HUMIRA - HUMIRA - CT 10819 9855 - English version
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HUMIRA - HUMIRA - CT 10819 9855 - English version

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15 Pages
English

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Introduction HUMIRA 40 mg, solution for injection in pre-filled syringe B/2x 0.8 ml pre-filled glass syringes with 2 alcohol wipes (CIP code: 362 230-5) HUMIRA 40 mg, solution for injection in pre-filled pen B/2x 0.8 ml pens with 2 alcohol wipes (CIP code: 378 014-5) Posted on Dec 15 2011 Active substance (DCI) adalimumab ATC Code L04AB04 Laboratory / Manufacturer ABBOTT FRANCE HUMIRA 40 mg, solution for injection in pre-filled syringe B/2x 0.8 ml pre-filled glass syringes with 2 alcohol wipes (CIP code: 362 230-5) HUMIRA 40 mg, solution for injection in pre-filled pen B/2x 0.8 ml pens with 2 alcohol wipes (CIP code: 378 014-5) Posted on Dec 15 2011

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Published 21 September 2011
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   The legally binding text is the original French version   TRANSPARENCY COMMITTEE  OPINION   21 September 2011   HUMIRA 40 mg, solution for injection in pre-filled syringe B/2x 0.8 ml pre-filled alcohol wipes (CIP code: 362 230-5)glass syringes with 2  HUMIRA 40 mg, solution for injection in pre-filled pen B/2x 0.8 ml pens with 2 alcohol wipes (CIP code: 378 014-5)  Applicant: ABBOTT FRANCE  adalimumab  ATC code: L04AB04 (TNF inhibitor)  List I  Medicine for annual hospital prescription only. Prescription restricted to specialists in rheumatology, gastroenterology, gastrointestinal surgery,dermatology, paediatrics and internal medicine.  Date of Marketing Authorisation: 8 September 2003 (centralised procedure)  Date of amendments to the Marketing Authorisation: - 1 July 2010 (amendment to wording of indication in Crohn's Disease) - March 2011 (amendment to the indication and the dosage for juvenile idiopathic 18 arthritis)  Exception drug status  Reason for request: - to the inclusion conditions in the indication for juvenile idiopathic arthritis Amendment (JIA). The indication is no longer restricted to adolescents from 13 to 17 years but has been expanded to include paediatric patients and adolescents aged from 4 to 12 years. -by National Insurance and approved for use on the list of medicines refundable  Inclusion by hospitals of a new form for paediatric use only (separate opinion). - Amendment to the conditions of inclusion in the indication for Crohn's Disease (removal of the need to combine with corticosteroids when starting treatment with HUMIRA). - of Therapeutic Information Sheet. Update    Medical, Economic and Public Health Assessment Division
 
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1.
 
CHARACTERISTICS OF THE MEDICINAL PRODUCT
 1.1. Active ingredient  Adalimumab  1.2. Indication  Polyarticular juvenile idiopathic arthritis  Previous wording: “HUMIRA, combined with methotrexate, is indicated for the treatment of progressive polyarticular juvenile idiopathic arthritis in adolescents aged 13 to 17 years who have not had a satisfactory response to one or more disease-modifying treatments. HUMIRA may be given as monotherapy in cases of methotrexate intolerance or where continued treatment with methotrexate is inappropriate.”  New wording forming the subject of the application: “HUMIRA, combined with methotrexate, is indicated for the treatment of progressive polyarticular juvenile idiopathic arthritis in children and adolescents aged4 to 17 yearswho have not had a satisfactory response to one or more disease-modifying treatments. Humira can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate. (For the efficacy in monotherapy see SPC).Humira has not been studied in children aged less than 4 years."  Note: the age range now referred to in the indication of HUMIRA for JIA is identical to that of ENBREL.  Crohn's Disease  Previous wording: HUMIRA 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/or an immunosuppressant; or who are intolerant to or have medical contraindications for such therapies. In the case of induction treatment, HUMIRA must be administered in combination with corticosteroids. HUMIRA may be given as monotherapy in cases of corticosteroid intolerance or where continued treatment with corticosteroids is inappropriate" .  New wording forming the subject of the application: HUMIRA 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/or an immunosuppressant; or who are intolerant to or have medical contraindications for such therapies.  Note: the wording for HUMIRA is now identical to that of REMICADE, with the exception of the induction for fistulating Crohn's disease.  
 
