The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION. 3 October 2012

Transcription

1 The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 3 October 2012 REMICADE 100 mg, powder for concentrate for solution for infusion B/1 vial (CIP code: ) Applicant: MSD FRANCE Infliximab ATC code: L04AB12 (TNF inhibitor) List I Medicinal product reserved for hospital use Date of initial Marketing Authorisation: 13 August 1999 (centralised procedure) Date of revision of Marketing Authorisation: concerning amendments to the wording of the indication for Crohn's disease in adults (inclusion of moderate forms): 20 April 2011 Date of latest revision of Marketing Authorisation: 04 April 2012 (extension of the indication for paediatric ulcerative colitis) Reason for the examination: Amendment to the conditions for inclusion on the list of medicines approved for hospital use for Crohn s disease in adults (extension of the indication to moderate forms). Medical, Economic and Public Health Assessment Division 1/12

2 1. CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active ingredient Infliximab 1.2. Indication Indication forming the subject of the application Crohn's disease (non fistulising) in adults Previous wording: "REMICADE is indicated for: treatment of severely active Crohn's disease, in adult patients who have not responded despite a full and adequate course of therapy with a corticosteroid and/or an immunosuppressant; or who are intolerant to or have medical contraindications for such therapies. New wording: "REMICADE is indicated for: treatment of moderately to severely active Crohn's disease, in adult patients who have not responded despite a full and adequate course of therapy with a corticosteroid and/or an immunosuppressant; or who are intolerant to or have medical contraindications for such therapies Indications not included in this evaluation Gastroenterology Fistulising Crohn's disease in adults "REMICADE is indicated for treatment of fistulising, active Crohn's disease, in adult patients who have not responded despite a full and adequate course of therapy with conventional treatment (including antibiotics, drainage and immunosuppressive therapy)." "Paediatric Crohn's disease: REMICADE is indicated for treatment of severe, active Crohn's disease, in children and adolescents aged 6 to 17 years, who have not responded to conventional therapy including a corticosteroid, an immunomodulator and primary nutrition therapy; or who are intolerant to or have contraindications for such therapies. REMICADE has been studied only in combination with conventional immunosuppressive therapy. Ulcerative colitis: REMICADE is indicated for: treatment of moderately to severely active ulcerative colitis in adult patients who have had an inadequate response to conventional therapy including corticosteroids and 6-mercaptopurine (6-MP) or azathioprine, or who are intolerant to or have medical contraindications for such therapies. Paediatric ulcerative colitis (new indication yet to be evaluated by the Committee) REMICADE is indicated for treatment of severely active ulcerative colitis, in children and adolescents aged 6 to 17 years, who have had an inadequate response to conventional 2/12

3 therapy including corticosteroids and 6-MP or azathioprine, or who are intolerant to or have medical contraindications for such therapies." Rheumatology Rheumatoid arthritis: REMICADE, in combination with methotrexate, is indicated for: The reduction of signs and symptoms, as well as the improvement of physical function in: patients with active disease when the response to disease-modifying anti-rheumatic drugs (DMARDs), 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 progression of joint damage, as measured by x-ray, has been demonstrated. Ankylosing spondylitis: REMICADE is indicated for treatment of severe, active ankylosing spondylitis, in adult patients who have responded inadequately to conventional therapy. Psoriatic arthritis: REMICADE is indicated for treatment of active and progressive psoriatic arthritis in adult patients when the response to previous DMARD therapy has been inadequate. REMICADE should be administered - in combination with methotrexate - or alone in patients who show intolerance to methotrexate or for whom methotrexate is contraindicated. REMICADE has been shown to improve physical function in patients with psoriatic arthritis, and to reduce the rate of progression of peripheral joint damage as measured by X-ray in patients with polyarticular symmetrical subtypes of the disease." Dermatology Psoriasis: "REMICADE is indicated for: treatment of moderate to severe plaque psoriasis in adult patients who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapy including cyclosporine, methotrexate or PUVA." 1.3. Dosage "REMICADE is to be initiated and supervised by qualified physicians experienced in the diagnosis and treatment of rheumatoid arthritis, inflammatory bowel diseases, ankylosing spondylitis, psoriatic arthritis or psoriasis. REMICADE should be administered intravenously. REMICADE infusions should be administered by qualified healthcare professionals trained to detect any infusion related issues. Patients treated with REMICADE should be given the package leaflet and the special Alert card. During REMICADE treatment, other concomitant therapies, e.g., corticosteroids and immunosuppressants should be optimised. Dosage in moderately to severely active Crohn's disease: 5 mg/kg given as an intravenous infusion followed by an additional 5 mg/kg infusion two weeks after the first infusion. If a patient does not respond after two doses, no additional treatment with infliximab should be given. Available data do not support further infliximab treatment, in patients not responding within six weeks of the initial infusion. In responding patients, the alternative strategies for continued treatment are: 3/12

