TRANSPARENCY COMMITTEE OPINION. 16 July 2008

Transcription

1 TRANSPARENCY COMMITTEE OPINION 16 July 2008 ENBREL 25 mg, solution for injection in pre-filled syringe Box of ml pre-filled syringes with needles and alcohol swabs (CIP: ) ENBREL 50 mg, solution for injection in pre-filled syringe Box of 4 1 ml pre-filled syringes with needles and alcohol swabs (CIP: ) ENBREL 25 mg/ml, powder and solvent for solution for injection for paediatric use Box of 4 4 ml bottles and 4 pre-filled syringes, with 8 syringes, 20 needles and 24 alcohol swabs (CIP: ) ENBREL 25 mg, powder and solvent for solution for injection Box of 4 vials and 4 1 ml pre-filled syringes with 4 needles, 4 vial adaptors and 8 alcohol swabs (CIP: ) ENBREL 50 mg, powder and solvent for solution for injection Box of 4 vials and 4 1 ml pre-filled syringes with 4 needles, 4 vial adaptors and 8 alcohol swabs (CIP: ) Applicant: WYETH PHARMACEUTICALS FRANCE etanercept List I Medicinal product for initial annual hospital prescription only. Initial prescription and renewal only by specialists in rheumatology, internal medicine, paediatrics or dermatology. Marketing authorisation (MA) date: ENBREL 25 mg, solution for injection in pre-filled syringe: 26 September 2006 ENBREL 50 mg, solution for injection in pre-filled syringe: 26 September 2006 ENBREL 25 mg/ml, powder and solvent for solution for injection for paediatric use: 4 August 2006 ENBREL 25 mg, powder and solvent for solution for injection: 16 September 2002 ENBREL 50 mg, powder and solvent for solution for injection: 28 April 2005 Reason for request: For re-examination following submission of new data concerning the rheumatoid arthritis indication Health Technology, Economic and Public Health Assessment Division 1

2 1 CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active substance etanercept 1.2. Indications Indications relevant to this request: - Enbrel in combination with methotrexate is indicated for the treatment of moderate to severe active rheumatoid arthritis in adults when the response to disease-modifying antirheumatic drugs, including methotrexate (unless contraindicated), has been inadequate. - Enbrel can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate. - Enbrel is also indicated in the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate. - Enbrel, alone or in combination with methotrexate, has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function. Other indications: - Treatment of active polyarticular juvenile idiopathic arthritis in children and adolescents from the age of 4 years who have had an inadequate response to, or who have proved intolerant of, methotrexate. Enbrel has not been studied in children aged less than 4 years. - Treatment of active and progressive psoriatic arthritis in adults when the response to previous disease-modifying antirheumatic drug therapy has been inadequate. Enbrel 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. - Treatment of adults with severe active ankylosing spondylitis who have had an inadequate response to conventional therapy. - Treatment of adults with moderate to severe plaque psoriasis who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapy including ciclosporin, methotrexate or PUVA Dosage Enbrel treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis or plaque psoriasis. Adults (18-64 years) Rheumatoid arthritis 25 mg Enbrel administered twice weekly is the recommended dose. Alternatively, 50 mg administered once weekly (equivalent to two 25 mg injections given close together) has been shown to be safe and effective. Psoriatic arthritis and ankylosing spondylitis The recommended dose is 25 mg Enbrel administered twice weekly, or 50 mg administered once weekly. 2

3 Plaque psoriasis The recommended dose of Enbrel is 25 mg administered twice weekly or 50 mg administered once weekly. Alternatively, 50 mg given twice weekly may be used for up to 12 weeks followed, if necessary, by a dose of 25 mg twice weekly or 50 mg once weekly. Treatment with Enbrel should continue until remission is achieved, for up to 24 weeks. Treatment should be discontinued in patients who show no response after 12 weeks. If re-treatment with Enbrel is indicated, the above guidance on treatment duration should be followed. The dose should be 25 mg twice weekly or 50 mg once weekly. Elderly patients (> 65 years) No dose adjustment is required. Posology and administration are the same as for adults years of age. Children and adolescents (>4 and < 18 years old) 0.4 mg/kg (up to a maximum of 25 mg per dose) after reconstitution of 25 mg Enbrel in 1 ml of solvent, given twice weekly as a subcutaneous injection with an interval of 3-4 days between doses. Renal and hepatic impairment No dose adjustment is required. 2 SIMILAR MEDICINAL PRODUCTS 2.1. ATC Classification (2008) L : Antineoplastic and immunomodulatory agents L04 : Immunosuppressants L04A : Immunosuppressants L04AB : Tumour Necrosis Factor alpha (TNFα) Inhibitors L04AB01 : etanercept 2.2. Medicines in the same therapeutic category Other TNFα inhibitors indicated for treatment of rheumatoid arthritis: adalimumab : HUMIRA infliximab : REMICADE (approved for use in healthcare institutions only) HUMIRA in combination with methotrexate is indicated for: - the treatment of moderate to severe, active rheumatoid arthritis in adult patients when the response to disease-modifying anti-rheumatic drugs including methotrexate has been inadequate. - the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate. HUMIRA can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate. Humira has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function, when given in combination with methotrexate. REMICADE, in combination with methotrexate, is indicated for the reduction of signs and symptoms as well as the improvement in physical function in: - patients with active disease when the response to disease-modifying anti-rheumatic drugs (DMARDs), including methotrexate, has been inadequate. 3

