The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION. 18 January 2012

Transcription

1 The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 18 January 2012 EPIDUO, gel Tube of 30 g (CIP code: ) Tube of 60 g (CIP code: ) Applicant: GALDERMA Benzoyl peroxide Adapalene List I ATC code: D10AD53 Date of Marketing Authorisation: 23 January 2008 (decentralised procedure) Reason for request: Inclusion on the list of medicines refundable by National Health Insurance and approved for hospital use. Medical, Economic and Public Health Assessment Division 1/14

2 1 CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active ingredient Benzoyl peroxide 2.5% Adapalene 0.1% 1.2. Indication Cutaneous treatment of acne vulgaris when comedones, papules and pustules are present Dosage EPIDUO gel should be applied to the entire acne affected areas once a day in the evening on a clean and dry skin. A thin film of gel should be applied, with the fingertips, avoiding the eyes and lips. If irritation occurs, the patient should be directed to apply non-comedogenic moisturizers, to space out the applications of EPIDUO gel (e.g., every other day), to suspend use temporarily or to discontinue use completely. The duration of treatment should be determined by the doctor based on a clinical examination. The first signs of clinical improvement usually appear after 1 to 4 weeks of treatment. The safety and effectiveness of EPIDUO have not been studied in children below 12 years of age. 2/14

3 2 SIMILAR MEDICINAL PRODUCTS 2.1. ATC Classification (2011) D: Dermatologicals D10: Anti-acne preparations D10A: Anti-acne preparations for topical use D10AD: Retinoids for topical use in acne D10AD53: Adapalene combinations 2.2. Medicines in the same therapeutic category This is the only combination of adapalene and benzoyl peroxide. Proprietary medicinal products containing adapalene as their sole active ingredient are DIFFERINE cream and gel (moderate AB), and their generics. Proprietary medicinal products qualifying for reimbursement and containing benzoyl peroxide as their only active ingredient are the following: CUTACNYL gel 2.5%, 5% and 10% (moderate AB) ECLARAN gel 5% and 10% (moderate AB) PANNOGEL gel 5% and 10% (moderate AB) PANNOXYL gel 5% and 10% (moderate AB) 2.3. Medicines with a similar therapeutic aim The other anti-acne proprietary medicinal products for local administration are based on tretinoin alone or in combination with a local antibiotic, or local antibiotics alone. There are acne medicines for systemic administration, in particular cyclines, non-androgenic hormonal treatments, and isotretinoin. 3 USAGE DATA The product has been on the market since Until now there has been no application for its registration. According to IMS data (moving annual total August 2010), 119,000 prescriptions were issued for EPIDUO gel. In over 99% of cases the diagnosis was acne, and in 89% of cases the prescription was made out by a dermatologist. 3/14