4 Maintenance: Additional infusion of 5 mg/kg at six weeks after the initial dose, followed by infusions every eight weeks or Re-administration: Infusion of 5 mg/kg if signs and symptoms of the disease recur. Although comparative data are lacking, limited data in patients who initially responded to 5 mg/kg but who lost response indicate that some patients may regain response with dose escalation. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit after dose adjustment." For other indications see the SPC. 2. SIMILAR MEDICINAL PRODUCTS 2.1. ATC Classification (2012) L: Antineoplastic and immunomodulating agents L04: Immunosuppressants L04A: Immunosuppressants L04AB: Tumour necrosis factor alpha (TNF-α) inhibitors L04AB12: Infliximab 2.2. Medicines in the same therapeutic category There are no other TNF inhibitors indicated for the treatment of moderate forms of Crohn's disease resistant to corticosteroids and/or immunosuppressants. HUMIRA (adalimumab) is only indicated for active and severe forms, resistant to corticosteroids and immunosuppressants Medicines with a similar therapeutic aim** High dose corticosteroids (oral/iv) Immunosuppressants (azathioprine, methotrexate*, 6-mercaptopurine*) ** Dignass et al. The second European evidence-based consensus on the diagnosis and management of Crohn s disease: Current management. Journal of Crohn s and Colitis 2010; 4: * Medications with an established use but without marketing authorisation in this indication 4/12

5 3. ANALYSIS OF AVAILABLE DATA 3.1. Context It should be noted that REMICADE was the first TNF inhibitor to receive marketing authorisation in the treatment of severe, active or fistulising Crohn's disease, despite treatment with a corticosteroid and/or an immunosuppressant as an induction therapy (13 August 1999) then as a maintenance treatment (15 May 2003). On 5 January 2000, The Transparency Committee attributed a substantial actual benefit to REMICADE and considered that "within the scope of indications limited to patients resistant to other treatments for active, severe or fistulising Crohn's disease, REMICADE represents a major therapeutic benefit. On 1 September 2004, as a maintenance treatment, the Committee considered that its actual benefit was substantial and that: "REMICADE provided a moderate (level III) improvement in actual benefit compared with receiving no maintenance treatment at all." According to the results from the SONIC study presented below, the applicant is requesting confirmation of previous Committee opinions on the new indication for REMICADE concerning moderate forms of Crohn's disease Efficacy SONIC Study (carried out between March 2005 and November 2008) 1 Objective To compare the efficacy and safety of infliximab alone or in combination with azathioprine to that of azathioprine alone in patients with moderate to severe Crohn's disease (CDAI 2 score between 220 and 450) and in patients who are immunosuppressant and biological treatment naive. Method A controlled, randomised, double-blind study up to Week 30, followed by a blind extension phase with maintenance treatment up to Week 50. Main inclusion criteria Patients aged at least 21 years, with moderate to severe Crohn's disease (220 CDAI 450) for at least six weeks with colitis, ileitis, or ileocolitis confirmed by x- ray or endoscopy and meeting at least one of the following criteria: o o corticosteroid-dependent (score CDAI 220 after reduction in corticosteroid dose); have started at least their second treatment with oral corticosteroids over the last 12 months; o a failed treatment with 5-ASA (inadequate response after treatment lasting at least four weeks at a dose of 2.4 g/day or equivalent in sulfasalazine); o a failed treatment with budesonide (inadequate response after treatment lasting at least four weeks at a dose of 6 mg/day). immunosuppressant or biological treatment naive. 1 Colombel et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med. 2010; 362(15): Crohn s Disease Activity Index (CDAI) evaluates the signs and symptoms of the disease. It comprises eight components: the number of liquid or very soft stools in one week, abdominal pain, general well-being, other elements linked to the disease (fistulas, arthritis, fever, uveitis), abdominal mass, the taking of anti-diarrhoea medication, packed cell volume and weight. The score ranges from 0 to 600. Disease activity is judged according to the CDAI score value: 150 > CDAI > 220: mild, 220 > CDAI > 450: moderate, CDAI> 450: severe. It is considered as a clinical response if the reduction in CDAI score is 70 or /12

