Summary Basis of Decision for Aklief

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:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Aklief is located below.

Recent Activity for Aklief

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 Aklief

Updated:

2022-11-02

The following table describes post-authorization activity for Aklief, a product which contains the medicinal ingredient trifarotene. 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 and Applications Guidance.

Drug Identification Number (DIN):

  • DIN 02494175 - 50 mcg/g trifarotene, cream, topical administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control numberDate submittedDecision and dateSummary of activities
Drug product (DIN 02494175) market notificationNot applicableDate of first sale:
2019-11-28

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NDS # 2219452018-12-14Issued NOC
2019-11-25

NOC issued for New Drug Submission.

Summary Basis of Decision (SBD) for Aklief

Date SBD issued: 2020-03-05

The following information relates to the new drug submission for Aklief.

Trifarotene

Drug Identification Number (DIN):

  • DIN 02494175 - 50 mcg/g cream, topical administration

Galderma Canada Inc.

New Drug Submission Control Number: 221945

On November 25, 2019, Health Canada issued a Notice of Compliance to Galderma Canada Inc. for the drug product Aklief.

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 Aklief is favourable for the topical treatment of acne vulgaris of the face and/or trunk in patients 12 years of age and older.

1 What was approved?

Aklief, a retinoid for topical use in acne, was authorized for the topical treatment of acne vulgaris of the face and/or trunk in patients 12 years of age and older.

The safety and effectiveness of Aklief have not been established for children under 12 years of age. Aklief is therefore not authorized for use in this subpopulation of pediatric patients.

The safety and effectiveness of Aklief in geriatric patients (≥65 years of age) have not been established.

Aklief is contraindicated in patients who are hypersensitive to trifarotene or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. Aklief is also contraindicated in patients with eczema or seborrheic dermatitis, during pregnancy, and in women planning a pregnancy.

Aklief was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Aklief (50 mcg/g trifarotene) is presented as a cream. In addition to the medicinal ingredient, the cream contains allantoin, copolymer of acrylamide and sodium acryloyldimethyltaurate with isohexadecane, polysorbate 80 and sorbitan oleate, cyclomethicone 5, ethanol (96%), phenoxyethanol, propylene glycol, purified water, and medium-chain triglycerides.

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 Aklief Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Aklief approved?

Health Canada considers that the benefit-harm-uncertainty profile of Aklief is favourable for the topical treatment of acne vulgaris of the face and/or trunk in patients 12 years of age and older.

Acne vulgaris, one of the most common skin diseases, is a multifactorial inflammatory condition which affects pilosebaceous follicles. An estimated 5.6 million Canadians (almost 20% of the population) are affected by acne, including approximately 85% of adolescents. Treatment options include retinoids and antibiotics.

Retinoids have a keratolytic activity, and can modulate the proliferation and differentiation of keratinocytes. This contributes to the elimination of comedones, the primary lesions of acne. Trifarotene, the medicinal ingredient in Aklief, is a potent retinoic acid receptor (RAR) agonist with particularly high selectivity for the RARγ subtype, which is known to be largely present in the skin.

The efficacy and safety of Aklief were demonstrated primarily in two pivotal Phase III clinical studies of identical design: Study 18251 (RD.03.SPR.18251) and Study 18252 (RD.03.SPR.18252). Both studies were 12 weeks in duration, multicenter, randomized, parallel-group, double-blind, and vehicle-controlled. Together, the two studies included 2,420 patients aged 9 years and older with moderate facial and truncal acne vulgaris.

The co-primary efficacy endpoints in both studies were:

  • The Investigator's Global Assessment (IGA) success rate at Week 12 (the percentage of subjects who achieve "clear" or "almost clear" scores [0 or 1 on IGA scale], with at least a two-grade improvement from baseline),
  • The absolute changes from baseline in inflammatory facial lesion counts at Week 12, and
  • The absolute changes from baseline in non-inflammatory facial lesion counts at Week 12.

The co-secondary endpoints of both studies are similar to the co-primary endpoints, applied to truncal acne rather than facial acne. The Physician's Global Assessment (instead of the IGA) was used to determine the success rate.

Statistically significant differences were observed between patients treated with Aklief and those who received the vehicle cream, with respect to all co-primary and co-secondary endpoints (p<0.001).

The most commonly reported treatment-emergent adverse events (TEAEs) in the two pivotal studies were application site irritation, nasopharyngitis, sunburn, application site pruritus, upper respiratory tract infection, and headache (at least 1% of patients in any treatment group).

