non-medicinal ingredients: butylated hydroxytoluene, edetate calcium disodium, mono- and diglycerides, paraffin, propylene glycol, white petrolatum.
For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Eucrisa Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Eucrisa approved?
Health Canada considers that the benefit-harm-uncertainty profile of Eucrisa is favourable for topical treatment of mild to moderate atopic dermatitis in patients 2 years of age and older.
Atopic dermatitis, often referred to as eczema, is a distinctive inflammatory, highly pruritic, chronic eczematous condition with onset in early childhood that usually occurs in people who have a personal or family history of other atopic conditions such as asthma or allergic rhinitis. Atopic dermatitis is characterized by intense pruritus and eczematous lesions often affecting large areas of the skin. Other manifestations of the disease include erythematous papules, excoriations, exudation, lichenification, and bacterial colonization, including serious skin infections. The onset of atopic dermatitis commonly occurs between 3 and 6 months of age and approximately 60% of patients develop atopic dermatitis within the first year of life and 90% by 5 years of age. Most patients observe improvement in their skin disease with age; however, 10 to 30% experience symptoms that persist into adulthood. A small proportion of patients develop the disease as adults. It is estimated that up to 17% of Canadians suffer from atopic dermatitis at some point in their lives.
Currently, there is no cure for atopic dermatitis, and treatment is focused on alleviating the debilitating signs and symptoms and gaining control over recurrent flares throughout the extended natural history of the disease. Approved therapies for the treatment of atopic dermatitis include topical corticosteroids and topical calcineurin inhibitors (as second line therapy). These therapies may provide effective treatment options for patients with atopic dermatitis; however, both carry significant risk of inducing undesirable and serious side effects that may be of particular concern for young children, hence the approved indications are accompanied by restrictions in use.
Crisaborole (the medicinal ingredient in Eucrisa) is a phosphodiesterase-4 inhibitor which has been shown to increase intracellular cyclic adenosine monophosphate levels. While the specific mechanism(s) by which crisaborole exerts its therapeutic action is not well defined, crisaborole reduces the production of some inflammatory cytokines implicated in the pathophysiology of atopic dermatitis.
Eucrisa has been shown to be efficacious in patients with mild to moderate atopic dermatitis. The market authorization was based on two Phase III multicentre, randomized, double-blind, parallel-group, vehicle-controlled clinical trials, AN2728-AD-301 and AN2728-AD-302, with identical study design. The primary efficacy endpoint in both pivotal trials was the proportion of patients at Day 29 who achieved success, defined as an Investigator's Static Global Assessment (ISGA) grade of Clear (score of 0) or Almost Clear (score of 1) with a 2-grade or greater improvement from baseline, comparing Eucrisa-treated patients to vehicle-treated patients. The results of the primary efficacy endpoint showed that patients treated with Eucrisa had a statistically significant higher rate (32.8% and 31.4%) of success in ISGA at Day 29 when compared with those treated with Vehicle (25.4% and 18.0%) in both pivotal trials, respectively.
The most common drug-related adverse events reported in both pivotal trials were application site pain. Based on the pooled safety data, application site pain was reported in 4.4% of patients in the Eucrisa treatment group and 1.2% of patients in the vehicle group. Application site pain was reported in a greater proportion of Eucrisa-treated patients than vehicle-treated patients across all three age groups (2-11, 12-17, and ≥18 years). No patients experienced a serious adverse event due to application site pain. Less common (<1%) adverse reactions in patients treated with Eucrisa included application site reactions (including contact dermatitis and pruritus) and flare of atopic dermatitis.
A Risk Management Plan (RMP) for Eucrisa was submitted by Pfizer Canada to Health Canada. Upon review, the RMP was considered to be acceptable. Pfizer has initiated post-marketing clinical studies supporting pediatric population; no additional post-authorization studies were requested by Health Canada. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
A Look-alike Sound-alike brand name assessment was performed and the proposed name Eucrisa was accepted.
Eucrisa has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Eucrisa 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.
