Opinion 26 June 2013

Transcription

1 The legally binding text is the original French version TRANSPARENCY COMMITTEE Opinion 26 June 2013 PICATO 150 µg/g, gel 3 tubes of 0.47 g (CIP: ) PICATO 500 µg/g, gel 2 tubes of 0.47 g (CIP: ) Applicant: LEO PHARMA INN ATC code (year) Reason for the request Lists concerned Indication concerned Ingenol mebutate D06BX02 (Chemotherapeutics for topical use) Inclusion National Health Insurance (French Social Security Code L ) Hospital use (French Public Health Code L ) PICATO is indicated for the cutaneous treatment of non-hyperkeratotic, non-hypertrophic actinic keratosis in adults. HAS - Medical, Economic and Public Health Assessment Division 1/19

2 Actual Benefit The actual benefit of PICATO in the Marketing Authorisation indication is moderate. Improvement in Actual Benefit In the absence of comparative data versus cryotherapy (the standard treatment) and versus medicinal products that treat multiple actinic keratoses close together, PICATO gel does not provide an improvement in actual benefit (IAB V, non-existent) in the treatment of discrete, clinically typical, non-hyperkeratotic, non-hypertrophic actinic keratosis. Therapeutic use Because of its short-term local adverse effects, the low level of evidence for its long-term efficacy in comparison with placebo, and the absence of any data versus comparators, this is a second-line treatment. PICATO will therefore be limited to multiple clinically typical, discrete, non-hypertrophic, non-hyperkeratotic actinic keratoses that are close together, where there is a contraindication to first-line treatments and primarily cryotherapy. In cases where an initial well-conducted treatment fails, there is no data available that could guide the prescriber s decision. HAS - Medical, Economic and Public Health Assessment Division 2/19

3 01 ADMINISTRATIVE AND REGULATORY INFORMATION Marketing Authorisation (procedure) Prescribing and dispensing conditions / special status 15 November 2012 (centralised procedure) European RMP List I ATC Classification 2012 D D06 D06B D06BX D06BX02 Dermatologicals Antibiotics and chemotherapeutics for dermatological use Chemotherapeutics for topical use Other chemotherapeutics Ingenol mebutate 02 BACKGROUND This is an application for a new ingenol mebutate (IM) based medicinal product to be included on the lists of medicines refundable by National Health Insurance and approved for hospital use. The mechanism of action is not fully understood but it may be cytotoxic and induce an inflammatory response. 03 THERAPEUTIC INDICATION PICATO is indicated for the cutaneous treatment of non-hyperkeratotic, non-hypertrophic actinic keratosis in adults. 04 DOSAGE Actinic keratosis on the face and scalp in adults One tube of PICATO 150 µg/g gel (containing 70 µg ingenol mebutate) should be applied once daily to the affected area for 3 consecutive days. Actinic keratosis on the trunk and extremities in adults One tube of PICATO 500 µg/g gel (containing 235 µg ingenol mebutate) should be applied once daily to the affected area for 2 consecutive days. Method of administration The content of one tube covers a treatment area of 25 cm² (e.g. 5 cm x 5 cm). The content of the tube should be applied to one treatment area of 25 cm². The tube is for single use only and should be discarded after use. The gel from the tube should be squeezed onto a fingertip and spread evenly over the entire treatment area, allowing it to dry for 15 minutes. The content of one tube should be used for one treatment area of 25 cm². HAS - Medical, Economic and Public Health Assessment Division 3/19

