REBIF - Annex Re-assessment of interferon beta and glatiramer acetate in multiple sclerosis - English version

REBIF - Annex Re-assessment of interferon beta and glatiramer acetate in multiple sclerosis - English version

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Introduction REBIF 22 µg/0.5 mL solution for injection Prefilled syringe B/12 (CIP code: 347 417-0) REBIF 44 µg/0.5 mL solution for injection Prefilled syringe B/12 (CIP code: 350 809-3) REBIF 8.8 µg/0.2 mL solution for injection in prefilled syringe and REBIF 22 µg/0.5 mL, solution for injection in prefilled syringe 6 prefilled 0.2 mL glass syringes with stainless steel needle - 6 prefilled 0.5 mL glass syringes with stainless steel needle (CIP code: 375 902-7) REBIF 22 µg/0.5 mL solution for injection in cartridge 4 glass 1.5 mL cartridges (CIP code: 393 146-6) REBIF 44 µg/0.5 mL solution for injection in cartridge 4 glass 1.5 mL cartridges (CIP code: 393 147-2) Posted on Jan 24 2013 Active substance (DCI) interferon beta-1a Neurologie - Mise au point Progrès thérapeutique modéré dans la sclérose en plaques Deux interférons bêta-1a (AVONEX et REBIF), un interféron bêta-1b (BETAFÉRON, EXTAVIA) et l’acétate de glatiramère (COPAXONE) sont indiqués dans le traitement de fond de la sclérose en plaques (SEP). Ces spécialités ont une efficacité modeste sur la fréquence des poussées, qui est réduite de 30 % à court terme. Leur efficacité sur l’évolution à long terme du handicap n’est pas démontrée. Ces médicaments représentent un progrès thérapeutique modéré. Les interférons bêta ou l’acétate de glatiramère (notamment en cas d’intolérance aux interférons) restent le traitement de fond de première intention de la SEP. Pour en savoir plus télécharger la synthèse ou l'avis complet ci-dessous ATC Code L03AB07 Laboratory / Manufacturer MERCK SERONO REBIF 22 µg/0.5 mL solution for injection Prefilled syringe B/12 (CIP code: 347 417-0) REBIF 44 µg/0.5 mL solution for injection Prefilled syringe B/12 (CIP code: 350 809-3) REBIF 8.8 µg/0.2 mL solution for injection in prefilled syringe and REBIF 22 µg/0.5 mL, solution for injection in prefilled syringe 6 prefilled 0.2 mL glass syringes with stainless steel needle - 6 prefilled 0.5 mL glass syringes with stainless steel needle (CIP code: 375 902-7) REBIF 22 µg/0.5 mL solution for injection in cartridge 4 glass 1.5 mL cartridges (CIP code: 393 146-6) REBIF 44 µg/0.5 mL solution for injection in cartridge 4 glass 1.5 mL cartridges (CIP code: 393 147-2) Posted on Jan 24 2013

