首页 > 资讯 > WHO 生物等效性研究方案中的常见缺陷（下）

出自识林

2020-12-03

昨日的识林资讯【WHO 生物等效性研究方案中的常见缺陷（上）】中介绍了 WHO 对于生物等效性（BE）研究方案中比较产品、待测产品、入组和排除标准、给药方法、采样时间、药代动力学分析方面的缺陷总结。今天我们接着来看看在样本量计算、统计分析、数据排除、生物分析方法以及其它方面的一些问题。【生物等效性研究方案中的常见缺陷】

SAMPLE SIZE CALCULATION 样本量计算

23.The sample size of replicate cross-over designs where Cmax acceptance range is widened based on intra-subject coefficient of variation (CV) of the comparator product but AUC acceptance range is the classical 80-125%, should be calculated for Cmax with widening and AUC without widening. Sometimes AUC without widening requires a larger sample size than Cmax with widening.

重复交叉设计的样本量，其中Cmax接受范围根据比较产品的受试者内部变异系数（CV）扩大，但AUC接受范围为经典的80-125％，应针对扩大的范围计算Cmax和没有扩大的范围计算AUC。有时，没有扩大的AUC需要比扩大的Cmax更大的样本量。

24. The sample size calculation for a replicate design with widening of the acceptance range should be calculated as described by Tothfalusi and Endrenyi in "Sample Sizes for Designing Bioequivalence Studies for Highly Variable Drugs". J Pharm Pharmaceut Sci 15(1) 73-84, 2012. The conventional methods for replicate designs do not take into account the impact of acceptance range widening on the sample size calculation.

对于扩大可接受范围的重复设计的样本量，应按照Tothfalusi和Endrenyi在“高变异药物设计生物等效性研究的样本量” J Pharm Pharmaceut Sci 15(1) 73-84, 2012中所述计算。用于重复设计的常规方法未考虑可接受范围扩大对样本量计算的影响。

25. The sample size calculation for 2x2 cross-over designs or parallel designs are often not justified adequately or presented with sufficient detail. For more information on sample size calculation see Julious S.A. "Sample sizes for clinical trials with Normal data." Statistics in Medicines 2004; 23: 1921-1986. The sample size should be based on the desired power (e.g., 80 or 90%), consumer risk (5%), pre-defined equivalence margins (usually 80 – 125%), expected difference between formulations (e.g., 5%), and the expected inter-subject variability for parallel designs or intra-subject variability for the cross-over designs.

对于2x2交叉设计或并行设计的样本量计算通常没有充分的理由或没有提供足够的细节。有关样本量计算的更多信息，参见Julious S.A.“具有正常数据的临床试验样本量” Statistics in Medicines 2004; 23: 1921-1986。样本量应基于所需功效（例如，80％或90％）、消费者风险（5％）、预先定义的等效界值（通常为80％至125％）、配方之间的预期差异（例如，5％）以及平行设计的预期受试者间变异性或交叉设计的预期受试者内变异性。

26. The number of subjects that are added to the sample size calculation to compensate for potential dropouts or withdrawals should be realistic and consistent with the study design (e.g., more dropouts expected in longer studies) and tolerability profile of the drug.

添加到样本量计算中以补偿可能的脱落或退出人数的受试者数量应切合实际，并且与研究设计（例如，在较长的研究中预期会有更多的脱落人数）和药物的耐受性相一致。

27. The sample size calculation is sometimes based on assumptions that are not consistent with differences observed in previous pilot studies and the expected variability based on previous pilot studies or the variability described in the literature.

样本量的计算有时是基于与先前试点研究中观察到的差异不一致的假设，以及基于先前试点研究或文献中描述的变异性得出的预期变异性。

28. Sample size is sometimes calculated to detect a difference between treatments instead of being based on a calculation aimed to show equivalence.

有时计算样本量是为了检测治疗之间的差异，而不是基于旨在显示等效性的计算。

29. In case of a parallel design, it is extremely important to obtain balanced groups in all demographic characteristics that might impact the pharmacokinetics of the drugs. The methods employed to ensure balanced groups are generally not described in the protocols.