4 05 THERAPEUTIC NEED 1, 2, 3, 4, 5, 6, 7 The available therapies are cryotherapy (destruction with liquid nitrogen), electrocoagulation and curettage, dermabrasion, CO 2 laser treatment, topical cytostatic drugs (5-FU and imiquimod), topical diclofenac (not refundable for actinic keratosis) and photodynamic therapy using a sensitiser (methyl aminolevulinate hydrochloride or 5-aminolevulinic acid). The standard treatment is cryotherapy. This technique is currently used in dermatology, is rapid and does not require any specific equipment. However, its efficacy is operator dependent 8. Where there are multiple lesions close together in the same area, as an alternative to cryotherapy, a medicinal product may be used that allows the entire precancerous region to be treated: topical 5-FU, imiquimod, photodynamic therapy using a sensitiser (methyl aminolevulinate hydrochloride or 5-aminolevulinic acid), or possibly mechanical dermabrasion. The aim is to prevent the development of any new actinic keratosis lesions in this area. The choice of medicinal product depends on the severity of the lesions, their location, any contraindications and the prescriber s preference. CO 2 laser therapy or electrocoagulation and curettage may also be treatment options. 1 Dubertret et al. Thérapeutique dermatologique. Médecine Sciences Flamarion (2001) 2 Skin Cancer (PDQ ): Treatment Health Professional Version. National Cancer Institute (2006). 3 Saurat J.-H. et al. Dermatologie et infections sexuellement transmissibles (Éditions MASSON, 4 th edition) 4 De Berker D. et al. on behalf of the British Association of Dermatologists Therapy Guidelines and Audit Subcommittee. Guidelines for the management of actinic keratosis. British Journal of Dermatology 2007;156: Cox N.H. et al. on behalf of the British Association of Dermatologists Therapy Guidelines and Audit Subcommittee. Guidelines for management of Bowen s disease: 2006 update British Journal of Dermatology 2007;156: Morton C.A. et al. Guidelines for topical photodynamic therapy: report of a workshop of the British Photodermatology Group (British Association of Dermatologists). British Journal of Dermatology 2002;146: National Institute for Health and Clinical Excellence. Photodynamic therapy for non-melanoma skin tumours (including premalignant and primary non-metastatic skin lesions). Understanding NICE guidance information for people considering the procedure, and for the public. February Société Française de Dermatologie. Carcinome épidermoïde cutané (carcinome spinocellulaire) : recommandations de pratique clinique pour la prise en charge diagnostique et thérapeutique. Argumentaire - Mai Annales de dermatologie et de vénéréologie. 2009; 136: S189-S242. HAS - Medical, Economic and Public Health Assessment Division 4/19

5 06 CLINICALLY RELEVANT COMPARATORS 06.1 Medicinal products ALDARA NAME (INN) Company Imiquimod Meda Pharma EFUDIX 5-fluorouracil Meda Pharma METVIXIA Methyl aminolevulinate hydrochloride Galderma International Same PTC * Yes / No No (immunomodulator) No (chemotherapy) No (PDT) Indications Clinically typical, non-hypertrophic, nonhyperkeratotic AK of the face or scalp in immunocompetent adults, when the size or number of lesions limits the efficacy and/or safety of cryotherapy and if other topical treatments are either contraindicated or less appropriate. Pre-epitheliomatous keratosis. Treatment of fine or non-hyperkeratotic and non-pigmented AK of the face and scalp. MA (date) TC opinion (date) MA: extension of indication to AK 24/04/2007 TC opinion 26/11/2008 Most recent opinion 10/03/2010 Visa 19/10/1970 Most recent opinion 22/09/2010 MA 28/03/2007 TC opinion 28/03/2007 Actual benefit Substantial Improvement in Actual Benefit (Wording) IAB V in the treatment of superficial facial or scalp AK in adults, but does constitute an additional treatment resource. (26/11/2008) Refunded Yes/No Yes - Yes IAB V compared with cryotherapy in the treatment of fine or non-hyperkeratotic and non-pigmented AK of the face and scalp, but does constitute an additional treatment resource. Yes EFFALA 8 mg, medicated plaster 5-aminolevulinic acid Spirig Pharma No (PDT) Single-use device for the treatment of mild AK of the face and scalp (bald/hairless areas) with a maximum diameter of 1.8 cm. MA 15/02/2010 TC opinion 06/03/2013 IAB IV in terms of efficacy compared with cryotherapy. Yes PTC: pharmaco-therapeutic class PDT: photodynamic therapy AK: actinic keratosis HAS - Medical, Economic and Public Health Assessment Division 5/19

6 06.2 Other health technologies The other health technologies used in the treatment of actinic keratosis are cryotherapy (the standard treatment for actinic keratosis), CO 2 laser therapy, and electrocoagulation and curettage. Conclusion The most relevant comparators are cryotherapy, which remains the standard treatment for superficial actinic keratoses, and the various medicinal products (METVIXIA, EFFALA, ALDARA and EFUDIX). 07 INTERNATIONAL INFORMATION ON THE MEDICINAL PRODUCT The product is refunded in Ireland for the indication in the Marketing Authorisation. Applications for reimbursement have been made in the following countries since October 2012: Scotland, the UK, the Netherlands, Belgium, Sweden, Denmark and Germany. The procedure was still ongoing in January 2013, the date this application was submitted by the company. HAS - Medical, Economic and Public Health Assessment Division 6/19

