Drugs, Health Technologies, Health Systems
Indication: For the topical treatment of actinic keratosis lesions of the face, ears, and/or scalp
Sponsor: Hill Dermaceuticals, Inc.
Recommendation: Reimburse with conditions
Summary
What Is the Reimbursement Recommendation for Tolak?
Canada’s Drug Agency (CDA-AMC) recommends that Tolak be reimbursed by public drug plans for the topical treatment of actinic keratosis lesions of the face, ears, and/or scalp if certain conditions are met.
Why Did CDA-AMC Recommend Reimbursement?
The subcommittee determined that Tolak demonstrates acceptable clinical value compared with fluorouracil 5% cream in patients with actinic keratosis lesions of the face, ears, and/or scalp. This determination was enough for the Canadian Drug Expert Committee (CDEC) to recommend that Tolak be reimbursed.
Evidence from a pivotal phase III trial, Study 48, demonstrated that 4 weeks of treatment with Tolak in patients with actinic keratosis lesions of the face, ears, and/or scalp likely resulted in similar clinical benefit compared with fluorouracil 5% cream, as measured by the proportion of patients achieving at least 75% clearance and by the percent change from baseline in total lesion counts assessed 4 weeks after completing treatment. However, Study 48 did not demonstrate noninferiority of Tolak for the primary end point of the proportion of patients achieving 100% clearance at 4 weeks off treatment. Due to the nature of actinic keratosis, the clinical expert consulted by CDA-AMC for this review noted that achieving at least 75% clearance is a more meaningful end point in clinical practice for evaluating the efficacy of Tolak in the treatment of actinic keratosis lesions of the face, ears, and/or scalp compared with 100% clearance. On this basis, it was concluded that Tolak is likely comparable to fluorouracil 5% cream. In addition, evidence from another pivotal phase III trial, Study 49, demonstrated superiority of Tolak over its vehicle for the primary end point and all secondary end points. Overall, the observed safety profile of Tolak is consistent with the product monograph and clinical expert input.
Which Patients Are Eligible for Coverage?
Tolak should only be covered for topical treatment in patients with actinic keratosis lesions of the face, ears, and/or scalp. Eligibility for reimbursement of Tolak should be similar to each public drug plan’s current initiation criteria for fluorouracil 5% cream for the topical treatment of actinic keratosis of the face, ears, and/or scalp.
What Are the Conditions for Reimbursement?
Tolak should only be reimbursed if each public drug plan’s current renewal, discontinuation, and prescribing criteria for fluorouracil 5% cream for the topical treatment of actinic keratosis of the face, ears, and/or scalp are met and the total cost of Tolak does not exceed the total cost of treatment with fluorouracil 5% cream.
Disease background:
Actinic keratosis is a skin disease involving atypical keratinocytes within the epidermis. It can be either in situ or a precursor to squamous cell carcinoma.
According to Canadian clinical practice guidelines, the incidence and prevalence of actinic keratosis have not specifically been studied in Canada. However, they suggest that Canadian rates may be comparable to those reported in northwest England, where point prevalence is approximately 15% among men older than 40 years and 6% among women older than 40 years.
Indication and reimbursement request: 4% weight per weight (w/w) fluorouracil sodium cream has been approved by Health Canada for the topical treatment of actinic keratosis lesions of the face, ears, and/or scalp. The sponsor is seeking reimbursement for individuals with actinic keratosis lesions of the face, ears, and/or scalp.
Drug under review: 4% w/w fluorouracil sodium cream is a topical antineoplastic agent. It is available as a topical cream that is applied once daily for 4 weeks in an amount sufficient to cover the actinic keratosis lesions of the face, ears, and/or scalp with a thin film, as tolerated.
Treatment costs: At the submitted price of $40.00 per 40 g tube, the cost of 4% w/w fluorouracil sodium cream for an initial 4-week course of treatment of actinic keratosis lesions is expected to be $40 per patient.
