title: New antirheumatic drugs: any real added value? A critical overview of regulatory criteria for their marketing approval.
abstract: OBJECTIVE
  Rheumatoid arthritis (RA) is a systemic autoimmune disorder causing chronic polyarticular synovial inflammation and progressive joint damage. New anti-rheumatic drugs, such as leflunomide, infliximab, etanercept, adalimumab and anakinra, have recently become available. The aim of this paper is to summarize and critically evaluate the type of studies and clinical endpoints accepted by the European Medicines Agency (EMEA) to approve these new drugs.
  
  
  METHODS
  Information regarding the approval of antirheumatic drugs was obtained from European Public Assessment Reports (EPARs) and published pivotal studies.
  
  
  RESULTS
  Leflunomide is the only non-biological disease-modifying anti-rheumatic drug (DMARD) to receive recent approval for RA treatment, but strong evidence of its superiority over conventional therapies is lacking. Anakinra in combination with methotrexate received approval as a DMARD for RA on the basis of two pivotal trials in which American College of Rheumatology response criteria (ACR 20 response) were used as the sole primary endpoint. For easier demonstration of efficacy, studies leading to first approval of etanercept, infliximab and adalimumab were carried out on non-responders to DMARDs. Once on the market, these drugs gained an extension of the indication to methotrexate-naïve patients. Studies that provided the basis for approval were not adequately designed, given the lack of an active control and the choice of ACR response as the only clinical endpoint. Consequently, only a weak proof of efficacy emerged for the treatment of signs and symptoms of RA, and these drugs failed to show real benefit in slowing radiographic progression. Serious infections, changes in blood cell counts, severe skin and hepatic infections were the main adverse events that emerged from the clinical studies. Therefore, the unconvincing benefit of the new antirheumatic drugs can scarcely outweigh the risk associated with their use. Moreover, the monthly costs in Italy of the new biological preparations are several fold higher than those of the reference drugs.
  
  
  CONCLUSIONS
  Recently approved anti-RA products should be a therapeutic option only for patients refractory to conventional drugs.
authors.affiliation: Laboratory of Regulatory Policies, Mario Negri Institute for Pharmacological Research, Via Eritrea 62, 20157, Milan, Italy. bertele@marionegri.it
authors.forename: Vittorio
authors.initials: V
authors.lastname: Bertele'
authors.forename: Alessandro
authors.initials: A
authors.lastname: Assisi
authors.forename: Valeria
authors.initials: V
authors.lastname: Di Muzio
authors.forename: Danila
authors.initials: D
authors.lastname: Renzo
authors.forename: Silvio
authors.initials: S
authors.lastname: Garattini
mesh_terms: D000068879:Adalimumab; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D017326:Clinical Trials, Phase III as Topic; D017277:Drug Approval / Q000331:legislation & jurisprudence* / Q000379:methods / Q000458:organization & administration; D000068800:Etanercept; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology / Q000627:therapeutic use; D000069285:Infliximab; D007555:Isoxazoles / Q000494:pharmacology / Q000627:therapeutic use; D007558:Italy; D000077339:Leflunomide; D007880:Legislation, Drug / Q000592:standards; D040541:Marketing / Q000331:legislation & jurisprudence* / Q000379:methods; D015201:Meta-Analysis as Topic; D016032:Randomized Controlled Trials as Topic; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D007555:Isoxazoles; D018124:Receptors, Tumor Necrosis Factor; D000069285:Infliximab; D000068879:Adalimumab; D000077339:Leflunomide; D000068800:Etanercept