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Re-assessment of interferon beta and glatiramer acetate in multiple sclerosis
  The legally binding text is the original French version  TRANSPARENCY COMMITTEE         Re-assessment of  interferon beta and glatiramer acetate  in multiple sclerosis   
REPORT 
July 2010
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Re-assessment of interferon beta and glatiramer acetate in multiple sclerosis
CONTENTS
CONTENTS........................................................................................................................................................... 2  BACKGROUND AND INTRODUCTION ......................................................................................................... 3  I. Subject of this assessment made by HAS on its own initiative................................................................... 3 II. General description........................................................................................................................................ 3 II.1 Interferon beta (Centralised Procedures) ......................................................................................... 4 II.2  10Glatiramer acetate (national Marketing Authorisation) .................................................................  LITERATURE SEARCH................................................................................................................................... 11  I. Analysis of data in the literature................................................................................................................. 11 II. Search strategy and results ......................................................................................................................... 11 III. Dossiers submitted by companies ............................................................................................................... 11 IV. Data provided by AFSSAPS........................................................................................................................ 11  CLINICAL DATA ON EFFICACY .................................................................................................................. 12  I. Placebo-controlled studies with open follow-up ........................................................................................ 12 I.1 First neurological event consistent with MS........................................................................................ 12 I.2 Relapsing-remitting multiple sclerosis ................................................................................................ 13 I.3 Secondary progressive multiple sclerosis............................................................................................ 18 II. Observational studies................................................................................................................................... 19 II.1 Observational studies of patients treated with interferon beta,....................................................... 19 II.2 Observational studies of patients treated with glatiramer acetate.................................................. 20 II.3 with glatiramer acetate after treatment with interferonFollow-up of patients treated ,,................. 20 II.4 Post-Marketing Authorisation studies of patients treated with immunomodulators in France....... 20  ADVERSE EFFECTS......................................................................................................................................... 23  I. Interferons.......................................................................................................................................... 23 II. Glatiramer acetate............................................................................................................................. 24  TARGET POPULATION .................................................................................................................................. 24  USAGE DATA .................................................................................................................................................... 25  CONCLUSION ................................................................................................................................................... 26  ANNEXES ........................................................................................................................................................... 28  REFERENCES - COCHRANE REVIEWS...................................................................................................... 32 
 
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Re-assessment of interferon beta and glatiramer acetate in multiple sclerosis
BACKGROUND AND INTRODUCTION
HAS' Transparency Committee assesses drugs that have obtained a Marketing Authorisation, when the company marketing them wants them to be included on the list of drugs that may be reimbursed (articles L.162-17 of the French Social Security code and L.5123-2 of the French Public Health code) or on its own initiative. The Transparency Committee is a scientific body made up of doctors, pharmacists, methodologists and epidemiologists. Its missions are:
· deliver an opinion to the Ministers for Health and Social Security on whether there is to sufficient evidence to justify the reimbursement of medicines by Social Security and/or their use in hospital, notably in view of their actual benefit (AB) and any improvement in actual benefit (IAB) they are likely to contribute compared with treatments already available;
· contribute to the proper use of medicines by publishing relevant independent scientific to information.  These missions are defined in the French Social Security code, particularly in articles R.163-2 to R.163-21, L.161-37, L. 161-39 and L. 161-41. According to articles L. 162-17, L. 161-37, L.161-39,L. 161-41, L. 161-44, R. 163-2 to R. 163-21, R. 161-71, R. 161-76, R. 161-85 of the Social Security and L. 5123-2 and L. 5123-3 of the Public Health code, the Transparency Committee's opinion states the actual benefit and the improvement in actual benefit contributed by the medicinal product. The assessment is based on a critical analysis of the scientific literature according to the precepts of evidence based medicine and on the opinion of experts, in the indications and at the dosages given in the Marketing Authorisation.
I.
Subject of this assessment made by HAS on its own initiative
During the last fifteen years, the options for treating multiple sclerosis (MS) have been extended by the granting of a Marketing Authorisation in this indication to the immunomodulators interferon beta and glatiramer acetate. Some issues have not yet been resolved, notably the efficacy of these medicines against disease progression and long-term disability, the optimum dose and duration of treatment and the consequences of discontinuing them.  When the first opinions were delivered on the inclusion of these medicines reimbursed by National Health Insurance, the Transparency Committee assessed their efficacy against clinical criteria measured in the short term ( 2 years), mainly time to onset or frequency of onset of clinical exacerbations of MS (relapses). The data did not make it possible to assess the long-term impact of these medicines on progression of neurological deficit or patients' disability measured using the Kurtzke Expanded Disability Status Scale (EDSS).  As the inclusion of these medicines on the list for reimbursement is due for renewal, HAS has decided to deliver an opinion on its own initiative on their efficacy and tolerance in the light of recent published data and the dossiers submitted by the companies concerned. This re-assessment mainly concerns the impact of the existing four medicinal products on long-term (> 2 years) disability and tolerance in the indications given in their respective Marketing Authorisations (first demyelinating event, relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS)).
II. General description
A list of the medicinal products included in the assessment is given in Tables 1 and 2. The indications, doses and AB level granted by the Transparency Committee are included in the tables. The AB levels were substantial; the efficacy/adverse effects ratios were considered to be modest.
 