4 - 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 the progression of joint damage, as measured by X-ray, has been demonstrated Medicines with a similar therapeutic aim Other disease-modifying treatments for rheumatoid arthritis are: - products based on methotrexate, gold salts, azathioprine, D-penicillamine, leflunomide, hydroxychloroquine and sulfasalazine. - anakinra (KINERET) is indicated, in combination with methotrexate, for patients who have not had a satisfactory response to methotrexate alone. - ciclosporin-based products are indicated if other disease-modifying treatments are ineffective, poorly tolerated or contraindicated. - other immunomodulators indicated in combination with methotrexate if other diseasemodifying treatments, including at least one TNFα inhibitor, are contraindicated or poorly tolerated: abatacept (ORENCIA) and rituximab (MABTHERA). 3 ANALYSIS OF NEW DATA The manufacturer has provided a set of additional data containing information on the use of TNFα inhibitors (duration of treatment, frequency of injections and dose), emergence of anti- TNFα antibodies, infection risk, particularly the risk of tuberculosis, and the risk of tumours (lymphoma and solid tumours) in patients on TNFα inhibitors. The data provided are taken from various European and American registers and observational studies that have included patients with rheumatoid arthritis who have been treated with TNFα inhibitors Usage data Swiss register (Finckh ) Since 1998, this register has contained details of 70-80% of Swiss patients with rheumatoid arthritis who are treated with TNFα inhibitors. A total of 1,198 patients were followed up prior to September 2004 (etanercept n = 519, infliximab n = 362 and adalimumab n = 317), which represents 1,450 patient-years of exposure to TNFα inhibitor treatment, with a mean followup period of 23.7 months for etanercept, 18.8 months for infliximab and 10.7 for adalimumab. Duration of treatment observed A median drug survival period of 3.21 years was observed, with no significant difference between the products. In patients receiving a TNFα inhibitor in combination with a conventional disease-modifying treatment, patient discontinuation rates were significantly lower for etanercept than for infliximab or adalimumab (HR = 0.66; 95% CI = [0.45; 0.98]). 1 Finckh A, Simard JF, Gabay C et al. Evidence for differential acquired drug resistance to anti-tumor necrosis factor agents in rheumatoid arthritis. Ann Rheum 2006; 65:

5 Efficacy evaluation DAS28 changes were significantly different for the three products (ANOVA p=0.001), with a divergence of the curves after the 6th month of treatment: at one year, improvement in DAS28 was 1.05 for etanercept, 0.82 for infliximab and 0.68 for adalimumab. A stabilisation of improvement in DAS28 was observed for etanercept, with no increase in dose or intensification of concomitant therapies. With infliximab, a reduction in clinical efficacy was observed after around 8 months of treatment, and stabilisation occurred at a lower level than with etanercept. In this group, stabilisation was associated with a significant increase in infliximab dose and concomitant disease-modifying treatment. For adalimumab, the length of time for which data are available is limited (< 1 year) and such comparisons cannot be drawn. In addition, there are differences in the populations treated; disease activity was lower on average and adalimumab was used in preference as a secondline TNFα inhibitor. Changes in TNFα inhibitor dose over time There was no significant increase in etanercept dose over time, while a significant increase in infliximab dose was observed after 6 months. This increase continued: 12% at 1 year and 18% at 2 years. If no disease-modifying treatment was given in combination with infliximab, the dose increase was greater: 21% at 1 year. Data on adalimumab showed no significant alteration in dose, but treatment data only extends over < 12 months. NB: the authors note that the dosage change over time criterion is not the most appropriate, as dose increase is not covered in the SPCs for etanercept or adalimumab, but is in the infliximab SPC. Change in disease-modifying treatment given in combination with a TNFα inhibitor. Intensification of disease-modifying treatments (increase in dose or addition of a further disease-modifying treatment) in combination with TNFα inhibitor was significantly greater with infliximab than with etanercept or adalimumab (HR: 1.73; 99% CI = [1.19; 2.51]). No significant difference was observed between etanercept and adalimumab. The difference between treatments was statistically significant after 1.2 years of treatment. Predictors of disease-modifying treatment intensification were previous failure of another anti-tnf agent (HR = 2.14; 95% CI = [1.42; 3.23]), presence of rheumatoid factor (HR = 1.64; 95% CI = [1.07; 2.51] and duration of treatment (HR = 0.98; 95% CI = [0.96; 0.99]). Intensification was greater if treatment had been begun without a disease-modifying treatment given in combination, for infliximab (HR = 4.51; 95% CI = [2.64; 7.71] but not for etanercept or adalimumab. NB: The indications for infliximab given in the SPC state that infliximab is to be used in combination with methotrexate. These results should be interpreted with care, as there were some differences in baseline characteristics between the 3 groups. In particular, the adalimumab group contained a larger proportion of patients who had previously failed treatment with a TNFα inhibitor (39%, compared with 12% in the infliximab group and 7% in the etanercept group), patients in this group had less active disease (DAS28 = 4.19 versus 4.54 in the infliximab group and 4.72 in the etanercept group) and their functional status was lower (HAQ = 1.25 versus 1.37 in the etanercept and infliximab groups). 5