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  Other indications not concerned by this assessment:  “Rheumatoid arthritis HUMIRA in combination with methotrexate is indicated for:  - of moderate to severe active rheumatoid arthritis in adults responding treatment inadequately to disease-modifying treatments, including methotrexate.  
- 
treatment of severe, active, progressive rheumatoid arthritis in adults not previously treated with methotrexate.  HUMIRA may be given as monotherapy in cases of methotrexate intolerance or where continued treatment with methotrexate is inappropriate. It has been shown that HUMIRA, when administered in combination with methotrexate, slows the progression of radiographically measured structural joint damage and improves functional capabilities.  Psoriatic arthritis HUMIRA is indicated for the treatment of active, progressive psoriatic arthritis in adults previously responding inadequately to disease-modifying treatment. It has been shown that HUMIRA slows the progression of radiographically measured structural damage of peripheral joints in patients with symmetrical polyarticular forms of the disease and improves functional capabilities.  Ankylosing spondylitis HUMIRA is indicated for the treatment of severe, active ankylosing spondylitis in adults responding inadequately to conventional treatment.  Psoriasis HUMIRA is indicated in the treatment of moderate to severe plaque psoriasis in adults who have not responded to other systemic treatments, such as ciclosporin, methotrexate or PUVA treatment, or in whom these treatments are contraindicated or poorly tolerated."  1.3. Dosage  "“Treatment with HUMIRA must be initiated and supervised by a specialist experienced in the diagnosis and treatment of rheumatoid arthritis, juvenile idiopathic arthritis,psoriatic arthritis, ankylosing spondylitis,Crohn’s disease psoriasis. Patients being treated with or HUMIRA will be given a special alert card. After proper training in the injection technique, patients may self-inject with HUMIRA if their doctor considers it feasible, subject to appropriate medical monitoring.  Dosage relating to the amendment to the wording of the indication for JIA:  JIA in children from 4 to 12 years: "The recommended dosage of HUMIRA for patients with polyarticular juvenile idiopathic arthritis, aged 4-12 years, is 24 mg/m2body surface area up to a maximum single dose of 40 mg adalimumab administered every other week via subcutaneous injection. The volume for injection is selected based on the patients' height and weight (table 1).
 
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  Table 1. Dosage in millilitres (ml) by height and weight of children for polyarticular juvenile idiopathic arthritis Height Total body weight (kg) (cm) 10 15 20 25 30 35 40 45 50 55 60 65 70 80 0.2 0.3 0.3 0.3         90 0.2 0.3 0.3 0.4 0.4 0.4       100 0.3 0.3 0.3 0.4 0.4 0.4 0.5 0.5     110 0.3 0.3 0.4 0.4 0.4 0.5 0.5 0.5 0.5 0.6 0.6  120 0.3 0.4 0.4 0.4 0.5 0.5 0.5 0.6 0.6 0.6 0.6 0.7 0.7 130 0.4 0.4 0.5 0.5 0.5 0.6 0.6 0.6 0.6 0.7 0.7 0.7 140  0.7 0.7 0.7 0.7 0.8*0.4 0.4 0.5 0.5 0.6 0.6 0.6 150   0.7 0.7 0.7 0.8*0.5 0.5 0.6 0.6 0.6 0.7 0.8* 160   0.8* 0.8* 0.8* 0.7 0.8*0.5 0.5 0.6 0.6 0.7 0.7 170   0.6 0.6 0.6 0.7 0.7 0.8* 0.8* 0.8* 0.8* 0.8* 180     0.8* 0.8* 0.8* 0.8* 0.8*0.6 0.7 0.7 0.8* * Maximum single dose is 40 mg (0.8 ml) Limited data is available for treatment with HUMIRA in children weighing less than 15 kg."   JIA in adolescents from 13 to 17 years: For adolescents aged 13-17 years, the recommended dosage is 40 mg is administered every other week regardless of body surface area. A 40 mg pen and a 40 mg prefilled syringe are also available for patients to administer a full 40 mg dose.  For all patients with juvenile idiopathic arthritis treated with HUMIRA, available data suggest that clinical response is usually achieved within 12 weeks of treatment. Continuation of treatment must be carefully reconsidered in patients who have not responded to the treatment within this period.  Crohn's Disease: The recommended HUMIRA induction dose regimen for adult patients with severe Crohn's disease is 80 mg at Week 0 followed by 40 mg at Week 2. In case there is a need for a more rapid response to therapy, the regimen 160 mg at Week 0 (dose can be administered as four injections in one day or as two injections per day for two consecutive days), 80 mg at Week 2, can be used with the awareness that the risk of adverse events is higher during induction. After induction treatment, the recommended dosage is 40 mg every other week via subcutaneous injection. Alternatively, if a patient has stopped HUMIRA treatment and signs and symptoms of disease recur, HUMIRA may be re-administered. There is little experience from re-administration after more than 8 weeks since the previous dose. During maintenance treatment, corticosteroids may be tapered in accordance with clinical practice guidelines. Some patients who experience a decrease in their response to treatment may benefit from an increase in dosing frequency to 40 mg HUMIRA every week. Some patients who have not responded by Week 4 may benefit from continued maintenance therapy through to Week 12. Continued therapy should be carefully reconsidered in a patient not responding within this time period.  Note: no amendment has been made to the dosage of HUMIRA for Crohn's disease.  For other indications already assessed by the Committee, see SPC.      
 
