Quality of Reporting of Bioequivalence Trials Comparing Generic to Brand Name Drugs: A Methodological Systematic Review Ame´ lie van der Meersch1,2,3, Agne` s Dechartres1,2,3*, Philippe Ravaud1,2,3 1 INSERM, U738, Paris, France, 2 AP-HP (Assistance Publique des Hoˆ pitaux de Paris), H oˆpital H oˆtel Dieu, Centre d9E´pide´miologie Clinique, Paris, France, 3 Universite´ Paris Descartes, Sorbonne Paris Cite´, Faculte´ de Me´decine, Paris, France Abstract Background: Generic drugs are used by millions of patients for economic reasons, so their evaluation must be highly transparent. Objective: To assess the quality of reporting of bioequivalence trials comparing generic to brand-name drugs. Methodology/Principal Findings: PubMed was searched for reports of bioequivalence trials comparing generic to brand- name drugs between January 2005 and December 2008. Articles were included if the aim of the study was to assess the bioequivalency of generic and brand-name drugs. We excluded case studies, pharmaco-economic evaluations, and validation dosage assays of drugs. We evaluated whether important information about funding, methodology, location of trials, and participants were reported. We also assessed whether the criteria required by the Food and Drug Administration (FDA) and the European Medicine Agency (EMA) to conclude bioequivalence were reported and that the conclusions were in agreement with the results. We identified 134 potentially relevant articles but eliminated 55 because the brand-name or generic drug status of the reference drug was unknown. Thus, we evaluated 79 articles. The funding source and location of the trial were reported in 41% and 56% of articles, respectively. The type of statistical analysis was reported in 94% of articles, but the methods to generate the randomization sequence and to conceal allocation were reported in only 15% and 5%, respectively. In total, 65 articles of single-dose trials (89%) concluded bioequivalence. Of these, 20 (31%) did not report the 3 criteria within the limits required by the FDA and 11 (17%) did not report the 2 criteria within the limits required by the EMA. Conclusions/Significance: Important information to judge the validity and relevance of results are frequently missing in published reports of trials assessing generic drugs. The quality of reporting of such trials is in need of improvement. Citation: van der Meersch A, Dechartres A, Ravaud P (2011) Quality of Reporting of Bioequivalence Trials Comparing Generic to Brand Name Drugs: A Methodological Systematic Review. PLoS ONE 6(8): e23611. doi:10.1371/journal.pone.0023611 Editor: Margaret Sampson, Children’s Hospital of Eastern Ontario, Canada Received February 21, 2011; Accepted July 21, 2011; Published August 17, 2011 Copyright: 2011 van der Meersch et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors have no support or funding to report. Competing Interests: The authors have declared that no competing interests exist. * E-mail: agnes.dechartres@htd.aphp.fr Introduction To lower healthcare costs, substituting brand-name drugs for low- cost bioequivalent generic drugs has greatly increased. In the United States, generic drugs represented 47% of all prescriptions dispensed in 1999, 61% in 2006 and 69% by the end of 2008 [1]. According to the Generic Pharmaceutical Association, the use of generics saved the US healthcare system approximately $121 billion in 2008. Generic and brand-name drugs have the same active principle, but generic drugs could differ in inert binder, color of tablet and manufacturing process. To approve new generic drugs, the US Food and Drug Administration (FDA) and the European Medicine Agency (EMA) relies on the results of bioequivalence trials based on pharmacokinetic criteria: rate of absorption as determined by the peak plasma concentration (Cmax), area under the plasma concentration–time curve from time 0 to time t = end of the study (AUC|0 to t) and to infinity (AUC|0 to infinity). The FDA requires the 90% confidence intervals (CIs) of the ratio of the generic and brand name drugs for these 3 criteria to be within 80% and 125% [2] whereas the EMA [3] requires only Cmax and AUC|0 to t. Reports of some studies and letters have warned about generic- drug substitution, suggesting lower efficacy and higher rates of adverse events [4,5,6,7,8,9], but data are scarce, and most studies had a low level of evidence. More importantly, drug companies may be implicated in this anti-generic-drug campaign [10]. Recently, 2 meta-analyses [11,12] comparing the efficacy of brand-name and generic drugs in the field of cardiovascular diseases and seizures did not show any superiority of the brand-name over the generic drugs. In this study, we aimed to investigate published reports of bioequivalence trials comparing generic to brand-name drugs to assess their quality of reporting. Methods Search strategy We performed an electronic search of MEDLINE via PubMed to identify all reports of trials published from Jan. 1, 2005, to Dec. 31, 2008. The following search equation was used: "Therapeutic Equivalency"[Mesh] OR "Drugs, Generic"[Mesh] OR "Biological PLoS ONE | www.plosone.org 1 August 2011 | Volume 6 | Issue 8 | e23611