6 Swedish register (Kristensen ) This register compared adherence to therapy in patients with rheumatoid arthritis recruited in 8 hospitals and treated with etanercept or infliximab as a first-line TNFα inhibitor. The aim of this study was to analyse predictors of treatment termination and the impact of methotrexate given in combination. This study was carried out between March 1999 and December 2004, and enrolled 1,161 patients with active rheumatoid arthritis who had failed to respond to at least 2 diseasemodifying treatments, including methotrexate, and who were then treated with etanercept (n = 440) or infliximab (n = 721). Patients were divided into 6 groups, depending on the TNFα inhibitor received and the disease-modifying treatment given in combination: TNFα inhibitor given as monotherapy, in combination with methotrexate, in combination with another disease-modifying treatment. At 5 years the adherence rate for etanercept in combination with methotrexate (65%, 89% at 1 year) was greater (p<0.001) than that for infliximab in combination with methotrexate (36%, 69% at 1 year). Treatment adherence rates for etanercept as monotherapy were 53% at 4 years (74% at 1 year), and for infliximab they were 18% (47% at 1 year). NB: The indications for infliximab given in the SPC state that infliximab is to be used in combination with methotrexate. There were significantly fewer terminations: - because of treatment failure, in the etanercept group than in the infliximab group, for the subgroup of patients receiving a TNFα inhibitor in combination with methotrexate (p = 0.026) - because of adverse effects; in the etanercept group than in the infliximab group (p < 0.001) Change in TNFα inhibitor dose An increase in infliximab and adalimumab dose was observed in the Swiss register (see above) and in French usage data: Monitoring of numbers of boxes dispensed on prescription each month in non-hospital pharmacies (source: Télépharma, Gers) has shown: - ENBREL (50 mg equivalent) is dispensed in quantities of 0.9 boxes/month, which is equivalent to less than 4 vials/month, while the dosage is 4 vials/month according to the MA. - HUMIRA is dispensed in quantities of 1.1 boxes/month, which is equivalent to more than 2 vials/month, while the dosage is 2 vials/month according to the MA. Monitoring of REMICADE use in hospital pharmacies has shown that the number of vials dispensed per patient per month rose from 2.0 in 2005 to 2.35 in April In addition, the time between infusions was observed to narrow (from every 7.2 weeks in 2005 to every 6.8 weeks in 2006) (source: Etude délivrance hospitalière A+A [A + A hospital dispensing survey]), while the MA mentions infusion every 8 weeks as a maintenance treatment. 2 Kristensen LE, Saxne T, Nilsson J.A et al. Impact of concomitant DMARD therapy on adherence to treatment with etanercept and infliximab in rheumatoid arthritis. Results from a six-year observational study in southern Sweden. Arthritis Res Ther 2006;8: R174 6

7 3.2. Emergence of anti-tnfα antibodies Anti-etanercept antibodies Dore (2007) 3 study: An open-label study to evaluate the immunogenicity of etanercept over 28 weeks, involving 214 patients with rheumatoid arthritis. Twelve patients (5.6%) developed anti-etanercept antibodies during the study, of whom 7 had a low titre which was at the limit of the test s detection capabilities. None of these patients developed neutralising antibodies. These antibodies did not affect the safety or efficacy of the treatment. SPC: It is stated in the SPC that in clinical trials submitted in the MA dossier, anti-etanercept antibodies were reported in less than 3% of patients, and that these antibodies were nonneutralising Anti-adalimumab antibodies Bartelds (2007) 4 study: This was a prospective, non-comparative cohort study over 28 weeks, which evaluated the incidence of emergence of anti-adalimumab antibodies, the correlation between serum adalimumab concentration and the presence of anti-adalimumab antibodies, and treatment efficacy in 121 patients with rheumatoid arthritis. Anti-adalimumab antibodies were detected in 21 patients (17%) over the 28 week treatment period, with a greater proportion of non-responders in the group that had significantly more anti-adalimumab antibodies than good responders (34% vs 5%; p = 0.032). Similarly, improvement in disease activity, as evaluated by mean variation in DAS28, was greater in patients with no antibodies (1.70 ± 1.35) than in patients in whom antibodies were detected (0.65 ± 1.35, p = 0.001). Serum adalimumab levels were higher in patients with no antibodies than in those who had developed anti-adalimumab antibodies (mean: 11 mg/l vs 1.2 mg/l, p < 0.001). Conversely, good responders had adalimumab concentrations that were significantly higher than those for moderate responders (p=0.021) and non-responders (p=0.001). SPC: on the basis of the clinical data in the MA dossier, it is stated in the SPC that a higher level of antibodies was observed when the product was given as a monotherapy than when it was given in combination with methotrexate. The SPC mentions the possibility of doubling the dose to 40 mg/week, if used as a monotherapy for rheumatoid arthritis Anti-infliximab antibodies Wolbink (2006) 5 study: This was a prospective, non-comparative study over 52 weeks in 51 patients with rheumatoid arthritis treated using the consensus regimen for initiation of TNFα inhibitor treatment, with an infusion of 3 mg/kg of infliximab on day 0, at week 2 and week 6, and then every 8 weeks. 3 Dore RK, Mathews S, Schechtman J, Surbeck W, Mandel D, Patel A, Zhou L, Peloso P. The immunogenicity, safety, and efficacy of etanercept liquid administered once weekly in patients with rheumatoid arthritis: Clin Exp Rheumatol. 2007; 25: Bartelds GM, Wijbrandts CA, Nurmohamed MT et al. Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Ann Rheum Dis 2007; 66: Wolbink GJ, Vis M, Lems W et al. Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. Arthritis Rheum 2006; 54:

8 After 14 weeks of treatment, the protocol states that it is possible to increase the infliximab dose to 7.5 mg/kg every 8 weeks if the response has been inadequate. Anti-infliximab antibodies were detected in 22 patients (43%) during the study. Patients with no detectable anti-infliximab antibodies (n = 29) were more frequently classified as responders than patients with detectable antibodies. After 52 weeks, 11 patients (29%) had detectable levels of anti-infliximab antibodies. The 3 patients who experienced allergic reaction to the infusion during the study all had detectable serum anti-infliximab antibodies. The level of anti-infliximab antibodies was relatively low in 5 patients and became undetectable during follow-up. For 3 patients, an increase in dose coincided with an improvement in DAS28. In addition, the emergence of anti-infliximab antibodies coincided with a previous reduction in serum infliximab levels. SPC (March 2007): this mentions the possibility of increasing the dose up to 7.5 mg/kg or to give infusions as often as every 4 weeks to patients with rheumatoid arthritis. The SPC also mentions that a relationship has been observed between the emergence of anti-infliximab antibodies and a reduction in response to treatment. NB: The studies presented in this chapter have shown that anti-tnfα antibodies have emerged in patients treated with etanercept, infliximab and adalimumab. However, no conclusions can be drawn on differences between the treatments in terms of % of patients with anti-tnfα antibodies, as these studies were not comparative. However, the antibodies that emerged in patients on etanercept were non-neutralising Infection risk Overall infection risk Data from the German national biologics monitoring register (Listing 2005)*, and from the meta-analysis by Bongartz (2006) show an increase in the risk of infection (by around a factor of 2) in patients with rheumatoid arthritis treated with anti-tnfα biotherapy, with no significant difference between etanercept, infliximab and adalimumab. Data from the national register of the British Society of Rheumatology (Dixon 2006) showed no excess risk of severe infection for patients treated with a TNFα inhibitor in comparison with those receiving a disease-modifying treatment, after adjustment for initial risk factors Tuberculosis Evaluation of tuberculosis risk RATIO, French national observational study (Tubach and ): This was a prospective observational study, established in France in February 2004 and lasting 3 years, the aim of which was to take an inventory of cases of severe bacterial infection and lymphoma in patients currently or previously treated with TNFα inhibitors, for any indication, and to identify risk factors. Data were collected from 486 hospitals likely to prescribe TNFα inhibitors, pharmacovigilance centres and drug manufacturers. All reported cases were validated by a committee of experts. * Listing J, Strangfeld A, Kary S, Rau R, von Hinueber U, Stoyanova-Scholz M et al. Infections in patients with rheumatoid arthritis treated with biologic agents. Arthritis Rheum 2005; 52: Tubach F, Salmon-Ceron D, Ravaud P, Mariette X et al. The RATIO observatory: French registry of opportunistic infections, severe bacterial infections, and lymphomas complicating anti-tnfα therapy. Joint Bone Spine ;72: Tubach F, Salmon D et al. Definitive results of the national French prospective RATIO 3-year observatory on tuberculosis in patients treated with TNF blockers: the risk persists but depends on drug. Abstract.ACR 2007 ISAAC

