TRANSPARENCY COMMITTEE OPINION. 26 April 2006

Transcription

1 TRANSPARENCY COMMITTEE OPINION 26 April 2006 REMICADE 100 mg powder for concentrate for solution for infusion Box of 1 (CIP code: ) Applicant : laboratoires Schering Plough List I Drug for hospital use only. Date of marketing authorisation (AMM): 13 August 1999 Date indication extended: 29 September 2005 (indication extended) Reason for request: inclusion on list of drugs for hospital use in new indications (rheumatoid arthritis in patients not previously treated with methotrexate, psoriasis and psoriatic arthritis). Health Technology Assessment Division 1

2 1 CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active ingredient 1.2. Background is a monoclonal antibody directed against TNF-alpha Indications Changes to the text for the indication of rheumatoid arthritis Rheumatoid arthritis Remicade, in combination with methotrexate, is indicated for: The reduction of signs and symptoms as well as improvement in physical function in: patients with active disease when the response to disease-modifying drugs, including methotrexate, has been inadequate. Patients with severe, active and progressive disease not previously treated with methotrexate or other DMARDs. In these patient populations, a reduction in the rate of joint progression, as measured by X- ray, has been demonstrated. New indications subject to the application Psoriatic arthritis In combination with methotrexate, Remicade is indicated for: treatment of active and progressive psoriatic arthritis in patients who have responded inadequately to DMARDs. Psoriasis Remicade is indicated for: treatment of moderate to severe plaque psoriasis in adults who failed to respond to, or who have a contraindication for, or are intolerant to other systemic therapy including cyclosporine, methotrexate or PUVA. Indications prior to the application Crohn s disease Remicade is indicated for: treatment of severe, active Crohn s disease in patients who have not responded despite a full and adequate course of therapy with a corticosteroid and an immunosuppressive agent; or who are intolerant to or have medical contraindications for such therapies. treatment of fistulising, active Crohn s disease, in patients who have not responded despite a full and adequate course of therapy with conventional treatment (including antibiotics, drainage and immunosuppressive therapy). Ankylosing spondylitis Remicade is indicated for: treatment of ankylosing spondylitis in patients who have severe axial symptoms, elevated serological markers of inflammatory activity and who have responded inadequately to conventional therapy. 2

3 1.4. Dosage Rheumatoid arthritis 3 mg/kg given as an intravenous infusion over a 2-hour period followed by additional 3 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. Remicade must be given concomitantly with methotrexate. Available data suggest that the clinical response is usually achieved within 12 weeks of treatment. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within this time period. Psoriatic arthritis 5 mg/kg given as an intravenous infusion over a 2-hour period followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. Efficacy and safety have been demonstrated in combination with methotrexate. Psoriasis 5 mg/kg given as an intravenous infusion over a 2-hour period followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. If a patient shows no response after 14 weeks (i.e. after 4 doses), no additional treatment with infliximab should be given. Indications prior to the application: see SPC 2 SIMILAR MEDICINAL PRODUCTS 2.1. ATC classification (2005) L : Antineoplastic and immunomodulating agents 04 : Immunosuppressive agents A : Immunosuppressive agents A : Selective immunosuppressive agents 12 : Rheumatoid arthritis Medicines in the same therapeutic category Comparator medicines are selective immunosuppressive agents indicated for the treatment of rheumatoid arthritis in adults. TNFα inhibitors: Enbrel (etanercept) Humira (adalimumab) Interleukin-1 receptor antagonist: Kineret (anakinra) Medicines with a similar therapeutic aim Disease-modifying treatments for rheumatoid arthritis with medicinal products containing methotrexate, sulfasalazine, leflunomide, hydroxychloroquine, gold salts, azathioprine, D- penicillamine and tiopronine. 3

4 Psoriatic arthritis Medicines in the same therapeutic category Comparator medecines Enbrel (etanercept) Humira (adalimumab) MedIcines with a similar therapeutic aim Disease-modifying treatments for psoriatic arthritis: leflunomide and methotrexate; in practice other disease-modifying treatments without marketing authorisation in this indication are used, particularly sulfasalazine. Psoriasis Medicines in the same therapeutic category Enbrel (etanercept) Raptiva (efalizumab) Medicines with a similar therapeutic aim Local treatments Local treatment indicated for topical treatment of psoriasis: keratolytic agents (containing salicylic acid), potent corticosteroids for topical application, vitamin D analogues and vitamin A derivatives. Systemic treatments Soriatane (acitretine), Neoral and Sandimunn (cyclosporine), Novatrex 2.5 mg tablet Methotrexate Bellon (methotrexate) Other therapeutic procedures Photochemotherapy or PUVA (in combination with photosensitising agents) UVB phototherapy. 3 ANALYSIS OF AVAILABLE DATA 3.1. Efficacy and safety Rheumatoid arthritis in patients not previously treated with methotrexate ASPIRE trial 1 A 54-week, randomized, placebo-controlled, double-blind, phase III trial to assess the efficacy and safety of the combination Remicade + methotrexate versus methotrexate alone in 1004 methotrexate naive patients with early, active rheumatoid arthritis ( 3 years disease duration). Inclusion criteria: patients aged from 18 to 75 years 12 tender joints 10 swollen joints positive rheumatoid factor no previous treatment with MTX 2 or TNF inhibitors no DMARDs 3 for at least 4 weeks before entry into the trial. 1 St Clair EW. Combination of and Methotrexate therapy for early Rheumatoid arthritis. Arthritis & Rheumatism 2004; 50: MTX = methotrexate 3 Disease Modifying Anti-Rheumatic Drugs 4

