The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 24 June 2009

HUMIRA 40 mg, solution for injection in pre-filled syringe B/2 x 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/2 x 0.8 ml pens with 2 alcohol wipes (CIP code: 378 014-5)

Applicant: ABBOTT adalimumab ATC code: L04AB04 List I Medicine for initial hospital prescription annually. Prescription restricted to specialists in rheumatology, gastroenterology, gastrointestinal surgery, dermatology, paediatrics and internal medicine. Date of Marketing Authorisation: 08 September 2003 (centralised procedure) Date of latest revision of Marketing Authorisation: 25 August 2008 (extension for the indication polyarticular juvenile idiopathic arthritis) Exception drug status Reason for the request: Inclusion on the list of medicines refundable by National Health Insurance and approved for hospital use in the extension of indication “progressive polyarticular juvenile idiopathic arthritis in adolescents aged 13 to 17 years who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs)”.

Medical, Economic, and Public Health Assessment Division 1/10

1.

CHARACTERISTICS OF THE MEDICINAL PRODUCT

1.1. Active ingredient adalimumab 1.2. Indications Indications prior to the application: “Rheumatoid arthritis 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. Psoriatic arthritis Humira is indicated for the treatment of active and progressive psoriatic arthritis in adults when the response to previous disease-modifying anti-rheumatic drug therapy has been inadequate. Humira has been shown to reduce the rate of progression of peripheral joint damage as measured by X-ray in patients with polyarticular symmetrical subtypes of the disease (see Section 5.1) and to improve physical function. Ankylosing spondylitis Humira is indicated for the treatment of adults with severe active ankylosing spondylitis who have had an inadequate response to conventional therapy. Crohn's disease HUMIRA is indicated for the treatment of severe, active Crohn's disease in patients who have not responded to treatment with corticosteroids and/or immunosuppressants, even though it was suitable and administered properly, or in those for whom the treatment is contraindicated or who find difficulty tolerating it. 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.” Psoriasis Humira is indicated for the treatment of moderate to severe chronic 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. New indication forming the subject of the application: “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.” 2/10

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 or psoriasis. Patients being treated with 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. During treatment with HUMIRA, other concomitant treatments (such as corticosteroids and/or immunomodulators) should be optimised. Children and adolescents (aged 13 to 17 years): Polyarticular juvenile idiopathic arthritis The recommended dosage in patients aged 13 years or older with polyarticular juvenile idiopathic arthritis is a single 40 mg subcutaneous injection of adalimumab every other week. The available data permit the assumption that a 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.” For other indications already evaluated by the Committee, refer to the SPC. 2.

SIMILAR MEDICINAL PRODUCTS

2.1. ATC Classification (2009) L : Antineoplastic and immunomodulating agents L04 : Immunosuppressants L04A : Immunosuppressants L04AB : Inhibitors of tumour necrosis factor alpha (TNF alpha) L04AB04 : adalimumab 2.2. Medicinal products in the same therapeutic category Only one other anti-TNF alpha is indicated in the treatment of juvenile idiopathic arthritis: ENBREL (etanercept) ®

®

Table 1: Table comparing Humira and Enbrel in polyarticular JIA ®

JIA

Dose Interval between doses Route

Humira - active polyarticular JIA - 13 to 17 years - In cases of insufficient response to one or more disease-modifying treatments • combined with MTX

•

®

Enbrel - active polyarticular JIA - 4 to 17 years - in cases of an inadequate response or intolerance to MTX

•

as monotherapy (without MTX)

as monotherapy (without MTX) in cases of intolerance to MTX or when continuation of MTX is inappropriate

40 mg 2 weeks Subcutaneous

0.4 mg/kg (25 mg maximum) twice per week Subcutaneous

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2.3. Medicinal products with the same therapeutic aim These are other disease-modifying immunosuppressants commonly used in the treatment of JIA. Medicinal products with an MA for children: - Methotrexate: METHOTREXATE BELLON, METOJECT Other disease-modifying treatments used off-label: - Biotherapies • anakinra – KINERET • abatacept – ORENCIA – (MA currently under evaluation) • tocilizumab – ROACTEMRA – under evaluation, available on a temporary licence since 2008

-

Classic disease-modifying treatments: products based on the following active substance: • ciclosporin • salazopyrine • leflunomide 3.