7 08 ANALYSIS OF AVAILABLE DATA The company has provided seven studies: - four randomised, double-blind, placebo-controlled short-term studies (57 days), comprising two on the face and scalp and two on the trunk and extremities - three 12-month open-label studies - safety data from all these studies No study comparing PICATO to cryotherapy or to a medicinal product has been carried out. However, the company presented a face-to-face comparison with data for ALDARA used on the face and scalp. The patients in the seven studies presented were included between September 2008 and October Efficacy Actinic keratosis of the face and scalp 9 Two placebo-controlled pivotal studies were performed in actinic keratoses of the face and scalp with the concentration of 150 µg/g applied for three successive days. The protocol, which is identical for both studies, is presented below. Studies PEP and PEP Primary objective: Method: Study population: Main exclusion criteria: Study timeline: Primary efficacy endpoint: Secondary endpoints included: Statistical analysis: To evaluate the efficacy and safety at D57 of 3 days of treatment with IM 150 µg/g versus placebo Placebo-controlled, randomised, double-blind study Patients aged over 18 years with 4 to 8 typical, visible and discrete AK lesions on the face or scalp within a 25 cm² contiguous area Atypical lesions (hypertrophic, hyperkeratotic) or lesions within 5 cm of an incompletely healed wound or within 10 cm of a basal cell carcinoma or squamous cell carcinoma (SCC) Chronic local disease Recalcitrant disease after 2 sessions of cryotherapy or previous application of ingenol mebutate Cryotherapy within 2 cm of the area to be treated within 2 weeks prior to inclusion Systemic cytotoxic agent or immunosuppressant in the 4 previous weeks Application of 5-FU, imiquimod, diclofenac or photodynamic therapy within 2 cm of the area to be treated within 8 weeks prior to inclusion 3 days of treatment 57-day follow-up Safety evaluation on D4, D8, D15, D29 and D57 Number of patients with complete clearance of clinically visible AK lesions from the area treated at 57 days Partial clearance of lesions: 75% reduction in lesions on D57 in comparison with the initial number of lesions Safety: local cutaneous reactions and other adverse events Analysis of efficacy in the ITT population (Cochran-Mantel-Haenszel test) 9 Lebwohl M. Ingenol Mebutate Gel for Actinic Keratosis. N Engl Med. 2012; 366: HAS - Medical, Economic and Public Health Assessment Division 7/19

8 Results of study PEP : Number of patients included: 135 in the IM 150 group and 134 in the placebo group. Patients who completed the study: 121 in the IM 150 group and 125 in the placebo group. Mean age: 63 years in both groups. Phototypes I to IV on the Fitzpatrick scale (see Table 1 below). Location of lesions: 81% on the face and 19% on the scalp. Table 1: Phototypes according to the Fitzpatrick scale Phototype Minimum Colour of nonphotoexposed erythemainducing dose skin in MJ/cm² UV sensitivity Sunburn / Tanning I Pale white Very sensitive Always burns, never tans II White Very sensitive Usually burns, tans with difficulty III White to olive Sensitive Sometimes mild burn, tans lightly and uniformly (light brown) IV Light brown Moderately Rarely burns, tans with ease sensitive (moderate brown) V Dark brown Very slightly Very rarely burns (dark brown) VI Very dark brown/black sensitive Not sensitive or hardly sensitive at all Never burns (black) Table 2: Number of patients with complete clearance of lesions on D57 (primary efficacy endpoint) IM 150 Placebo p All locations Face Scalp 50/135 (37.0) 3/134 (2.2) < /109 (42.2) 3/109 (2.8) < /26 (15.4) 0/ Table 3: Number of patients with partial (>75%) clearance of lesions on D57 (secondary endpoint) All locations Face Scalp IM 150 Placebo p 81/135 (60.0) 9/134 (6.7) < /109 (68.8) 8/109 (7.3) < /26 (23.1) 1/25 (4.0) Results of study PEP : Number of patients included: 142 in the IM 150 group and 136 in the placebo group, all of whom at least received treatment. Patients who completed the study: 136 in the IM 500 group and 130 in the placebo group. Mean age: 64.9 years. Phototypes I to IV on the Fitzpatrick scale (see Table 1). Lesion sites equally distributed between the two groups: 79.9%% on the face and 20.1% on the scalp. HAS - Medical, Economic and Public Health Assessment Division 8/19