6 Treatments The patients included were randomised into three groups to receive over the double-blind phase either: infliximab + azathioprine IFX+AZA (infusions of infliximab 5 mg/kg on Weeks 0, 2, 6, 14 and 22 and azathioprine tablets 2.5 mg/kg/day), n=169 infliximab + placebo IFX+PBO (infusions of infliximab 5 mg/kg on Weeks 0, 2, 6, 14 and 22 and azathioprine placebo tablets 2.5 mg/kg/day), n=169 azathioprine + placebo AZA+PBO (infusions of placebo on Weeks 0, 2, 6, 14 and 22 and azathioprine tablets 2.5 mg/kg/day), n=170 Concomitant treatment with 5-ASA, systemic corticosteroids and budesonide were authorised. Endpoints Primary efficacy endpoint: The primary efficacy endpoint was corticosteroid-free clinical remission at Week 26, defined as the proportion of patients with a CDAI score <150 and who have not received systemic oral corticosteroids (prednisolone or equivalent or, budesonide at a dose of > 6 mg/day for at least three weeks). The secondary endpoints included: level of mucosal healing measured via endoscopy at Week 26 in patients with ulceration on inclusion, corticosteroid-free clinical remission at Week 50, dose of corticosteroid therapy over time. Results The medical characteristics of patients were comparable in the three treatment groups; see Table 1. The mean age of patients was 36.3 years; 41% of patients were treated with corticosteroids or budesonide and 54% with 5-ASA. 6/12

7 Table 1. Characteristics of patients included in the SONIC study. IFX+AZA IFX+PBO AZA+PBO Total Randomised patients Median age (years) Duration of disease (years) mean ± SD median CDAI Patients evaluated mean ± SD 5.8 ± ± ± ± ± ± ± ± CRP (mg/dl) Patients evaluated mean ± SD ± ± ± ± IBDQ Patients evaluated mean ± SD ± ± ± ± Treatments on inclusion Corticosteroids and budesonide for Crohn's disease Mean corticosteroid dose 0 mg < 20 mg 20 mg 66 (39.1%) 122 (72.2%) 14 (8.3%) 33 (19.5%) 79 (46.7%) 117 (69.2%) 19 (11.2%) 33 (19.5%) 65 (38.2%) 130 (76.5%) 14 (8.2%) 26 (15.3%) 210 (41.3%) 369 (72.6%) 47 (9.3%) 92 (18.1%) Mean budesonide dose 6 mg > 6 mg 19 (11.2%) 6 (3.6%) 13 (7.7%) 28 (16.6%) 8 (4.7%) 20 (11.8%) 25 (14.7%) 8 (4.7%) 17 (10.0%) 72 (14.2%) 22 (4.3%) 50 (9.8%) Patients treated with at least 5- ASA 85 (50.3%) 87 (51.5%) 104 (61.2%) 276 (54.3%) Of the 508 patients randomised, five patients were not treated (one in the IFX+AZA group, three in the IFX+PBO group and one in the AZA+PBO group). Among the 503 patients treated, 190 (37.4%) stopped treatment prematurely (48 in the IFX+AZA group, 58 in the IFX+PBO group and 84 in the AZA+PBO group). The main reason for stopping treatment prematurely was due to the occurrence of adverse events (16.9%). Results for the primary efficacy endpoint The proportion of patients achieving corticosteroid-free remission at Week 26 was statistically higher with: - IFX+AZA (96/169, 56.8%) than with AZA+PBO (51/170, 30.0%), which is an absolute benefit of 26.8%, p <0.001; - IFX+AZA (96/169, 56.8%) than with IFX+PBO (75/169, 44.4%), which is an absolute benefit of 12.4%, p = 0.02; - IFX+PBO (75/169, 44.4%) than with AZA+PBO (51/170, 30.0%), which is an absolute benefit of 14.4%, p = Results for certain secondary endpoints o Level of mucosal healing The proportion of patients achieving mucosal healing at Week 26 was statistically higher with: - IFX+AZA (47/107, 43.9%) than with AZA+PBO (18/109, 16.5%), p<0.001; - IFX+PBO (28/93, 30.1%) than with AZA+PBO (18/109, 16.5%), p= /12

