European Journal of Clinical Pharmacology

, Volume 65, Issue 1, pp 33–41

Limits of add-on trials: antirheumatic drugs

  • Laura Ottolenghi
  • Vittorio Bertele’
  • Silvio Garattini
Clinical Trial



This paper assesses the design of clinical studies used in the process of regulatory approval, focusing on how add-on studies affect regulatory decisions.


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.


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.


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.


Add-on studies Registration trials Marketing authorisation European Medicine Agency Rheumatoid arthritis Disease-modifying antirheumatic drugs Infliximab Etanercept Adalimumab Rituximab Anakinra Abatacept Methotrexate 



new drug


active comparator






American College of Rheumatology criteria






Area under the curve


chronic heart failure






cytochrome P450


disease activity score




disease modifying antirheumatic drug


European Medicine Agency


European Public Assessment Report








marketing authorisation




not significant


nonsteroidal anti-inflammatory drug


parallel group


randomised clinical trial




rheumatoid arthritis


serious adverse event




tumour necrosis factor


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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Laura Ottolenghi
    • 1
  • Vittorio Bertele’
    • 1
  • Silvio Garattini
    • 1
  1. 1.Laboratory of Regulatory PoliciesMario Negri Institute for Pharmacological ResearchMilanItaly

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