5 At randomisation into 3 groups all patients received methotrexate and either placebo, 3 mg/kg (the posology in the marketing authorisation) or 6 mg/kg Remicade at weeks 0, 2 and 6 and every 8 weeks thereafter. Methotrexate was initiated at the 7.5 mg/week dose at week 0 and the dose was increased progressively by 2.5 mg every 1 to 2 weeks to reach 15 mg/week at week 4 and 20 mg/week at week 8. Concurrent use of stable doses of folic acid (5 mg/week), oral corticosteroids ( 10 mg/day) and/or NSAIDs was permitted. Concomitant administration of other disease-modifying treatments was not allowed during the trial. NB: Concomitant use of folic acid may cause reduced methotrexate efficacy. No data are available on the mean posology of methotrexate used and on the number of patients in each group treated with folic acid. Primary endpoints Percentage improvement in ACR 4 -N response at week 54. The prevention of structural joint damage as measured by change from baseline in total van der Heijde modified Sharp score 5 at week 54 HAQ 6 Results for efficacy Patient characteristics at baseline MTX + placebo n =282 MTX + 3 mg/kg n = 359 MTX + 6 mg/kg n = 363 Mean age (years) 50±13 51±12 50±13 Duration of RA (years) 0.9± ± ±0.8 % patients not previously treated with disease-modifying treatment % corticosteroids Swollen joint count (0-66) 22±11 21±10 22±11 Tender joint count (0-66) 34±15 32±15 33±15 Response at week 54 MTX + placebo n =282 MTX + 3 mg/kg n = 359 MTX + 6 mg/kg n = 363 ACR 20 (%) ACR 50 (%) ACR 70 (%) Mean change in total modified Sharp score 3.7 ± ± ± 5.6 After 54 weeks of treatment a statistically significant difference was observed in the groups treated with infliximab plus methotrexate compared to methotrexate alone measured by the 4 ACR (American College of Rheumatology) score assesses the patients response to treatment including joint swelling and tenderness, self assessment of pain, overall self and physician assessment, level of disability and an objective marker of inflammation. 5 A radiological scoring method used to assess structural joint damage. A one unit increase in TSS marks the appearance of erosion in a joint. A 7-point increase indicates almost total joint destruction. 6 HAQ = Health Assessment Questionnaire. The higher the scores are the less disabled the patient. 5

6 proportion of patients achieving ACR 20, 50 and 70 responses and by their mean change in total modified Sharp score at week 54 (p<0.001). A significant difference in HAQ was seen in the groups treated with Remicade 3 mg/kg and 6 mg/kg compared to the group treated with methotrexate alone (p<0.003 and p<0.004 respectively). Results for safety treatment was relatively well tolerated. There were no reports of undesirable effects not mentioned in the SPC. The most common undesirable effects were upper respiratory infections (8.5% on infliximab versus 5.8% on placebo). The incidence of pneumonia was 2% on infliximab versus 0% on placebo Psoriatic arthritis The development plan of Remicade in this indication is based on three clinical trials: an open label trial 7 which is not discussed in detail because it is methodologically weak (low number (10 patients), not comparative) a pivotal trial which was used as the basis of the marketing authorisation application (IMPACT) a larger scale trial whose aim was to confirm the results of the IMPACT trial (IMPACT II). IMPACT trial (C. Antoni et al 2005) 8 A 50-week, placebo-controlled, double-blind, randomised trial to evaluate efficacy and safety of infliximab in 104 patients with polyarticular psoriatic arthritis, who have had an inadequate response to at least one DMARD. Inclusion criteria active psoriatic arthritis characterised by both swollen joint and tender joint counts 5 failure after at least one DMARD This trial was performed in two phases: in phase 1, lasting 16 weeks and conducted double-blind, patients received either 5 mg/kg infliximab (n=52) or placebo (n=52) in weeks 0, 2, 6 and 14. in phase 2, lasting 34 weeks (week 16 to 50), the patients initially on placebo were switched to 5 mg/kg infliximab in weeks 16, 18, 22, 30, 38 and 46 and patients in the infliximab group received placebo in weeks 16 and 18, then 5 mg/kg infliximab in weeks 22, 30, 38 and 46. All patients who initially received MTX continued to take it throughout the trial. It should be noted that taking MTX and corticosteroids was more common in the placebo group. Primary efficacy endpoint: ACR 20 response at week 16 Secondary endpoints ACR 50/70, tender and swollen joint count, PASI 9, HAQ 10, DAS 28 11, PsARC 12, VAS, CRP, ESR, enthesopathy, dactylitis. 7 Antoni et al. Open label study of infliximab treatment for psoriatic arthritis: Clinical and Magnetic resonance Imaging Measurements of reduction of inflammation. Arthritis & Rheumatism 2002:47: Antoni et al. Sustained Benefits of infliximab therapy for dermatologic and articular manifestations of Psoriatic Arthritis. Arthritis & Rheumatism 2005;52: PASI (Psoriasis Area Severity Index) assesses erythema, induration, desquamation and body surface area affected. It ranges from 0 (clear) to 72 (maximum severity). However the score is only of value in cases where at least 3% of body surface is affected as it is a composite measure of erythema, induration and area. A PASI 50 response indicates at least a 50% reduction in initial PASI score. 10 Health Quality Assessment. A reduction of 0.22 is considered the clinically meaningful minimum change. 11 The Disease Activity Score (DAS28) is calculated on 28 joints and assesses tender joint count, swollen joint count 6