Tailored review process: This application was reviewed through the tailored review process. When submitting an application for a tailored review, the sponsor does not claim added clinical benefit with the drug under review compared with the most appropriate comparators. A subcommittee of the relevant expert committee deliberates on the reimbursement request and, when there is unanimous agreement, issues the recommendation for tailored review applications. The focus of the subcommittee deliberations is on whether the evidence supports that the drug under review demonstrates comparable clinical benefit and harms to 1 or more appropriate comparators and whether the evidence supports the drug being reimbursed in accordance with the existing reimbursement criteria for the most appropriate comparators.
No patient group or clinician group input was received for this review.
The clinical expert consulted by CDA-AMC noted the following regarding unmet needs arising from the disease and the place in therapy for the drug under review:
Alternative topical treatment options, such as fluorouracil 5% cream and 5% imiquimod cream, may result in severe skin irritation in patients. Thus, patients may experience challenges adhering to the treatment. Cryotherapy and other forms of destructive therapy (such as curettage) may be inadequate and miss lesions.
4% w/w fluorouracil cream is expected to be an alternative to fluorouracil 5% cream and to be used in the first line for field treatment and first or second line for individual lesions.
The participating public drug programs raised potential implementation issues related to considerations for initiation and renewal of therapy.
The CDEC subcommittee recommends that 4% w/w fluorouracil sodium cream be reimbursed for the topical treatment of actinic keratosis lesions of the face, ears, and/or scalp only if the conditions listed in Table 1 are met.
Table 1: Reimbursement Conditions and Reasons
Reimbursement condition | Reason | Implementation guidance |
|---|---|---|
Initiation, renewal, discontinuation, and prescribing | ||
1. Eligibility for reimbursement of 4% w/w fluorouracil sodium cream should be similar to each public drug plan’s current criteria for fluorouracil 5% cream for the topical treatment of actinic keratosis of the face, ears, and/or scalp. This alignment should apply to all aspects of coverage, including initiation, renewal, discontinuation, and prescribing requirements. | Evidence from Study 48 showed that 4% w/w fluorouracil sodium cream was noninferior to fluorouracil 5% cream in achieving key clinical outcomes: 75% skin clearance and percent change from baseline in total lesion counts. The CDEC subcommittee considered 4% w/w fluorouracil sodium cream to have comparable clinical benefit to fluorouracil 5% cream. The CDEC subcommittee considered it appropriate to align the reimbursement conditions for 4% w/w fluorouracil sodium cream with current Canadian public drug plan reimbursement conditions for fluorouracil 5% cream. | 4% w/w fluorouracil sodium cream is an alternative treatment to fluorouracil 5% cream and is not intended as a second-line treatment after lack of response to fluorouracil 5% cream. |
Pricing | ||
2. The total cost of 4% w/w fluorouracil sodium cream should be negotiated so that it does not exceed the total cost of treatment with fluorouracil 5% cream for the same indication. | Based on the CDEC subcommittee’s assessment of the evidence, 4% w/w fluorouracil sodium cream is expected to have comparable clinical benefits and harms as fluorouracil 5% cream. Therefore, the total cost of 4% w/w fluorouracil sodium cream should not exceed that of fluorouracil 5% cream. | — |
CDEC = Canadian Drug Expert Committee; w/w = weight per weight.
The CDEC subcommittee deliberated on whether the evidence supports that 4% w/w fluorouracil sodium cream demonstrates comparable clinical benefit and harms to 1 or more appropriate comparators in patients with actinic keratosis lesions of the face, ears, and/or scalp. Based on the totality of the clinical evidence, the subcommittee concluded that 4% w/w fluorouracil sodium cream has acceptable clinical value because it demonstrates comparable clinical benefit and harms compared with fluorouracil 5% cream, which is considered the most relevant comparator.
Evidence from a pivotal phase III trial, Study 48, demonstrated that treatment for 4 weeks with 4% w/w fluorouracil sodium cream likely resulted in similar clinical benefit for patients with actinic keratosis lesions of the face, ears, and/or scalp compared with fluorouracil 5% cream, as measured by the proportion of patients achieving at least 75% clearance and the percent change from baseline in total lesion counts at 4 weeks off treatment. However, Study 48 did not demonstrate noninferiority of 4% w/w fluorouracil sodium cream for the primary end point of the proportion of patients achieving 100% clearance at 4 weeks off treatment. Due to the nature of actinic keratosis, the clinical expert consulted by CDA-AMC for this review noted that achieving at least 75% clearance is a more meaningful end point in clinical practice for evaluating the efficacy of 4% w/w fluorouracil sodium cream in the treatment of actinic keratosis lesions of the face, scalp, or ears than complete (100%) clearance. On this basis, it was concluded that 4% w/w fluorouracil sodium cream is likely comparable to fluorouracil 5% cream.