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II.1
Re-assessment of interferon beta and glatiramer acetate in multiple sclerosis
Interferon beta (Centralised Procedures)
IAB
List I Exception drug status Medicine requiring special monitoring during treatment. Medicine requiring prescription initiation and renewal by neurology specialists only.  ATC classification (2010): L Antineoplastic and immunomodulating agents L03 Immunostimulants L03A Cytokines and immunomodulators L03AB Interferons   Medicinal oAfd audlt mdionisset/rraotiutne  Datof Marketing Aut horisation/Indications product/INN o e   30 November 1995 14 Februar 1996 Inclusion for rela sin -remittin MS  Reduction of fre uenc and de ree of severit of clinical rela ses in  mbulator atients i.e. atients who are able to walk unaided with BETAFERON is the first dru to have roved its efficac in the treatment o rela sin -remittin MS, characterised b at least two attacks of neurolo ical rela sin -remittin multi le sclerosis RRMS . Com ared with the curren sfunction over the recedin two ear eriod, followed b com lete o strate based on immunosu ressants, which are oorl tolerated and incom lete recover . BETAFERONaininite remes,sd selar leaclf icinerev oita cns dnrf neueoniucti reds ofetmri  nnideboats ltsurel canilic eht ,nevornu ohesa tcviti siw 250 mcg/mL , constitute im ortan about disease ro ression and disabilit BETAFERON showed a reduction in fre uenc -30% uncertaintiesPatients receivin   as well as the number of hos ses, italisationsnd severit clinical rela of Inbteetrfae-r1obn  ue250 mcg SC/2 days se-free IAB ( ation of the rela to disease. Furthermore, there was a rolonlevel II).   interval.  BAYERhere is no evidence of an effect of BETAFERON on the duration o SANTEht noisserortibaeracr  os,on.e f thon osease dicaxabresmi -nebwtee nxetions, on smto he effect of BETAFERON on erformance of dail activities or in the social ield is not known.
 
 
 
BETAFERON has not et been investi ated in patients with pro ressiv multiple sclerosis.
here is no evidence of any efficacy against disability. linical studies have shown that not all patients respond to BETAFERON. In ddition in some atients clinical rela ses have worsened des ite reatment. There are no criteria redictive of absence of res onse o orsenin in an individual patient.  
 
      
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Re-assessment of interferon beta and glatiramer acetate in multiple sclerosis
26 Januar 1999 16 June 1999 Extension of indication to SPMS Indicated for slowin ro ression of disease and for the reduction o  requenc of clinical relapses. The effect of treatment is obtained in patients BETAFERON is the first medicinal product to have been shown to dela ith or without clinical relapse, and irrespective of the level of disabilit isease pro ression in secondar pro ressive multiple sclerosis. This patients with mild disease and those unable to walk were not studied . results in major improvement in actual benefit (level I). BETAFERON has not et been studied in patients with immediatel progressive multiple sclerosis.
   24 May 2000   InformationAmendment to IAB text in the Prescribin     its lon -termBETAFERON was the first medicine to have roved efficac in   forms of MS. Since then, AVONEX andhe treatment of rela sin -remittin   rela sin -remittin MS.REBIF have also demonstrated their efficac in  hese three interferons have the same level of IAB level I .    11 September 2002 19 November 2001 of INCOMIN studRenewal of inclusion submission reatment of patients with secondar  ressive multiple scler i with pro b evidenced text for SPMS Authorisation of Marketin eand chan ctive disease, evidenced b rela ses. os srela ses   INCOMIN stud  onclusion: this is the first ublished trial com arin two interferons in the reatment of rela sin -remittin MS. O en treatment was ethicall ustified but reduced the relevance of the stud .  fter administration accordin to the re imens iven in the Marketin  uthorisation, a difference was observed in favour of BETAFERON a ainst  linical relapses and disease pro ression.   beta interferons were in favour of comparin twoData from this stud  ose effect and/or a frequenc of administration effect, but did not confirm  he security of one interferon over another.   IAB e in the text of the indication in secondar: The chan MS ro ressive  oes not chan e the level of im rovement in actual benefit contributed b   established.BETAFERON from that initiall    12 July 2004
reatment of atients with rela sin -remittin multi le sclerosis with at least wo clinical rela ses durin the revious two ears.
 