7 Results for safety ITT analysis Patient characteristics at baseline Placebo n =52 5 mg/kg n = 52 Mean age (years) 45.2 ± ± 11.1 Patients who had used MTX 65.4% 46.2% Patients who had used DMARDs other than MTX 13.5% 17.3% Patients who had used NSAIDs 88.5% 78.8% Patients who had used corticosteroids 17.3% 28.8% Duration of psoriatic arthritis (years) 11 ± ± 9.8 Duration of psoriasis (years) 19.4 ± ± 10.9 Number of swollen joints 14.6 ± ± 8.2 HAQ 1.2 ± ± 0.7 Primary endpoint: The proportion of patients achieving ACR 20 response at week 16 was higher in the group treated with infliximab (34/52, 65.4%) than in the placebo group (5/52, 9.6%) (p<0.001). Secondary endpoints: A significant difference in favour of the Remicade group became apparent in all the secondary endpoints compared to placebo (p<0.001). Response at week 16* Placebo n =52 5 mg/kg n = 52 ACR 50 n (%) 0 (0) 24 (46.2) ACR 70 n (%) 0 ( 0) 15 (28.8) Change in tender joint count (%) -23.6± ± 9.7 Change in swollen joint count (%) -1.8± ± 9.1 Change in CRP (%) 3.6± ± 9.5 Change in HAQ (%) -1.6± ± 8.2 PsARC n (%) -11 (21) 39 (75) *negative values indicate deterioration from baseline. Results for safety The incidence of undesirable effects was 65% in the placebo group and 73% in the infliximab group. IMPACT 2 trial (Antoni et al ) A 24-week, placebo-controlled, double-blind, randomized trial to assess efficacy and safety of infliximab (5 mg/kg at weeks 0, 2, 6 then every 8 weeks) in 200 patients with psoriatic arthritis. Inclusion criteria Active psoriatic arthritis characterised by both swollen joint and tender joint counts 5 and self assessment of pain. The disease is very active if the score is > 5.1 and inactive if the score is less < PsARC (Psoriatic Arthritis Response Criteria) measures improvement or worsening of the disease based on 4 parameters (overall self and physician assessment, the sum of tender joint scores in 78 joints and the sum of swollen joint scores in 76 joints) 13 Antoni et al. improves signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trial. Ann Rhum Dis 2005; 64:

8 Failure of one DMARD and of NSAIDs Primary efficacy endpoint: ACR 20 response at week 14 Secondary endpoints assessed at weeks 2, 6, 14 and 24: ACR 50, 70, dactylitis in feet and hands, enthesopathy in the feet, PASI 50, 75 and 90 assessed in patients with an affected body surface area greater than 3% (or 85% of patients), tender joint count, swollen joint count, PsARC, HAQ, CRP, overall pain, overall self and physician assessment, SF36, duration of morning stiffness. Results for efficacy Patient characteristics at baseline Placebo n =100 5 mg/kg n = 100 Mean age (years) 46.5 ± ± 12.8 % patients who had used MTX 45% 47% Duration of psoriatic arthritis (years) 7.5 ± ± 7.2 Swollen joint count 14.4 ± ± 7.9 Tender joint count 25.1 ± ± 14.1 HAQ 1.1 ± ± 0.6 Primary endpoint: The proportion of patients achieving ACR20 was higher in the Remicade group than in the placebo group (58% versus 11%, p<0.001). The results were maintained at week 24. Secondary endpoints: A significant difference in favour of Remicade was apparent in all secondary endpoints at week 14 and week 24. Response at weeks 14 and 24* Week 14 Week 24 REMICADE () Placebo P REMICADE () Placebo p ACR 50 response (%) 36 3 < <0.001 ACR 70 response (%) 15 1 < <0.001 PsARC (%) < <0.001 Patients with at least 75% improvement in PASI (%) Change in tender joint count (%) Change in swollen joint count (%) 64 2 < < ± ±78.7 < ± ±36.5 < ± ± 68.9 < ± ±39.8 <0.001 Change in CRP (%) 33.8 ± ±64 < ± ±55 <0.001 Change in HAQ (%) 48.6± ± 90.5 < ± ± <0.001 *negative values indicate deterioration from baseline. SF36 and HAQ criteria were also significantly improved in the infliximab group compared to the placebo group at weeks 14 and 24. Results for safety The incidence of undesirable effects was comparable in the two groups (infections: 10% on 8