9 Table 4: Number of patients with complete clearance of lesions on D57 (primary efficacy endpoint) Face and scalp Face Scalp IM 150 Placebo p 67/142 (47.2) 7/136 (2.2) < /111 (52.3) 6/111 (5.4) < /31 (29.0) 1/25 (4.0) Table 5: Number of patients with partial (>75%) clearance of lesions on D57 (secondary endpoint) Face and scalp Face Scalp IM 150 Placebo p 96/142 (67.6) 11/136 (8.1) < /111 (73.9) 10/111 (9.0) < /31 (45.2) 1/25 (4.0) < In conclusion, IM at a concentration of 150 µg/g for 3 days was shown to be more effective than placebo in terms of the number of patients with complete clearance of actinic keratosis lesions at 57 days in the PEP study (37.0% for IM 150 versus 2.2% for placebo) and in the PEP study (47.2% for IM 150 versus 2.2% for placebo). Subgroup analysis according to lesion location confirmed that IM 150 was effective on actinic keratoses of the face in both studies and on actinic keratoses of the scalp in one study, but due to the small number of patients included, no conclusions could be drawn in the second study. This efficacy was also confirmed in terms of the number of patients with partial (>75%) clearance of the lesions (secondary endpoint) Actinic keratosis of the trunk and extremities 9 Two placebo-controlled pivotal studies were performed in actinic keratoses of the trunk and extremities with the concentration of 500 µg/g applied for two successive days. The protocol, which is identical for both studies, is presented below. HAS - Medical, Economic and Public Health Assessment Division 9/19

10 Studies PEP and PEP Primary objective: Method: Study population: Main exclusion criteria: Study timeline: Primary efficacy endpoint: Secondary endpoints included: Statistical analysis: To evaluate the efficacy and safety at D57 of 2 days of treatment with IM 500 µg/g versus placebo Placebo-controlled, randomised, double-blind study Patients aged over 18 years with 4 to 8 typical, visible and discrete AK lesions on the trunk or extremities within a 25 cm² contiguous area Atypical lesions (hypertrophic, hyperkeratotic) or lesions within 5 cm of an incompletely healed wound or within 10 cm of a basal cell carcinoma or squamous cell carcinoma (SCC) Chronic local disease Recalcitrant disease after 2 sessions of cryotherapy or previous application of ingenol mebutate Cryotherapy within 2 cm of the area to be treated within 2 weeks prior to inclusion Systemic cytotoxic agent or immunosuppressant in the 4 previous weeks Application of 5-FU, imiquimod, diclofenac or photodynamic therapy within 2 cm of the area to be treated within 8 weeks prior to inclusion 2 days of treatment 57-day follow-up Safety evaluation on D4, D8, D15, D29 and D57 Number of patients with complete clearance of clinically visible AK lesions from the area treated at 57 days Partial clearance of lesions: 75% reduction in lesions on D57 in comparison with the initial number of lesions Safety: local cutaneous reactions and other adverse events Analysis of efficacy in the ITT population (Cochran-Mantel-Haenszel test) Results of study PEP : Number of patients included: 126 in the IM 500 group and 129 in the placebo group. Patients who completed the study: 112 in the IM 500 group and 113 in the placebo group. Mean age: 67 years. Phototypes I to IV on the Fitzpatrick scale (see Table 1). Location of lesions: arms (65.1%), back of hands (21.2%), chest (6.7%), lower limbs (4.3%), shoulders (2.0%), back (2.0%). Table 6: Number of patients with complete clearance of lesions on D57 (primary efficacy endpoint) All locations Arm Back of hand Chest Other IM 500 Placebo p 35/126 (27.8) 6 /129 (4.7) < /84 (26.2) 4/82 (4.9) - 4/25 (16.0) 0/29-8/9 (88.9) 1/8 (12.5) - 1/8 (12.5) 1/10 (10) - HAS - Medical, Economic and Public Health Assessment Division 10/19

11 Table 7: Number of patients with partial (>75%) clearance of lesions on D57 (secondary endpoint) All locations Arm Back of hand Chest Other IM 500 Placebo p 56/126 (44.4) 9/129 (7.0) < /84 (47.6) 7/82 (8.5) - 6/25 (24.0) 0/29-8/9 (88.9) 1/8 (12.5) - 2/8 (25.0) 1/10 (10) - Results of study PEP : Number of patients included: 100 in the IM 500 group and 103 in the placebo group. Patients who completed the study: 90 in the IM 500 group and 95 in the placebo group. Mean age: 65 years. Phototypes I to IV on the Fitzpatrick scale (see Table 1). Location of lesions: arms (62.1%), back of hands (27.1%), chest (3.9%), lower limbs (3.9%), shoulders (1.5%), back (1.5%). Table 8: Number of patients with complete clearance of lesions on D57 (primary efficacy endpoint) All locations Arm Back of hand Chest Other IM Placebo p 42/100 (42.0) 5 /103 (4.9) < /59 (45.8) 3/67 (4.5) < /28 (21.4) 0/ /5 (60.0) 1/3 (33.3) NS 6/8 (75.0) 1/6 (16.7) NS Table 9: Number of patients with partial (>75%) clearance of lesions on D57 (secondary endpoint) All locations Arm Back of hand Chest Other IM Placebo p 55/100 (55) 7/103 (6.8) < /59 (61.0) 4/67 (5.9) < /28 (32.1) 1/27 (3.7) /5 (80.0) 1/3 (33.0) NS 6/8 (75.0) 1/6 (16.6) NS HAS - Medical, Economic and Public Health Assessment Division 11/19