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2.
 
SIMILAR MEDICINAL PRODUCTS
 2.1. ATC Classification (2011)  L : Antineoplastic and immunomodulating agents L04 : Immunosuppressants L04A : Immunosuppressants L04AB : Inhibitors of tumour necrosis factor alpha (TNF alpha) L04AB04 : adalimumab  2.2. Juvenile idiopathic arthritis  Medicines in the same therapeutic category Only one other TNF inhibitor is indicated from 4 years in the treatment of juvenile idiopathic arthritis: ENBREL 25 mg (etanercept) powder and solvent for solution for injection in pre . Table 1: Table comparing HUMIRA®and ENBREL®in polyarticular JIA HUMIRA®ENBREL®     - active polyarticular JIAactive polyarticular JIA -- 4 to 17 years - 4 to 17 years  - In cases of insufficient response to one or - in cases of an inadequate response or more disease-modifying treatments intolerance to MTX JIA Indication· combined with MTX· monotherapy (without MTX) as · monotherapy (without MTX) in as cases of intolerance to MTX or when continuation of MTX is inappropriate. Route ofSubcutaneous Subcutaneous administration From 4 to 12 years : 24 mg/m2 mg/ kg twice a week 0,4 body
Dosage  
surface area (maximum de 40 mg) every other week, For adolescents aged 13-17 years, 40 mg is administered every other week,
(25 mg maximum per injection)
   Medicines with a similar therapeutic aim These are medicinal products with a Marketing Authorisation for juvenile idiopathic arthritis: - (abatacept): selective immunosuppressant acting through selective ORENCIA modulation of T cell co-stimulation is also indicated in combination with methotrexate in the treatment of polyarticular JIA in children from 6 years who have had an inadequate response to one or more disease-modifying medicinal products including at least one TNF inhibitor (AB substantial and IAB V in the opinion plan of the Transparency Committee of 5 January 2011). - ROACTEMRA (tocilizumab) has a Marketing Authorisation for JIA from 2 years, but it is yet to be assessed by the Transparency Committee - methotrexate (MTX); METHOTREXATE BELLON, METOJECT, LEDERTHREXATE®  - Local corticosteroid therapy (HEXATRIONE).
 