Moreover, evidence from another pivotal phase III trial, Study 49, demonstrated superiority of 4% w/w fluorouracil sodium cream over its vehicle for the primary end point and all secondary end points. For most weeks, the mean severity values for erythema, scaling and dryness, crusting, pruritus, stinging and burning, edema, and erosions were lower in the 4% w/w fluorouracil sodium cream group than in the fluorouracil 5% cream group. More patients in the fluorouracil 5% cream group (15%) discontinued treatment due to adverse events compared to those in the 4% w/w fluorouracil sodium cream group (10%). Therefore, 4% w/w fluorouracil sodium cream may address clinical expert–identified unmet needs related to patient adherence.
Overall, the observed safety profile is consistent with the product monograph and clinical expert input.
Further information on the subcommittee’s discussion around clinical value is provided in the Summary of Deliberation section.
The determination of acceptable clinical value was sufficient for the CDEC subcommittee to recommend reimbursement of 4% w/w fluorouracil sodium cream.
Because the CDEC subcommittee recommended that 4% w/w fluorouracil sodium cream be reimbursed, CDEC also deliberated on whether reimbursement conditions should be added to address important economic considerations, health system impacts, social and ethical considerations, or to ensure clinical value is realized. The resulting reimbursement conditions, with accompanying reasons and implementation guidance, are stated in Table 1.
The subcommittee considered all domains of value of the deliberative framework before developing its recommendation: clinical value, unmet clinical need, distinct social and ethical considerations, economic considerations, and impacts on health systems. For further information on the domains of value, refer to Expert Committee Deliberation at Canada’s Drug Agency.
The subcommittee considered the following key discussion points, organized by the 5 domains of value.
Appropriate comparators: The subcommittee considered fluorouracil 5% cream to be an appropriate comparator for the 4% w/w fluorouracil sodium cream.
Efficacy versus fluorouracil 5% cream: In one evaluator-blinded, multicentre, phase III, randomized controlled trial (Study 48), 4% w/w fluorouracil sodium cream did not demonstrate noninferiority for the primary end point of the proportion of patients achieving 100% clearance at 4 weeks off treatment. However, noninferiority was demonstrated for the secondary end points of the proportion of patients achieving at least 75% clearance and the percent change from baseline in total lesion counts at 4 weeks off treatment. Due to the nature of actinic keratosis, the clinical expert consulted by CDA-AMC for this review noted that achieving at least 75% clearance is a more meaningful end point in clinical practice for evaluating the efficacy of 4% w/w fluorouracil sodium cream in the treatment of actinic keratosis lesions of the face, ears, and/or scalp compared with complete (100%) clearance. On this basis, 4% w/w fluorouracil sodium cream is likely comparable to fluorouracil 5% cream. No notable safety concerns for 4% w/w fluorouracil sodium cream relative to fluorouracil 5% cream were identified.
Clinical importance of treatment effects: Input from patient and clinician groups was not received. Input from the clinical expert consulted by CDA-AMC highlighted that alternative topical treatment options, such as fluorouracil 5% cream and 5% imiquimod cream may result in severe skin irritation in patients. Thus, patients may experience challenges adhering to the treatment. Moreover, Study 48 did not demonstrate noninferiority of 4% w/w fluorouracil sodium cream for the primary end point of the proportion of patients achieving 100% clearance at 4 weeks off treatment. However, noninferiority was demonstrated for the secondary end points of the proportion of patients achieving at least 75% clearance and the percent change from baseline in total lesion counts at 4 weeks off treatment. The clinical expert indicated that the most clinically meaningful end point for evaluating the efficacy of 4% w/w fluorouracil sodium cream in the treatment of actinic keratosis is the proportion of patients achieving at least 75% clearance of actinic keratosis lesions. Complete (100%) clearance was considered a relatively subjective outcome because actinic keratosis lesions may be subtle, difficult to identify, or potentially missed. Although assessment of 75% clearance is subject to similar limitations regarding lesion identification, an approximate 75% clearance is considered clinically meaningful because it may account for lesions that are difficult to detect. Overall, the CDEC subcommittee concluded that the unmet need identified by the clinical expert was addressed and 4% w/w fluorouracil sodium cream is likely comparable to fluorouracil 5% cream.