12 In conclusion, IM at a concentration of 500 µg/g for two days was shown to be more effective in terms of the number of patients with complete clearance of actinic keratosis lesions at 57 days in the PEP study (27.8% for IM versus 4.7% for placebo) and in the PEP study (42.0% for IM versus 4.9% for placebo). Subgroup analysis according to lesion location confirmed that IM 500 was effective at complete clearance of actinic keratosis lesions situated on the arms and backs of the hand in one of the two studies. For other locations, the number of patients included was too low to draw any conclusions. The efficacy of IM 500 was shown to be superior to placebo on the number of patients with partial (>75%) clearance of lesions (secondary endpoint) for all lesions taken as a whole and for lesions located on the arms and backs of the hands month follow-up studies The company submitted three 12-month prospective observational follow-up studies. - Study PEP was the open-label follow-up of two double-blind, placebo-controlled studies (PEP and PEP ) on the face and scalp. - Study PEP was the open-label follow-up of two double-blind, placebo-controlled studies (PEP and PEP ) on the trunk and extremities. - Study PEP was an extension of an open-label safety study on the trunk and extremities (a study that was not included in the company s application). The patients included in these three follow-up studies had been monitored up to D57 and had complete clearance of actinic keratosis lesions on that date. Some of these patients had been treated with placebo and were a control group. During the follow-up between D57 and 12 months, the patients could be treated with cryotherapy for actinic keratosis. The primary efficacy endpoint in the three studies was the recurrence rate at 12 months. Recurrence was defined from the number of actinic keratoses (new or recurrent) in the area treated. They were analysed using the Kaplan-Meier method. The rate of new lesions (number of new lesions reported compared with the number of pre-existing lesions before treatment in the initial study) was also analysed. In addition, local tolerance was evaluated in the three studies at 12 months in patients who had received PICATO. The follow-up results for efficacy at 12 months are presented in the table below according to location of actinic keratosis and endpoint, in patients who received PICATO. Table 10: AK recurrence at 12 months in patients who received PICATO PEP PEP IM 150 IM 500 Face and scalp Trunk and n = 108 extremities Percentage of patients with AK lesions at 12 months (95% CI) Number of new lesions / number of lesions before treatment (%) 53.9% ( ) 69 / % n = % ( ) 13 / % PEP IM 500 Trunk and extremities n = 38 50% ( ) 19 / % HAS - Medical, Economic and Public Health Assessment Division 12/19

13 8.1.4 Quality of life results from pivotal studies Quality of life was examined in the four pivotal studies as a secondary endpoint. This was measured using the 16-item, self-administered Skindex-16 quality of life questionnaire, 10 which evaluates the emotional, symptomatic and functional dimensions of skin disease. In the PEP and PEP studies on the face and scalp, as well as in the PEP and PEP studies on the trunk and extremities, the impact of treatment on D8 was negative. On D29 and D57, a positive effect was observed for all three dimensions Adverse effects Safety results from clinical trials Monitoring of adverse effects During clinical development, 1,165 patients received PICATO. According to the SPC, the overall incidence of adverse events attributable to treatment was 29% on the face and scalp and 17% on the trunk and extremities. Also according to the SPC, the most common adverse effects were administration site conditions: pustules/vesicles, erosion, oedema, exfoliation, scabs, erythema and pain. Three cases of cancer or precancerous lesions that were possibly related to treatment were reported in phase I-II studies between D57 and 12 months. These were one case of Bowen s disease and two cases of squamous cell carcinoma. These three patients were treated with local surgery. No serious adverse effects occurred during the seven phase III studies. Short-term study of local tolerance In the four pivotal studies, local tolerance was analysed using the LSR score (secondary endpoint). The LSR (local skin response) score is defined as follows: six clinical criteria (erythema, oedema, desquamation, vesicles/pustules, scabs and erosion/ulceration) are scored between 0 and 4, then added together to obtain a composite overall local severity score that ranges from 0 to 24. In the four studies combined, 95% of patients who received IM had a modified LSR score, versus 36% of patients who received placebo. On the face and scalp, the LSR score peaked on D4 and then decreased, returning to baseline within two weeks. The mean peak score for patients treated with IM 150 was 9.1 ± 4.1 versus 1.8 ± 1.6 for patients on placebo. On the trunk and extremities, the LSR score in patients treated with IM 500 peaked: - on D3 for over half of patients (55.1%) - on D8 and D15 for 32.4% and 8.4% of patients respectively The mean peak LSR score for patients treated with IM was 6.8 ± 3.5 versus 1.6 ± 1.5 for patients on placebo. These local skin reactions resolved in an average of four weeks from the start of treatment. Safety results during 12-month studies No adverse effects attributable to treatment were reported in the 12-month studies (these studies started on D57 after application of PICATO and did not include the initial lesions). 10 Chren M.M. Measurement properties of Skindex-16: a brief quality-of-life measure for patients with skin diseases. J Cutan Med Surg 2001; 5: HAS - Medical, Economic and Public Health Assessment Division 13/19