4 4 ANALYSIS OF AVAILABLE DATA The company provided 7 clinical studies evaluating the efficacy and tolerance of EPIDUO gel, a fixed-dose combination of adapalene 0.1% and benzoyl peroxide 2.5%. - three studies comparing EPIDUO to each of the active ingredients taken separately and to placebo in moderate acne, - two studies comparing EPIDUO gel in combination with one cycline versus the same cycline on its own in moderate to severe or severe acne; - one study comparing EPIDUO gel versus placebo in maintenance treatment; - one 52-week non-comparative tolerance study Studies of EPIDUO gel versus each of its ingredients and versus placebo Study by Thiboutot 1 This was a multicentre, randomised, double-blind superiority study conducted in the United States; it compared the efficacy and tolerance of EPIDUO gel with adapalene 0.1% on its own, with benzoyl peroxide 2.5% (BP) on its own and with placebo applied once a day for 12 weeks. The inclusion and non-inclusion criteria relating to the severity of the acne were: - presence of 30 to 100 retentional lesions and 20 to 50 inflammatory lesions on the face. - severe forms of acne requiring treatment with isotretinoin were not included. Two co-primary efficacy endpoints were: - success rate defined as the percentage of patients with an IGA 2 score of 0 or 1. - percentage reduction in the number of total lesions (inflammatory + retentional + other) The superiority of EPIDUO gel for each of these criteria needed to be demonstrated for the study to be regarded as conclusive. Results: Number of patients included: 517 The mean age of the patients was 16 years. The acne was moderate (IGA = 3) in over 75% of the patients. The other patients mainly had mild forms of acne (between 10% and 19%, depending on the groups). In women, no information was given about possible contraception. At 12 weeks the results for the two co-criteria were as follows (see Table 1): - the success rate was higher among the patients treated with the EPIDUO gel fixed-dose combination (27.5%) than those receiving adapalene (15.5%; p = 0.008), BP (15.4%; p = 0.003) or placebo (9.9%; p = 0.002). - the median percentage reduction in the number of total lesions in relation to inclusion was higher with EPIDUO gel (-51.0%) than with adapalene (-35.4%; p < 0.001). BP (-35.6%; p < 0.001) and placebo (-31.0%; p < 0.001). 1 Thiboutot DM et al. Adapalene-benzoyl peroxide, a new fixed-dose combination for the treatment of acne vulgaris: results of a multicenter, randomized double-blind, controlled study. J Am Acad Dermatol 2007; 57: The IGA (Investigator Global Assessment) score is a 6-point scale from 0 to 5 (0 = Clear: residual hyperpigmentation and erythema may be present. 1 = Almost clear: a few scattered comedones and a few small papules. 2 = Mild: some comedones and some papules and pustules present. No nodules. 3 = Moderate: many comedones, papules and pustules present. One nodule may be present. 4 = Severe: covered with comedones, numerous papules and pustules and few nodules and cysts may be present. 5 = Very severe: highly inflammatory acne covering the face with nodules and cysts present). 4/14

5 Table 1: Results for the 2 primary criteria at week 12 (ITT) EPIDUO gel Adapalene BP Placebo Number of patients included: Number of drop-outs Success rate (%) p * Median reduction in the number of total lesions (%) * p vs EPIDUO gel p * - < < < Study by Gollnick 3 This was a multicentre, randomised, double-blind superiority study conducted in the United States, Canada and Poland; it compared the efficacy and tolerance of adapalene 1% - BP 2.5% combination with adapalene 0.1% on its own, with BP 2.5% on its own and with placebo, applied once a day for 12 weeks in moderate acne. Only cases of moderate acne were included (IGA 3); 30 to 100 retentional lesions and 20 to 50 inflammatory lesions on the face needed to be present. Three co-primary efficacy endpoints were envisaged: - success rate defined as the percentage of patients with an IGA score of 0 or 1; - percentage reduction in the number of inflammatory lesions; - percentage reduction in the number of non-inflammatory lesions. The superiority of EPIDUO gel needed to be demonstrated for all of these criteria for the study to be regarded as conclusive. Results: Number of patients included: 1670, of whom 1459 completed the study. The mean age of the patients was 19 years. The initial number of inflammatory lesions was 26 to 27 depending on the groups and the number of retentional lesions from 45 to 46. Oestroprogestogen contraception was in place in 5.3% of the total patients included, with no details regarding the type of pill. At week 12, a difference between the groups was observed for the three primary endpoints (see Table 2): - the success rate was higher in the patients treated with EPIDUO gel (37.9%) than with adapalene (21.8%), BP (26.7%) or placebo (17.9%) (p < 0.001). - The difference in terms of the median variation in the number of lesions was three inflammatory lesions and four non-inflammatory lesions between EPIDUO gel versus adapalene and two inflammatory lesions and five non-inflammatory lesions between EPIDUO gel versus BP. 3 Gollnick HP. Adapalene-benzoyl peroxide, a unique fixed-dose combination topical gel for the treatment of acne vulgaris: a transatlantic, randomized, double-blind, controlled study in 1670 patients. Br J Dermatol 2009; 161: /14