8 No statistical difference was highlighted between the infliximab/azathioprine combination (47/107, 43.9%) and infliximab as monotherapy (28/93, 30.1%). o Corticosteroids Variations in parameters linked to the taking of corticosteroids (mean systemic corticosteroid dose, percentage of patients receiving corticosteroids and the total number of days of corticosteroid administration) were similar in all groups. The proportion of patients who received a systemic corticosteroid during the main phase of the trial was 34.3% in the IFX+AZA group, 35.5% in the IFX+PBO group and 35.3% in the AZA+PBO group. o Corticosteroid-free clinical remission at Week 50 During the extension phase of the trial (between Week 30 and Week 50), patients initially treated with IFX+AZA and IFX+PBO continued with their treatment with 5 mg/kg of IFX every eight weeks at Week 30, 38 and 46 and those initially treated with AZA+PBO were treated with placebo. Of the 280 patients included, 13.6% (16.7% with IFX+AZA, 12.4% with IFX+PBO and 10.7% with AZA+PBO) stopped treatment prematurely due to adverse events (6.8%). The proportion of patients achieving corticosteroid-free clinical remission at Week 50 was greater in the IFX+AZA group (78/108, 72.2%) than in the AZA+PBO group (41/75, 54.7%), p=0.01. No statistical difference was highlighted between the IFX+PBO (60.8%) and AZA+PBO (54.7%) groups or between IFX+ AZA and IFX+PBO Adverse effects During the SONIC study (both the double-blind and the extension phases), the proportion of patients who had at least one adverse event was similar between the treatment groups (89.9% in the IFX+AZA group, 89% in the IFX+PBO group and 89.4% in the AZA+PBO group). The most common adverse events were gastrointestinal disorders (61%). The percentage of patients stopping treatment due to adverse events was 18% during the double-blind period and 6.4% during the extension phase, primarily due to gastrointestinal disorders. The most common serious adverse event was acute pancreatitis, including one reported case in the IFX+AZA (0.6%) group, no cases in the IFX+PBO group and four cases in the AZA+PBO group (2.5%). Serious infections linked to treatment were noted in 3.9% of patients in the IFX+AZA group, 4.9% in the IFX+PBO group and in 5.6% of patients in the AZA+PBO group. One case of tuberculosis with a favourable outcome was observed in one patient in the IFX+AZA group. Bowel cancer was diagnosed in two patients in the AZA+PBO group. One death occurred following a colon resection in a patient in the AZA+PBO group; the cause of death was not attributed to the treatment by the clinical investigator. Events linked to infusion occurred in 5% of patients in the IFX+AZA group, 16.6% in the IFX+PBO group and 5.6% in the AZA+PBO group. The most common events were reactions linked to infusion, pyrexia, dizziness and paraesthesia. One case of an anaphylactic reaction leading to the discontinuation of treatment was observed in one patient in the IFX+PBO group. This case had a favourable outcome. In summary, no new adverse effects with REMICADE were identified in this study. 8/12