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   2.3. Crohn's Disease  Medicines in the same therapeutic category Only one other TNF inhibitor is indicated in the treatment of Crohn's Disease in adults: REMICADE (infliximab) IV infusion.  Table 2. Comparison of indications of HUMIRA and REMICADE in Crohn's Disease  HUMIRA® REMICADE  HUMIRA is indicated for treatment of Treatment of moderate to severe, active severe, active Crohn's disease, in patients Crohn's disease, in patients who have not who have not responded despite a full and responded despite a full and adequate adequate course of therapy with a course of therapy with a corticosteroid corticosteroid and/or an and/or an immunosuppressant; or who immunosuppressant; or who are intolerant are intolerant to or have medical Indication for Crohn's contraindicationsto or have medical contraindications for for such therapies. Disease in adultssuch  teharipse Cngtila 'shnrocaito  fsiutevf  Tmentreat  disease, in patients who have not responded despite a full and adequate course of therapy (including antibiotics, drainage and immunosuppressant therapy).  No 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 Indication for Crohn'simmunomodulator and first-line nutrition Disease in childrentherapy; or who are intolerant to or have contraindications for such therapies. REMICADE has only been evaluated in combination with a conventional immunosuppressant treatment.   Medicines with a similar therapeutic aim These are medicinal products with a Marketing Authorisation for severe Crohn's Disease: - Azathioprine - dose corticosteroids (oral/IV). High  
 
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3.
 