9 infliximab versus 14% on placebo; infusion reactions: 7% on infliximab versus 6% on placebo). Indirect comparison: The pharmaceutical company suggested that these results should be compared with those obtained in clinical trials performed on other TNF inhibitors. However, such an indirect comparison is not possible as no data are available on: the comparability of the populations the comprehensiveness of the trials included concomitant treatments Psoriasis Three placebo-controlled, randomized, double-blind trials tested the efficacy and safety of infliximab in the treatment of psoriasis. The EXPRESS trial included an induction and a maintenance phase, whereas the CHAUDHARI and SPIRIT trials tested infliximab as induction treatment only. CHAUDHARI (2001) 14 A total of 33 patients with moderate-to-severe plaque psoriasis received either infliximab 5mg/kg (n=11) or 10 mg/kg (n=11) or placebo (n=11) at weeks 0, 2 and 6. Inclusion criteria: moderate-to-severe plaque psoriasis, disease duration 6 months, at least 5% of total body surface area affected, failure of topical corticosteroids. Primary endpoint: PGA (Physician Global Assessment score) at week 10. Results for efficacy and safety The proportion of patients achieving a good or excellent PGA score at week 10 was significantly higher in the infliximab 5 mg/kg (9/11) and infliximab 10 mg/kg (10/11) groups than in the placebo group (2/11). The safety of infliximab was shown to be satisfactory in this trial. SPIRIT trial (Gottlieb et al. 2004) 15 A total of 249 patients with severe plaque psoriasis who had previously been treated with PUVA or other systemic psoriasis treatments were included in this phase II, 26-week trial. The patients received either infliximab 3 mg/kg (n=99) or 5 mg/kg (n=99) or placebo (n=51) as induction treatment at weeks 0, 2 and 6. Patients who scored >3 on the physician global assessment score received an additional infusion of their assigned study treatment at week 26 (the same as the one received previously). Inclusion criteria patients aged over 18 years moderate-to-severe plaque psoriasis (baseline PASI score of 12 and at least 10% of body surface area affected) previous PUVA or systemic treatment 14 Chaudhari. et al. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet 2001;357: Gottlieb et al. induction therapy for patients with severe plaque-type psoriasis: a randomized, doubleblind, placebo-controlled trial. J Am Acad Dermatol 2004;51:

10 disease duration 6 months. Primary endpoint: proportion of patients achieving PASI at week 10. Secondary endpoints: number of PASI 75 responders at week 26 safety - proportion of patients with positive antibodies to infliximab - proportion of patients with infusion-related allergic reactions at week 26 - proportion of antibody positive patients with infusion-related allergic reactions at week 26. Results for efficacy Patient characteristics at baseline Placebo n=51 3 mg/kg n=99 5 mg/kg n=99 Mean age Duration of psoriasis (years) % total body surface area Psoriatic arthritis n, (%) 17 (33.3) 32 (32.3) 29 (29.3) PASI score DLQI (Dermatology Life Quality Index) Primary endpoint: A higher percentage of patients achieved PASI 75 at 10 treatment weeks on infliximab 3 mg/kg (72%) and 5 mg/kg (88%) than on placebo (6%), p< Secondary endpoints: PASI 75 responders at week 26 Placebo 3mg/kg PASI 75 responders at week 26 4/42 (9.5%) 12/87 (13.8%) (NS) 5 mg/kg 27/90 (30%) p= 0.01 Assessment of retreatment at week patients (PGA 3) were retreated with a single infusion of their assigned initial treatment at week 26. The efficacy of retreatment was assessed after 4 weeks at week 30. Placebo 3mg/kg 5 mg/kg Proportion of PASI responders 2/11 (18.2%) 12/52 (23.1%) 17/50 (34.0%) PASI score A single administration of an additional 3 mg/kg dose of infliximab to patients with a PGA score <3 failed to show an efficacy superior to that of placebo.. 16 The Psoriasis Area Severity Index is a score ranging from 0 (clear) to 72 (max, severity).it is a composite measure of body surface area affected (from 0 to 100%) and severity. Plaques are graded by 3 criteria, thickness, redness and scaliness on a scale from 0 to 4 according to severity on a body surface area divided into 4 regions comprising the head, lower extremities, upper extremities and trunk. There is no consensus about how the various degrees of severity are defined. Scores of PASI 75 or PASI 90 are equivalent to a reduction in PASI score by at least 75% or of at least 90% respectively between 2 assessments. 10