ANALYSIS OF AVAILABLE DATA

3.1. Efficacy The efficacy of HUMIRA in the treatment of polyarticular juvenile idiopathic arthritis (JIA) was assessed in a controlled randomised clinical study (DE0381) in which the primary aim was to demonstrate the efficacy of monotherapy with HUMIRA versus placebo in patients aged 4 to 17 years. The study design was complex: stratified study “with MTX” and “without MTX” in 3 periods A, B, C, open-label during periods A (pre-inclusion) and C (extension) and double-blind during period B. The patients in the stratum “without MTX” were naive for MTX or had to have discontinued MTX at least two weeks prior to inclusion into the study. A stable dose of NSAID and corticosteroids was permitted during the study (≤0.2 mg/kg/day and 10 mg maximum prednisone equivalent). Period A The aim of this open-label, pre-inclusion period was to select patients who were responders to HUMIRA. All the patients included (n = 171) received HUMIRA 24 mg/m2 (maximum dose 40 mg) every two weeks for 16 weeks. At the end of period A, patients with an ACR* paediatric 30 response were able to be included into period B. The ACR paediatric 30 response corresponds to an improvement of at least 30% compared to baseline with respect to 3 of the 6 factors and aggravation of a maximum of one factor of the ACR paediatric score. The 6 factors are: • overall assessment of disease severity by the doctor (on a visual analogue scale VAS 0-100 mm) • overall assessment of the patient’s general well-being by a parent (on VAS 0-100 mm)

1 Daniel J. Lovell et al. Adalimumab with or without Methotrexate in Juvenile Rheumatoid Arthritis. N Engl J Med 2008;359:81020.

*American College of Rheumatology 4/10

• • • •

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)

Period B: double-blind randomised period of 32 weeks. The responder patients with ACR paediatric 30 at the end of phase A (n = 133) were randomised within each stratum (with or without MTX) to receive HUMIRA® 24 mg/m2 (maximum dose 40 mg) or placebo every two weeks for 32 weeks or until the onset of an inflammatory flare-up. Period C: open-label extension period (n = 129) The aim of this period was to assess the maintenance of efficacy and the tolerance profile of HUMIRA® over the long term. Patients who had completed the 32 weeks of the double-blind period B were eligible for period C. In addition, patients with an inflammatory flare-up in period B had the possibility of immediate inclusion into period C. This open-label extension period consisted of two phases, one phase during which the patients received one dose of HUMIRA, the size varying with body surface area: 24 mg/m² body surface area SC every 2 weeks (maximum dose 40 mg) and a 2nd phase during which, following an amendment to the protocol, they received a fixed dose which was dependent on body weight: 20 mg SC every 2 weeks if weight < 30 kg and 40 mg if weight ≥ 30 kg. Principal inclusion criteria: - JIA defined by ACR criteria - age between 4 and 17 years - active disease defined as > 5 swollen joints and > 3 joints with reduced mobility - the diagnosis should have been established sufficiently long ago to have enabled the implementation of appropriate treatment with NSAID - patients naive for MTX or patients with an inadequate response to MTX or intolerance to MTX. Primary efficacy endpoint: Proportion of patients with an inflammatory flare-up in the “without MTX” stratum during the double-blind period (B). An inflammatory flare-up was defined as: - an aggravation of at least 30% in the score for at least 3 of the 6 factors in the “ACR paediatric” criteria and, - the presence of at least 2 swollen joints and, - improvement of > 30% in a maximum of 1 factor out of 6 in the “ACR paediatric” criteria. The baseline characteristics of the patients are described in table 2 below.