ANALYSIS OF AVAILABLE DATA
 3.1. Juvenile idiopathic arthritis  Context: In 2008, the extension in the indication of HUMIRA (at a set dose of 40 mg every two weeks) in polyarticular juvenile idiopathic arthritis (JIA) was restricted by EMA to the age range of between 13 and 17 years due to there being insufficient data to specify a set dose, and in the absence of a form that allows administration of a dose modified to body surface area, as evaluated in the only efficacy clinical study available.  After having developed a new paediatric form with a graduated syringe allowing the required quantity to be drawn, based on the body surface area, the laboratory requested an amendment to the indication reimbursable for HUMIRA pen and pre-filled syringe (extension for children from 4 to 12 years) and the inclusion of the new paediatric form.  This extension in indication for children from 4 to 12 years was carried out based on the main results from the DE038 study, previously evaluated by EMA in 2008 and by the Transparency Committee in 2009. No other clinical study was included in the file. Only the additional results from an intermediate analysis of the open-label extension of the DE038 study were supplied and are described below.  The Marketing Authorisation for other forms of HUMIRA 40 mg pen and pre-filled syringes (although not allowing for dosage based on body surface area) was expanded to cover children aged between 4 and 12 years, for ease of use for children in this age range who need a set 0.8 ml or 40 mg dose, based on their body surface area (see dosage table below).   Table 3. Dosage of HUMIRA in JIA Height Total body weight (kg) (cm) 10 15 20 25 30 35 40 45 50 55 60 65 70 80 0.2 0.3 0.3 0.3         90 0.2 0.3 0.3 0.4 0.4 0.4       100 0.3 0.3 0.3 0.4 0.4 0.4 0.5 0.5     110 0.3 0.3 0.4 0.4 0.4 0.5 0.5 0.5 0.5 0.6 0.6  120 0.3 0.4 0.4 0.4 0.5 0.5 0.5 0.6 0.6 0.6 0.6 0.7 0.7 130 0.4 0.4 0.5 0.5 0.5 0.6 0.6 0.6 0.6 0.7 0.7 0.7 140  0.7 0.7 0.7 0.7 0.8*0.4 0.4 0.5 0.5 0.6 0.6 0.6 150  0.5 0.5 0.6 0.6 0.6 0.7 0.8* 0.7 0.7 0.7 0.8* 160  0.5 0.5 0.6 0.6 0.7 0.7 0.70.8* 0.8* 0.8* 0.8* 170   0.6 0.6 0.6 0.7 0.70.8* 0.8* 0.8 0.8* 0.8* * 180    0.6 0.7 0.70.8* 0.8* 0.8* 0.8* 0.8* 0.8*   From data from the DE0381evaluated by the Transparency Committee, 24 June 2009:study "The efficacy of HUMIRA in the treatment of JIA was evaluated in a clinical study versus placebo (DE038). The patients were divided into two strata: "with MTX" and "without MTX". The principal objective of this study was to demonstrate the superior efficacy of HUMIRA monotherapy (without MTX) over placebo.                                                 1 Daniel J. Lovell et al. Adalimumab with or without Methotrexate in Juvenile Rheumatoid Arthritis. N Engl J Med 2008; 359: 810-20. *American College of rheumatology 7/15  
  This study consisted of three phases. During the pre-inclusion first phase of the study, 171 patients aged 4 to 17 years (102 patients aged 4-12 years and 69 aged 13-17 years) were treated for 16 weeks on an open-label basis, with HUMIRA 24 mg/m² administered every 2 weeks (maximum dose 40 mg). The proportion of patients with an ACR paediatric 30 response2 74.4% in the was HUMIRA “without MTX” stratum and 94.1% in the HUMIRA “with MTX” stratum.  Of the 144 patients responding by Week 16, 133 were included into the second double-blind phase, to receive either HUMIRA 24 mg/m² every 2 weeks (maximum dose 40 mg) or placebo in each of the strata. The proportion of patients experiencing an inflammatory flare-up3by Week 32 in the stratum without MTX (primary efficacy endpoint of the study) was significantly smaller in the HUMIRA without MTX group (13/30, 43.3%) than in the placebo group (20/28, 71.4%), p = 0.031. The proportion of patients experiencing an inflammatory flare-up by Week 32 in the stratum with MTX (secondary endpoint) was significantly smaller in the HUMIRA + MTX group (14/38, 36.8%) than in the placebo + MTX group (24/37, 64.9%), p = 0.015. However, given the study methodology, an overestimation of the size of the effect of HUMIRA cannot be ruled out " .  