11 The SPC states that limited experience from retreatment with one single infliximab dose in psoriasis after an interval of 20 weeks suggests reduced efficacy and a higher incidence of mild to moderate infusion reactions when compared to the initial induction regimen. Results for safety The incidence of undesirable effects was higher on infliximab 3 mg/kg (78%) and 5 mg/kg (79%) than on placebo (63%). However, a higher number of infusions were given in the Remicade group (341 at 3 mg and 343 at 5 mg) than in the placebo group (147). The most common undesirable effects were respiratory infections, headaches, nausea and sinusitis. 8% of patients in the infliximab 3 mg/kg group and 14% of patients in the 5 mg/kg group had allergic infusion reactions at week 26. No data are available on allergic reactions in the placebo group. At 30 weeks, 3 cases of skin carcinoma were seen in patients treated with infliximab. Two of these patients had previously received PUVA therapy. Antibodies to infliximab were seen in 27% of patients in the infliximab 3 mg/k group and in 20% of patients in the infliximab 5 mg/kg group at week 26. Changes in PASI score according to anti-infliximab antibody status PASI score 3 mg/kg 5 mg/kg Ab negative Ab positive Ab negative Ab positive Baseline Week Changes in PASI score according to anti-infliximab antibody status after retreatment PASI score Ab negative (n=34) 3 mg/kg Ab positive (n=14) 5 mg/kg Ab negative (n=39) Ab positive (n=8) Week Week EXPRESS trial (Reich et al. 2005) 17 A total of 378 patients with moderate-to-severe plaque psoriasis were given induction therapy consisting of either infliximab 5 mg/kg (n=301) or placebo (n=77) at weeks 0, 2 and 6, followed by maintenance therapy every 8 weeks until week 24 in the placebo group and week 46 in the infliximab group. 71.4% of the patients included had received previous treatment with PUVA, methotrexate, cyclosporine or acitretine and had not necessarily been resistant to these treatments. At week 24, patients receiving placebo were treated with infliximab 5 mg/kg. Patient characteristics at baseline Placebo n=77 5 mg/kg n=301 Mean age Duration of psoriasis (years) Reich et al. induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double blind trial. Lancet 2005;366:

12 % total body surface area affected Psoriatic arthritis (n, %) 22 (29) 92 (31) PASI score Primary endpoint: Percentage of patients achieving PASI at week 10. Secondary endpoints: PASI 75 at 24 weeks Percentage of patients achieving a PGA score (Physician s Global assessment) of clear or minimal at week 10 DLQI week 10 and 24 Percentage improvement from baseline in NAPSI (Nail Psoriasis and Severity Index) at week 50. Results for efficacy Primary endpoint: A higher percentage of patients achieved PASI 75 at 10 treatment weeks on infliximab 5 mg/kg (80%) than on placebo (3%), p< These results were maintained at week 24 (82% versus 4%). Secondary endpoints: Remicade was more effective than placebo on all secondary endpoints, p< Placebo (n= 77) 5 mg/kg (n=301) PASI 75 Week 24 (n, %) 3 (3.9%) 227 (82.2%) Week 50 (n, %) (60.5%) PGA (clear or minimal) Week 10 3 (3.9%) 242 (82.9%) Change in DLQI from baseline (median) * Week Week Percent improvement in NAPSI from baseline Week Week * DLQI: Dermatology Life Quality Index a low score indicates a higher life Results for safety Undesirable effects occurred in a higher percentage of patients in the infliximab group. 81.9% of patients treated with infliximab versus 71.1% of patients treated with placebo experienced at least one undesirable effect. 27 patients in the infliximab group versus 5 in the placebo group stopped treatment because of undesirable effects. The incidence of infections was 42% on infliximab versus 40% on placebo. The incidence of infusion-related reactions was 3% on infliximab versus 2% on placebo. Six patients treated with infliximab developed malignancies. Five of these had been treated with PUVA. 18 The Psoriasis Area Severity Index is a score ranging from 0 (clear) to 72 (max. severity).it is a composite measure of body surface area affected (from 0 to 100%) and severity. Plaques are graded by 3 criteria, thickness, redness and scaliness on a scale from 0 to 4 according to severity on a body surface area divided into 4 regions comprising the head, lower extremities, upper extremities and trunk. There is no consensus about how the various degrees of severity are defined. Scores of PASI 75 or PASI 90 are equivalent to a reduction in PASI score by at least 75% or of at least 90% respectively between 2 assessments. 12