6 Table 2: Results for the three primary criteria at week 12 (ITT) EPIDUO gel Adapalene BP Placebo Number of patients Drop-outs Success rate (%) p * - < < < Median variation in the number of inflammatory lesions p * - < < < Median variation in the number of noninflammatory lesions p * - < < < * p for the comparison vs EPIDUO gel Study (unpublished) This was a multicentre, randomised, double-blind superiority study conducted in the United States, Canada and Puerto Rico; following the same protocol as the Gollnick, it compared the efficacy and tolerance of EPIDUO gel with adapalene 0.1% on its own, BP 2.5% on its own, and with placebo, applied once a day for 12 weeks in moderate acne. Only cases of moderate acne were included (IGA 3); 30 to 100 retentional lesions and 20 to 50 inflammatory lesions on the face needed to be present. Three co-primary efficacy endpoints were envisaged: - success rate defined as the percentage of patients with an IGA score of 0 or 1; - percentage reduction in the number of inflammatory lesions; - percentage reduction in the number of non-inflammatory lesions. The superiority of EPIDUO gel for each of these criteria needed to be demonstrated for the study to be regarded as conclusive. Results: Number of patients included: 1668, of whom 1429 completed the study. The mean age of the patients was 18 years. The number of inflammatory lesions was 27 in the four groups and the number of non-inflammatory lesions was 44 to 47 depending on the groups. Oestroprogestogen contraception was in place in 3.1% of the total patients included, with no details regarding the type of pill. At week 12, the results of study in moderate acne showed a difference between the groups for two of the three co-primary endpoints (see Table 3): - the success rate was significantly higher in the patients receiving EPIDUO gel (30.1%) than in those receiving adapalene (19.8%; p < 0.001), BP (22.2%; p = 0.006) or placebo (11.3%; p < 0.001). - the difference in terms of the median variation in the number of lesions was two inflammatory lesions and two non-inflammatory lesions versus adapalene and four non-inflammatory lesions versus BP on its own. - on the other hand, there was not shown to be any difference in the median variation in the number of inflammatory lesions versus BP on its own. 6/14

7 The superiority of EPIDUO gel with respect to BP in this study has therefore not been demonstrated. Table 3: Results for the three primary criteria at week 12 (ITT) EPIDUO gel Adapalene BP Placebo Number of patients Drop-outs Success rate 30.1% 19.8% 22.2% 11.3% p * - < < Median variation in the number of inflammatory lesions p * - < NS < Median variation in the number of noninflammatory lesions p * - < < < * p for the comparison vs EPIDUO gel Grouped results for the Thiboutot and Gollnick studies and Study The applicant has grouped together and reanalysed the results of the three studies described above, stratifying them into three sub-groups according to the number of total lesions. The aim was to show a difference in efficacy versus placebo depending on the number of initial lesions. This analysis is not described on account of its methodology Studies with EPIDUO gel combined with a cycline versus cycline on its own TEAM study 4 in combination with lymecycline (moderate to severe acne) This multicentre, randomised, double-blind superiority study assessed the efficacy and tolerance of EPIDUO gel in combination with lymecycline 300 mg versus placebo in combination with lymecycline 300 mg on its own, applied once daily for 12 weeks in the treatment of moderate to severe acne. The patients included had to have facial acne with an IGA score of 3 or 4. They also had to have at least 20 inflammatory lesions and between 30 and 120 retentional lesions. The primary efficacy endpoint was the median percentage reduction in the number of total lesions at week 12. The success rate was measured as one of the secondary endpoints (percentage of patients with an IGA score of 0 or 1). Results: Number of patients included: Gold LS. Adapalene-BPO Study Group. A North American study of adapalene-benzoyl peroxide combination gel in the treatment of acne. Cutis 2009; 84: /14