9 3.4. Conclusion A randomised, double-blind study (SONIC) compared three treatment groups: infliximab alone (5 mg/kg in Week 0, Week 2, Week 6, Week 14 and Week 22), infliximab combined with azathioprine, (2.5 mg/kg/day) and azathioprine alone, over 30 weeks in 508 patients with moderate to severely active Crohn's disease (CDAI score between 220 to 450). Between Week 30 and Week 50, patients initially treated with infliximab alone or combined with azathioprine were treated with infliximab alone in Week 30, 38 and 46 and those initially treated with AZA+PBO were given the placebo. Patients included were TNF inhibitor and immunosuppressant naïve, but could be corticosteroid-dependent, corticosteroid-resistant or have had a failed treatment with aminosalicylic acid (5 ASA) and those included also had Crohn's disease that had recently developed (median disease duration: 2.3 years). 5-ASA, systemic and topical use corticosteroids (budesonide) were authorised as concomitant treatments. The primary efficacy endpoint was the percentage of patients in clinical remission (CDAI<150) not having received systemic oral or topical use corticosteroids (budesonide > 6 mg/day) for at least three weeks, up to Week 26. The follow-up results with the blind administration of maintenance treatment for 50 weeks are also provided. Patients included had a mean age of 36.3 years, while 41% of patients were treated with systemic or topical use (budesonide) corticosteroids at inclusion and 54% with 5-ASA. The percentage of patients in corticosteroid-free clinical remission at Week 26 was higher with the infliximab/azathioprine combination than with azathioprine alone (56.8% vs. 30.0%, difference 26.8%, p < 0.001) and than with infliximab alone (56.8% vs. 44.4%; difference 12.4%, p = 0.02). The percentage of patients in corticosteroid-free clinical remission at Week 26 was higher with infliximab alone than with azathioprine alone (44.4% vs. 30.0%, difference 14.4%, p = 0.006) The combination of infliximab/azathioprine was also superior to azathioprine alone in the proportion of patients with mucosal healing (secondary endpoint) at Week 26 (43.9% vs. 16.5%; p<0.001). The proportion of patients who achieved corticosteroid-free clinical remission at Week 50 was higher in the IFX+AZA group (72.2%) than in the AZA+PBO group (54.7%), p<0.01. Between Week 30 and Week 50, of the 280 patients included, 16.7%, 12.4% and 10.7% with infliximab/azathioprine, infliximab alone and azathioprine alone respectively stopped treatment early, mainly due to adverse events (6.8%). No new adverse effects associated with infliximab were identified in this study. The proportion of patients who had at least one adverse event was similar between infliximab/azathioprine (89.9%), infliximab alone (89%) and azathioprine alone (89.4%), the most common being gastrointestinal issues (61%). Among the serious adverse effects, infections (3.9%, 4.9% and 5.6% with infliximab/azathioprine, infliximab alone and azathioprine alone, respectively) and infusion reactions (5%, 16.6% and 5.6% with infliximab/azathioprine, infliximab alone and azathioprine alone, respectively) were reported in patients treated with infliximab during this study. 9/12

10 3.5. Supplementary data The applicant has highlighted: - the ACCENT I study, the results of which have already been analysed by the Committee in their previous opinions; - an open-label comparative study of two treatment strategies (early treatment with infliximab+azathioprine or treatment with corticosteroids then in cases of worsening, treatment with azathioprine then infliximab; - a long-term follow-up study (median follow-up period 55 months) of a cohort of patients with luminal and fistulising Crohn's disease. In summary, the results of these studies do not enable the degree of effect of REMICADE to be determined in moderate forms of Crohn's disease, which is the subject of this evaluation. 10/12