New clinical data for the open-label extension of the DE038 study: intermediate results at 176 weeks (more than 3 and a half years) The Transparency Committee regretted the absence of long-term efficacy data for this paediatric population and has taken note of the extension of the ongoing open-label study, running for 5 years. Only the intermediate results for 16 weeks were available at the time of the evaluation in 2009. The aim of this period was to assess the maintenance of efficacy and the tolerance profile of HUMIRA over the long-term. The patients that had completed 32 weeks of the double-blind period, or that had had an inflammatory flare-up during this period could be included in the extension phase, which comprised of two sub-periods: - one period during which patients (n=128) received a variable dose of HUMIRA based on body surface area: 24 mg/m² of the body surface area, SC every 2 weeks (maximum dose 40 mg) over a maximum of 136 weeks and, - other, during which the patients (n=106) received, after an amendment to the the protocol, a set dose based on weight: 20 mg, SC, every 2 weeks if they weighed < 30 kg and 40 mg if they weighed³30 kg  The final analysis was scheduled for the 224thweek of the set dose sub-period. Intermediate analyses were carried out.  Results: All 128 patients completed the double blind period and were included in the first "dose based on body surface area" sub-period of the extension. Of these 128 patients, 22 stopped treatment prematurely for the following reasons: - withdrawn consent (n=9; 7.0%), - lack of efficacy (n=4; 3.1%),
                                            2 The ACR paediatric 30 response corresponds to an improvement of at least 30% compared to baseline with respect to three of the six factors and aggravation of a maximum of one factor of the ACR paediatric score. The six factors are:  overall assessment of disease severity by the doctor (on a visual analogue scale VAS 0-100 mm)   overall 0 - 100 mm) VASassessment of the patient’s general well-being by a parent (on  patient’s functional capacity (Disability index of Childhood Health Assessment Questionnaire – CHAQ)  number of swollen joints  number of joints with restricted mobility  CRP (C-reactive protein) 3 An inflammatory flare-up was defined as: - aggravation of at least 30% in the score for at least three of the six factors in the “ACR paediatric” criteria and, an - the presence of at least two swollen joints and, -                   8/15  
  - adverse event (n=2; 1.6%), - violation of protocol (n=1; 0.8%), - other reasons (n=6; 4.7%).  Analysis of the efficacy of HUMIRA during this first extension phase was carried out on the patients that had received at least one dose based on the body surface area between Week 32 and Week 136 of the trial. The median duration of treatment for patients during this phase was not stated. Efficacy data is presented at Week 104 (Table 4), the number of patients that stopped at 120 or 136 weeks of treatment was very low (17 patients at Week 120 and 5 patients at Week 136). A total of 106 patients were included in the second open-label, set dose sub-period. The final analysis was scheduled for the 224th but only an intermediate analysis at Week 176 week, was available at the time of submitting the file to request an amendment to the indication of HUMIRA in JIA. At 176 weeks, 43 patients had stopped treatment for the following reasons: - lost to follow-up (n=13; 12.3%); - withdrawn consent (n=9; 8.5%) - adverse event (n=4; 3.8%) - lack of efficacy (n=3; 2.8%) - violation of protocol (n=2; 1.9%)  - other reasons (n=12; 11.3%)   The analysis at the 176thweek was carried out on 38 patients, with no missing data (table 4).
 