8 At inclusion, 83% of the patients had an IGA score of 3 (moderate acne), 17% of the patients had an IGA of 4 (severe acne). In women, no information was given about possible contraception. At 12 weeks, the median percentage reduction in the total lesions was -74% in the EPIDUO gel + lymecycline group versus -56% in the placebo + lymecycline arm (p < 0.001) (see Table 4). Table 4: Results for the primary endpoint (ITT) EPIDUO gel + lymecycline Placebo + lymecycline Number of patients included Median reduction in the number of total lesions (%) p < The success rate (secondary endpoint) was greater in the EPIDUO gel + lymecycline group (47.6%) than in the placebo + lymecycline group (33.7%) (p = 0.002) Access 1 Study in combination with doxycycline (severe acne) This multicentre, randomised, double-blind superiority study evaluated the efficacy and tolerance of EPIDUO gel fixed-dose combination with doxycycline 100 mg versus doxycycline 100 mg on its own, applied once daily for 12 weeks in the treatment of severe acne. The patients included had to have facial acne with an IGA score of 4. They also had to have at least 30 inflammatory lesions and a maximum of 120 non-inflammatory lesions. Among the inclusion criteria, women had to be taking effective birth control measures, but had to have stopped taking oestroprogestogen for the treatment of acne at least six months previously. The primary efficacy endpoint was the median percentage reduction in the number of total lesions at week 12. Among the secondary endpoints was the success rate defined as the percentage of patients having an IGA of 0 or 1 at week 12. Results: Number of patients included: 459 The mean age was 18 years On inclusion, the mean number of lesions was similar for total, inflammatory and retentional lesions. At 12 weeks, the median percentage reduction in the number of total lesions was greater under EPIDUO gel in combination with doxycycline (-64%) than under doxycycline on its own (-41%) (p < 0.001) (see Table 5). Table 5: Results for the primary criterion at week 12 (ITT) EPIDUO gel + doxycycline Placebo + doxycycline Number of patients included Median % reduction in the -64% -41% number of total lesions p < /14

9 The success rate (secondary endpoint) was greater in the EPIDUO gel + doxycycline group (31.5%) than in the placebo group (8.4%) (p < 0.001) Studies with EPIDUO gel in maintenance treatment Access 2 study in maintenance treatment This was a randomised double-blind study which over a 24-week period compared EPIDUO gel with placebo as maintenance treatment in patients with severe facial acne treated in the Access 1 study and whose improvement was judged good by investigators at the conclusion of the Access 1 study. The primary efficacy endpoint was the percentage of patients who maintained the efficacy obtained in terms of the number of total lesions at week 24. Maintained success was defined as maintaining at least 50% of the improvement obtained during the course of the treatment administered previously in terms of the number of total lesions. Maintenance of efficacy was also studied with inflammatory and non-inflammatory lesions. Among the inclusion criteria, women using oestroprogestogen contraception had to have started it at least 6 months previously. Results: Number of patients included: 459 Mean age: 18 years Patients on oestroprogestogen contraception: 5.1% On inclusion, half the patients (48.6%) were classed mild (IGA 2), 31.7% almost clear (IGA 1) and 19.3% moderate (IGA 3). After 24 weeks of maintenance treatment, maintenance of the success rate obtained during the preceding treatment in terms of the number of total lesions was superior in the case of patients treated with EPIDUO gel (78.9%) versus placebo (45.8%) (< ) (see Table 6). Table 6: Access 2 study: severity level and results for the primary endpoint after 24 weeks of maintenance treatment Adapalene BP Placebo Number of patients included % maintained success in terms of the number of total lesions 78.9% 45.8% p < Among the secondary endpoints, maintenance of the success rate at week 24 was also demonstrated in terms of the inflammatory lesions [78% versus 48% (p = )] and retentional lesions [78% versus 43% (p < )] in comparison with placebo Adverse effects Safety study (unpublished) The non-comparative study assessed the safety of EPIDUO gel applied once daily for 52 weeks. On inclusion the patients had to have facial acne with an IGA score of 3. They also had to have between 20 and 50 inflammatory lesions and between 30 and 100 retentional lesions. 9/14