13 Indirect comparison: Indirect comparison of PASI 75 scores achieved at 12 weeks Dose PASI 75 score (% patients) Cyclosporine > 5 mg/kg mg/kg 22 Methotrexate 15 mg/week 60 Etanercept 100 mg/week mg/week 30 Efalizumab 1 mg/kg Source: Stern et al. A promising step forward in psoriasis therapy. JAMA 2003;290: However, it is impossible to base conclusions on this comparison for the following reasons: methotrexate was used at a lower posology than that generally used in France (17.5 and 20 mg/week or as high as 25 mg/week in certain cases) although PASI score has been validated by the EMEA and FDA to assess the efficacy of psoriasis treatment, it is a poor reflection of clinical reality (Stern et al, JAMA 2003) no data on concomitant treatments are available no test for heterogeneity was performed to assess the comparability of the populations length of follow-up differs from trial to trial it has not been established whether the trials included in the direct comparison were comprehensive. Finally, the total number of patients included in all the trials is relatively low in relation to disease frequency. It is difficult to conclude that Remicade is more effective compared to other systemic treatments on the basis of this indirect comparison alone. A direct comparison would be more useful Conclusion Rheumatoid arthritis The ASPIRE trial demonstrated the efficacy of Remicade in combination with methotrexate in treatment of rheumatoid arthritis in methotrexate naïve patients. This trial showed that at week 54 the Remicade + methotrexate combination was more effective than methotrexate alone measured by ACR-N and total Sharp score. At week 54, ACR-N response in the Remicade + methotrexate 3 mg/kg group (38.9%) was significantly greater than in the group treated with methotrexate alone (26.4%), p< The rate of progression of structural joint damage was 0.4± 5.8 on Remicade + methotrexate versus 3.7± 9.6 on methotrexate alone. Pneumonia was more common on the Remicade + methotrexate combination than on placebo Psoriatic arthritis Two placebo-controlled trials involving 304 patients, including 152 treated with infliximab, assessed the efficacy and safety of Remicade in the treatment of psoriatic arthritis. The results of both trials support the superiority of Remicade compared to placebo with 65% of patients on Remicade achieving ACR 20 at week 16 versus 10% on placebo (IMPACT trial). In the IMPACT 2 trial 58% of patients treated with Remicade achieved ACR 20 at week 14 compared with 11% on placebo. 13

14 The most common undesirable effects in both trials were infection and infusion-related reactions. The Transparency Committee would have found a direct comparison with other TNF inhibitors and methotrexate useful Psoriasis The efficacy and safety of infliximab compared with placebo were assessed in two clinical trials on 627 patients with moderate to severe psoriasis. SPIRIT evaluated the efficacy of infliximab induction therapy and EXPRESS evaluated infliximab induction and maintenance therapy. 88% of patients on infliximab 5 mg/kg achieved PASI 75 (primary endpoint) at week 10 versus 6% on placebo (SPIRIT), as did 80% of patients on infliximab 5 mg/kg versus 3% on placebo (EXPRESS). The Transparency Committee would have found a direct comparison with etanercept and methotrexate useful. As is the case with all the TNF inhibitors, no long-term data on the safety profile of Remicade are available. 4 TRANSPARENCY COMMITTEE CONCLUSIONS 4.1. Actual benefit Rheumatoid arthritis Rheumatoid arthritis is a chronic, serious and disabling disease. The efficacy/safety ratio for infliximab is substantial. Public health benefit of Remicade in rheumatoid arthritis Burden of rheumatoid arthritis Public health need Anticipated impact on morbidity and quality of life Conclusion a substantial burden to public health. The burden represented by the subpopulation of patients who could benefit from treatment is moderate, as the number of patients is limited. Like other TNF inhibitors, Remicade contributes towards meeting a public health need. It is worth having an additional therapeutic alternative available. Like other TNF inhibitors, Remicade is expected to have a low impact, and no additional impact compared with other TNF inhibitors. Remicade is expected to provide some public health benefit. This is expected to be as low as that provided by other TNF inhibitors in this indication. Remicade is a symptomatic treatment. Therapeutic alternatives are available. The actual benefit of Remicade is substantial. 14

