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

Abstract

Purpose

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.

Keywords

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

Abbreviations

A

new drug

B

active comparator

PLB

placebo

ABA

abatacept

ACR

American College of Rheumatology criteria

ADL

adalimumab

ANK

anakinra

AUC

Area under the curve

CHF

chronic heart failure

Cl

clearance

CTX

cyclophosphamide

CYP

cytochrome P450

DAS

disease activity score

DB

double-blind

DMARD

disease modifying antirheumatic drug

EMEA

European Medicine Agency

EPAR

European Public Assessment Report

ETN

etanercept

IFX

infliximab

LFE

leflunomide

MA

marketing authorisation

MTX

methotrexate

NS

not significant

NSAID

nonsteroidal anti-inflammatory drug

PG

parallel group

RCT

randomised clinical trial

RTM

rituximab

RA

rheumatoid arthritis

SAE

serious adverse event

SSZ

sulphasalazine

TNF

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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