在平行设计的情况下，在所有可能影响药物药代动力学的人口统计学特征中获得平衡的群组非常重要。方案中通常没有描述用于确保平衡群组的方法。

STATISTICAL ANALYSIS 统计分析

30. The protocol should indicate the software to be used for the statistical calculations.

方案应指明用于统计计算的软件。

31. The factors to be included in the ANOVA should be defined in the protocol.

应在方案中定义方差分析中要包括的因素。

32. The calculation of the 90% confidence interval (CI) of the mean test/comparator ratio for the primary PK parameters should not be confused with the two one-sided t-tests employed to reject the null hypothesis of non-equivalence. The end result is the same, but these are not the same calculations.

不应将主要PK参数的平均待测产品/比较产品比率的90％置信区间（CI）的计算与用来拒绝不等价零假设的两个单侧t检验相混淆。最终结果是相同的，但计算不同。

33. In cases of two-stage designs, the consumer risk should be adjusted to preserve the type I error at or below 5%. It is not acceptable to use 90% confidence interval in both the interim and the final analyses. Due to the statistical complexity of the alpha level expenditure in two-stage bioequivalence cross-over trials, two stage designs are not encouraged and, if used, the design should be as simple as possible e.g., with equal sizes in both stages. The Applicant should demonstrate that the consumer risk is not inflated above 5% with the proposed design and alpha expenditure rule, taking into account that simulations are not considered sufficiently robust and analytical solutions are preferred.

在两阶段设计的情况下，应调整消费者风险，以将 I 类错误保持在 5% 或以下。在期中和最终分析中使用 90% 置信区间是不可接受的。由于在两阶段生物等效性交叉试验中 α 水平消耗的统计复杂性，因此不建议进行两阶段设计，如果使用该设计，则其设计应尽可能简单，例如，两阶段的大小均应相等。申请人应证明，使用拟议的设计和 α 消耗规则，不会将消费者风险夸大到5％以上，考虑到这些，模拟被认为不够稳健，首选分析解决方案。

34. While in cases of 2x2 cross-over or parallel trials only the data of subjects who complete the study can be considered for the pharmacokinetic and statistical comparison, in cases of replicate designs, data from subjects who did not complete all periods of treatment may still be considered. All subjects with two observations of the comparator product should be considered for the calculation of the intra-subject CV of the comparator. Those subjects with at least one observation for the test and one observation for the comparator should be considered for the average bioequivalence assessment.

尽管在2x2交叉或平行试验的情况下，只有完成研究的受试者的数据才可用于药代动力学和统计学比较，但在重复设计的情况下，未完成所有治疗期的受试者的数据仍可能被考虑。计算比较产品的受试者内部CV时，应考虑比较产品两次观察结果的所有受试者。对于平均生物等效性评估，应考虑那些至少具有一项待测产品观察值和一项比较产品观察值的受试者。

35. The statistical procedure should be conducted without imputing values to the missing observations.

执行统计程序时，不应将数值推算到缺失的观察值上。

36. In those cases where the subjects are recruited and treated in groups, it is appropriate to investigate the statistical significance of the group-by-formulation interaction e.g., with the following ANOVA model: Group, Sequence, Formulation, Period (nested within Group), Group-by-Sequence interaction, Subject (nested within Group*Sequence) and Group-by-Formulation interaction. If this interaction is significant, the study results are not interpretable. However, it is not considered to be correct to report the results of the 90% confidence interval of the ratio test/comparator based on the standard error derived from this ANOVA. If the group-by-formulation interaction is not significant, the 90% confidence interval should be calculated based on the ANOVA model defined in the protocol. This model may or may not include the group effect as pre-defined in the protocol. This depends on whether the group effect is believed to explain the variability observed in the data.

在受试者被分组招募和分组治疗的情况下，研究制剂和分组交互的统计学显着性是合适的，例如，使用以下方差分析模型：分组、序列、配方、时期（嵌套在组内）、顺序和分组交互，制剂与受试者（嵌套在“分组*序列”中）和分组交互。如果这种交互是显著的，则研究结果无法解释。但是，基于此方差分析模型得出的标准误差来报告待测/比较产品比率的90％置信区间的结果并不正确。如果制剂和分组之间的交互不显着，则应根据方案中定义的方差分析模型计算90％的置信区间。该模型可能包含也可能不包含方案中预定义的分组效果。这取决于是否相信群组效应可以解释数据中观察到的变异性。

37. The a posteriori power of the study does not need to be calculated. The power of interest is that calculated before the study is conducted to ensure that the adequate sample size has been selected. Furthermore, the calculated power is often the power to detect differences, which is not relevant. The relevant power is the power to show equivalence within the pre-defined acceptance range.

