should be on improving the reporting of bioequivalence data with registration of trial protocols and publication of trial results. The reference drug used should be systematically documented as the drug with demonstrated efficacy. Important information for judging both internal and external validity should be systematically reported, as should the 90% CIs for the 3 criteria (mean Cmax , AUC|0 to t, and AUC|0 to infinity) for the ratio of generic to brand- name drug required by the FDA, so that readers can judge the reliability of the conclusions. Supporting Information Table S1 General characteristics of bioequivalence trials comparing generic to brand-name drugs according to narrow therapeutic index (NTI) of the drugs (n = 79 reports). (DOC) Table S2 Study design and methodology of bioequivalence studies comparing generic to brand-name drugs according to narrow therapeutic index (NTI) of the drugs (n = 79 reports). (DOC) Table S3 Reporting of setting and population characteristics of bioequivalence studies comparing generic to brand-name drugs according to narrow therapeutic index (NTI) of the drugs (n = 79 reports). (DOC) References 1. Frank RG (2007) The ongoing regulation of generic drugs. N Engl J Med 357: 1993–1996. 2. FDA Guidance for Industry - Bioavailability and Bioequivalence Studies for Orally Administered Drugs Products - General Considerations. Available:http:// www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/ucm070124.pdf. Assessed 2011Jul 25. 3. EMEA Committee for medicinal products for human use (CMPH). Guideline on the investigation of bioequivalence. Available: http://www.ema.europa.eu/ pdfs/human/qwp/140198enrev1fin.pdf Assessed 2011 Jul 25. 4. Lesser RP, Krauss G (2001) Buy some today: can generics be safely substituted for brand-name drugs? Neurology 57: 571–573. 5. Borgheini G (2003) The bioequivalence and therapeutic efficacy of generic versus brand-name psychoactive drugs. Clin Ther 25: 1578–1592. 6. Mastoraki E, Michalopoulos A, Kriaras I, Mouchtouri E, Falagas M, et al. (2008) Incidence of postoperative infections in patients undergoing coronary artery bypass grafting surgery receiving antimicrobial prophylaxis with original and generic cefuroxime. J Infect 56: 35–39. 7. Sabatini S, Ferguson RM, Helderman JH, Hull AR, Kirkpatrick BS, et al. (1999) Drug substitution in transplantation: a National Kidney Foundation White Paper. Am J Kidney Dis 33: 389–397. 8. Wassef AA, Winkler DE, Roache AL, Abobo VB, Lopez LM, et al. (2005) Lower effectiveness of divalproex versus valproic acid in a prospective, quasi- experimental clinical trial involving 9,260 psychiatric admissions. Am J Psychiatry 162: 330–339. 9. Wilner AN (2004) Therapeutic equivalency of generic antiepileptic drugs: results of a survey. Epilepsy Behav 5: 995–998. 10. McCartney M (2010) Generic drugs: protest group was not quite what it seemed. BMJ 340: c1514. 11. Kesselheim AS, Misono AS, Lee JL, Stedman MR, Brookhart MA, et al. (2008) Clinical equivalence of generic and brand-name drugs used in cardiovascular disease: a systematic review and meta-analysis. JAMA 300: 2514–2526. Appendix S2 tic index drugs. (DOC) Appendix S4 (DOC) Appendix S3 Studies excluded because the name of the reference drug was not clearly reported. (DOC) PRISMA checklist. Author Contributions Conceived and designed the experiments: AD PR. Performed the experiments: AvdM AD. Analyzed the data: AvdM AD. Contributed reagents/materials/analysis tools: AvdM AD. Wrote the paper: AvdM AD PR. 12. Kesselheim AS, Stedman MR, Bubrick EJ, Gagne JJ, Misono AS, et al. Seizure outcomes following the use of generic versus brand-name antiepileptic drugs: a systematic review and meta-analysis. Drugs 70: 605–621. 13. WHO Anatomical Therapeutic Chemical classification system with defined daily doses (ATC DDD). Family of international classifications. 14. CFR code of federal regulation Bioavailability and bioequivalence requirement. Available http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch. cfm?fr = 320.33. Assessed 2011 Jul 25. 15. Higgins JPT, Green S, eds (2008) Cochrane handbook for systematic reviews of interventions version 5.0.0. Cochrane Collaboration. 16. Le Henanff A, Giraudeau B, Baron G, Ravaud P (2006) Quality of reporting of noninferiority and equivalence randomized trials. JAMA 295: 1147–1151. 17. Wangge G, Klungel OH, Roes KC, de Boer A, Hoes AW, et al. Room for improvement in conducting and reporting non-inferiority randomized controlled trials on drugs: a systematic review. PLoS One 5: e13550. 18. FDA Drug approval reports. Available: http://www.accessdata.fda.gov/scripts/ cder/drugsatfda/index.cfm?fuseaction = Reports.ReportsMenu. Assessed 2011 Jul 25. 19. Dickersin K (1990) The existence of publication bias and risk factors for its occurrence. JAMA 263: 1385–1389. 20. D’Agostino RB, Sr, Massaro JM, Sullivan LM (2003) Non-inferiority trials: design concepts and issues - the encounters of academic consultants in statistics. Stat Med 22: 169–186. 21. Djulbegovic B, Clarke M (2001) Scientific and ethical issues in equivalence trials. JAMA 285: 1206–1208. 22. Walker SE, Friesen MH (1999) Are the current bioequivalence standards sufficient for the acceptance of narrow therapeutic index drugs? Utilization of a computer simulated warfarin bioequivalence model. J Pharm Pharm Sci 2: 15–22. 23. Yim DS (2009) Simulation of the AUC changes after generic substitution in patients. J Korean Med Sci 24: 7–12. Quality of Reporting of Generic Drug Trials Table S4 Synthesis of the results according to the conclusions reported for the single-dose bioequivalence studies comparing generic to brand-name drugs according to narrow therapeutic index (NTI) of the drugs (n = 73 reports). (DOC) Appendix S1 Bioequivalence studies assessing therapeutic index drugs. (DOC) non-narrow Bioequivalence studies assessing narrow therapeu- PLoS ONE | www.plosone.org 7 August 2011 | Volume 6 | Issue 8 | e23611