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Table 2. Characteristics of patients at inclusion (period A and period B) Period A, open label, preinclusion Humira Humira with without MTX MTX (n = 85) (n=86) Mean age (years)

Stratum without MTX Humira Placebo without MTX without MTX (n=30) (n = 28)

Stratum with MTX ® Placebo Humira with MTX with MTX (n = 38) (n = 37)

11.1 + 3.8

11.4 + 3.3

11.1 + 4.1

11.3 + 3.8

11.7 + 3.3

10.8 + 3.4

21 (24) 32 (37) 33 (38)

19 (22) 30 (35) 36 (42)

8 (27) 10 (33) 12 (40)

8 (29) 7 (25) 13 (46)

6 (16) 17 (45) 15 (40)

12 (32) 10 (27) 15 (41)

40.9 ± 19.28

43.8 ± 18.31

4.13 ± 17.3

45.4 ± 24.4

42.1 ± 17.9

44.3 ± 18.9

4.0 + 3.67

3.6 + 4.0

2.9 + 3.3

4.3 + 4.1

4.0 + 3.5

58.0 + 17.08

59.8 + 17.83

60.1+ 18.57

56.4 + 18.42

60.1+ 16.28

43.2 + 22.11

53.2 + 25.82

56.9 + 20.94

46.2 + 18.85

41.1 + 24.52

15.0 + 7.65

18.8 + 11.30

20 + 13.20

15.4 + 8.35

15.2 + 7.68

12.7 + 8.30

13.3 + 8.99

15.4 + 11.99

14.5 + 9.55

11.1+ 7.11

100

27

14

100

100

Age groups n (%) 4-8 years 9-12 years 13-17 years*

Mean weight (kg)

Period B, double-blind

Mean duration of JIA 3.6 + 4.04 (years) Overall assessment by doctor – mean (VAS 0- 59.7 + 19.41 100) Overall assessment by parent – mean (VAS 0- 53.4 + 22.99 100) Number of swollen 19.4 + 12.15 joints (mean out of 75) Number of joints with reduced mobility 14.3 + 9.99 (mean out of 69) Previous treatment 21 with MTX%

* The MA for HUMIRA only covers children aged 13-17 years

Results:

Pre-inclusion period: During the pre-inclusion period (A), of 171 selected patients aged 4 to 17 years, 144 patients (84.2%) had an ACR 30 paediatric response in W16. The proportion of responders was greater with HUMIRA combined with MTX than with HUMIRA monotherapy: 74.4% (64/86) responders in the stratum without MTX and 94.1% (80/85) in the stratum with MTX. Table 3. Distribution of patients by age and adalimumab dose received during the open-label preinclusion phase Age group

Number of patients at the start of the study n(%)

Minimum, median and maximum dose

4 to 7 years

31 (18.1)

10, 20 and 25 mg

8 to 12 years

71 (41.5)

20, 25 and 40 mg

13 to 17 years

69 (40.4)

25, 40 and 40 mg

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At the end of this period, 133 responders were included into the double-blind period. Double-blind period (analysis of primary endpoint) Analysis of the results was performed in ITT. Missing data were taken as inflammatory flareups. In Week 32, the proportion of patients with an inflammatory flare-up was significantly lower in the group given HUMIRA without MTX (13/30, 43.3%) than in the placebo group (20/28, 71.4%), p = 0.031. For information, in the stratum with MTX (secondary endpoint), the proportion of patients with an inflammatory flare-up was significantly lower in the group given HUMIRA + MTX (14/38, 36.8%) than in the placebo + MTX group (24/37, 64.9%), p = 0.015. Open-label 5-year extension period The open-label extension period is currently underway. Comments Given the complex study design (with selection of responders), an overestimation of the efficacy of HUMIRA cannot be excluded, particularly due to the use of a technique of debatable accountability. In addition, a study to confirm efficacy and tolerance in everyday clinical practice was requested by EMA.