研究的后验功效不需要计算。感兴趣的功效是在进行研究之前计算得出的，以确保选择了足够的样本量。此外，计算出的功效通常是检测差异的功率，这是不相关的。相关功效是显示在预定接受范围内等效的功效。

38. In case of multiple comparisons, the consumer risk should be adjusted. Another option is a hierarchical approach, where it is required first to show BE in the easiest or most desired comparison (e.g., when a dispersible tablet is administered with a glass of water) and if bioequivalence is shown, then the second comparison is performed (e.g., when the dispersible tablet is administered dispersed in the glass of water). However, if the first comparison is not able to show equivalence, the second is not conducted.

如果进行多次比较，则应调整消费者风险。另一种选择是分层方法，首先需要在最简单或最期望的比较中显示BE（例如，当将分散片与一杯水一起给药时），如果显示出生物等效性，则进行第二次比较（例如，当将分散片分散在一杯水中给药时）。但是，如果第一个比较无法显示等效性，则不执行第二个比较。

39. In case of dose-normalization when the same dose is not administered in both treatments, it is not necessary to normalise all PK values individually. It is possible to dose-normalise only the point estimate of the ratio T/R used for the calculation of the 90% CI. Dose-normalisation of the point estimate of the test/comparator ratio in log scale is done by adding the ln(dose of comparator/dose of test).

在剂量归一化的情况下，如果在两种治疗方法未以相同剂量给药，无需单独对所有PK值进行归一化。可以仅对用于计算90％CI的T/R比值的点估计进行剂量归一化。通过添加ln（比较产品剂量/待测产品剂量）来完成对数标度中待测产品/比较产品比值的点估计剂量归一化。

40. It is not necessary to calculate the non-parametric 90% CI of Tmax. A numerical comparison of the median values and its range is considered sufficient.

不必计算Tmax的非参数90％CI。中值及其范围的数值比较被认为是足够的。

EXCLUSION OF DATA 数据排除

41. In order to exclude the pharmacokinetic results of those subjects who vomit during the study, the protocol should define in hours the value of two times median Tmax (as documented in the literature) since the decision to exclude or include the subject should be made before analysing the study samples and as soon as possible, when emesis occurs. This time may differ for different drugs of a fixed dose combination.

为了排除那些在研究期间呕吐的受试者的药代动力学结果，方案应在数小时内定义中值Tmax的两倍（如文献所记载），因为应该在分析研究样品之前，在呕吐发生时尽快做出排除或纳入受试者的决定。对于复方的不同药物，此时间可能有所不同。

42. Statistical tests to identify "outlier observations" are not acceptable in case of parallel or 2x2 cross-over designs. Therefore, these tests should not be conducted. In case of replicate cross-over designs where the acceptance range is widened based on the intra-subject CV of the comparator product, outliers may inflate the estimation of intra-subject variability of the comparator and outliers should be investigated. The outliers of interest in case of a replicate design are not those subjects that are discordant with the rest of subjects, because if the subject behaves in a similarly discordant way in both periods, the behaviour is confirmed. The outliers of interest in a replicate design are those that behave differently in the periods where the comparator product is replicated and, consequently, inflate the intra-subject variability of the comparator product. Then, the application of a conventional statistical test is not sufficient to detect the outliers and the type of outlier should be discussed. In any case, a sensitivity analysis with and without the detected outliers is considered essential to assess the impact of the outliers.

在并行或2x2交叉设计的情况下，不能使用统计检验来识别“离群观察”。因此，不应进行这些检验。在重复交叉设计的情况下，可接受范围基于比较产品的受试者内CV扩大，离群值可能会增加对比较产品受试者内部变异性的估计，因此应研究离群值。在重复设计的情况下，关注的离群值不是与其余受试者不一致的那些受试者，因为如果该受试者在两个时期内的表现均有类似的不一致方式，则可以确认该表现。重复设计中关注的离群值是那些在比较产品被重复期间表现不同，从而夸大了比较产品受试者内变异性的值。然后，常规统计检验的应用不足以检测离群值，因此应讨论离群值的类型。在任何情况下，在有或没有检测到的离群值时，进行敏感性分析都被认为对评估离群值的影响至关重要。

43. Re-dosing in case of suspected outliers is not considered acceptable as a method to confirm the outlier behaviour of the subject.