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  Table 4. Analysis of the ACR paediatric 30 response for the different patient groups during the open-label “dose based on body surface area –BSAD" and "set dose - SD " extension period.  ACR 30 with MTX without MTX "BSAD" and Humira®with MTX Humira® Humirawith MTX®without Humira®without "SD" Period (Dose unchanged (Dose increased) MTX MTX or reduced) (n=31) (Dose unchanged (Dose increased) n=28 N1/N2* (%) or reduced n=22 N1/N2* (%) (n=25) N1/N2* (%) N1/N2* (%) Week -120 10/10 (100.0%) 6/6 (100.0%) 5/7 (71.4%) 3/3 (100.0%) Period C "BSAD" PeriWoed eCk  -"1B0S4A D" 16/18 (88.9%) 8/9 (88.9%) 10/10 (100.0%) 8/8 (100.0%) PeriWode eCk "-B 8S8A D" 22/23 (95.7%) 22/24 (91.7%) 14/15 (93.3%) 13/13 (100.0%)  2 PeriWode eCk  "-B 7SAD" 23/23 (100.0%) 26/27 (96.3%) 20/20 (100.0%) 18/18 (100.0%) PeriWode eCk  "- B5S6 AD" 23/23 (100.0%) 30/30 (100.0%) 21/22 (95.5%) 19/20 (95.0%) PeriWode eCk  "- B4S0 AD" 20/22 (90.9%) 25/28 (89.3%) 22/23 (95.7%) 18/20 (90.0%) PeriWode eCk  "-B 2S4A D" 24/24 (100.0%) 22/26 (84.6%) 23/23(100.0%) 20/21 (95.2%) PerioWde eC k" -B 8S AD" 16/16 (100.0%) 28/29 (96.6%) 24/24 (100.0%) 15/17 (88.2%) Baseline Period C "SD" 24/24 (100.0%) 29/29 (100.0%) 24/24 (100.0%) 20/21 (95.2%) PeWrieoed k C+  "1S2D " 1/1 (100.0%) 25/27 (92.6%) 2/2 (100.0%) 16/18 (88.9%) 16 23/24 (95.8%) 2 (94.7%) PeWrieoedk  C+  "SD" 8/29 (96.6%) 23/24 (95.8%) 18/19 PeWrieoed k C+  "3S2D " 22/22 (100.0%) 28/29 (96.6%) 22/23 (95.7%) 18/18 (100.0%) PeWrieoed k C+  "4S8D " 20/22 (90.9%) 27/29 (93.1%) 23/23 (100.0%) 17/17 (100.0%) PeWrieoedk  C+  "6S4D " 22/22 (100.0%) 28/29 (96.6%) 19/20 (95.0%) 17/17 (100.0%) eek + 80 .9%) 26/28 (92.9%) 19/19 (100.0% PeWriod C "SD" 20/22 (90) 16/16 (100.0%) PeWrieoed k C+  "9S6D " 17/19 (89.5%) 24/26 (92.3%) 18/18 (100.0%) 16/16 (100.0%) PWerieoedk  C+  1S1D2 " 16/1 " 6 (100.0%) 23/25 (92.0%) 16/16 (100.0%) 15/15 (100.0%) PeWrieoedk  C+  "1S2D8 " 13/13 (100.0%) 23/24 (95.8%) 15/15 (100.0%) 11/11 (100.0%) Week + 144 Period C SD" 8/8 (100.0%) 20/21 (95.2%) 13/13 (100.0%) 7/7 (100.0%) " PWereioedk  C+  "1S60D " 7/7 (100.0%) 19/19(100.0%) 9/9 (100.0%) 6/6 (100.0%) Week + 176 " 5/5 (100.0%) 19/20 (95.0)% 7/7 (100.0%) 6/6 (100.0%) Period C "SD PeWrieoedk  C+  "1S9D2 " 1/1 (100.0%) 3/3 (100.00%)  2/2 (100.0%) *N1 = number of patient responders; N2 = number of patients with no missing data  Overall, this data from the intermediate analysis of the open-label extension phase of the DE038 study and carried out on a small number of participants is limited: only five patients were treated to 136 weeks with one dose based on body surface area and 38 patients at 176 weeks with a set dose of HUMIRA. At 192 weeks the number was only six patients.  Given this information, in 2009, the Transparency Committee asked to receive the results from the real time evaluation of the study on the efficacy and long-term tolerance of HUMIRA, requested by EMA (STRIVE registration) within the scope of the Risk Management Plan. According to the information sent by the laboratory, this registration, which plans to monitor patients over 10 years, was implemented in 2009 in the United States and Europe 10/15  
  and only concerns patients aged 13 to 17 years. It plans to include 800 patients who will be divided into two arms: - patients treated with HUMIRA (as monotherapy or in combination with MTX): the number of patients to be included is approximately 500. - patients treated with MTX without HUMIRA: the number of patients to be included is approximately 300 patients (this group is considered as the reference group).  On 16 March 2011, a total of 398 patients were included, of which five patients were in France (implementation of this trial in France was later / opinion of CNIL obtained in January 2010).  During the previous assessment in 2009, the Committee concluded that no tolerance issues were noted during the clinical trial in the children and adolescent populations treated, compared with the known tolerance profile for HUMIRA in adults. As for the adults, the most common adverse effects were infections and reactions at the injection site. No cases of death, cancer, congestive heart failure or opportunistic infections were reported. However, long-term tolerance data was limited in the paediatric population. Data from the open-label extension period (up to 176 weeks of the set dose period) did not highlight any unexpected adverse effects. The maximum exposure duration of HUMIRA was 6.65 years. The most common adverse events were infections (115.4 events for 100 patient  3.2. Crohn's Disease  Context: In 2007, during the initial Marketing Authorisation, the combined analysis of the two clinical studies (CLASSIC I and GAIN) demonstrated a statistically higher efficacy for HUMIRA at week 4 in patients receiving concomitant treatment with corticosteroids compared with those not receiving it (40.3% of patients in clinical remission at Week 4 in the HUMIRA + corticosteroid group versus 8.2% in the placebo + corticosteroid group, 19% of patients in clinical remission at Week 4 in the HUMIRA without corticosteroid group versus 9.2% in the placebo without corticosteroid group). As a result, the following was added to the wording of the indication: "For induction treatment, HUMIRA should be administered with corticosteroids. HUMIRA may be given as monotherapy in cases of corticosteroid intolerance or where continued treatment with corticosteroids is inappropriate.”  In July 2010, based on post-hoc analysis of four trials (three of which have already been assessed by the Transparency Committee): CLASSIC I, GAIN, CHARM, EXTEND, showing no statistical difference in terms of efficacy between patients receiving concomitant therapy with corticosteroids and those not, EMA removed the obligation to combine HUMIRA with corticosteroids during the induction phase of treatment.  Presentation of data:  Only the EXTEND study was not assessed by the Transparency Committee in 2007. It was a controlled, randomised, double-blind trial versus placebo, with the principal objective of demonstrating the efficacy of HUMIRA on mucosal healing in 135 patients with moderate to severe Crohn's disease. The trial comprised of a 4 week, open-label induction period, during which all patients were treated with HUMIRA 40 mg. Patients were then included in a double  Results of the post-hoc analysis of data from the EXTEND, CHARM, GAIN and CLASSIC I trials  The aim of these analyses was to evaluate the level of concomitant effect of corticosteroids on the clinical remission rate and response at Week 4 during the therapeutic induction phase for HUMIRA.
 
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