3.1.2 Data for clinical efficacy versus etanercept - ENBREL The transparency Committee regrets that no study has been conducted to compare the efficacy of HUMIRA with that of etanercept. The elements of indirect comparison presented in the dossier do not enable any conclusions to be made because: - no heterogeneity test has been performed to ensure population comparability, - the patients included had differing profiles: Nearly 40% of patients in the HUMIRA study were naive for MTX at inclusion while all the patients in the Enbrel study had experienced treatment failure or intolerance with MTX, - the duration of the evaluation period differed between the studies (8 months for HUMIRA vs. 4 months for Enbrel). - different methods were used to analyse the results in the two studies. 3.2. Adverse effects During this clinical study, no tolerance issues arose in the population of treated children and adolescents compared to the already known tolerance profile of HUMIRA in adults. As in adults, the most common adverse effects were infections and reactions at the site of injection. No cases of death, cancer, congestive heart failure or opportunistic infections were reported. There are only limited data on the tolerance of the fixed dose of HUMIRA proposed by the SPC, of 40 mg every 2 weeks by subcutaneous injection. Moreover, no data are available on long-term tolerance in this paediatric population. A European risk management plan for all the indications in common has been established, particularly for monitoring the occurrence of infections and cancers. EMA has requested a study, specific for the indication polyarticular JIA, to evaluate the long-term efficacy and tolerance of HUMIRA in everyday clinical practice. The patients will be followed up for 10 years (STRIVE register). 7/10

3.3. Conclusion The efficacy of HUMIRA in the treatment of progressive polyarticular juvenile idiopathic arthritis in adolescents aged 13 to 17 years in cases of an inadequate response to one or more disease-modifying treatments was evaluated in a placebo-controlled clinical study. 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. This study consisted of 3 phases. During the pre-inclusion 1st phase of the study, 171 patients aged 4 to 17 years were treated for 16 weeks on an openlabel basis with HUMIRA 24 mg/m² administered every 2 weeks (maximum dose 40 mg). The proportion of patients with an ACR 30 paediatric response was 74.4% in the HUMIRA “without MTX” stratum and 94.1% in the HUMIRA “with MTX” stratum. Of the 144 patients responding by W16, 133 were included into the 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-up by week 32 in the stratum without MTX (primary 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, in view of the study methodology, an overestimation of the magnitude of the HUMIRA effect cannot be excluded. No long-term efficacy data are available for this paediatric population, but a 5-year, openlabel extension of this study is under way. Furthermore, there are only limited efficacy data for the fixed dose of 40 mg every 2 weeks cited in the MA. The lack of a comparative study versus ENBREL is regrettable, since it is not possible to judge HUMIRA against this medicinal product. In this study, the tolerance of HUMIRA in the population of treated children and adolescents was similar to that already known in adults. As in adults, the most common adverse effects were infections and reactions at the site of injection. However, these tolerance data are limited. Consequently, in addition to the risk management plan for all the HUMIRA indications in common, which will monitor the risks of infection and cancers, EMA has requested the establishment of a study, specific for the indication polyarticular JIA, to evaluate the longterm efficacy and tolerance of HUMIRA in everyday clinical practice. The patients will be followed up for 10 years.

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4.

TRANSPARENCY COMMITTEE CONCLUSIONS

4.1. Actual benefit Juvenile idiopathic arthritis is the term used for all inflammatory conditions of the joints without an identified cause, starting before the age of 16 years and with a duration of more than 6 weeks2. These are serious and disabling chronic conditions. HUMIRA is intended for symptomatic treatment. Public health benefit: The burden on public health caused by juvenile idiopathic arthritis is small because of the small number of patients affected (orphan condition). Improvement of the management of this orphan disease is an integral part of public health priorities (“rare diseases” plan, paediatric medicinal products). In view of the available study data, it is expected that the impact of HUMIRA on the morbidity and quality of life of treated patients can be considered to be at best small. Consequently, in the current state of knowledge and in view of the restricted size of the population concerned, it is not expected that HUMIRA will benefit public health in this indication. The efficacy/adverse effects ratio for these medicinal products is high. These products are a second-line treatment following the failure of classic diseasemodifying treatments including methotrexate. There is only one alternative medicine with an MA that specifically includes children at this stage of the disease: ENBREL (etanercept). The actual benefit of these products in this indication is substantial.