14 8.2.2 Safety results from PSURs The product has been marketed in the USA since January Two PSURs were submitted concerning the use of PICATO between 23 January 2012 and 31 July During this period, no new signals were detected Perspectives from existing data Dosages and studies for comparator products The table below presents the main studies analysed in Transparency Committee opinions and establishing the efficacy of products in the actinic keratosis indication. HAS - Medical, Economic and Public Health Assessment Division 14/19

15 Comparison of dosages and studies presented in TC opinions for actinic keratosis NAME (INN) Company ALDARA Imiquimod Meda Pharma Indications Dosage Studies submitted Clinically typical, non-hypertrophic, nonhyperkeratotic AK of the face or scalp in immunocompetent adults, when the size or number of lesions limits the efficacy and/or safety of cryotherapy and if other topical treatments are either contraindicated or less appropriate. Apply 3 times a week for 4 weeks Follow-up period 4 weeks Repeat for 4 weeks if needed 2 randomised, double-blind, placebo-controlled studies in adult patients with AK of the head and neck, in 246 and 259 patients. Primary efficacy endpoint: % of patients with complete clearance of AK. Results: After 1 cycle (8 weeks): 26.8% versus 4.1% and 37.2% versus 0.8% After 2 cycles (16 weeks): 53.7% versus 14.6% and 55.0% versus 2.3% 1-year extension phase: Recurrence rate at 1 year after 1 or 2 cycles (secondary endpoint): 39% and 17.4% of patients EFUDIX 5-fluorouracil Meda Pharma Pre-epitheliomatous keratosis. 2 applications per day / 4 weeks 1 open-label, randomised study versus 5FU and cryotherapy / 75 patients Primary efficacy endpoint: quantitative change in silent p53 and p16 INK4A tumour markers 6 weeks after cryotherapy, 4 weeks after stopping 5FU and 8 weeks after stopping imiquimod Results: 74% of imiquimod patients, 36 5FU patients and 14 cryotherapy patients had a reduction in markers. Assessment prior to The studies are not available. METVIXIA Methyl aminolevulinate hydrochloride Galderma International Treatment of fine or non-hyperkeratotic and non-pigmented AK of the face and scalp. Apply for 3 hours before a session of photodynamic therapy Repeat after 3 months if needed 1 randomised, double-blind, placebo-controlled study on non-hyperkeratotic lesions of the face and neck % of patients with complete clearance at 3 months: 79% versus 21% 2 open-label non-inferiority studies versus cryotherapy: 1 session of PDT vs. double freeze-thaw: non-inferiority not demonstrated on the % of clearance of at least 75% of AK 2 PDT sessions vs. single freezing: non-inferiority demonstrated for percentage of response per patient, weighted by the number of initial lesions per patient EFFALA 8 mg, medicated plaster Single-use device for the treatment of mild AK of the face and scalp (bald/hairless areas) with a maximum diameter of 1.8 cm. Apply for 4 hours before the session of photodynamic therapy Repeat after 3 months if needed 1 phase IV randomised study of METVIXIA (1 or 2 sessions) vs. cryotherapy (1 or 2 sessions). Results: no difference in reduction of number of lesions after 6 months. 1 randomised, double-blind, placebo-controlled study in 103 patients over 3 months: % of lesions completely cleared: 82% vs. 19% (primary efficacy endpoint) % of patients with complete clearance of lesions: 62% vs. 6% (secondary endpoint) 1 open-label study vs. cryotherapy and vs. placebo in 346 patients over 3 months: % of lesions completely cleared: 89% on EFFALA vs. 77% on cryotherapy and 29% on placebo (primary efficacy endpoint) % of patients with complete clearance of lesions: 67% on EFFALA vs. 52% on cryotherapy vs. 12% on placebo (secondary endpoint) 12-month extension of both studies: superiority of EFFALA maintained and reduction in % of patients with no new lesions HAS - Medical, Economic and Public Health Assessment Division 15/19