 
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Re-assessment of interferon beta and glatiramer acetate in multiple sclerosis
 4 October 2006 Extension of indication to a sin le dem elinatin event 1 June 2006  In view of the uncertainties related to indirect comparisons, in this extension reatment of atients with a sin le dem elinatin event with an activ f indication the Transparenc Committee notes that the amount of effect inflammator rocess, severe enou h to warrant treatment with intravenous btained in the BENEFIT study for BETAFERON seems to be similar to that orticosteroids, where alternative dia noses are excluded and who ar btained in the CHAMPS stud for AVONEX Transparenc Committee onsidered to be at hi h risk of develo in clinicall definite multi le pinion dated 8 January 2003). clerosis. onse uentl , the Committee considers that the medicinal roduc BETAFERON does not rovide an im rovement in actual benefit com ared ith the medicinal product AVONEXIAB V).
  20 May 2008  EXTAVIA with an active eventreatment of patients with a sin le dem elinatin 250 mc /mL to warrant treatment with intravenous severe enou hinflammator process, orticosteroids, where alternative dia noses are excluded and who ar3 September 2008   multi clinicall definiteto be at hi h risk of develo inonsidered  le Interferonβ1-b rovement in actual250 mcg SC/2 days clerosis. his medicinal roduct does not contribute an im  benefit in the treatment of multi le sclerosis. NOVARTIS le multi ses sclerosis and two or more rela sin -remittinPatients with rela PHARMA ears.ithin the last two   multiple sclerosis with active disease, ressive proPatients with secondar videnced b relapses.  13 March 1997 8 June 1997 AVONEX based on immunosuom ared with the current strate which ressants, iraegantomseendt  owf itpha trieelnatsp siwnhgo- rearmei ttaibnle  tmo ulwtiapllke  usncalsersiossties d aMnSd , wdheof ihnaevd e abse eanre oorl tolerated and whose activit is unroven, AVONEX not onl 30 / 0.5 mLs three ears reduces the fre uenc of clinical rela ses, but is also the first medicinal Inbteertfa e-1roa n  stli sihuseremovt enr aorimfod siaes oliw nssion. Tse roret dlreaaesrt  httwiow  nueoroliac lvenee nitfsl alreebetscasudnuia  hinlierIe,h tw veerl  tu olievitµeg  iIvoh30tu  efoedcnnution cor krese wo/uMb noisser neewteeoldarses.  VhOtNoEtX ucomed evadetartsn lows the ro ression of disabilit and decreases the fre uenc of rela ses n m over a two- ear eriod . interferon beta-1b, com ared with the same strate , the uncertainties  oncernin lon disease -term ression ro arenc led the Trans Committee Biogen IdecVONEX has not et been studied in atients with ro ressive multi le o recognise its important improvement in actual benefit (level II). Franceclerosis. Authorisation dated 14 Februar 2005deletion - Marketin VONEX should be discontinued in patients who develop pro ressive MS.
 