A supportive Phase III safety study (Study RD.06.SRE.18250) was also conducted to examine the long-term safety of Aklief in 453 patients for up to 52 weeks. Clinically meaningful, continuous improvements of acne vulgaris were observed in the face and trunk.

The safety and efficacy of trifarotene, the medicinal ingredient in Aklief, has not been established in women who are pregnant or nursing. Trifarotene behaves similarly to other retinoids and was shown to be teratogenic in toxicology studies. It is therefore contraindicated in pregnant women and women planning a pregnancy, and precaution should be exercised if it is administered to a nursing mother.

The risks observed in the Aklief drug development program are known and expected drug class pharmacological effects of synthetic retinoids.

A Risk Management Plan (RMP) for Aklief was submitted by Galderma Canada Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. 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.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Aklief Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A Look-alike Sound-alike brand name assessment was performed and the proposed name Aklief was accepted.

Aklief has an acceptable safety profile based on the non-clinical and clinical data. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Aklief 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 Aklief?

Submission Milestones: Aklief

Submission MilestoneDate
Submission filed:2018-11-30
Screening
Screening Acceptance Letter issued:2019-01-31
Review
Review of Risk Management Plan complete:2019-09-17
Biostatistics Evaluation complete:2019-10-07
Quality Evaluation complete:2019-11-13
Labelling Review complete, including Look-alike Sound-alike brand name assessment:2019-11-19
Clinical/Medical Evaluation complete:2019-11-20
Notice of Compliance issued by Director General, Therapeutic Products Directorate:2019-11-25

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.

5 What post-authorization activity has taken place for Aklief?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization 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 decisions were negative or positive. The PAAT will continue to be updated during the product's life cycle.

The PAAT for Aklief is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

Up to date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision

Clinical Pharmacology

Trifarotene (the medicinal ingredient in Aklief) is a potent modulator of cellular differentiation, keratinization and inflammatory processes, which are important features in the pathology of acne vulgaris. Although its exact mechanism of action is unclear, trifarotene exhibits high retinoic acid receptor (RAR) activity and very high selectivity for the RARγ subtype, which is understood to be the most relevant of the RARs with respect to acne vulgaris.

The clinical pharmacology of trifarotene was examined in six studies; four of which were pharmacokinetic studies in healthy subjects. After five days of applications, trifarotene was recovered mainly from the stratum corneum (the outermost layer of skin). Following four weeks of repeated applications, plasma levels of trifarotene were non-quantifiable (i.e., <10 pg/mL) in most healthy subjects.

Trifarotene displayed marked comedolytic activity in the rhino mouse model, including a decreased comedone count and increased thickness of the epidermis. Additionally, trifarotene produced the same comedolytic effect, at a dose approximately ten times lower than required for other known retinoids. Anti-inflammatory and depigmenting activities were also observed.

In clinical studies, systemic exposure levels were similar between male and female patients and between adults and pediatric patients (12-18 years old). Overall, systemic exposure was low, and steady state was achieved in adults and pediatric patients after two weeks of topical administration. The terminal half-life of trifarotene ranged from 2 to 9 hours in patients receiving once daily cutaneous application.

No drug accumulation is expected with long-term use.

No clinically relevant effects were observed on cardiac parameters including the QT interval using Fridericia's correction formula (QTcF), QRS duration, PR interval, and heart rate. These outcomes were observed following the administration of trifarotene to healthy subjects for 15 days, with the intent of achieving supratherapeutic exposure levels.

Topical application of Aklief was not shown to influence the circulating concentration of orally administered hormonal contraceptives (ethinyl estradiol and levonorgestrel).

Additionally, it was not found to inhibit or induce cytochrome P450 (CYP450) enzymes at therapeutic concentrations.

The pharmacokinetics of trifarotene have not been examined in subjects with a history of hepatic or renal disease.

Collectively, the clinical pharmacology data support the use of Aklief for the recommended indication.

For further details, please refer to the Aklief Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Aklief was demonstrated primarily in two pivotal Phase III studies of identical design: Study 18251 (RD.03.SPR.18251) and Study 18252 (RD.03.SPR.18252). Both studies were 12 weeks in duration, multicenter, randomized, parallel group, double-blind, and vehicle-controlled.