16 8.3.2 Comparative data presented by the company In the absence of any comparative studies, the company selected the data from four randomised, double-blind studies in actinic keratosis of the face and scalp: two studies using PICATO and two using ALDARA. The results for the primary efficacy endpoint and the secondary endpoint of recurrence rate at 12 months were presented head-to-head. However, because of the lack of an indirect comparison meta-analysis, the different protocols for application, and the different times to measurement of the primary efficacy endpoint, no conclusions can be drawn from these results and they are not presented here Summary & discussion The efficacy of ingenol mebutate has been evaluated primarily in four randomised, double-blind, placebo-controlled studies, two on actinic keratoses of the face and scalp and two on actinic keratoses of the trunk or extremities. The patients were aged over 18 years and had four to eight typical, visible and discrete, nonhypertrophic and non-hyperkeratotic actinic keratosis lesions within a 25 cm² contiguous area. Ingenol mebutate 500 µg/g applied for two consecutive days to the trunk and extremities was superior to placebo on complete clearance of actinic keratosis lesions at 57 days in the first study (27.8% versus 4.7%) and in the second study (42.0% versus 4.9%). Ingenol mebutate 150 µg/g applied for three consecutive days to the face and scalp was superior to placebo on complete clearance of actinic keratosis lesions at 57 days in the first study (37.0% versus 2.2%) and in the second study (47.2% versus 2.2%). Three open-label observational studies evaluated the recurrence rate (at least one new actinic keratosis lesion in the area treated) at 12 months. The recurrence rate at 12 months was 53.9% ( ) on the face and scalp and 62.5% and 50.0% on the trunk and extremities. No conclusions as to the efficacy of PICATO can be drawn from these non-comparative studies which are limited to a 12-month period. No study has compared the efficacy of ingenol mebutate to cryotherapy, the standard treatment for actinic keratosis, nor to a medicinal product for actinic keratosis. The indirect comparison provided by the company between PICATO and ALDARA on actinic keratosis of the face and scalp cannot be taken into consideration for methodological reasons. No adverse events have been reported in the long term after application. HAS - Medical, Economic and Public Health Assessment Division 16/19

17 Safety at the application site was measured using an overall local severity score with six clinical criteria (erythema, oedema, desquamation, vesicles/pustules, scabs and erosion/ulceration) which ranges from 0 to 24 for the whole application surface: - On the face and scalp, the score peaked on D4 (9.1 ± 4.1 with PICATO versus 1.8 ± 1.6 with placebo) and then decreased to return to baseline within two weeks. - On the trunk and extremities, the score peaked (6.8 ± 3.5 with PICATO versus 1.6 ± 1.5 avec placebo) on D3 (55.1% of patients), D8 (32.4%) or D15 (8.4%) and the local effects resolved within approximately four weeks Planned studies In the RMP, the company has agreed to carry out two studies: - one study of repeated use of PICATO: study ongoing, results expected in one study of the risk of developing squamous cell carcinoma in the area treated by PICATO: protocol currently being drawn up, results expected in THERAPEUTIC USE Actinic keratosis is a skin condition associated primarily with exposure to ultraviolet rays (whether natural or artificial). The occurrence of these skin lesions can therefore be prevented by avoiding exposure to ultraviolet rays or other physical or chemical triggers (ionising radiation). The aim of treatment is to destroy the lesions; the patient must be followed up regularly after treatment to screen for any recurrence. The standard treatment is cryotherapy. This technique is currently used in dermatology, is rapid and does not require any specific equipment. However, its efficacy is operator dependent. 11 If there is any diagnostic doubt as to squamous cell carcinoma, a biopsy must be performed before cryotherapy with histological examination. Where there are multiple lesions close together in the same area, an alternative to cryotherapy may be used to prevent the occurrence of new lesions in this area: topical 5-FU, imiquimod, photodynamic therapy using a sensitiser (methyl aminolevulinate hydrochloride or 5-aminolevulinic acid), or possibly mechanical dermabrasion. The choice of medicinal product depends on the severity of the lesions, their location, any contraindications and the prescriber s preference. Because of the low level of evidence for its long-term efficacy in comparison with placebo, the lack of any data versus comparators, and the frequent appearance of lesions at the application site in the weeks following application, this is a second-line therapy. PICATO will therefore be limited to multiple clinically typical, discrete, non-hypertrophic, non-hyperkeratotic actinic keratoses that are close together, where there is a contraindication to first-line treatments and primarily to cryotherapy. In cases where an initial well-conducted treatment fails, there are no data available that could guide the prescriber s decision. 11 Société Française de Dermatologie. Carcinome épidermoïde cutané (carcinome spinocellulaire) : recommandations de pratique clinique pour la prise en charge diagnostique et thérapeutique. Argumentaire - Mai Annales de dermatologie et de vénéréologie. 2009; 136: S189-S242. HAS - Medical, Economic and Public Health Assessment Division 17/19

