title: Limits of add-on trials: antirheumatic drugs.
abstract: OBJECTIVE
  This paper assesses the design of clinical studies used in the process of regulatory approval, focusing on how add-on studies affect regulatory decisions.
  
  
  METHODS
  The sample case taken is that of the new agents for rheumatoid arthritis (RA) authorised by the European Medicine Agency (EMEA). The European Public Assessment Reports (EPARs) accompanying the marketing authorisations were the source of information on the studies presented in the registration dossiers.
  
  
  RESULTS
  The recently approved anti-RA agents are all indicated in combination with methotrexate (MTX) for treating adults with active RA who have responded inadequately to disease-modifier drugs (DMARDs). The add-on design was frequently used in registration studies. For infliximab, etanercept, adalimumab and rituximab, add-on trials contributed, together with parallel-group trials, to gaining the approval as combination therapy. Anakinra and abatacept were authorised on the basis of add-on trial results only.
  
  
  CONCLUSIONS
  Add-on trials do not allow assessment of the intrinsic efficacy and safety of new agents and their value as alternatives to available treatments. The indications granted for the new anti-RA agents do not specify whether newer drugs can replace standard treatments in nonresponders, can do better in the overall patient population or can be used as first-line treatment.
authors.affiliation: Laboratory of Regulatory Policies, Mario Negri Institute for Pharmacological Research, Via Giuseppe La Masa 19, 20156 Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Ottolenghi
authors.forename: Vittorio
authors.initials: V
authors.lastname: Bertele'
authors.forename: Silvio
authors.initials: S
authors.lastname: Garattini