Zeitschrift für Rheumatologie

, Volume 73, Issue 1, pp 65–73 | Cite as

Nichtinterventionelle Phase-IV-Studien zur Behandlung der rheumatoiden Arthritis mit Biologicals in Deutschland

Praxisbezogene klinische Daten
  • J. Ruof
  • C. Iking-Konert
  • S. Simianer
  • G.-R. Burmester
Originalien
  • 200 Downloads

Zusammenfassung

Hintergrund

Im Gegensatz zur strikten Natur randomisierter kontrollierter Studien (RCT) untersuchen nichtinterventionelle Studien (NIS) Merkmale einer Therapie im klinischen Alltag. Beobachtungspläne von NIS legen die Therapiestrategie nicht im Voraus fest, orientieren sich an der Fachinformation und besitzen somit keine eigentlichen Ein- und Ausschlusskriterien im Gegensatz zu klinischen Studien, sodass umfassende heterogene Patientenpopulationen erfasst werden können.

Methodik

In Deutschland mit Unterstützung der pharmazeutischen Industrie durchgeführte NIS zur Behandlung der rheumatoiden Arthritis mit Biologicals wurden ermittelt und deren Resultate mit den jeweiligen RCT verglichen.

Ergebnisse

Die Auswertung der ermittelten NIS ergab: 1) die NIS-Population war im Schnitt mehr als doppelt so groß wie die in RCT, 2) die Patientencharakteristika in NIS und RCT waren verschieden, 3) die Wirksamkeit der Biologicals in NIS und RCT ist vergleichbar und 4) NIS erheben zusätzliche Daten, z. B. über Gebrauch und Dosierung im klinischen Alltag.

Schlussfolgerung

NIS stellen ein wichtiges Instrument zur Erfassung des klinischen Alltags dar. Trotz methodischer Einschränkungen liefern NIS wertvolle Daten, welche zu einem kompletteren Bild des Werts von Behandlungen mit Biologicals beitragen.

Die englische Originalversion dieses Beitrags steht auf SpringerLink (unter Supplemental) zur Verfügung.

Schlüsselwörter

Randomisierte kontrollierte Studie Klinische Studien Therapie mit Biologcials Nichtinterventionell Praxisalltag 

Phase IV non-interventional studies in the treatment of rheumatoid arthritis with biologicals in Germany

Real-life clinical practice data

Abstract

Background

In contrast to the restrictive nature of randomised controlled trials (RCT), non-interventional studies (NIS) investigate the features of a therapy in daily clinical practice. The observational plan of NIS does not dictate a treatment strategy, but is based on the product label. Unlike RCT, NIS therefore have no actual inclusion and exclusion criteria, allowing the study of broad heterogeneous patient populations.

Methods

NIS carried out in Germany with support from the pharmaceutical industry and investigating the use of biologics for the treatment of rheumatoid arthritis were identified and their findings were compared with those from the RCT of the respective biologic.

Results

Analysis of the identified NIS revealed the following: (1) populations in NIS were on average more than twice as large as in RCT, (2) patient characteristics in NIS and RCT were different, (3) the effectiveness of biologics in NIS was comparable to the efficacy observed in RCT, and (4) NIS collected supplementary data, e.g. on usage and dosing in clinical practice.

Conclusion

NIS represent an important tool for the assessment of daily clinical practice. Despite methodological drawbacks, NIS provide valuable data that contribute to a more complete picture of the value of treatment with biologics.

The English version of this article is available at SpringerLink (under “Supplemental”).

Keywords

Randomized controlled trial Clinical trial Biological therapy Non-interventional Daily clinical practice 

Supplementary material

393_2013_1264_MO1_ESM.pdf (995 kb)
Real life clinical practice data: Phase IV non-interventional studies in the treatment of rheumatoid arthritis with biologics in Germany (PDF 1MB)