Collectively, the two studies included 2,420 patients aged 9 years and older. All patients had moderate acne vulgaris on the face, and 99% of patients also had moderate acne vulgaris on the trunk (defined as the shoulders, upper back, and upper anterior chest). Acne severity was evaluated using the five-point Investigator's Global Assessment (IGA) scale for the face, and the Physician's Global Assessment (PGA) scale for the trunk. Both scales range from Grade 0 (clear) to Grade 4 (severe). Moderate acne vulgaris is assigned a score of Grade 3.

Of the 2,420 patients, 1,214 were treated with Aklief once daily and 1,206 patients received the vehicle cream. Thirty-four (1.4%) patients were 9-11 years old, 1,128 patients (47%) were 12-17 years old, and 1,258 patients (52%) were 18 years of age or older.

The co-primary efficacy endpoints in both studies were:

  • The IGA success rate at Week 12 (the percentage of subjects who achieve "clear" or "almost clear" scores [0 or 1 on IGA scale], with at least a two-grade improvement from baseline),
  • The absolute changes from baseline in inflammatory facial lesion counts at Week 12, and
  • The absolute changes from baseline in non-inflammatory facial lesion counts at Week 12.

Statistically significant differences were observed between patients treated with Aklief and those who received the vehicle cream, with respect to the co-primary endpoints (p<0.001).

The onset of effect for the IGA success rate was detected at Week 4 in Study 18251, and at Week 8 in Study 18252. Patients treated with Aklief had IGA success rates 9.8% and 16.6% higher than patients who received the vehicle cream in Studies 18521 and 18252, respectively (29.4% versus 19.5% in Study 18521 and 42.3% versus 25.7% in Study 18252).

Greater improvements were also observed in patients treated with Aklief than in patients who received the vehicle cream with respect to the mean absolute change in inflammatory and non-inflammatory facial lesions.

Compared to baseline values, patients treated with Aklief had, on average, 19.0 (Study 18521) and 24.2 (Study 18252) fewer inflammatory facial lesions at Week 12. Patients who received the vehicle cream had 15.4 (Study 18521) and 18.7 (Study 18252) fewer inflammatory facial lesions at Week 12.

Also at Week 12, patients treated with Aklief had an average of 25.0 (Study 18521) and 30.1 (Study 18252) fewer non-inflammatory facial lesions compared to baseline values. The corresponding values observed in patients who received the vehicle cream were 17.9 (Study 18521) and 21.6 (Study 18252).

The co-secondary endpoints in both studies were:

  • The PGA success rate at Week 12 (the percentage of subjects who achieve "clear" or "almost clear" scores [0 or 1 on PGA scale], with at least a two-grade improvement from baseline),
  • The absolute changes from baseline in inflammatory truncal lesion counts at Week 12, and
  • The absolute changes from baseline in non-inflammatory truncal lesion counts at Week 12.

Consistent with the co-primary endpoints, statistically significant differences were observed between patients treated with Aklief and those who received the vehicle cream with respect to the co-secondary endpoints (p<0.001).

The onset of effect for the PGA success rate was detected at Week 8 in each of the two pivotal studies. Patients treated with Aklief had PGA success rates 10.7% and 12.7% higher than patients who received the vehicle cream in Studies 18521 and 18252, respectively (35.7% versus 25% in Study 18521 and 42.6% versus 29.9% in Study 18252).

Greater improvements were also observed in patients treated with Aklief than in patients who received the vehicle cream with respect to the mean absolute change in inflammatory and non-inflammatory truncal lesions.

Compared to baseline values, patients treated with Aklief had an average of 21.4 (Study 18521) and 25.5 (Study 18252) fewer inflammatory truncal lesions at Week 12. Patients who received the vehicle cream had an average of 18.8 (Study 18521) and 19.8 (Study 18252) fewer inflammatory truncal lesions at Week 12.

With respect to non-inflammatory truncal lesion counts, patients treated with Aklief had average reductions of 21.9 (Study 18521) and 25.9 (Study 18252) relative to baseline values. Patients who received the vehicle cream had average reductions of 17.8 (Study 18521) and 20.8 (Study 18252) compared to baseline values.

Indication

Sponsor's proposed indicationHealth Canada-approved indication
Aklief (trifarotene 50 mcg/g) topical cream is indicated for the treatment of acne vulgaris of the face and/or trunk in patients 9 years of age and older.Aklief (trifarotene 50 mcg/g) topical cream is indicated for the topical treatment of acne vulgaris of the face and/or trunk in patients 12 years of age and older.