 
 
Not all atients res ond to treatment with AVONEX. No clinical criteria predictive of response to treatment have been identified.deletion arketing Authorisation dated 14 February 2005)
 
 
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REBIF 22 µg / 0.5 mL 44 µg / 0.5 mL 8.8 / 22  Interferon beta-1a   MERCK SERONO
 
 
 
 
22/44 SC 3x/week
 
Re-assessment of interferon beta and glatiramer acetate in multiple sclerosis
 reatment of atients able to walk unassisted, with rela sin -remittin multi le sclerosis MS , defined as at least two neurolo ical event relapses durin the previous three ears without evidence of re ula pro ression between relapses. AVONEX slows disease pro ression and reduces frequenc of relapses.  8 Januar 2003 7 May 2002 Extension of indication to a sin le dem elinatin event  reatment of atients with a sin le dem elinatin event with an active he results obtained in this extension of indication a sin le dem elinatin inflammator process, severe enou h to warrant treatment with intravenous vent confirm the improvement in actual benefit previousl established for orticosteroids, where alternative dia noses are excluded and who ar h inal ro etermined to be at hi h risk of developin clinicall definite multiple is medic p duct (major improvement,level I). clerosis.  
 3 March 2008  reatment of atients with rela sin -remittin multi le sclerosis RRMS . In linical trials, this is characterised b two or more clinical rela ses occurrin urin the revious three ears without evidence of re ular ro ression between rela ses; AVONEX slows disease ro ression and reduce re uenc of clinical rela ses.
VONEX should be discontinued in patients who develop pro ressive MS.
 4 May 1998 3 June 1998 Inclusion of REBIF 22 reatment of atients who are able to walk unassisted and who have been ianosed with relasin-remittin multile sclerosis RRMS, defined as atroe moaroerld  wtiotlhe rtahtee dc urarnedn t wsthroatsee  abctaivsited  iosn  iumnmruonvoesn,u three srseadnutsc,t iwhicihn least two neurolo ical events rela ses durin the revious two ears. on REBIF 22 reduces the fre uenc and severit of rela ses over a 2- ea re uenc and severit of clinical rela ses obtained with BETAFERON INF-eriod. -1b) led the Transparency Committee to recognise its importan improvement in actual benefit (level II, while this improvement was ma or REBIF has not et been studied in patients with pro ressive multiple or AVONEX INF- -1a which was the first medicinal rod clerosis; treatment should be discontinued in atients who develo p uct to als emonstrate slowing of disease progression. ro ressive MS. REBIF is the second INF- 1-a after AVONEX. The level of clinicall efficac urrentl demonstrated onl in reventin rela ses, to ether with the tri-eekl mode of administration, uts REBIF on the same level a BETAFERON. However, com ared with BETAFERON, the Committee reco nises a minor otential advanta e in terms of efficac a ainst disease ro ression in view of the first results obtained in clinical trials, but their relevance needs to be confirmed.  
 
    
 
 
    