Certainty of the evidence: The assessment of the proportion of participants in Study 48 with 100% clearance at 4 weeks off treatment with 4% w/w fluorouracil sodium cream was rated as moderate certainty (compared to fluorouracil 5% cream) using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach due to serious risk of imprecision. Likewise, the assessment of the proportion of participants in Study 48 with 75% clearance at 4 weeks off treatment was rated as moderate certainty (compared to fluorouracil 5% cream) due to serious risk of imprecision.
Clinical value: Based on the preceding considerations, the subcommittee determined that 4% w/w fluorouracil sodium cream has comparable or added clinical value compared with the most appropriate comparator (5% fluorouracil cream).
Input on unmet clinical need: The subcommittee did not note a significant unmet clinical need. However, they noted that 4% w/w fluorouracil sodium cream may have better tolerability for some patients, which may help patients complete the full course of treatment.
Deliberation on significant nonclinical need or health inequity: The subcommittee reviewed the considerations for unmet nonclinical need and health inequity. Given that deliberations for tailored reviews have a specific focus, further deliberation on whether the drug under review addresses a significant unmet nonclinical need or health inequity was not required.
Cost of 4% w/w fluorouracil sodium cream versus fluorouracil 5% cream: At the submitted price of $40.00 per 40 g tube, the cost of 4% w/w fluorouracil sodium cream for an initial 4-week course of treatment of actinic keratosis lesions is expected to be $40 per patient. Reimbursement of 4% w/w fluorouracil sodium cream may be associated with lower drug costs to the health care system versus 5% fluorouracil cream (incremental savings = $5 per initial 4-week course of treatment based on publicly available prices).
Anticipated budget impact: The sponsor estimates that the budget impact of reimbursing 4% w/w fluorouracil sodium cream for actinic keratosis will be a savings of approximately $262,000 over the first 3 years of reimbursement compared to the amount currently spent on 5% fluorouracil cream, with a predicted expenditure of $2 million on 4% w/w fluorouracil sodium cream over this period. CDA-AMC was unable to provide a more robust estimate of the expected budget impact owing to the extent of the uncertainty in several key parameters. Whether there will be cost savings to the public drug plans, the extent of any savings, and the expenditure on 4% w/w fluorouracil sodium is highly uncertain and will depend on the drug acquisition costs for 4% w/w fluorouracil sodium cream and comparators, the number of eligible patients, the uptake of fluorouracil 4% cream and its displacement of comparators, and the number of tubes prescribed.
To make its recommendation, the subcommittee considered the following information (links to the full documents for the review can be found on the project web page):
the CDA-AMC review of the clinical and pharmacoeconomic evidence submitted by the sponsor (refer to the Main Report and the Supplemental Material document)
the sponsor’s comments on the draft report and the CDA-AMC responses
input from public drug programs that participate in the reimbursement review process (refer to the Supplemental Material document)
input from 1 clinical expert with expertise in the management of actinic keratosis who was consulted by CDA-AMC.
Dr. Peter Jamieson (Chair), Dr. Kerry Mansell (Vice-Chair), Sally Bean, Daryl Bell, Dan Dunsky, Dr. Ran Goldman, Dr. Trudy Huyghebaert, Dr. Dennis Ko, Dr. Christine Leong, Dr. Alicia McCallum, Dr. Srinivas Murthy, Dr. Nicholas Myers, Dr. Krishnan Ramanathan, Dr. Marco Solmi, Carla Velastegui, Dr. Edward Xie, and Dr. Peter Zed.
A subcommittee composed of 5 CDEC members was convened. None had a conflict of interest that precluded their participation.
Meeting date: March 10, 2026
ISSN: 2563-6596
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