15 4.1.2 Psoriatic arthritis Psoriatic rheumatism is a chronic disease which can be serious and disabling in some of its forms. The efficacy/safety ratio for infliximab is substantial. Public health benefit of Remicade in psoriatic arthritis Burden of psoriatic arthritis a moderate burden to public health. The burden represented by patients with inadequate response to disease-modifying treatment is low because they are few. Public health need Like other TNF inhibitors, Remicade contributes towards meeting a public health need. It is worth having an additional therapeutic alternative available. Anticipated impact on morbidity and quality of life Conclusion Like other TNF inhibitors, Remicade is expected to have a low impact, and no additional impact compared with other TNF inhibitors. Remicade is expected to provide some public health benefit. This is expected to be as low as that provided by other TNF inhibitors in this indication. Remicade is a symptomatic treatment. Therapeutic alternatives are available. The actual benefit of Remicade is substantial Psoriasis Psoriasis is a chronic inflammatory skin disease, which is benign in most cases, although certain forms can have substantial impact on quality of life. The short-term efficacy/safety ratio for infliximab was substantial in the patients included in the trials (PASI>10, BSA>10%, patients with prior systemic treatment). The therapeutic gain at week 10 ranged from 80 to 88% according to trial. The Committee was provided with long-term data for rheumatoid arthritis but lacked similar data on patients with psoriasis who have already received several systemic treatments. Public health benefit of Remicade in psoriasis Burden of psoriasis arthritis a substantial burden to public health. However, the burden represented by the small population who could benefit from treatment is moderate. Public health need Given that there are rare but serious cases of psoriasis where the other systemic treatments cannot be used, and that these systemic treatments are associated with cumulative toxicity restricting their use, it is fair to state that there is an unmet therapeutic need. This need may be considered to be substantial in public health terms because the condition of the patients who could benefit is serious. Anticipated impact on morbidity and quality of life Conclusion Like other TNF inhibitors, Remicade is expected to have a low short-term impact It is not expected to have any long-term impact because: - there are doubts about its safety, in particular about the risk of malignancy - it is uncertain whether results obtained in trials performed over relatively limited periods - and including very few data on the limited population who have experienced real therapeutic failure - can be transposed to the population in question. In the current state of knowledge, and as for other TNF inhibitors, no public health benefit is expected for Remicade. 15

16 Remicade is a suspensive treatment for signs and symptoms and is used as second-line treatment. The Committee considered the actual benefit of Remicade to be substantial in patients with chronic, severe plaque psoriasis 19, who have failed at least 2 systemic treatments including phototherapy, methotrexate or cyclosporine (non-responders, with contraindications or who are intolerant). For patients who do not meet these criteria for receiving treatment, actual benefit is insufficient Improvement in actual benefit Rheumatoid arthritis When compared with conventional treatments, including treatment with methotrexate alone, Remicade combined with methotrexate provides a similar improvement in actual benefit (level II) as other TNF inhibitors, in terms of clinical efficacy and inhibition of the progression of structural joint damage Psoriatic arthritis Remicade combined with methotrexate provides a similar improvement in actual benefit (level II) as other TNF inhibitors in patients with active and progressive psoriatic arthritis whose response to previous disease-modifying treatment has been inadequate. However, the committee would have found a direct comparison with other TNF inhibitors and methotrexate useful Psoriasis The committee considered that Remicade provides the same moderate improvement in actual benefit (level III) as Enbrel in adult patients with chronic severe plaque psoriasis, who have failed to respond to at least two systemic treatments including phototherapy, methotrexate and cyclosporine and for whom there are few or no therapeutic alternatives. However, the committee would have found a direct comparison with Enbrel and with methotrexate useful Therapeutic use Rheumatoid arthritis Standard management of rheumatoid arthritis includes prescription of a rapid-acting antiinflammatory (NSAID, corticosteroids) and a disease-modifying treatment in order to induce remission in terms of clinical signs and laboratory test results. NSAIDs and corticosteroids are used during the clinically active phases of the disease. They should be used at the minimum effective dose and, if necessary, their use can be extended on condition that they are well tolerated. Loss of response or intolerance to various disease-modifying treatments can be managed by switching to other disease-modifying treatments. Methotrexate is one of the most effective disease-modifying treatments for rheumatoid arthritis. 19 Severity of psoriasis is assessed mainly in terms of PASI, extent of lesions and psychosocial impact. 16