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Re-assessment of interferon beta and glatiramer acetate in multiple sclerosis
 7 Jul 1999 1 Februar 1999 the indication of of wordinChan e reatment of patients who are able to walk unassisted and who have been iagnosed with relapsing-remittin multiple sclerosis RRMS , defined as at Reco nition of REBIF activit a ainst disease ro ression is based on a a ses ars. new anal sis of the efficac data in the Marketin Authorisation dossier. lReEasBtI Ft®ih selae-2 a revo surecennd aev stirefo ler esa 22 r decuset ehf SS scpaellet,hn riduoiverp ee owt suneurwo ac lloiostr vened feoi,nerssorncrean i as ined tsael ta fo esa Ehe tont ino1 c nolcsu dott eh the roion that foeitatro noiis dseeas ntthwi eriodand slows disease ression ro." D onfirmed at three months, was reduced from 39% lacebo to 30% REBIF 22 .
29 March 1999  Marketin Authorisation REBIF 44   
/ 0.5mL
In atients with rela sin -remittin multi le sclerosis RRMS , REBIF, as the ther beta interferons, has therefore roved its efficac in slowin disease ro ression. This reinforces the substantial actual benefit of interferon beta in mana in these atients. Unlike AVONEX, which demonstrated slowin f disease pro ression over a six-month period but in patients with mild to moderate forms of the disease EDSS score between 1 and 3.5 , REBIF, as BETAFERON, has demonstrated similar efficac but over a shorter period three months ; however, the patients concerned had more severe forms o isease (with disability up to 5 and 5.5 respectively on the EDSS scale).
onsequently, in RRMS,REBIF 22 µg shares the same actual benefit as BETAFERON and AVONEX.  6 August 1999 (Inclusion of REBIF 44 µg) 
REBIF 44 shares the im rovement in actual benefit IAB contributed b VONEX, BETAFERON and REBIF 22 .   6 March 2002 21 November 2001Extension of indication to SPMS   In the extension of indication, the improvement in actual benefit IAB RhErBaIFc teirsi siendd ibca ttewdo  foor r mtohree  tarceuattem eexnat ceorf bataitoinesn tisn  twhiet h remvuilotiusl et wsoc leeraorssi. remains maor level I and REBIF shares the same IAB as BETAFERON a(INF-b-1b). Its efficac has not been demonstrated in patients with secondar ro ressive multi le sclerosis without on oin rela se activit .  11 September 2002 Submission of follow-up results at 48 weeks from the stud EVIDENCE REBIF 44 vs AVONEX 30
 
fter administration accordin to the re imens iven in the Marketin uthorisation, the difference between the two rou s in favour of REBIF bserved at 24 weeks was confirmed at 48 weeks, and remained stable between 24 and 48 weeks.  
 
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Re-assessment of interferon beta and glatiramer acetate in multiple sclerosis
Data from this stud com arin two beta-1a interferons was in favour of a ose effect and/or a fre uenc effect of administration effect but did no onfirm the su eriorit of one interferon over another.    19 Januar 2006    orisation starte BIF Marketin Auth r kit RE 8 µ / 22 µ   31 M ay 2006 r tment of rela sin multi le sclerosis. In clinical trials, this wa ea haracterised b two t exacerbations in the revious two or more acu e ears.  Its efficac has not been demonstrated in atients with secondar pro ressive multiple sclerosis without on oin relapse activit .  
 
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II.2
Re-assessment of interferon beta and glatiramer acetate in multiple sclerosis
Glatiramer acetate (national Marketing Authorisation)
List I Exception drug status Medicine requiring special monitoring during treatment. Medicine requiring prescription initiation and renewal by neurology specialists only.  ATC classification (2010): L Antineoplastic and immunomodulating agents 03 Immunostimulants A Cytokines and immunomodulators X Other cytokines and immunomodulators 13 glatiramer acetate   Medicinal Adult dose/route product/INN of administration Date of Marketin Authorisation/Indications   25 January 2002
 
 COPAXONE 20 m /mL   Glatiramer acetate
SANOFI-AVENTIS   
20 mg SC/ day
 
IAB
Glatiramer acetate is indicated for the reduction in fre uenc of rela ses in20 November 2002 mbulator atients i.e. who can walk unaided with rela sin -remittin  least two attacks o In view of its ood tolerance rofile and des ite the absence of evidence for nmeuultriolloe icsacll edrossfius nctiRoRn MovSe r tchhea rarectceeridsined  twbo- eatar eriod.  lowin of disease roression, Coaxone shares the IAB o Glatiramer acetate has not demonstrated an beneficial effect on diseas Iinterferons level MS. sin -remittin with rela atientsin the treatment of progression. Glatiramer acetate is not indicated for the treatment of rimar or secondar ro ressive MS. 
26 March 2004  Copaxone 20 mg/mL, solution for injection in pre-filled syringe
 19 Ma 2004
his new resentation does not contribute an im rovement in actual benefit com ared with the resentation as owder and solvent for solution or in ection which is alread included on the reimbursement list.
 
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