In the case of multi-source (generic) preparations, Bio-equivalence study based on the WHO⁷ guidelines is required. Bio-equivalence data is required from all oral preparations except aqueous solutions at the time of administration. Orally or parenterally administered aqueous solutions will be assessed by chemical-pharmaceutical characteristics only. Also, Bio-equivalence study is required from preparations indicated for serious conditions requiring assured therapeutic response. All compounds in the present list correspond to this characteristic.

⁷ WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-fourth report. Geneva, World Health Organization, 1996:114-154 (WHO Technical Report Series, No. 863

Instead of Bio-equivalence trial, comparative clinical trial using clinical or pharmacodynamic endpoints can be presented. These endpoints should be justified and validated for the compound and trial should be designed to show equivalence. Trial showing the absence of significant difference can not be accepted.

Bio-equivalence study report should contain at least the following items:

• Description of study design. The most appropriate study type is two-period randomized cross-over study. If other study types were used (e.g. parallel group design), these should be justified by the applicant. In general, single-dose study with sufficiently long period for blood samples collection is acceptable.

• Information about investigators, study site, study dates.

• Data about preparations used: manufacturer, place of manufacture, batch number used in most countries of the world. The best acceptable reference is innovator preparation or product from WHO⁸ list of international comparator products if listed.

⁸ International comparator products for Bio-equivalence testing “Who Drug information, Vol 13, No 3, 1999 pp 158-161

• Characterization of study subjects. Bio-equivalence study should be normally performed in healthy volunteers. If patients were used, this should be justified by the applicant. Number of subjects should not be smaller than 12. Study report should contain inclusion and exclusion criteria, listing of demographic data of all subject.

• Description of study procedures. Administration of test products, meals, times of blood sampling or urine collection periods should be described in the clinical report.

• Description and validation of drug determination methods in investigated material. Analytical method should be validated over the measured drug concentration range. Validation should contain methodology and results of sensitivity, specificity, accuracy, precision and repeatability determination.

• All measured drug concentrations should be presented.

• Calculation methodology of pharmacokinetic parameters. Preferred is non-compartmental analysis. If modelled parameters were used, these models should be validated for the compound. All measured and calculated pharmacokinetic parameters should be presented in the report.

• Description of statistical methodology and results of statistical calculation. Statistical calculations should be based on the equivalence evaluation. The statistical method of choice is the tow one-sided test procedure and the calculation of 90% confidence intervals of the test/reference ratios of pharmacokinetic parameters. The main parameters to asses the Bio-equivalence are area under the plasma concentration-time curve (AUC) and maximum concentrations (Cmax) ratios. The 90% confidence interval for AUC-ratio should like within a Bio-equivalence range of 80-125%, the 90% confidence interval for Cmax-ratio within a range of 70-143%.