Resolution by the Federal Joint Committee on an amendment to the Pharmaceutical Directive (AM-RL): Appendix XII Resolutions on the benefit assessment of pharmaceuticals with new active ingredients, in accordance with the German Social Code, Book Five (SGB V), section 35a Teriflunomide from 20 March 2014 In its session on 20 March 2014, the Federal Joint Committee resolved to amend the Pharmaceutical Directive (AM-RL), version published 18 December 2008/22 January 2009 (Federal Gazette, number 49a of 31 March 2009), last amended on 16 May 2013 (Federal Gazette, AT 25 February 2014 B2), as follows: Appendix XII shall be amended in alphabetical order to include the active ingredient teriflunomide: Teriflunomide Therapeutic indication: Teriflunomide (Aubagio ) is indicated for the treatment of adult patients with relapsing-remitting multiple sclerosis (MS). 1. Additional benefit of the pharmaceutical over appropriate comparator : I. The appropriate comparator for the treatment of adult patients with relapsing-remitting multiple sclerosis (MS) is interferon beta (IF-ß) 1a or IF-ß 1b or glatiramer acetate under consideration of the respective therapeutic indication. Extent and probability of additional benefit over appropriate comparator: An additional benefit has not been proved.
Study results according to endpoints (TEERE) Mortality category Result/ event rate Result/ event rate mg vs. IF ß-1a 44 µg RR Deaths 1 110 0 (0 %) 101 0 (0 %) no deaths Morbidity Relapse-related endpoints (EDSS-based) 2 Patients with confirmed relapse 111 26 (23.4 %) 104 16 (15.4 %) 1.52 [0.87; 2.67] p = 0.143 Probability of a relapse by week 96 111 KM-estimators 104 KM-estimators HR 0.29 [0.19; 0.40] 0.19 [0.10; 0.27] 1.46 [0.78; 2.73] p = 0.229 category Relapse rate Annual relapse rate 111 0.26 [0.15; 0.44] Relapse rate 104 0.22 [0.11; 0.42] mg vs. IF ß-1a 44 IDR 1.20 [0.62; 2.30] p = 0.590 At least 12 weeks of continual disability progression (EDSS-based) Patients with disability progression 111 Pat. with event (%) 104 Pat. with event (%) RR 10 (9.0 %) 9 (8.7 %) 1.04 [0.44; 2.46] p = 0.927 Time until disability progression 111 KM-estimators 0.12 [0.05; 0.20] 104 KM-estimators 0.10 [0.04; 0.16] HR 0.98 [0.40; 2.42] p = 0.969 Health-related quality of life after 48 weeks 3 mg vs. IF ß-1a 44 µg MD s SB MV SE change SB MV SE change FIS overall score 4 106 42.5 4.10 97 34.2 9.10-5.00 [-12.31; 2.31] p = 0.179 Cognitive dimension 106 10.2 0.87 97 7.8 2.34-1.47 [-3.51; 0.58] p = 0.160 Physical dimension 106 12.6 1.19 97 11.1 1.51-0.32 [-2.37; 1.73] p = 0.762 Psychosocial dimension 106 19.7 2.70 97 15.4 5.52-2.81 [-6.51; 0.89] p = 0.136 1 2 3 4 Deaths refer to safety population with at least one administration of the pharmaceutical. Relapse: worsening of symptoms by 0.5 points on the EDSS (unless initial EDSS = 0, then 1 point) or increase by 1 point in 2 FS or by 2 points in one FS that lasts for more than 24 hours and is not accompanied by fever. Symptom-specific health-related quality of life associated with fatigue. High FIS scores correspond to low symptom-specific health-related quality of life.