10 Local tolerance was evaluated using a 4-point score for the following four signs: burns/dryness/redness/pruritus Information about general symptoms was also collected as well as performing routine biological tests. Results: The number of patients included that had received the treatment at least once was 452. No patients withdrew from the study for lack of efficacy, 2% withdrew on account of adverse events. The following side effects were common (> 1%): redness, erythema, peeling, cutaneous discomfort, pruritus, burning or irritation at the product application site and sunburn, most of them occurring during the first three months (84%). No serious adverse effects were identified. Category Patient with 1 treatmentrelated adverse effect Study period (months) 0 to 3 (N = 452) 3 to 6 (N = 397) 6 to 9 (N = 366) 9 to 12 (N = 334) 127 (28.1%) 16 (4.0%) 11 (3.0%) 5 (1.5%) Dermatological adverse effect 94 (20.8%) 8 (2.0%) 8 (2.2%) 4 (1.2%) Non-dermatological adverse effect 94 (20.8%) 8 (2.0%) 8 (2.2%) 4 (1.2%) Tolerance in efficacy studies During the course of the grouped tolerance analysis in the three studies (those by Thiboutot and by Gollnick, and study 18087), the proportion of patients presenting at least one adverse event regarded as treatment-related was greater with EPIDUO gel (21%) than with each of its ingredients on their own: adapalene (15%), BP (8.5%), or with placebo (6%). Most of these adverse events were of a dermatological nature (irritation, dry skin, etc.) and of mild to moderate intensity. For the most part they occurred at the start of the study. During the course of studies of moderate to severe acne in combination with a cycline, the safety profile between adapalene-bp and vehicle groups also included local adverse effects such as burning sensation and itching, occasionally severe (7% of the local effects reported in the Access 1 study), in the group treated with EPIDUO gel SPC In addition to the common cutaneous adverse effects reported in the studies, a change in the SPC of January 2011 refers to the possibility of allergic contact dermatitis and facial swelling whose frequency could not be determined in the absence of sufficient data. In the "Pregnancy" section of the SPC it states that due to the limited available data and because a weak cutaneous passage of adapalene is possible, EPIDUO gel should not be used during pregnancy. In case of unexpected pregnancy, treatment should be discontinued Conclusion In three studies, EPIDUO gel was compared with each of its active ingredients used on their own and with placebo in mild to moderate acne. Its efficacy was judged on several criteria: on the reduction in the number of lesions and success (percentage of patients with a score of 0 or 1 on a 6-point scale). Based on these criteria, the adapalene/bp combination proved superior in the three studies to adapalene and to placebo. The adapalene/bp combination 10/14

11 was superior to adapalene on its own and to placebo in the three studies and to BP in two studies (in the third study, EPIDUO gel was not superior to BP). In moderate to severe acne and in severe acne, EPIDUO gel/cycline proved superior to cycline alone in two studies as regards the reduction in the number of total lesions; -74.1% vs -56.8% (p < 0.001) with lymecycline and -64% vs -41% (p < 0.001) with doxycycline. The difference in efficacy between EPIDUO gel and each of its active ingredients is small. In the maintenance treatment of severe acne, EPIDUO gel over 24 weeks was superior to placebo in maintaining the success rate obtained with doxycycline as regards the number of total lesions (78.9% versus 45.8%); (p < ). As none of the studies compared the fixed-dose combination of EPIDUO gel with the two active ingredients applied separately, the synergy of the two active ingredients applied at the same time was not proven. There were more patients who had had at least one adverse event with EPIDUO gel than with the active ingredients used on their own: 21% with EPIDUO gel, 15% with adapalene, 8.5% with BP and 6% with placebo. Similarly, there were more treatment drop-outs in the EPIDUO gel group than in the groups using the ingredients on their own. Local cutaneous effects (irritation, sensation of burning, etc.) were more common. Cases of facial oedema were also reported (SPC). The fixed-dose combination of 2.5% benzoyl peroxide and 1% adapalene was not always suitable for the type of acne encountered, according to whether retentional or inflammatory lesions predominated. 11/14

