Availability"[Mesh] OR "Intellectual Property"[Mesh] OR non proprietary OR brand name OR innovator AND (Humans[Mesh] AND English[lang] AND ("2005/01/01"[PDat]: "2008/12/ 31"[PDat])). We also electronically searched the table of contents of journals (Arzneimittel-forschung, International Journal of Clinical Pharmacology and Therapeutics, Clinical Therapeutics) known to publish reports of bioequivalence trials assessing generic drugs for additional references missed during the PubMed search. Selection of relevant articles One of us (A.V.D.M) selected potentially relevant articles after screening the titles and abstracts. In case of uncertain eligibility, the full text was screened. 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, meta-analyses, commentaries and validation dosage assays of drugs. Studies were also excluded if the active principle was not approved by the FDA or EMA and if they involved animals or in vitro analysis. If information about the products being tested lacked, FDA or EMA websites were searched to obtain further information. A second reviewer (A.D) assessed all articles of uncertain eligibility, and the final decision for inclusion was obtained by consensus between the 2 reviewers. Data extraction We generated a standardized data collection form based on the guidelines of the FDA [2] and EMA [3], a review of the literature and a priori discussion. Before data extraction, as a calibration exercise, 2 members of the team (A.D., A.V.D.M) evaluated a random set of 10 reports. All disagreements were resolved by consensus, and the form was modified accordingly. The following data were extracted from each article: 1. General characteristics of the selected studies: category of the journal (pharmacology, general medicine, specialty medicine) and year of publication; whether the funding source was reported and whether it was public or private. 2. Characteristics of the drugs: the class of drug according to the Anatomical Therapeutic Chemical classification [13]; the name of the reference drug and whether the drug had a narrow therapeutic index (NTI) (i.e., a drug with less than a 50% difference between the minimum toxic concentration, minimum effective concentration in blood and median effective dose[14]) and whether this information was reported in the article. For NTI drugs, the EMA requires narrower limits than for non-NTI drugs: the 90% CIs for the generic to brand-name ratio should be between 90% and 111% instead of between 80% and 125%.[3]. 3. Study design: whether the study design was reported, the type of design (i.e., randomized controlled, parallel or cross-over), and the sample size. We also noted whether a registration number in an international database was reported. 4. Administration of the drugs: whether the mode of administra- tion of the drugs was reported: the route of administration (i.e., oral, parenteral), the dose of the drugs (i.e., single or multiple) and how the drugs were administered (i.e., under fasting or fed condition). 5. Methodology of the study: whether the methods used to generate the randomization sequence and conceal allocation were reported and adequate according to the definitions provided by the Cochrane Collaboration [15]; whether study participants, care providers and outcome assessors were Quality of Reporting of Generic Drug Trials reported to be blinded to the treatment arm; whether the number of participants excluded from data analysis and the reasons for exclusion were reported; whether a sample size calculation was reported; and whether the statistical analysis performed was reported and the type of analysis (i.e., ANOVA, t test). 6. Setting and population characteristics: whether the article reported the country where the study was performed and the main characteristics of the study participants (age, weight, height, sex, exclusion criteria). 7. Results and conclusions: the results of the trial (i.e., 90% CI of the generic to brand-name ratio for Cmax, AUC|0 to t and, AUC|0 to infinity of the generic to brand-name drug and the conclusions (i.e., bioequivalence, non-bioequivalence, unclear). The same reviewer (A.V.D.M) independently completed all the data extractions. A second member of the team (A.D.) reviewed a random sample of 30 articles to assess inter-rater reliability. PRISMA checklist is provided in Appendix S4. Statistical analysis The analysis was descriptive. Data were summarized as number and percentages for qualitative variables, and median, interquar- tile range (IQR) and range for continuous variables. Inter-rater agreement between the 2 assessors (A.V.D.M. and A.D.) was assessed by the kappa coefficient for qualitative variables. All analyses involved use of R v2.9.0. Results Selection of relevant trials A flow chart of the selected articles of trials comparing generic to brand-name drugs is in Figure 1. Briefly, the electronic search yielded 5,522 citations, 215 articles were selected for further evaluation, and a final 79 reports of bioequivalence trials were selected after reading the full text. Of these, 63 articles described non-NTI drugs (Appendix S1) and 16 NTI drugs (Appendix S2). Only 5 articles reported that the drug was an NTI drug. In total, 55 articles (Appendix S3) out of 134 (41%) were eliminated because only the compendium name of the reference drug was reported, and we could not determine whether the reference drug was a brand-name or another generic drug. In general, the kappa for data extraction was good, ranging from 0.71 to 1. General characteristics of the trials Table S1 provides the general characteristics of the selected bioequivalence trials. Most of the studies were published in pharmacology journals (78%). The studies concerned a wide range of pharmacological areas, the most common being study of anti- infective agents for systemic use (37%) and of the cardiovascular system (18%) and nervous system (14%). Funding was reported in 41% of the articles and was private in 25%. In total, 73 reports (92%) described single-dose administra- tion and 6 (8%) multiple-dose administration. In 66 (83%), the administration was under the fasting condition. Study design and methodology Table S2 shows the study design and methodology of the bioequivalence trials. Only one trial reported a registration number in an international database. The study design was reported in most articles (99%) and was a randomized cross-over controlled trial in these studies. The median sample size was 24 (IQR 24 to 28; range 12 to 70). A sample size calculation was reported in 27 articles (34%). In one article, the authors reported PLoS ONE | www.plosone.org 2 August 2011 | Volume 6 | Issue 8 | e23611