9 Each case in the register was assigned two control cases, one currently or previously treated with a TNFα inhibitor for rheumatoid arthritis, ankylosing spondylitis or Crohn s disease and one control that had never received TNFα inhibitor treatment. After 3 years, 45 cases of tuberculosis had been declared in patients treated with TNFα inhibitors, of whom 3 were treated with etanercept, 23 with infliximab and 19 with adalimumab. These were patients with rheumatoid arthritis in 29 cases, ankylosing spondylitis in 13 cases and Crohn s disease, Takyasu s arteritis and psoriasis in 1 case each. No patient received tuberculosis prophylaxis before starting TNFα inhibitor treatment, and 15 of the 45 patients had not undergone tuberculin testing (Mantoux test). However, for 20 of the 30 patients who had been tested, the result was < 5 mm. NB: currently, these results cannot be used to compare TNFα inhibitors, as they have only been published in summary form and the data themselves are not available. Swedish national register, ARTIS (Asking, 2005) 8 : This was a study that involved 2,500 patients treated with TNFα inhibitor, from 3 cohorts of patients with rheumatoid arthritis, of whom 1,565 were treated with infliximab and 983 with etanercept between 1999 and Data were compared with 2 other Swedish cohorts in the general population. During this period, patients with rheumatoid arthritis who were not treated with a TNFα inhibitor had a risk of tuberculosis that was twice as high as that in the general population (95% CI = [1.2; 3.4]) and patients on TNFα inhibitor treatment had a risk that was 4 times greater (95% CI = [1.3; 12.0]) than the risk for patients with rheumatoid arthritis not on TNFα inhibitor treatment. Fifteen cases of tuberculosis were reported between 1999 and 2004, of which 9 were in patients on infliximab (incidence: 1.5/1000 patient-years) and 4 were in patients on etanercept (incidence: 0.8/1000 patient-years). Two cases were reported in patients who had received both TNFα inhibitors (incidence: 1.3/1000 patient-years). British national register, BSR (Dixon 2006) 9 : This was a prospective observational study involving 7,664 patients treated with a TNFα inhibitor (etanercept, infliximab and adalimumab) and 1,354 patients treated with a diseasemodifying treatment, between December 2001 and September There was a lower incidence of tuberculosis in patients on etanercept than there was for those on infliximab or adalimumab: of 10 reported cases of tuberculosis, 2 occurred in patients on etanercept (incidence: 0.5/1000 patient-years) and infliximab (incidence: 1.5/1000 patient-years) and 1 in a patient on adalimumab (incidence: 0.9/1000 patient-years). Register of the Spanish rheumatology society (Gomez-Reino 2003) 10 : Register of the Spanish rheumatology society, which included 1,540 patients treated with a TNFα inhibitor between February 2000 and February One hundred and eight-teen cases of infection were observed, of which 17 were tuberculosis. Of the 17 patients who developed tuberculosis, 15 had rheumatoid arthritis and all were on infliximab treatment (incidence: 1,893 cases per 100,000 inhabitants in 2000 and 1,113 cases per 100,000 inhabitants in 2001, incidence having been 21 cases per 100,000 inhabitants in the general population in Spain in 2000). A further Spanish cohort had an incidence, adjusted for spanish 8 Askling J et al. Risk and case characteristics of tuberculosis in rheumatoid arthritis associated with tumor necrosis factor antagonists in Sweden. Arthritis Rheum 2005;52: Dixon WG et al. Rates of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy. Results from the British Society for Rheumatology Biologics Register. Arthritis Rheum 2006; 54: Gomez-Reino JJ, Carmona L, Valverde VR et al. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum 2003; 48:

10 population data, of 95 cases per 100,000 inhabitants between 1990 and 2000, in patients with rheumatoid arthritis who were not treated with a TNFα inhibitor. After the introduction in 2002 of tuberculosis prevention measures for patients treated with a TNFα inhibitor, just one new case was recorded. Data from the USA: The incidence of tuberculosis in patients with rheumatoid arthritis in the US who are on TNFα inhibitor treatment is greater than the incidence of tuberculosis in patients with rheumatoid arthritis who are not on TNFα inhibitor treatment. - Wallis (2004) 11 study: a study carried out on FDA data concerning notified adverse effects between January 1998 and September In this study, the number of patients developing tuberculosis was 35/100,000 patient-years for etanercept and 144/100,000 patient-years for infliximab. Adalimumab had not yet received marketing authorisation at that time. Median time to emergence of tuberculosis was 11.2 months on etanercept, while 75% of cases of tuberculosis reported in patients on infliximab arose during the 6 weeks following treatment start, with 97% occurring within 7 months. - Data from the NDB (National Data Bank for Rheumatic Disease, Wolfe, ): This was an observational study involving 15,940 patients with rheumatoid arthritis who were followed up between January 2000 and June Of the 15,940 patients included, 2,327 were treated with etanercept, 6,460 with infliximab and 558 with etanercept and infliximab. In this study, the risk of developing tuberculosis was the same for patients not treated with TNFα inhibitors as for the general population, and was estimated at 6.2 per 100,000 patient-years. No cases of tuberculosis were reported in patients on etanercept treatment between January 2000 and June 2002, while over the same period 4 cases of tuberculosis were reported in 6,460 patients treated with infliximab (incidence 52.5 cases/100,000 patient-years). The authors observed that all cases occurred in patients who had neither had a tuberculin test before treatment nor received prophylactic treatment Other opportunistic infections Other non-tb granulomatous infections were reported in patients on TNFα inhibitor treatment (results from a study done on the FDA adverse effect notification database from January 1998 to September 2002, Wallis ). These were infections involving atypical mycobacteria, aspergillosis, histoplasmosis, candidiasis and listeriosis. These infections were less frequent in patients on etanercept (incidence: 74/100,000 patients exposed) than in those on infliximab (239/100,000 patients exposed, p<0.001). In the RATIO observational study, an increase in cases of legionellosis in patients on TNFα inhibitor treatment was noted, with a total of 10 cases reported between February 2004 and January 2005, including 8 in patients with rheumatoid arthritis, of whom 2 were on etanercept treatment, 6 on adalimumab and 2 on infliximab. When these data are compared with the annual incidence of legionellosis in France in 2004, it can be seen that there is an overall excess risk in patients on TNFα inhibitor treatment, which is estimated at between 16.5 and 21 in comparison with the French population (Tubach ). NB: it is currently not possible to make comparisons between TNFα inhibitors using data from the RATIO study. 11 Wallis RS, Broder M, Wong J, Beenhouwer D. Granulomatous infections due to tumor necrosis factor blockade: Correction. Clin Infect Dis 2004;39: Wolfe F, Michaud K, Anderson J, Urbansky K. Tuberculosis infection in patients with rheumatoid arthritis and the effect of infliximab therapy. Arthritis Rheum 2004;50: Tubach F, Ravaud P, Salmon-Ceron D et al. Recherche Axée sur la Tolérance des biothérapies (RATIO) Group. Emergence of Legionella pneumophila Pneumonia in patients receiving tumor necrosis factor-alpha antagonists. Clin Infect Dis. 2006;43:

11 3.4. Risk of malignant disease Risk of lymphoma Data from North America - Data from the NDB (National Data Bank for Rheumatic Disease, Wolfe, ): This study involved 19,591 patients with rheumatoid arthritis, with a 7-year follow-up period ( ). In this study, the risk of lymphoma was no greater for patients with rheumatoid arthritis treated with a TNFα inhibitor than it was for those with rheumatoid arthritis who were not treated with a TNFα inhibitor (OR = 1; 95% CI = [0.6; 1.8]). In particular, there was no excess risk for patients on etanercept, with an OR of 0.7 (95% CI = [0.3; 1.6], p=0.422). - Collated data from three North American cohort studies (Setoguchi ): This study involved 7,306 patients with rheumatoid arthritis who were treated with methotrexate and 1,152 patients with rheumatoid arthritis treated with biologics, including TNFα inhibitors and IL-1 inhibitors. The results did not show any difference in terms of increase in the risk of malignant blood disease for patients on TNFα inhibitors compared with those on methotrexate. (HR = 1.37 ; 95% CI = [0.71; 2.65]). European data - Swedish national register (Asking, ): excess risk of lymphoma by a factor of 2 (95% CI = [1.2; 3.4]) in patients with rheumatoid arthritis in comparison with the general population, and no increased risk in patients on TNFα inhibitors. - Swedish SSATG register (Geborek 2005) 16 : register in which 90% of patients were treated with infliximab or etanercept, for a population of 1.3 million Swedish patients included between 01/02/1999 and 31/12/2002. Unlike the Swedish national register, this study showed that the risk of lymphoma was 11.5 times greater (95% CI = [3.7; 26.7]) in patients with rheumatoid arthritis on TNFα inhibitor treatment in comparison with a control population of patients with rheumatoid arthritis not receiving TNFα inhibitor treatment. No adjustments were made for the level of inflammatory activity of the disease. In this study, in contrast to what is usually reported, the risk of lymphoma was not increased in the population of patients with rheumatoid arthritis treated with conventional treatments, including methotrexate, in comparison with the general population. 14 Wolfe F, Michaud K. The effect of methotrexate and anti-tumor necrosis factor therapy on the risk of lymphoma in rheumatoid arthritis in 19,562 patients during 89,710 person-years of observation. Arthritis Rheum ; 56 : Setoguchi S, Solomon DH, Weinblatt ME, Katz JN, Avorn J, Glynn RJ et al. Tumor necrosis factor alpha antagonist use and cancer in patients with rheumatoid arthritis. Arthritis Rheum 2006;54: Geborek P, Bladstrom A, Turesson C, Gulfe A, Petersson IF, Saxne T et al. Tumour necrosis factor blockers do not increase overall tumour risk in patients with rheumatoid arthritis, but may be associated with an increased risk of lymphomas. Ann Rheum Dis 2005;64:

12 - French national observational study, RATIO (Mariette, 2006, abstract) 17 : an observational study of all cases of lymphoma occurring in patients on TNFα inhibitor treatment, taken from 486 hospitals and all pharmacovigilance centres over 2 years. For each case in the register, there were 2 control cases: one uncomplicated patient treated with TNFα inhibitor, the other not on TNFα inhibitor treatment. During this period, 16 cases of lymphoma were declared, with the following distribution:. by condition: 11 patients had rheumatoid arthritis, 2 had ankylosing spondylitis, 1 had Crohn s disease, 1 had Gougerot-Sjögren syndrome. by treatment: 9 patients were receiving infliximab, 4 adalimumab and 3 etanercept. This study did not demonstrate any particular alteration in risk for patients on TNFα inhibitor treatment in comparison with the general population, apart from a slight increase in the incidence of Hodgkin s lymphoma in men. If the number of patients on TNFα inhibitor treatment is estimated at around 30,000 in France between 2004 and 2005, the Standardised Mortality Ratio was 5.13 (p = 0.20) for men and 0 (p = 0.39) for women for Hodgkin s lymphoma, and 0.96 (p = 0.93) for men and 0.64 (p = 0.39) for women for non- Hodgkin s lymphoma. NB: Currently, these results cannot be taken into account, as they have only been published in abstract form and incidence data for each TNFα inhibitor have not been reported in the summary Solid tumour risk Meta-analysis by Bongartz (2006) 18 : This was a meta-analysis of 9 randomised placebo-controlled trials carried out solely on monoclonal antibodies (infliximab and adalimumab). It involved 3,943 patients with rheumatoid arthritis treated with infliximab or adalimumab and 1,512 patients with rheumatoid arthritis who were given placebo. An excess risk of neoplasia was identified for infliximab and adalimumab in comparison with placebo (OR = 3.3; 95% CI = [1.2; 9.1]) with 29 cancers (in 3,192 patients) in the monoclonal antibody group and 3 cancers (in 1,428 patients) in the placebo group. These cancers were mostly skin cancers (in almost 50% of cases). This excess risk was observed at high doses, for infliximab (> 6 mg/kg every 8 weeks) and adalimumab (> 40 mg every 2 weeks). Conversely, at standard doses no excess risk was noted in comparison with placebo (OR = 2.3; 95% CI = [0.6; 8.4]). The same team is currently carrying out a meta-analysis on studies involving etanercept. NB: the results of this meta-analysis should be interpreted with care, as no tests were carried out to assess heterogeneity of treatment effects, publication bias and study quality. It should be noted that in 2 studies, patients had not experienced failure of methotrexate treatment. 17 Mariette X, Tubach F, Ravaud P, Berthelot JM, Proust A, Hermine O et al. Lymphomas in patients treated with TNF blockers in the French national prospective RATIO study: 16 cases in 2 years with diversity of the histologic subtypes and no evidence of an increased risk. Arthritis Rheum 2006; 54:S Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006;295:

13 FDA data Okada (2006) 19 : NB: this reference is a letter in response to Bongartz (2006) meta-analysis. The author criticises Bongartz meta-analysis, which did not include adjustment for patient characteristics (sex, ethnic origin and age) and restates the results of a FDA meta-analysis 20. The FDA concluded that there was no excess risk of neoplasia associated with TNFα inhibitors: - infliximab: incidence was 0.65 per 100 patient-years, versus 0.13 per 100 patient-years in the control group, with a relative risk of 1.00 (95% CI = [0.67; 1.43] (for all indications) - adalimumab: incidence was 0.7 per 100 patient-years, versus 0.4 per 100 patient-years in the control group, with a relative risk of 0.97 (95% CI = [0.77; 1.20] (for rheumatoid arthritis) - etanercept: relative risk was 0.86 (95% CI = [0.56; 1.31]). Data from registers At present, no register that has contained a study of tumour risk (the Swedish national register, the SSATG Swedish register, the 3 combined North American cohorts) has shown that there is an excess risk of solid tumours for patients on TNFα inhibitors in comparison to matched populations of rheumatoid arthritis patients Conclusion Long term treatment adherence and dosages observed: The Swedish and Swiss registers, which each evaluated over 1,100 patients treated with a TNFα inhibitor over a period of 6 years under real conditions in Switzerland and Sweden, showed: - that in one of the two studies, treatment adherence period was longer with etanercept than with infliximab - that the prescribed etanercept dose did not increase over time, while the infliximab dose did increase, which is in line with the SPC for infliximab, which allows for the possibility of dose increases over time - that no increase in dose was observed for adalimumab, although treatment experience was limited to less than 1 year - that dosage of disease-modifying treatment increased after 1.2 years in combination with infliximab, along with the infliximab dosage, in contrast to etanercept and adalimumab. Emergence of anti-tnfα antibodies: Data from various registers (non-comparative) have shown that anti-tnfα antibodies emerge for all three TNFα inhibitors. In the case of etanercept, antibodies were non-neutralising, unlike those seen for adalimumab and infliximab. These results are in line with the content of the SPCs for these products. Creation of neutralising antibodies is a factor that should be taken into account when administering treatment over the medium or long term, considering efficacy and dosage to be administered. The emergence of anti-tnfα antibodies coincided with a reduction in circulating quantities of the TNFα inhibitor, a reduction in efficacy and progressive dose increase for infliximab and adalimumab, while the dose of etanercept remained stable. These results were expected, and were in line with information in the SPCs for these products, which advised increase of adalimumab or infliximab dose if a reduction in efficacy is observed. 19 Okada SK, Siegel JN. Risk of serious infections and malignancies with anti-tnf antibody therapy in rheumatoid arthritis. Letter JAMA 2006;296 (18): Surveillance Epidemiology and Ends Results Cancer Statistic Review. Accessed August 4,

