Ethics and trials

Journal of Hepatology 51 (2009) 792–797 www.elsevier.com/locate/jhep

Review

Ethics in clinical researchq
Silvio Garattini*, Vittorio Bertele’
Mario Negri Institute for Pharmacological Research, Via G. La Masa 19, 20156 Milan, Italy

R&D of new drugs is driven by pharmaceutical companies that invest considerable amounts of money for this purpose. This may introduce bias, to emphasize theclinical value of drugs to be allowed onto the market. Bias is caused by methodological flaws including the population under study, the choice of inadequate comparators or of their dosage, the adoption of surrogate or composite endpoints, the decision to publish mainly positive findings or to overlook some safety concerns, etc. All this happens in a legal context that requires no added value fornew drugs to be approved for the market. This encourages the use of placebo even when active comparators are available, or the search for non-inferiority of new products in comparison with active comparators. Superiority over placebo and non-inferiority to active comparators may allow drugs onto the market that are in fact less active (or safe, tolerable, convenient, etc.) than those alreadyavailable, usually with consolidated properties and lower costs. In addition, they do not meet patients’ or physicians’ needs of defining the place in therapy and respective roles of new and available treatments. The current legislative and regulatory setting seems designed to meet commercial interests rather than public health needs. Ó 2009 European Association for the Study of the Liver. Published byElsevier B.V. All rights reserved. Keywords: Clinical research; Clinical trials; Ethics; Clinical methodology

1. Introduction Planning, conducting and concluding clinical trials has always been a matter for ethical discussion because patients may risk receiving treatments that are not always potentially in their interest. A vast amount of literature deals with the principles for recruitingpatients for clinical studies, who are free to participate and can withdraw at any time. Trials with patients such as prisoners who were obliged to participate, or studies done in
Associate Editor: M. Colombo q The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. * Correspondingauthor. Tel.: +39 02 39014312; fax: +39 02 3546277. E-mail address: garattini@marionegri.it (S. Garattini). Abbreviations: RCT, randomized clinical trial; EMEA, European Medicines Agency; EU, European Union; DMARD, disease modifying anti-rheumatic drugs; Hb A1c, glycosylated hemoglobin; FDA, Food and Drug Administration; HDL, high-density lipoprotein; SSRI, selective serotonin reuptake inhibitors.developing countries without adequate external control have been condemned. Although there is always a need for active vigilance the ethics of clinical trials today is essentially confined to the preparation and conduct of the protocol because the results can be considerably influenced by apparently minor details. These details require attention considering that most clinical trials are supported,executed and analyzed by pharmaceutical companies which have an obvious conflict of interest in testing new drugs whose development has incurred considerable expenditure. Clinical trials that require thousands of patients have a high cost, sometimes running to hundreds of millions of euros. Possibly unintentionally, this may introduce bias that affects the outcome of the study. There is also asubstantial gap between the capacity of industry to utilize experts in clinical trial methodology and the specific knowledge of the members of the ethical committees responsible in many countries for approval of the protocols. This article underlines some of the biases in the scientific literature concerning phase 3 randomized controlled trials (RCT).

0168-8278/$36.00 Ó 2009 European Association for...