12 5 TRANSPARENCY COMMITTEE CONCLUSIONS 5.1. Actual benefit Acne is not a serious disease, but its psychological impact can be considerable in its severe forms. These proprietary products fall under the category of symptomatic treatment. The efficacy of EPIDUO is moderate. Local adverse effects are common. The efficacy/adverse effects ratio of EPIDUO gel in this indication is moderate. These proprietary medicinal products are second-line therapies. They are not recommended during pregnancy. Alternatives are available. Public health benefit: Acne is a very common condition. This skin disease is as a rule benign, and though it can have repercussions for patients quality of life, its burden from a public health point of view is slight. The treatment of acne vulgaris does not represent a public health need and the therapeutic need is covered by existing treatments. In light of the clinical trial data, this proprietary medicinal product is not expected to have any impact on morbidity or on quality of life, including in comparison with the coadministration of the separately presented ingredients of the combination. It is not expected, therefore, that the proprietary medicinal product EPIDUO gel will have any public health benefit when used in the treatment of acne vulgaris. The actual benefit of EPIDUO gel is moderate Improvement in actual benefit (IAB) EPIDUO gel does not offer any improvement in actual benefit (IAB V) in comparison to the free combination of each of its active ingredients Therapeutic use Therapeutic strategy for acne 5 Proper hygeine is recommended in every case: - daily or twice-daily cleansing with soap-free hypoallergenic gels or cleansing bars; - daily application of a moisturiser suitable for problem skin. Drug treatment generally takes time, alternating between aggressive therapy (at least three months) and maintenance treatment. The approach to the treatment of minimal to moderate acne depends on its clinical presentation (with either retentional or inflammatory lesions predominating). The retentional component relies principally on topical treatment, while severe forms of acne require a specific therapeutic approach. 5 Afssaps. Topical and systemic treatment of acne. Good practice recommendations. November Publications/Recommendations/Medications 12/14

13 Predominantly retentional acne - 0.1% adapalene or 0.025% tretinoin, applied once daily Predominantly inflammatory acne (papulopustular acne) Localised form - first-line treatment: 5% benzoyl peroxide applied once daily; - in cases of benzoyl peroxide intolerance: either 0.1% adapalene applied once daily or a topical antibiotic (4% erythromycin or 1% clindamycin) combined with a topical retinoid (0.025% tretinoin or 0.1% adapalene (applied in the evening or alternating morning and evening). Extended and/or slow-developing form - first-line treatment: cyclines (doxycycline 100 mg/day or lymecycline 300 mg/day) orally ( 3 months of continuous treatment); - in case of contraindication to cyclines: erythromycin. It is recommended to combine topical treatment with systemic antibiotic therapy: benzoyl peroxide, or a topical retinoid, or a combination of the two. Combining a topical with systemic antibiotic therapy is not recommended. In the event of failed previous treatments: oral isotretinoin (0.5 mg/kg/day by way of an attack dose up to a cumulative dose of between 100 and 150 mg/kg) (see MA). In cases of contraindication, inefficacy or poor tolerance of other systemic treatments, zinc gluconate may be prescribed for mild to moderate inflammatory acne. Nodular acne and other severe forms - oral isotretinoin see SPC for warnings regarding treatment with isotretinoin Maintenance treatment - topical retinoids, in particular 0.1% adapalene, possibly in combination with oral zinc gluconate; - in women wishing to use contraception: non-androgenic hormone therapy Place of EPIDUO gel in the treatment strategy In localised forms of acne EPIDUO gel should be prescribed as a second-line treatment after the failure of an initial topical treatment. In extended forms, EPIDUO gel is recommended in combination with oral antibiotics, as is each of the two products used on its own. The choice between these strategies will depend on the characteristics of the lesions and on the prescriber s choice Target population The prevalence of acne in 12 to 20-year-old adolescents is estimated to be depending on the study 6,7 between 72% and 91%, regardless of the severity of the disease. In other words, there are between 5.0 and 5.7 million individuals aged from 12 to 20 years suffering from acne. 6 Ghodsi SZ et al. Prevalence, severity and severity risk factors of acne in high school pupils: a community-based study. J Invest Dermatol 2009; 129: Daniel F. Epidémiologie descriptive de l acné dans la population scolarisée en France métropolitaine pendant l automne Ann Dermatol Vénéréol 2000; 127: /14

14 Acne can also affect adults. According to an English publication, 8 12% of women and 3% of men over the age of 25 could have mild to moderate acne. Extrapolated to the French population, this would mean there are 1.8 million adults between the ages of 20 and 49 who are suffering from acne. In all, there are some 7 million people with acne Transparency Committee recommendations The transparency Committee recommends inclusion on the list of medicines refundable by National Health Insurance and on the list of medicines approved for hospital use and various public services in the indications and at the dosages given in the Marketing Authorisation Packaging: Appropriate for the prescription conditions Reimbursement rate: 30% 8 Goulden V, Stables GI, Cunliffe WJ. Prevalence of facial acne in adults. J Am Acad Dermatol 1999; 41: 4: /14