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Limits of add-on trials: antirheumatic drugs

  • Clinical Trial
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

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.

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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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Acknowledgments

The authors are grateful to Giuseppina Petruzzelli of the G.A. Pfeiffer Memorial Library, to Judith Baggott for editorial assistance and to Elena Pozzoli for secretarial support.

Conflict of interests

None of the authors has any financial or personal relationships with other people or organisations that could be considered conflicts of interest for this work.

Source of funding

Institutional funds from the Mario Negri Institute

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Authors and Affiliations

  1. Laboratory of Regulatory Policies, Mario Negri Institute for Pharmacological Research, Via Giuseppe La Masa 19, 20156, Milan, Italy

    Laura Ottolenghi, Vittorio Bertele’ & Silvio Garattini

Authors
  1. Laura Ottolenghi
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  2. Vittorio Bertele’
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  3. Silvio Garattini
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Corresponding author

Correspondence to Vittorio Bertele’.

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Ottolenghi, L., Bertele’, V. & Garattini, S. Limits of add-on trials: antirheumatic drugs. Eur J Clin Pharmacol 65, 33–41 (2009). https://doi.org/10.1007/s00228-008-0545-z

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  • DOI: https://doi.org/10.1007/s00228-008-0545-z

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