The minimum age was revised from 9 years to 12 years, as the primary efficacy endpoints were not met in the subpopulation of patients 9-11 years of age in the two pivotal studies (number of patients = 34).

Additionally, published data on the incidence and prevalence of acne vulgaris in children are limited. Children between 9 and 11 years of age do not normally produce significant levels of adrenal or gonadal androgens, and therefore acne in this age group is rare. When it does develop, it usually has a different underlying cause (e.g., endocrine abnormality), for which acne therapies would not be the first-line treatment option.

For more information, refer to the Aklief Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Aklief was evaluated in the two pivotal Phase III studies (Studies 18251 and 18252, described in detail in the Clinical Efficacy section), as well as in Study 18250, which aimed to assess long-term safety.

The most commonly reported treatment-emergent adverse events (TEAEs) in the two pivotal studies were application site irritation, nasopharyngitis, sunburn, application site pruritus, upper respiratory tract infection, and headache. Each of these TEAEs were reported by at least 1% of patients in any treatment group.

Local tolerability was assessed separately from the TEAEs in the pivotal studies, based on symptoms such as erythema, scaling, dryness, and stinging or burning. Local tolerability decreased relative to baseline values on both the face and trunk. On the face, decreases in tolerability were considered moderate for up to 29.7% of patients and severe for up to 6.2% of patients. On the trunk, decreases in tolerability were considered moderate for up to 18.9% of patients and severe for up to 5.2% of patients. The scores reached maximum severity at Week 1 for the face and Weeks 2-4 for the trunk, and decreased thereafter.

Study 18250 was a supportive Phase III safety study, in which 453 patients were treated with Aklief (50 mcg/g trifarotene) once daily for up to 52 weeks. Clinically meaningful, continuous improvements of acne vulgaris were observed in the face and trunk. The most frequently reported TEAE in this study was nasopharyngitis (10.6%), followed by cutaneous TEAEs including sunburn (6.0%), application site pruritus (5.1%), and application site irritation (4.9%). The number of subjects with cutaneous TEAEs decreased significantly over time.

The clinical safety of trifarotene has not been established in women who are pregnant or nursing. Trifarotene behaves similarly to other retinoids and was shown to be teratogenic in toxicology studies. It is therefore contraindicated in pregnant women and women planning a pregnancy, and precaution should be exercised if it is administered to a nursing mother.

The risks observed in the Aklief drug development program are known and expected drug class pharmacological effects of synthetic retinoids. These can be effectively managed though adequate labelling and medical supervision.

For more information, refer to the Aklief Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

All clinically and toxicologically relevant effects of trifarotene observed in multiple animal species were expected drug class pharmacological effects of retinoid acid receptor (RAR) agonists. Local skin reactions (irritation) occurred in all animal species, whether trifarotene was administered through the dermal or oral route. Repeat-dose dermal toxicity studies were conducted in minipigs for 13 weeks and 9 months, in which no adverse effects were observed except for skin irritation. In the submitted non-clinical studies, there were no unexpected adverse effects that have not been previously reported in animals or humans in connection with other synthetic retinoids.

Trifarotene was not found to be mutagenic or genotoxic in in vitro tests in bacterial cultures and cultured cell lines (bacterial, mammalian and human).

Trifarotene is contraindicated during pregnancy and in women planning to become pregnant based on toxicological findings. Trifarotene was teratogenic in pregnant rats at systemic exposures (as measured by the area under the concentration-time curve [AUC]) of 4,157-fold higher than those observed in humans. A high incidence of fetal malformations (especially skeletal malformations) was observed in rabbits at doses of 0.5 mg/kg/day and above. A teratogenic no-observed-effect level was not established in rats or rabbits. Additionally, the use of trifarotene should be avoided in nursing women, as lacteal transfer was demonstrated in neonatal rats. No adequate juvenile toxicity studies were conducted.

Overall, the results of non-clinical studies demonstrate that trifarotene has reasonable safety margins relative to the proposed human dose. The results of the non-clinical studies as well as the potential risks to humans have been included in the Aklief Product Monograph. Considering the intended use of Aklief, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Aklief 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 Aklief 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 the drug product is stored at room temperature (15ºC to 30ºC). The drug product must not be frozen.

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.

None of the excipients used in the formulation of Aklief is of human or animal origin.

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