14 Infection risk: Most observational studies of infection risk have shown that all TNFα inhibitors carry a similar increase in overall risk of severe bacterial infection, with no difference between etanercept, infliximab and adalimumab. Data from the US, Sweden, the UK and France suggest that etanercept carries less of a tuberculosis risk than infliximab. However, data from the US and France (the RATIO studies) have shown that tuberculosis was only observed in patients who had received no prophylactic treatment for tuberculosis, and a study by the Spanish rheumatology association has shown that preventative measures can reduce this risk. Cancer risk: The various studies do not enable any conclusions to be drawn as to possible risk of lymphoma in the population of rheumatoid arthritis patients treated with TNFα inhibitors. There are currently no data that suggest that there is an increased risk of solid tumours in patients with rheumatoid arthritis treated with TNFα inhibitors at the usual doses, in comparison with patients treated with disease-modifying treatments. Data from Europe and the US, taken from registers and meta-analyses, have shown that the overall risk of all-form cancer is not increased, except for melanoma and non-melanoma skin cancer. In conclusion, the scope of these results is limited, because they rely on usage and observational data, some of which have been published as abstracts. Overall, these data do not provide any new information in addition to that contained in the current SPCs for TNFα inhibitors and in HAS guidelines concerning the management of rheumatoid arthritis (September 2007), AFSSAPS guidelines on the prevention and management of tuberculosis in patients on TNFα inhibitors (July 2005) and the French Rheumatological Society s (SFR) guidelines on the use of TNFα inhibitors in rheumatoid arthritis (May 2007) (see paragraph 4.2 Therapeutic Use ). 4 TRANSPARENCY COMMITTEE CONCLUSIONS 4.1. Actual benefit The ACB for the rheumatoid arthritis indication is unchanged: Rheumatoid arthritis is a serious and disabling chronic disease. The efficacy/adverse effect ratio is high. This is a symptomatic treatment. There are few alternatives. This product plays a significant role in the management of rheumatoid arthritis in patients who have not responded or who are intolerant to other disease-modifying treatments, including methotrexate. The actual medical benefit of these medicinal products is substantial. 14

15 4.2. Therapeutic use The usual management of rheumatoid arthritis consists of prescription of a disease-modifying treatment in order to induce disease remission, prevent or slow down joint damage, and prevent or limit future disability. The gold standard disease-modifying treatment is methotrexate, because of its risk/benefit ratio. Given the fact that many disease-modifying treatments lead to treatment failure or intolerance, a change in disease-modifying treatment may be possible; the choice of such treatment depends on the clinical, laboratory and X-ray findings and the patient s pathophysiological background. TNFα inhibitors such as etanercept and adalimumab are used alone or in combination with methotrexate if there is inadequate response or intolerance to disease-modifying treatments, including methotrexate (except if contraindicated). Infliximab must be given in combination with a disease-modifying treatment, in particular methotrexate. TNFα inhibitors may be used as first-line treatment in some active severe forms of rheumatoid arthritis. According to HAS guidelines concerning management of rheumatoid arthritis in the established phase (September 2007): There are no data available in the literature that enable ranking of the 3 available medicinal products (in alphabetical order: adalimumab, etanercept, infliximab) by clinical or structural efficacy (grade A). Choice of product is to be made using a decision-making process shared between the rheumatology specialist and the patient, based on: - current safety data: The risk of severe infection appears to be similar at the recommended dose for all three available TNFα inhibitors; however, the risk of tuberculosis (grade C) seems to be greater for infliximab and adalimumab than for etanercept. - the patient s background and compliance, the fact that it is not possible to use diseasemodifying treatment (with professional agreement). AFSSAPS produced guidelines concerning the risk of tuberculosis in July 2005: Prevention and management of tuberculosis occurring in patients on TNFα inhibitors, according to which it is necessary to screen at-risk patients for latent or active tuberculosis, to implement preventative treatment if latent tuberculosis is present or curative treatment if active tuberculosis is present, before starting TNFα inhibitor treatment. In its guidelines concerning use of TNFα inhibitors in rheumatoid arthritis (May 2007), the French Rheumatology Society (SFR) drew the following conclusion: it is not possible to rank TNFα inhibitors according to efficacy. The choice of treatment must be made using a joint decision involving the patient, based on: - available safety data: the risk of infection appears similar with all 3 products at the usual doses however, the risk of tuberculosis seems to be greater for infliximab and adalimumab than for etanercept. - the patient s background. The SFR, when consulted by the Transparency Committee in October 2007, confirmed its recommendations: Currently, no scientifically validated information exists that would enable SFR to recommend the prescription of one particular drug as a first-line therapy, particularly etanercept. Likewise for safety data; although there are some indications to suggest that etanercept is better tolerated, particularly in terms of infection (see the updated SFR/CRI guidelines). There is therefore currently no adequate scientific argument to support the choice of any particular TNFα inhibitor in the first instance. 15

16 4.3. Transparency Committee recommendations The data provided, which concur with the current SPC for ENBREL, do not warrant amendment of the previous opinion of the Transparency Committee concerning ENBREL in its rheumatoid arthritis indication, and concerning the role of the various TNFα inhibitors in therapeutic management of rheumatoid arthritis. 16