title: A new design for registration trials in rheumatoid arthritis allowing secondary head-to-head comparisons with standard of care treatment including biologicals.
abstract: Current drug development programs produce high quality data on the efficacy of new drugs, substantial data on safety, but little data on actual applicability of the new product compared to standard of care. After successful registration and launch, such data require years to accumulate and often remain incomplete. This viewpoint proposes a new trial design for phase 2 and 3 drug trials in rheumatoid arthritis. In this design the trial starts conventionally: patients that are inadequate responders to standard treatment (usually methotrexate) are randomised to receive the experimental drug or placebo on the background of continued (methotrexate) treatment. However, after 3 months all patients in the placebo group are additionally treated with one and the same standard of care treatment (usually an inhibitor of tumour necrosis factor) and all patients in the experimental group are additionally treated with a placebo corresponding to the chosen standard of care treatment. This design allows primary assessment of efficacy and safety of the experimental drug compared with placebo at the ethically acceptable limit of 3 months, followed by secondary assessments of efficacy (including durability) and safety compared to standard of care. The secondary assessments are observational and thus more prone to bias, but it is argued that the potential for bias is limited in this setting. Widespread adoption of the design will greatly help to determine the place of a new product in the spectrum of treatment possibilities of rheumatoid arthritis.
authors.affiliation: Department of Epidemiology and Biostatistics, VU University Medical Center, PK 6Z 165, PO Box 7057, 1007 MB Amsterdam, The Netherlands. eb@vumc.nl
authors.forename: Maarten
authors.initials: M
authors.lastname: Boers
mesh_terms: D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D008727:Methotrexate / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D012107:Research Design; D013997:Time Factors; D017211:Treatment Failure; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D018501:Antirheumatic Agents; D007155:Immunologic Factors; D014409:Tumor Necrosis Factor-alpha; D008727:Methotrexate