Literatur

  1. 1.
    Hildebrandt M, Ludwig WD (2003) Clinical research and industrial sponsoring: avenues towards transparency and credibility. Onkologie 26:529–534PubMedCrossRefGoogle Scholar
  2. 2.
    Hahn M, Ruppert T et al (2010) Results of a survey on applied quality standards in non-interventional studies among the members of the German association of Research-based Pharmaceutical Companies. Ger Med Sci 8Google Scholar
  3. 3.
    EMA: European Medicines Agency post-authorisation procedural advice for users of the centralised procedure. http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500003981.pdf. Zugegriffen: 26. August 2013Google Scholar
  4. 4.
    EMA: European public assessment reports. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d124. Zugegriffen: 26. August 2013Google Scholar
  5. 5.
    Nüßlein H, Lorenz H et al (2011) Efficacy and safety of abatacept treatment for rheumatoid arthritis (RA) in a real-life setting in European and Canadian populations: a 6-months interim analysis of the ACTION study. Ann Rheum Dis 70:464Google Scholar
  6. 6.
    Behrens F, Koehm M et al (2011) A new definition of treatment response in rheumatoid arthritis: identification of the critical difference in disease activity. Arthritis Rheum 63:363CrossRefGoogle Scholar
  7. 7.
    Mittendorf T, Dietz BM et al (2006) HAQ and FACIT-F are better predictors of societal costs of rheumatoid arthritis than DAS28. ACR Scientific Meeting 142Google Scholar
  8. 8.
    Burmester G, Müller-Ladner U et al (2012) Rapid achievement of remission with certolizumab pegol was maintained for one year: interim results from FαST, a German non-interventional study in rheumatoid arthritis real life patients. Ann Rheum Dis 71:664Google Scholar
  9. 9.
    Löschmann P, Meng T et al (2006) Anwendungsbeobachtung zur Evaluierung der Sicherheit und Wirksamkeit von Etanercept bei der Behandlung von Patienten mit rheumatoider Arthritis (RA). Z Rheumatol 65:POFR1-10Google Scholar
  10. 10.
    Wendler J, Sörensen H et al (2009) Effectiveness and safety of rituximab (RTX)-monotherapy compared to RTX-combination therapy with methotrexate (MTX) or leflunomid (LEF) in the German RTX treatment of active rheumatoid arthritis (RA) in daily practice trial (EULAR Kongressvortrag). Ann Rheum Dis 68:76Google Scholar
  11. 11.
    Krause A, Aries P et al (2011) Rituximab bei rheumatoider Arthritis – erste Ergebnisse der nichtinterventionellen BRIDGING-Studie. Z Rheumatol 70:RA.33Google Scholar
  12. 12.
    Kekow J, Müller-Ladner U et al (2010) Real life treatment with rituximab in TNF blocker non-responders is superior to treatment with a second TNF blocker. Arthritis Rheum 62:406Google Scholar
  13. 13.
    Burmester GR, Hinüber U von et al (2013) Tocilizumab administered in daily clinical practice – final results of the German non-interventional study „ROUTINE“. Ann Rheum Dis 72:452Google Scholar
  14. 14.
    Keystone E, Heijde D et al (2008) Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum 58:3319–3329PubMedCrossRefGoogle Scholar
  15. 15.
    Smolen J, Landewe RB et al (2009) Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial. Ann Rheum Dis 68:797–804PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Jones G, Sebba A et al (2010) Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis 69:88–96PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Kremer JM, Blanco R et al (2011) Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year. Arthritis Rheum 63:609–621PubMedCrossRefGoogle Scholar
  18. 18.
    Smolen JS, Beaulieu A et al (2008) Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 371:987–997PubMedCrossRefGoogle Scholar
  19. 19.
    Genovese MC, McKay JD et al (2008) Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum 58:2968–2980PubMedCrossRefGoogle Scholar
  20. 20.
    Emery P, Keystone E et al (2008) IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis 67:1516–1523PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Cohen SB, Emery P et al (2006) Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 54:2793–2806PubMedCrossRefGoogle Scholar
  22. 22.
    Maini R, St Clair EW et al (1999) Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 354:1932–1939PubMedCrossRefGoogle Scholar
  23. 23.
    St Clair EW, Heijde DM van der et al (2004) Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum 50:3432–3443CrossRefGoogle Scholar
