WHO 生物等效性研究方案中的常见缺陷（上）
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WHO 生物等效性研究方案中的常见缺陷（上）
2020-12-02 WHO 于 11 月 30 日发布《生物等效性研究方案中的常见缺陷》，总结了 11 个大类的 57 条缺陷，帮助申请人可以在生物等效性（BE）方案制定过程中注意相关问题。 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). 应从具有严格监管机构（SRA）的良好监管市场购买比较产品，除非 PQT/MED 另行同意（例如，产品在 SRA 国家不可用）。 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. 比较产品应从 PQT/MED 网页上列出的产品中选择。应选择最合适的比较产品规格，以减少或避免服用多片剂。 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. 比较产品的购买、运输和贮存应妥善记录，并符合 PQT/MED 网站上可接受的比较产品列表中所述的要求。 TEST PRODUCT 待测产品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. 生物等效性研究通常在健康志愿者中进行，仅当受试者的健康状况得到充分确证（包括确证血清生物化学和血液学参数值在预先规定的正常范围内）时，才应招募其参加研究。研究中心的正常范围应作为研究方案的附录。 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. 除非罕见的例外情况，否则不应招募健康检查参数的测量值超出预先规定的正常值的受试者。在极少数情况下，尽管受试者的测量超出了场地正常范围，但仍参加了研究，研究的医生应有明确记录的医学严格证据以证明该例外情况。药物临床试验管理规范（GCP）要求，在进行的每项试验中，试验受试者的权利、安全和福祉应被放在首位。但是，入组标准通常认为，如果主要研究者认为临床上不重要，则可以将超出预先规定的正常范围值的研究受试者纳入研究。这种灵活性通常会导致所有或几乎所有受试者的数值超出预定的正常范围。应设计方案以最大程度地减少这种情况，尤其是在血液学参数方面，从而保护受试者的健康和安全。 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. 待测和比较产品应在常规使用条件下给药。因此，在黄色单色光下给药以避免降解是不可接受的。应采用正常的照明条件。 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). 待测和比较产品应在常规使用条件下使用。因此，像成人送服常规药片一样，用一整杯水来给儿童患者送服分散片是不可接受的。用于分散片剂的体积和用于冲洗容器的体积（如果有）应与产品标签中所述的体积相同。例如，如果剂量指示是将待测产品分散在少量水中，则待测产品（例如，颗粒）应在少量水中（例如，20 – 40 mL）分散。如果剂量说明是将待测产品撒在食物上，则生物等效性研究应遵循这些剂量说明。比较产品应按其标签给药。例如，如果比较产品是成人规格的常规释放片剂，则应使用一杯水（例如，180-240 mL）送服。 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. 餐后研究中使用的膳食组成应与产品标签和/或 PQT/MED 关于生物等效性研究设计的特定说明相一致。如果餐后研究将提交给需要空腹和餐后研究的监管机构（例如，美国 FDA），如果提交了两项研究，则 PQT/MED 也可以接受由这些监管机构要求的膳食组成的研究。 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. 在速释产品的单剂量研究中，AUC0-inf不被视为主要的PK参数。AUC0-t是评估暴露程度的主要参数。 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. 对于半衰期较长的药物，可以使用在72 h处截断的AUC。但是，如果在72小时缺失样本，则应排除该概况。在2x2设计的情况下，这意味着将排除该受试者的所有AUC数据。 有关样本量计算、统计分析、数据排除、生物分析方法等方面的常见问题将在明日文章中介绍。 编译：识林-椒 |