18 010 TRANSPARENCY COMMITTEE CONCLUSIONS In view of all the above information, and following the debate and vote, the Committee s opinion is as follows: Actual benefit Actinic keratoses are lesions occurring on areas exposed to the sun, most often in elderly persons. These lesions are frequently multiple and, in the absence of effective treatment, can develop into skin cancers (squamous cell carcinoma). This proprietary medicinal product is intended as curative therapy. The efficacy/adverse effects ratio is moderate, due to the poor demonstration of long-term efficacy and the very frequent adverse effects at the application site. There are several treatment alternatives: cryotherapy, METVIXIA, EFFALA, EFUDIX and ALDARA. PICATO is limited to multiple clinically typical, discrete, non-hypertrophic, non-hyperkeratotic actinic keratoses that are close together, where there is a contraindication to first-line treatments and primarily to cryotherapy. In cases where an initial well-conducted treatment fails, there are no data available that could guide the prescriber s decision. Public health benefit: In public health terms, although the condition is fairly common, actinic keratosis represents only a small burden inasmuch as the condition has a good prognosis. Improving the management of actinic keratosis does not constitute a public health need (there are effective non-medicinal alternatives for preventing the onset of cancer). In cases of multiple actinic keratoses, this treatment alternative could be beneficial. In light of the clinical trial data and given the existing treatment alternatives, no impact is expected in terms of morbidity for patients with keratosis. Consequently, in view of the available data and the existence of non-medicinal alternatives, the proprietary medicinal product PICATO is not expected to offer any public health benefit in this indication. Taking account of these points, the Committee considers that the actual benefit of PICATO gel is moderate in the treatment of discrete, clinically typical, non-hypertrophic, nonhyperkeratotic actinic keratosis. Due to its short-term local adverse effects and the low level of evidence of its long-term efficacy, it should only be used where first-line treatments, primarily cryotherapy, have failed or are contraindicated. The Committee recommends inclusion of PICATO on the list of medicines refundable by National Health Insurance and on the list of medicines approved for hospital use in this indication. Proposed reimbursement rate: 30% HAS - Medical, Economic and Public Health Assessment Division 18/19

19 010.2 Improvement in actual benefit (IAB) In the absence of comparative data versus cryotherapy (the standard treatment) and versus medicinal products that treat multiple actinic keratoses that are close together, PICATO gel does not provide an improvement in actual benefit (IAB V, non-existent) in the treatment of discrete, clinically typical, non-hyperkeratotic, non-hypertrophic actinic keratosis Target population The target population of PICATO is defined as patients with actinic keratosis in whom other treatments, primarily cryotherapy, have failed or are contraindicated. There are few epidemiological data on actinic keratosis. Data from the United Kingdom 12,13 and Ireland 14 have shown a prevalence of actinic keratosis in the order of 19% to 24% in the over 60s. In the Irish study, the prevalence in those over 21 years of age was estimated to be 13.6% in men and 7.6% in women. Extrapolating these values to the French population (INED 2012 data), the population of individuals with actinic keratosis may be estimated at between 3 and 5 million. Within this population, only patients who cannot be treated with cryotherapy (which remains the standard treatment), or with alternative medicinal products for the treatment of multiple lesions that are close together, are eligible for PICATO. This undoubtedly limited population is not quantifiable. 011 TRANSPARENCY COMMITTEE RECOMMENDATIONS Packaging This is appropriate for the prescription conditions in terms of indication, dosage and treatment duration. 12 Harvey I, Frankel S, Marks R et al. Non-melanoma skin cancer and solar keratosis. 1. Method and descriptive results of the South Wales skin cancer study. Br J Cancer 1996; 74: Memon AA, Tomenson JA, Bothwell J, Friedman PS. Prevalence of solar damage and actinic keratosis in a Merseyside population. Br J Dermatol 2000; 142: O Beirn SFO, Judge P, Maccon CF. Skin cancer in County Galway, Ireland. In: Proceedings of Sixth National Cancer Conference, sponsored by the American Cancer Society Inc. And the National Cancer Institute, September Philadelphia: Lippincott, 1970: HAS - Medical, Economic and Public Health Assessment Division 19/19