3 What steps led to the approval of Eucrisa?
Submission Milestones: Eucrisa
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2017-03-22 |
| Submission filed: | 2017-06-23 |
| Screening | |
| Screening Acceptance Letter issued: | 2017-08-11 |
| Review | |
| Quality Evaluation complete: | 2018-06-07 |
| Clinical Evaluation complete: | 2018-06-07 |
| Review of Risk Management Plan complete: | 2018-03-02 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2018-05-14 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate: | 2018-06-07 |
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
Crisaborole (the medicinal ingredient in Eucrisa) is a phosphodiesterase-4 inhibitor which has been shown to increase intracellular cyclic adenosine monophosphate levels. While the specific mechanism(s) by which crisaborole exerts its therapeutic action is not well defined, crisaborole reduces the production of some inflammatory cytokines implicated in the pathophysiology of atopic dermatitis. Once systemically absorbed, crisaborole is rapidly metabolized to inactive metabolites.
The clinical pharmacology data included reports on the human pharmacodynamic and pharmacokinetic studies.
Pharmacodynamics
QT Prolongation
At therapeutic doses, Eucrisa ointment is not expected to prolong QTc to any clinically relevant extent. In a thorough QT/QTc study of healthy volunteers, there was no clinically important prolongation of QT/QTc interval induced by either crisaborole (the medicinal ingredient in Eucrisa) or its metabolites and there were no clinically significant effects on heart rate or PR or QRS intervals.
Pharmacokinetics
The pharmacokinetics of Eucrisa were investigated in 33 pediatric patients 2 to 17 years of age with mild to moderate atopic dermatitis and a mean ± standard deviation (SD) body surface area involvement of 49 ± 20% (range 27% to 92%). In this study, patients applied approximately 3 mg/cm2 of Eucrisa ointment (dose range was approximately 6 g to 30 g per application) twice daily for 8 days. The lower limit of quantification for the pharmacokinetic assay used to detect presence of crisaborole in plasma was 0.2 ng/mL.
Plasma concentrations were quantifiable in all the patients. The mean ± SD maximum plasma concentration (Cmax) and area under the concentration-time curve from 0 to 12 hours post dose (AUC0-12) for crisaborole on Day 8 were 127 ± 196 ng/mL and 949 ± 1,240 ng*h/mL, respectively. Systemic concentrations of crisaborole were at steady state by Day 8. Based on the ratios of AUC0-12 between Day 8 and Day 1, the mean accumulation factor for crisaborole was 1.9.
For further details on clinical pharmacology, please refer to the Eucrisa Product Monograph, approved by health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Eucrisa was evaluated in two randomized Phase III trials (AN2728-AD-301 and AN2728-AD-302) that enrolled a total of 1,522 patients (age range: 2 to 79 years old), with mild to moderate atopic dermatitis.
Clinical Trials AN2728-AD-301 and AN2728-AD-302
The pivotal Phase III clinical trials AN2728-AD-301 and AN2728-AD-302 were multicentre, randomized, double-blind, parallel-group, vehicle-controlled clinical studies with an identical study design. Patients with mild to moderate atopic dermatitis were randomized 2:1 to receive Eucrisa or vehicle applied topically twice daily for 28 days. The primary efficacy endpoint was the proportion of patients at Day 29 who achieved success, defined as an Investigator's Static Global Assessment (ISGA) grade of Clear (score of 0) or Almost Clear (score of 1) with a 2-grade or greater improvement from baseline, comparing Eucrisa-treated patients to vehicle-treated patients. The secondary efficacy endpoints were the proportion of patients at Day 29 with ISGA grade of Clear (score of 0) or Almost Clear (score of 1), and the time to success in ISGA.
A total of 1,522 patients 2 to 79 years of age were enrolled in the pivotal trials. The mean age was 12.3 years in the Eucrisa group and 12.1 years in the vehicle group. About 62% of patients in both treatment groups were 2 to 11 years of age and 31 to 37% of patients were 2 to 6 years of age. At baseline, 38.5% of the patients had an ISGA score of 2 (mild), and 61.5% had an ISGA score of 3 (moderate), in the overall assessment of atopic dermatitis (erythema, induration/papulation, and oozing/crusting) on a severity scale of 0 to 4. The mean treatable percent body surface area at baseline was 18% (range between 5% and 95%). Moderate or severe baseline pruritus was reported in approximately 70% of patients. Overall, demographic characteristics and baseline disease characteristics were balanced between treatment groups.