如果怀疑存在离群值，则重新给药不被认为是确认受试者离群值表现的方法。

44. The clinical and analytical investigations conducted for suspected outliers are usually conducted only in the subjects that are considered as outliers or at least with more emphasis on those subjects, and this is not considered correct because all subjects should be treated equally. The findings that may justify an outlier behaviour might be found also in subjects that do not behave as outliers if these subjects are investigated in a similar fashion.

对可疑离群值进行的临床和分析研究通常仅在被视为离群值的受试者中进行，或者至少更加侧重于这些受试者，而这被认为并不正确，因为所有受试者均应得到同等对待。如果以类似的方式对这些受试者进行调查，那么在那些表现得不离群的受试者中也可能会发现可以证明的离群表现。

45. The exclusion from statistical analysis due to very low concentrations observed following administration of the comparator product requires the pre-definition of what is considered to be 'very low' in the protocol (e.g., in accordance with EMA guideline, <5% of the geometric mean of the other subjects).

由于在比较产品给药后观察到的浓度非常低，无法从统计分析中排除，因此需要预先定义方案中被认为“非常低”的含量（例如，根据EMA指南，<其他受试者几何平均值的5％）。

46. A single missed blood sample should not be considered as a reason for the exclusion of a subject by the principal investigator. If such a decision is to be made, it must be made prior to the initiation of the bioanalytical portion of the study.

一次遗漏的血液样本不应被视为主要研究者排除受试者的原因。如果要做出这样的决定，则必须在开始研究的生物分析部分之前做出决定。

47. Subjects with Cmax in the first sampling point should not necessarily be excluded. The study should be designed so Cmax does not occur at the first sampling time, but if that happens only in a small number of profiles the data can still be considered.

不必排除第一个采样点出现Cmax的受试者。研究应设计为在第一次采样时就不会出现Cmax，但是如果仅在少量中受试者中发生Cmax，则仍然可以考虑这些数据。

48. The samples of subjects that do not finish the study because of an adverse event should be measured for safety reasons in order to investigate whether the withdrawal was related to unexpectedly high drug concentrations causing the adverse events.

出于安全原因，应测量因不良事件而未完成研究的受试者样本，以便调查退出是否与引起不良事件的意外高药物浓度有关。

49. Subjects should not be excluded simply because three consecutive sampling points are missing.

不应仅仅因为缺少三个连续的采样点而排除受试者。

BIOANALYTICAL METHOD 生物分析方法

50. The list of parameters for the validation of the bioanalytical method that are included in the clinical protocol is often not complete.

临床方案中包含的用于验证生物分析方法的参数列表通常不完整。

51. Incurred sample reanalysis (ISR) does not need to be conducted in 7% of the study samples exceeding 1,000 samples, 5% of these samples is sufficient.

无需对超过1,000个样本的7％研究样本进行样本再分析（ISR），分析5％的样本就足够了。

52. ISR samples should not be selected based on concentrations above the low QC.

不应根据高于低QC浓度而选择ISR样品。

53. Manual integration should be performed only when the instrument is not able to correctly integrate the peak with the default settings and it cannot be solved by refining the settings such as the expected retention time.

仅当仪器无法正确使用默认设置对峰进行积分并且无法通过细化设置（例如预期保留时间）来解决时，才应执行手动积分。

54. Plasma samples from subjects that dropout or are withdrawn due to an adverse event should be analysed for a complete safety analysis of the data, in order to assess if the dropout or withdrawal is due to an adverse event that might be related to high concentrations. These data should not be considered for efficacy or bioequivalence analysis but, they are supportive for the safety analysis.

应对因不良事件而脱落或退出的受试者的血浆样本进行完整的安全性分析，以评估脱落或退出是否是由于可能与高浓度有关不良事件引起的。这些数据不应用于有效性或生物等效性分析，但可用于安全性分析。

OTHER ISSUES 其他问题

55. The protocol should include the centres where the study is going to be conducted.

方案应包括将要进行研究的中心。

56. All studies should be monitored. It is not acceptable to state that the study may be monitored at the discretion of the sponsor by any of its representatives.

所有研究应受到监测。声称由申办人的任何代表酌情对研究进行监测是不可接受的。

57. Monitoring and auditing activities should not be confused because they are different activities. Monitoring is conducted by the sponsor or a CRO contracted by the sponsor and the audits are performed by the centre where the study is conducted.

不应混淆监测和审计活动，因为它们是不同的活动。监测由申办者执行或由申办者签定的CRO执行，审计由执行研究的中心进行。

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