WHO 预认证药品小组（PQT/MED）强烈建议计划向 PQT/MED 提交 BE 研究的申请人在执行研究之前将研究方案的最终草案提交给 PQT/MED 征求意见。这一过程的目的是帮助申请人开展研究，以便能够最好地检测药物之间的体内表现差异，将可能把变异引入研究数据的因素降至最低，并与 WHO 的指南和要求保持一致。
WHO 指出在方案制定过程中应注意并解决以下问题：
COMPARATOR PRODUCT 比较产品
1. The selected comparator product should be identified by the Marketing Authorisation Holder (MAH) and the market of purchase, not the manufacturer and the country of manufacturing.
选定的比较产品应由上市许可持有人（MAH）和购买市场来标识，而不是制药商和生产国。
2. The comparator product should be purchased from a well-regulated market with a stringent regulatory authority (SRA), unless otherwise agreed with the PQT/MED (e.g., if not available in SRA countries).
3. The comparator product should be selected from those listed on the web page of PQT/MED. The most appropriate strength of the comparator product should be selected to minimise or avoid administration of multiple tablets.
4. The comparator product purchase, shipment, and storage should be properly documented and meet the requirements as described in the list of acceptable comparator products found on the PQT/MED website.
5. The proposed product / product strengths should be listed in the Expressions of Interest (EoI).
拟议产品/产品规格应列在意向书（EoI）中。
INCLUSION AND EXCLUSION CRITERIA 入组和排除标准
6. Bioequivalence studies are generally conducted in healthy volunteers. Subjects should be recruited into the study only if their health is fully verified, including verification that serum biochemistry and haematology parameter values are within pre-defined normal ranges. The normal ranges of the study centre should be included as an appendix to the study protocol.
7. The enrolment of a subject with measured values for the health verification parameters that fall outside the pre-defined site normal values should not occur, except on a rare, exceptional basis. On the rare occasion when a subject is enrolled in a study despite having a measurement outside the site normal range, the study physician should have a clearly documented and medically rigorous justification for making that exception. Good Clinical Practices (GCP) require that the rights, safety, and well-being of trial subjects be given top priority in every trial conducted. However, the inclusion criteria generally accept that the inclusion of study subjects with values outside of the pre-defined normal range is possible if considered clinically not significant by the principal investigator. This flexibility generally leads to values outside the pre-defined normal ranges in all, or almost all, included subjects. Protocols should be designed to minimise this, particularly with respect to haematological parameters, thus protecting the health and safety of the subjects.
8. The exclusion criterion for participation in any clinical study or blood donation should be 90 days.
参加任何临床研究或献血的排除标准应为90天。
METHOD OF ADMINISTRATION 给药方法
9. The test and comparator products should be administered under the usual conditions of use. Therefore, it is not acceptable to administer the products under yellow monochromatic light to avoid degradation; normal lighting conditions should be employed.
10. The test and comparator products should be administered under the usual conditions of use. Therefore, it is not acceptable to administer a dispersible tablet for paediatric patients with a full glass of water, like a conventional tablet would be administered to adults. The volume used to disperse the tablet and the volume used for rinsing the container (if any) should be those described in the labelling of the product. For example, if the dosing instructions are that the test product should be dispersed in a small amount of water, the test product (e.g., granules) should be dispersed in a small amount of water (e.g., 20 – 40 mL). If the dosing instructions are that the test product will be taken sprinkled on food, the bioequivalence study should follow these dosing instructions. The comparator product should be administered in keeping with its labelling. For example, If the comparator product is an adult strength, conventional-release tablet, it should be taken with a glass of water (e.g., 180 - 240 mL).
11. The meal composition employed in fed studies should be consistent with product labelling and/or the PQT/MED specific notes on the design of bioequivalence studies. If the fed study is going to be submitted to regulatory agencies (e.g., US-FDA) where both a fasted and a fed state study are required, a study with the meal composition required by these regulatory authorities may also be acceptable for PQT/MED if both studies are submitted.
12. The composition of the meal, including caloric content of carbohydrates, fat and proteins, should be described in the study protocol.
膳食的成分，包括碳水化合物、脂肪和蛋白质的热量，应在研究方案中说明。
SAMPLING TIMES 采样时间
13. Sampling times should be sufficiently frequent around the expected Tmax for a proper characterisation of Cmax.
采样时间应在预期的 Tmax 附近足够频繁，以正确表征Cmax。
14. Sampling times should cover at least 3 half-lives when calculating AUC0-t.
计算AUC0-t时，采样时间应至少涵盖3个半衰期。
15. Sample collection after 72 hours is not necessary.
72小时后无需采集样品。
16. The wash out period should not be excessively large compared with 5 times the largest expected half-life.
清洗期不应过长，不应超过最大预期半衰期的5倍。
PHARMACOKINETIC ANALYSIS 药代动力学分析
17. The protocol should indicate the software to be used for pharmacokinetic calculations as well as the trapezoidal method employed for AUC calculation.
方案应指明用于药代动力学计算的软件以及用于AUC计算的梯形方法。
18. Any below LLOQ value(s), including those between two valid concentration values, should be reported as zero.
任何低于LLOQ的值，包括两个有效浓度值之间的值，均应报告为零。
19. Plots should be provided in original scale and semi-logarithmic scale for each subject in addition to mean data plots.
除平均数据图外，还应以原始比例和半对数比例提供每个受试者的图。
20. Tmax is considered a primary PK parameter only in the exceptional cases where onset of action is clinically relevant.
仅在起效时间与临床相关的特殊情况下，才将Tmax视为主要的PK参数。
21. AUC0-inf is not considered to be a primary PK parameter in single dose studies of immediate release products. AUC0-t is the primary parameter for assessment of extent of exposure.
22. For drugs with long half-life, AUC truncated at 72 h could be used. However, in the event of a missing sample at 72 hours, that profile should be excluded. In the case of a 2x2 design, this implies the exclusion of all AUC data for that subject.