4.2. Improvement in actual benefit (IAB) In the treatment of progressive polyarticular juvenile idiopathic arthritis in adolescents aged 13 to 17 years, in cases of an inadequate response to one or more disease-modifying treatments, HUMIRA does not provide an improvement in actual benefit (level V) in the therapeutic strategy.

4.3. Therapeutic use 2, 3, 4 The aim of the treatment of juvenile idiopathic arthritis (JIA) is to combat inflammation, relieve pain and stiffness and prevent or slow down the progression of articular lesions. It makes use of fast-acting symptomatic treatments (NSAIDs, corticosteroids) and sometimes disease-modifying treatments, depending on the form of the juvenile idiopathic arthritis (systemic, oligoarticular or polyarticular). NSAIDs are usually the first-line treatment, but they are not always effective. If required, they can be combined with intra-articular infiltrations of corticosteroids.

2 Job deslandre et al. Juvenile idiopathic arthritis. Encyclopédie orphanet. September 2003. 3 Hull RG; British Paediatric Rheumatology Group. Guidelines for management of childhood arthritis. Rheumatology 2001 ; 40 (11) : 1309-12 4 Hashkes PJ, Laxer RM et al. Medical treatment of juvenile idiopathic arthritis. JAMA 2005 ; 294(13) : 1671-84

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The reference disease-modifying treatment is methotrexate (MTX), particularly where there is a polyarticular course without systemic signs. Other non-biological (namely classical) immunosuppressant disease-modifying treatments such as leflunomide, hydroxychloroquine, sulfasalazine, azathioprine, and ciclosporin are sometimes used off-label as alternatives to methotrexate, but their efficacy in JIA is not as well established. The biological immunosuppressant disease-modifying treatments can be considered for the treatment of polyarticular JIA in the event of failure of classical disease-modifying treatments. Only two anti-TNF alphas have an MA for JIA: - Enbrel – etanercept as monotherapy in children aged 4 to 17 years with an insufficient response or intolerance to MTX. - HUMIRA – adalimumab exclusively in adolescents aged 13 to 17 years with an insufficient response to one or more classical disease-modifying treatments, combined with MTX or as monotherapy in cases of intolerance to MTX or where continuation of MTX treatment is inappropriate. The recommended dosage of HUMIRA is 40 mg every two weeks by subcutaneous injection. Place of HUMIRA in the management of JIA: HUMIRA is an alternative to ENBREL in the management of JIA. In the absence of comparative data, its place in comparison to ENBREL remains to be defined.

4.4. Target population The prevalence of juvenile idiopathic arthritis in France is estimated to be approximately 2 to 3/10 000 children5,6. According to INSEE 2008 data, there would be approximately 3,760,000 children aged 13-17 years in France. Based on these data, the number of children aged 13 to 17 years with JIA will be of the order of 750 to 1130. Of these, approximately 30% will require disease-modifying treatment with methotrexate, and about 30% will have an inadequate response or overt intolerance to methotrexate (expert opinion). Based on this data, the target population for HUMIRA in this indication is likely to be a maximum of 100 children. 4.5. Recommendations of the Transparency Committee The transparency Committee recommends inclusion on the list of medicines refundable by National Health Insurance and on the list of medicines approved for hospital use and various public services in the new indication. 4.5.1 Packaging: appropriate for the prescription conditions. 4.5.2 Reimbursement rate: 65% 4.5.3

Exception drug status

The transparency Committee wishes to receive the results of the everyday clinical practice study requested by EMA (register) in the context of the Risk Management Plan.

5 PRIEUR AM. Management of children with chronic rheumatism. Similarities and differences with rheumatoid arthritis. Revue du rhumatisme 1990; 57 :280-286. 6 Job deslandre et al. Juvenile idiopathic arthritis. Encyclopédie orphanet. September 2003.

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