  24. 24.
    Kremer JM, Dougados M et al (2005) Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase IIb, double-blind, randomized, placebo-controlled trial. Arthritis Rheum 52:2263–2271PubMedCrossRefGoogle Scholar
  25. 25.
    Kremer JM, Genant HK et al (2006) Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial. Ann Intern Med 144:865–876PubMedCrossRefGoogle Scholar
  26. 26.
    Genovese MC, Becker JC et al (2005) Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med 353:1114–1123PubMedCrossRefGoogle Scholar
  27. 27.
    Weinblatt M, Combe B et al (2006) Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease-modifying antirheumatic drugs: a one-year randomized, placebo-controlled study. Arthritis Rheum 54:2807–2816PubMedCrossRefGoogle Scholar
  28. 28.
    Schiff M, Keiserman M et al (2008) Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis 67:1096–1103PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Westhovens R, Robles M et al (2009) Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors. Ann Rheum Dis 68:1870–1877PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Weinblatt M, Keystone EC et al (2003) Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum 48:35–45PubMedCrossRefGoogle Scholar
  31. 31.
    Putte LB van de, Atkins C et al (2004) Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed. Ann Rheum Dis 63:508–516PubMedCrossRefGoogle Scholar
  32. 32.
    Keystone EC, Kavanaugh AF et al (2004) Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum 50:1400–1411PubMedCrossRefGoogle Scholar
  33. 33.
    Furst DE, Schiff MH et al (2003) Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis). J Rheumatol 30:2563–2571PubMedGoogle Scholar
  34. 34.
    Breedveld FC, Weisman MH et al (2006) The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum 54:26–37PubMedCrossRefGoogle Scholar
  35. 35.
    Moreland LW, Schiff MH et al (1999) Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann Intern Med 130:478–486PubMedCrossRefGoogle Scholar
  36. 36.
    Bathon JM, Martin RW et al (2000) A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 343:1586–1593PubMedCrossRefGoogle Scholar
  37. 37.
    Klareskog L, Heijde D van der et al (2004) Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 363:675–681PubMedCrossRefGoogle Scholar
  38. 38.
    Keystone EC, Schiff MH et al (2004) Once-weekly administration of 50 mg etanercept in patients with active rheumatoid arthritis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 50:353–363PubMedCrossRefGoogle Scholar
  39. 39.
    Keystone EC, Genovese MC et al (2009) Golimumab, a human antibody to tumour necrosis factor alpha given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD study. Ann Rheum Dis 68:789–796PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Smolen JS, Kay J et al (2009) Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor alpha inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial. Lancet 374:210–221PubMedCrossRefGoogle Scholar
  41. 41.
    Emery P, Fleischmann RM et al (2009) Golimumab, a human anti-tumor necrosis factor alpha monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: twenty-four-week results of a phase III, multicenter, randomized, double-blind, placebo-controlled study of golimumab before methotrexate as first-line therapy for early-onset rheumatoid arthritis. Arthritis Rheum 60:2272–2283PubMedCrossRefGoogle Scholar
  42. 42.
    Specker C, Kaufmann J et al (2011) Tocilizumab bei rheumatoider Arthritis – erste Interimsanalyse der nichtinterventionellen ICHIBAN-Studie (DGRh-Kongressposter). Z Rheumatol 70:RA.42Google Scholar
  43. 43.
    Krause A, Aries P et al (2012) Rituximab in rheumatoid arthritis – interim analysis of the non-interventional BRIDGING study. Ann Rheum Dis 71:667Google Scholar
  44. 44.
    Burmester GR, Müller-Ladner U et al (2011) Über die Hälfte der mit Certolizumab pegol behandelten Patienten (CZP) behandelten Patienten erreichte Remission oder niedrige Krankheitsaktivität – erste Interim-Ergebnisse aus dem Praxisalltag von der nichtinterventionellen Studie (NIS) FαST. Z Rheumatol 70:RA.45Google Scholar
  45. 45.