Side effects Pat. with event Pat. with event (%) (%) AE 110 102 (92.7 %) 101 97 (96.0 %) mg vs. IF ß-1a 44 RR SAE 110 4 (3.6 %) 101 6 (5.9 %) 0.61 [0.18; 2.11] p = 0.525 Discontinuation due to AE, without pregnancy, examinations Discontinuation due to AE, without pregnancy 110 7 (6.4 %) 101 9 (8.9 %) 0.71 [0.28; 1.85] p = 0.529 110 12 (10.9 %) 101 20 (19.8 %) 0.55 [0.28; 1.07] p = 0.081 Pat. with event (%) Pat. with event (%) mg vs. IF ß-1a 44 AD 5 in percentages RR Reactions at injection site 110 0 101 22 (21.8 %) 21.8 0.10 [0.04; 0.24] Flu-like symptoms 110 3 (2.7 %) 101 54 (53.5 %) 50.7 0.05 [0.02; 0.16] Alopecia 110 22 (20.0 %) 101 1 (1.0 %) -19.0 7.01 [2.95; 16.65] Diarrhoea 110 23 (20.9 %) 101 8 (7.9 %) 13.0 2.64 [1.24; 5.63] p = 0.008 ausea and vomiting 110 15 (13.6 %) 101 5 (5.0 %) 8.7 2.75 [1.04; 7.31] p = 0.033 Data from IQWiG benefit assessment Abbreviations used: AD = absolute difference; EDSS = Expanded Disability Status Scale; FIS = Fatigue Impact Scale; FS = functional systems; HR = hazard ratio; IDR = incidence rate ratio; IF ß-1a = Interferon beta-1a; CI = confidence interval; KM = Kaplan-Meier; MV = mean value; = number; RR = relative risk; SB = study begin; SE = study end; SOC = MedDRA system organ class; (S)AE = (serious) adverse events 2. umber of patients and criteria for defining patients eligible for treatment umber: approx 85,000 105,000 patients 3. Requirements for quality-assured administration The specifications outlined in the product information are to be followed. The European Medicines Agency (EMA), the European regulatory authority, provides the product information for Aubagio (active ingredient: teriflunomide) at the following public link (last accessed: 13 February 2014): http://www.ema.europa.eu/docs/en_gb/document_library/epar_- _Product_Information/human/002514/WC500148682.pdf Treatment must be initiated and leading treatment decision taken by a specialist physician for neurology experienced in the treatment of multiple sclerosis. Treatment must be supervised by a specialist physician experienced in the treatment of multiple sclerosis. The EPAR states that upon market launch and following, all physicians/healthcare professionals expected to use 5 Figures shown for significant differences only.
Aubagio must receive a patient information card and consultation guideline for physicians/healthcare professionals, including the following information: Risk of impaired liver function and necessity of liver function tests before and regularly during treatment Signs and symptoms of liver disease Possible risk of teratogenicity, necessity of reliable contraception Risk of high blood pressure Risk of haematological effects Risk of infections 4. Costs of treatment Duration of treatment: umber of treatments per patient Duration of per treatment Treatment days per patient Mode of treatment per year (days) per year Teriflunomide (Aubagio ) 1 x daily ongoing 365 365 Glatiramer acetate (Copaxone ) Interferon beta 1a (e. g. Avonex ) Interferon beta 1b (e. g. Extavia ) Consumption: 1 x daily 1 x weekly every 2 days ongoing 365 365 ongoing 365 52 ongoing 365 182.5 Strength umber of application units (µg or mg) per pack Average annual consumption Teriflunomide (Aubagio ) 14 mg 84 coated tablets 365 coated tablets appropriate comparator Glatiramer acetate (Copaxone ) 20 mg 90 pre-filled syringes 365 pre-filled syringes Interferon beta 1a (e. g. Avonex ) 30 µg 12 pre-filled syringes 52 injections Interferon beta 1b (e. g. Extavia ) 250 µg 45 substance and injectable solution 182.5 injections Costs: Cost of pharmaceutical: Cost (pharmacy retail price) Cost after legally mandated rebates Teriflunomide (Aubagio ) 5,557.86 5,286.80 [ 1.80 6 ; 269.26 7 ] Glatiramer acetate (Copaxone ) 4,878.90 4,389.52 [ 1.80 6 ; 487.58 7 ] Interferon beta 1a (e. g. Avonex ) 5,112.60 4,678.72 [ 1.80 6 ; 432.08 7 ] Interferon beta 1b (e. g. Extavia ) 4,140.11 3,938.45 [ 1.80 6 ; 199.86 7 ] "Lauer-Taxe", effective: 1 March 2014 6 7 Rebate in accordance with SGB V, section 130. Rebate in accordance with SGB V, section 130a.
Costs for additional, necessary statutory health insurance (SHI) benefits: none Annual treatment costs: Annual treatment costs per patient Teriflunomide 22,972.40 Glatiramer acetate (Copaxone ) 17,801.95 Interferon beta 1a (e. g. Avonex ) 20,274.45 Interferon beta 1b (e. g. Extavia ) 15,972.60 II. This resolution takes effect on the day of its publication in the internet on the website of the Federal Joint Committee on 20 March 2014. The justification for this resolution will be published on the websites of the Federal Joint Committee at www.g-ba.de. Berlin, 20 March 2014 The Federal Joint Committee in accordance with SGB V, section 91 The Chair Hecken