11 4. TRANSPARENCY COMMITTEE CONCLUSIONS 4.1. Actual benefit Crohn's disease is a chronic, inflammatory bowel condition. It evolves with periods of flare-ups interspersed with periods of remission. It is a debilitating condition that can lead to a marked deterioration in quality of life. REMICADE is intended as a symptomatic treatment. Public health benefit: The prevalence of Crohn's disease has increased in adults, as has its incidence in children. It has a high morbidity due to the frequency of flare-ups, the chronic nature of the condition, and its complications (stenoses, perforations and abdominal or pelvic abscesses) and surgical treatment. It is also responsible for a marked change in quality of life in physical, psychological and social terms. The public health burden represented by Crohn's disease may be regarded as moderate. The burden corresponding to the restricted population defined by the new indication of REMICADE (moderate form of the disease in patients intolerant or non responders to treatment with corticosteroids and/or immunosuppressants), is low. Improvement in the management of Crohn's disease is a public health need which is already an established priority (Law n of 9 August 2004 on Public Health policy: objective 76 aiming to reduce the impact of CIBD on the quality of life of those affected, Plan for the improvement in quality of life of patients with chronic conditions). Given the clinical data available from a single study, it is realistic to expect that the proprietary medicinal product REMICADE will have a moderate impact on morbidity (associated corticosteroid-free clinical remission) and quality of life. However, the additional improvement in quality of life compared with azathioprine alone is not clinically relevant (difference observed below the minimum difference defined for IBDQ at 16 points). Furthermore, the transferability of clinical trial results to current practice is not assured due to the difficulty in sourcing actual patients with the moderate form of the disease (score used in the trial is difficult to use in everyday medical practice). In addition, data provided does not support the impact of early treatment with REMICADE resulting in fewer hospital admissions or in a delay to the need for abdominal surgery (stoma, resections). Thus, the proprietary medicinal product REMICADE should therefore be able to provide only a partial additional response to the identified public health need. Consequently, it is expected that REMICADE will be of benefit to public health in this indication. This benefit is low. Its efficacy / safety ratio is high in moderate forms that have not responded despite a full and adequate course of therapy with a corticosteroid and/or an immunosuppressant; or for those patients who are intolerant to or have medical contraindications for such therapies. REMICADE is a second-line treatment after failure of corticosteroids and/or immunosuppressants. There are very few treatment alternatives. The actual benefit of this proprietary medicinal product is substantial Improvement in actual benefit (IAB) Data submitted within the context of the extension of the indication of REMICADE to moderate forms of Crohn's disease after failed treatment with corticosteroids is not sufficient enough to change the IAB level previously given for Crohn's disease. 11/12

12 4.3. Therapeutic use According to recommendations from the consensus conference (European Crohn and Colitis Organization - ECCO 3 ), systemic corticosteroids or budesonide are highlighted as being treatments for moderate and active forms of Crohn's disease. Immunosuppressants, including azathioprine or methotrexate (without marketing authorisation) in combination with corticosteroids are also a treatment option. TNF alpha inhibitors may be used for patients with objective signs of the active disease, who are corticosteroid-resistant or are corticosteroid-dependent. The risk/benefit ratio should be carefully evaluated Target population The target population for REMICADE in this extension of the indication of Crohn's disease corresponds to patients with active, moderate Crohn's disease resistant to corticosteroids or immunosuppressants. According to a national study published in carried out on national health insurance data relating to long-term conditions for chronic inflammatory bowel disease (CIBD) between January 2000 and December 2002, the incidence rate for 100,000 was 8.1 [ ] for Crohn's disease and 7.1 [ ] for UC (ulcerative colitis). The prevalence of Crohn's disease in France is 110/100, By applying this figure to INSEE data at 1 January 2012 (50,893,000), the affected population in France may be estimated at 56,000 patients. On the basis of available epidemiological data 6, it is estimated that 6% to 30% of patients are resistant to corticosteroids and immunosuppressants. Thus, the population requiring treatment with a TNF alpha inhibitor, including REMICADE, would be between 3,360 and 16,800 patients. Among these patients, the amount of cases of moderate forms of the disease cannot be accurately determined from epidemiological data. Thus, the addition of moderate forms to the therapeutic indication of REMICADE in Crohn's disease does not change the target population beyond the update of INSEE data on 1 January 2012, the target population having been defined in previous Committee opinions independently of the severity of the disease due to the lack of epidemiological data. As a reference, 117,821 patients were covered at 100% by National Health Insurance in 2010 due to their long duration disease (LDD) No. 24 (developed UC and Crohn's disease) Transparency Committee recommendations The Transparency Committee recommends inclusion on the list of medicines approved for hospital use and various public services in the new indication (moderate Crohn's disease). 3 Dignass et al. The second European evidence-based consensus on the diagnosis and management of Crohn s disease: Current management. Journal of Crohn s and Colitis 2010; 4: Nerich V. et al. Geographical variations of inflammatory bowel disease in France: a study based on national health insurance data. Inflamm Bowel Dis 2006;12: Pr Cortot. Crohn s disease. Orphanet Encyclopedia, June Faubion WA Jr et al. The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study. Gastroenterology. 2001;121: /12