17 It can be combined with other disease-modifying treatments on condition that the patients clinical course and laboratory results are closely monitored. In patients who have an inadequate response to or contraindication for methotrexate another standard disease-modifying treatment or a TNF inhibitor (adalimumab, etanercept or infliximab) is used, depending upon the patients clinical signs and symptoms, laboratory test results, and the clinical context Psoriatic arthritis Management of psoriatic arthritis is the same as that of all chronic rheumatic diseases. It combines rapid-acting symptomatic treatment (anti-inflammatories with or without analgesics) with a disease-modifying treatment. The most widely used and most effective disease-modifying treatment is methotrexate. In cases where methotrexate is ineffective and patients do not respond, administration of TNFα inhibitors is recommended. Remicade is thus a treatment which can be used after failure, inadequate response, intolerance to, or contraindication for disease-modifying treatments, particularly methotrexate Psoriasis Current treatments for psoriasis are suspensive treatments for signs and symptoms. They do not cure patients but cause temporary, either complete or partial, disappearance of the plaques. The symptomatic treatments for severe forms of psoriasis are phototherapy, retinoids (sometimes administered combined with phototherapy), methotrexate, cyclosporine, and biologic therapies (etanercept, efaluzimab or infliximab). Response to phototherapy is high but its administration conditions (regular sessions, equipment) and its cumulative toxicity restrict accessibility and long-term use (risk of skin cancer). Experts consider methotrexate, despite its serious undesirable hepatic effects, to be the standard treatment for forms of psoriasis that are severe or that affect extensive areas of the skin. Retinoids alone are less effective than either phototherapy or methotrexate but when combined with phototherapy their efficacy is higher (synergetic action). This combination is used in particular for diffuse forms of psoriasis. Biological treatments including Remicade should be restricted to psoriasis patients with a PASI score 10 and a DLQI >10, who have not responded to other systemic treatments including cyclosporine, methotrexate or PUVA, or who have a contraindication for or who are intolerant of such therapies. The current strategy is using alternative treatments in rotation. Selection of treatment is influenced by the characteristics of the patient and disease (concomitant disease, extent of the lesions, treatment history) as well as of the medicinal product (undesirable effects, cumulative dose). In adult patients who have not responded to at least 2 systemic treatments out of phototherapy, methotrexate and cyclosporine, or who are intolerant of or who have a contraindication for such therapies, treatment with etanercept, efaluzimab or infliximab can be considered. 17

18 4.4. Target population Rheumatoid arthritis The prevalence of rheumatoid arthritis is about 130,000 to 240,000 patients. According to expert opinion, 45% to 60% of these patients are currently being treated with methotrexate. About 18% of patients treated with methotrexate fail to respond. The target population would appear to be between 10,000 and 26,000 patients. The fact that Remicade is a medicinal product restricted to hospital use reduces the target population Psoriatic arthritis According to the epidemiological study carried out in 2001 by the Epidemiology section of the French Rheumatology Society, the prevalence rate of psoriatic arthritis in the population aged 18 and above is 0.19%, IC 95 [ ], i.e. an estimated 88,000 adults (between 38,000 and 158,000 persons). The lack of precise epidemiological data on the frequency of severe, progressive forms of the disease with peripheral involvement, as well as on the response rate to disease-modifying treatment, has given rise to the following hypotheses (expert opinion): 50% to 60% of patients with psoriatic arthritis have a severe, progressive form with peripheral involvement requiring administration of methotrexate 15% to 20% of patients would appear to have an inadequate response to methotrexate. Consequently, 6,500 to 10,500 patients with severe, progressive psoriatic arthritis with peripheral involvement probably have an inadequate response to disease-modifying treatment Psoriasis The target population for Remicade is defined as adult patients with chronic severe plaque psoriasis who have failed to respond to at least 2 systemic treatments, in particular to phototherapy, methotrexate and cyclosporine. The prevalence of severe plaque psoriasis can be estimated on the basis of epidemiological data, but the literature does not give the proportion of patients who fail to respond to available systemic treatments (non-responders, intolerant patients or patients with a contraindication). This population may be broadly estimated by applying the mean response rates to current systemic treatments to disease prevalence data from the literature. The estimates thus obtained are similar to those obtained in surveys of dermatologists by pharmaceutical companies and to the estimate made on the basis of PMSI 20 data. On this basis, the Committee estimated that the number of patients likely to benefit from Remicade treatment is under 10, Transparency committee recommendations The Transparency Committee recommended inclusion on the list of medicinal products approved for use by hospitals and various public services in the new indications and at the posologies in the marketing authorisation. 18

19 For the indications rheumatoid and psoriatic arthritis: the Transparency Committee asked to be sent the results of the CORPUS study, which the pharmaceutical company has agreed to take part in. For the indication of psoriasis : the Transparency Committee requested that a representative cohort of patients be treated in France in order to specify: the profile of the populations who are candidates for treatment: disease history, previous treatments, reasons for and aims of prescription, and practical criteria to define (1) serious psoriasis, (2) treatment failure in an observational setting. assessment of benefit over time: following up the cohort for at least 5 years should yield a better understanding of patients individual journeys and of the real-life value of the treatment based on the following 4 factors: - whether benefit is maintained after several courses and whether there is a withdrawal effect - treatment strategy - long-term toxicity (particularly malignancies including skin cancers and the risk of infection) - quality of life changes given by multidimensional indicators as treatment can affect different aspects of the patient s quality of life in different ways. A single composite index will not reflect these differences. The Transparency Committee requested that: this trial be carried out jointly for Enbrel, Raptiva and Remicade, using a similar methodology and protocol results be communicated after one year of follow-up, then annually. 20 PMSI: French national computerised medical information system programme 19