The results of the primary efficacy endpoint showed that in both pivotal trials patients treated with Eucrisa (crisaborole ointment, 2%) had a statistically significant higher rate (32.8% and 31.4%) of success in ISGA at Day 29 when compared with those treated with vehicle (25.4% and 18.0%), respectively. Similarly, the results of the secondary efficacy endpoints showed that patients treated with Eucrisa (crisaborole ointment, 2%) had a statistically significant higher rate (51.7% and 48.5%) of Clear or Almost Clear ISGA ratings at Day 29 when compared with those treated with Vehicle (40.6% and 29.7%) in both pivotal trials, respectively. The time to success in ISGA was also statistically significantly earlier in Eucrisa group than in the vehicle group in both trials.
Uncertainties
In both pivotal trials, the duration of randomized treatment period was 4 weeks and the study population included patients 2 years of age and older with mild to moderate atopic dermatitis. The efficacy of Eucrisa in patients with severe atopic dermatitis, pediatric patients under 2 years of age, and beyond 4 weeks of treatment has not been established. Therefore, Health Canada has not authorized use of Eucrisa in pediatric patients below the age of 2 years.
Indication
The New Drug Submission for Eucrisa was filed by the sponsor with the following indication:
- Eucrisa is indicated for topical treatment of mild to moderate atopic dermatitis in patients 2 years of age and older.
To ensure safe and effective use of the product, Health Canada approved the following indication:
- Eucrisa (crisaborole ointment, 2 %) is indicated for topical treatment of mild to moderate atopic dermatitis in patients 2 years of age and older.
Overall Analysis of Efficacy
Based on the totality of evidence submitted in this New Drug Submission, the efficacy and safety data provided in support of Eucrisa for the recommended indication is considered acceptable.
For more information, refer to the Eucrisa Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The safety of Eucrisa was evaluated primarily in the two pivotal trials AN2728-AD-301 and AN2728-AD-302 (described in the Clinical Efficacy section). A total of 1,522 patients (2 to 79 years old) with mild to moderate atopic dermatitis were enrolled in these two trials. One long-term (48 weeks) safety trial AN2728-AD-303 was also included as part of the safety assessment.
Clinical trial AN2728-AD-303 was an open-label long-term clinical trial which included 517 patients aged 2 to 72 years (including 454 patients 2 to 17 years of age), who had completed one of the previous Phase III pivotal trials (AN2728-AD-301 and AN2728-AD-302) without any safety issues. These patients were treated with Eucrisa twice daily intermittently for up to 48 weeks in 28-day on-treatment or off-treatment cycles.
The most common drug-related adverse event occurring in ≥1% of patients in both pivotal trials was application site pain. Based on the pooled data, application site pain was reported in 4.4% of patients in the Eucrisa group and 1.2% of patients in the vehicle group. Reported application site pain was noted to be greater in Eucrisa-treated patients than vehicle-treated patients across all three age groups (2-11, 12-17, and ≥18 years). All adverse events for application site pain were considered possibly, probably, or definitely related to study drug. In addition, most events were mild or moderate in severity with exception of 8 patients (0.8%) in the Eucrisa group and no patients in the vehicle group who had severe application site pain. None of the patients in either treatment groups experienced a serious adverse event of application site pain. Two patients in AN2728-AD-301 and one patient in AN2728-AD-302 discontinued the treatment due to application site pain; all three of these patients were in the Eucrisa treatment group. In addition, five patients in trial AN2728-AD-301 and one patient in trial AN2728-AD-302 were withdrawn from study drug due to application site pain; all six of these patients were in the Eucrisa treatment group. Less common (<1%) adverse reactions in patients treated with Eucrisa included application site reactions (including contact dermatitis and pruritus) and flare of atopic dermatitis.
Although the safety trial AN2728-AD-303 consisted of a 48-week duration, patients were not treated for 48 weeks continuously. Rather, patients were treated with Eucrisa twice daily intermittently in 28-day on-treatment or off-treatment cycles. Safety data from post-marketing surveillance are warranted to further define the long-term safety profile of Eucrisa. In addition, the sponsor has initiated a post-marking clinical study in younger pediatric population. It is also not specifically known as to whether Eucrisa is more irritating to sensitive skin areas (e.g., head, face, neck, eyelid and intertriginous areas) than nonsensitive skin areas (e.g., trunk, arms, legs) among patients with atopic dermatitis. The most frequently reported adverse events in this trial included atopic dermatitis, application site pain, and application site infection.