    Kleinert S, Tony HP et al (2012) Impact of patient and disease characteristics on therapeutic success during adalimumab treatment of patients with rheumatoid arthritis: data from a German noninterventional observational study. Rheumatol Int 32:2759–2767PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Specker C, Kaufmann J et al (2012) Tocilizumab in rheumatoid arthritis – one year interim analysis of the non-interventional ICHIBAN study. Ann Rheum Dis 71:667Google Scholar
  47. 47.
    Behrens F, Thaci D et al (2011) Differences in comobidities related to rheumatoid arthritis and psoriatic arthritis: data from large prospective observational studies. Arthritis Rheum 63:534CrossRefGoogle Scholar
  48. 48.
    Krüger K, Wollenhaupt J et al (2011) Reduction in sickness absence in patients with rheumatoid arthritis receiving adalimumab: data from a German noninterventional study. Rheumatol Int 32:3977–3983PubMedCrossRefGoogle Scholar
  49. 49.
    Wendler J, Sörensen H et al (2009) Effizienz und Sicherheit von Rituximab (RTX) als Monotherapie verglichen mit der RTX-Kombinationstherapie mit Methotrexat (MTX) oder Leflunomid (LEF) bei Rheumatoider Arthritis (RA) in der täglichen Routine. Z Rheumatol 68:RA2.10Google Scholar
  50. 50.
    Wendler J, Blank N et al (2011) Safety and efficacy of rituximab (RTX) in combination with other biologicals in the „German RTX treatment of active rheumatoid arthritis (RA) in daily practice“ trial. Ann Rheum Dis 70:721Google Scholar
  51. 51.
    Kratzsch G, Richter C et al (2008) Infliximab im klinischen Alltag bei Rheumatoider Arthritis. Z Rheumatol 67:RA3.19Google Scholar
  52. 52.
    Tony HP, Krause A et al (2010) Is there a subgroup of rheumatoid arthritis patients who take longer to respond to anti-TNF-therapy. Ann Rheum Dis 69:520Google Scholar
  53. 53.
    Lal P, Su Z et al (2011) Inflammation and autoantibody markers identify rheumatoid arthritis patients with enhanced clinical benefit following rituximab treatment. Arthritis Rheum 63:3681–3691PubMedCrossRefGoogle Scholar
  54. 54.
    Wendler J, Wassenberg S et al (2010) Rheumafaktor (RF) als Prädikator für das Ansprechen auf Rituximab (RTX) in der nicht-interventionellen Studie (NIS) „RTX im klinischen Alltag zur Behandlung der Rheumatoiden Arthritis“. Z Rheumatol 69:RA1.24Google Scholar
  55. 55.
    Tony HP, Babinsky K et al (2009) Adalimumab (HUMIRA®) therapy for patients with rheumatoid arthritis (RA): impact of baseline characteristics on the therapeutic success from a German non-interventional study. Ann Rheum Dis 68:395Google Scholar
  56. 56.
    RABBIT: Rheumatoide Arthritis: Beobachtungen in der Biologika-Therapie. http://www.biologika-register.de/index.php. Zugegriffen: 28 August 2013Google Scholar
  57. 57.
    Kaufmann J, Feist E, Roske AE, Schmidt WA (2013) Monotherapy with tocilizumab or TNF-alpha inhibitors in patients with rheumatoid arthritis: efficacy, treatment satisfaction, and persistence in routine clinical practice. Clin Rheumatol (elektronische Publikation vor Drucklegung)Google Scholar
  58. 58.
    Nüßlein H, Alten R et al (2012) Real-world efficacy and safety of abatacept treatment for RA: 12-month interim analysis of the ACTION study. Ann Rheum Dis 71:668CrossRefGoogle Scholar
  59. 59.
    Behrens F, Tony HP et al (2013) Development and validation of a new DAS28-based treatment response criterion for rheumatoid arthritis. Arthritis Care Res (Hoboken) doi: 10.1002/acr.22037 (elektronische Publikaton vor Drucklegung)Google Scholar
  60. 60.
    Wendler J, Blank N et al (2011) Sicherheit und Wirksamkeit von Rituximab (RTX) in Kombination mit anderen Biologika in der deutschen nichtinterventionellen Studie „Therapie der aktiven rheumatoiden Arthritis (RA) mit RTX in der täglichen Routine“. Z Rheumatol 70:RA.37Google Scholar
  61. 61.
    Kekow J, Müller-Ladner U et al (2010) Überlegenheit von Rituximab nach Versagen des ersten TNF-Blockers. Z Rheumatol 38:RA2.27Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • J. Ruof
    • 1
  • C. Iking-Konert
    • 2
  • S. Simianer
    • 3
  • G.-R. Burmester
    • 4
  1. 1.Hoffmann-La Roche Ltd.Grenzach-WyhlenDeutschland
  2. 2.III. Medizinische Klinik und PoliklinikUniversitätsklinikum Hamburg-EppendorfEppendorfDeutschland
  3. 3.AbbVie GmbH& Co. KGWiesbadenDeutschland
  4. 4.Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische ImmunologieCharité Universitätsmedizin Berlin, Campus MitteBerlinDeutschland

Personalised recommendations