For more information, refer to the Eucrisa Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
In vitro safety pharmacology assays showed that crisaborole (the medicinal ingredient in Eucrisa) is a low potency human ether-a-go-go (HERG) channel blocker. In animal safety pharmacology studies, crisaborole did not induce behavioural changes with single oral doses up to 1,000 mg/kg in male rats. In a single-dose study in male dogs, one dog at the high dose (300 mg/kg) died from hypotensive shock. No adverse cardiovascular effects were observed at the lower doses (30 mg/kg and 100 mg/kg).
In vitro studies using human liver microsomes indicated that under the conditions of clinical use, crisaborole and metabolite 1 are not expected to inhibit cytochrome P450 (CYP) 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4. In vitro studies for metabolite 2 showed that it did not inhibit activities of CYP2C19, 2D6, and 3A4; was a weak inhibitor of CYP1A2 and 2B6; and a moderate inhibitor of CYP2C8 and 2C9. In vitro studies in human hepatocytes showed that under the conditions of clinical use, crisaborole and metabolites 1 and 2 are not expected to induce CYP enzymes.
Systemic exposure to crisaborole and its metabolites was confirmed following oral and dermal administration in the toxicology studies. In a 6-month oral toxicity study in rats, no systemic toxicity was observed up to the highest dose (450 mg/kg/day). In a 3-month dermal toxicity study in minipigs, twice daily dermal administration of crisaborole ointment (0.5%, 2%, and 5%) did not produce systemic toxicity up to the highest dose. Possible crisaborole-related application site erythema was observed.
Crisaborole revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitro genotoxicity tests (Ames assay and human lymphocyte chromosomal aberration assay) and one in vivo genotoxicity test (rat micronucleus assay). The two metabolites of crisaborole, metabolite 1 and metabolite 2, did not contain mutagenic alerts in silico and were indirectly evaluated for mutagenicity in the in vivo rat micronucleus test.
In a 104-week rat oral carcinogenicity study (30 mg/kg/day, 100 mg/kg/day, and 300 mg/kg/day crisaborole), a drug-related higher incidence of benign granular cell tumors in the uterus with cervix and vagina (combine) was noted with the high dose (300 mg/kg/day) in treated female rats (1.5 times the maximum human recommended dose [MHRD] based on area under the curve [AUC]). The clinical relevance of this finding is unknown. In a 99-week (female) and 104-week (male) dermal carcinogenicity study in mice administered topical doses of 2%, 5%, and 7% crisaborole ointment once daily, no drug-related neoplastic findings were noted.
Rat and rabbit embryo-fetal development was assessed following oral administration of crisaborole.
Crisaborole did not cause adverse effects to the fetus at oral doses up to 300 mg/kg/day in pregnant rats and 100 mg/kg/day in pregnant rabbits during the period of organogenesis (3 times the MRHD based on AUC). No drug-related effects on fetal development were noted in the rat prenatal/postnatal development study conducted at oral doses up to 600 mg/kg/day crisaborole administered to pregnant rats during gestation and lactation. No drug related effects on fertility were noted in male or female rats administered oral doses up to 600 mg/kg/day (13 times the MRHD based on AUC) prior to and during early pregnancy.
The toxicity in juvenile animals was evaluated in one 4-week oral study (30 mg/kg/day, 100 mg/kg/day, and 300 mg/kg/day) in juvenile rats and one 4-week dermal study (2%, 5%, and 7% ointment twice daily) in juvenile minipigs. In the oral rat study two deaths occurred at the highest dose with some clinical changes observed at the two higher doses. These findings may be attributed to higher systemic exposure and the small size of the rats at weaning. No drug-related changes were observed in the dermal study.
For more information, refer to the Eucrisa Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The Chemistry and Manufacturing information submitted for Eucrisa 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 36 months is acceptable when stored below 25oC.
Proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation limits and/or qualified from toxicological studies).
All sites involved in production are compliant with Good Manufacturing Practices.
All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.
There are no materials subject to transmissible bovine spongiform encephalopathy (BSE) or transmissible spongiform encephalopathy (TSE) used in the manufacture of Eucrisa.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| EUCRISA | 02476991 | PFIZER CANADA ULC | CRISABOROLE 2 % / W/W |