Bioequivalence and Bioavailability Forum

Hi BRB,

❝ […] It makes finding information about ANVISA requirements seem like a walk in the park :)

I have given up to find sumfink useful at ANVISA’s site. Some of my Portuguese friends told me that the site is terrible.

❝ Do you, or does anyone know where I could find more details about reference scaling for the CFDA?

THX to Shuanghe: Appendix 9011. Appetizers (original and translate):

9011 药物制剂人体生物利用度和生物等效性试验指导原则中国药典2015
1.9 生物等效性评价
[…] 髙度变异性药品的接受范围可能在某些情况下放宽。
1.11 高变异性药物或药品
高变异性药品是指药动学参数个体内变异大于30%的药品。如果申请者怀疑一个药品的吸收速度或程度可能是髙变异的，则可以进行一项重复交叉设计的试验。
对于那些高变异性药品，如果认为差异较大对于临床的影响不大，基于临床的充分理由，则可以放宽接受范围。在这种情况下， 的接受范围可以最宽为69.84%〜143.19%.为了放宽接受范围，生物等效性试验必须是一项重复设计，来证明对于试验的参比化合物受试者内变异>30%。
申请者应说明理由，计算的受试者内变异是可靠估计，而不是逸出值的结果。要求放宽区间必须在试验计划中 预先规定。
根据受试者内变异放宽接受限的可能性不适用于AUC，它的接受限保持在80.00%〜125.00%，不管变异如何。
在重复试验设计中，采用三周期或四周期交叉方案都是可以接受的。

9011 Pharmaceutical preparations Human BA and BE test guidelines – Chinese Pharmacopoeia 2015
1.9 Bioequivalence evaluation
[…] the range of acceptance of highly variable drugs may be relaxed in some cases.
1.11 Highly variable drugs or drug products
High variability drugs refers to pharmacokinetic parameters with an within-subject variability of more than 30%. If the applicant suspects that the rate of absorption or extent of a drug may be highly variable, a repeat crossover design may be performed.
For those high variability drugs, if the difference is considered to have little effect on the clinical [outcome], based on clinical justification, you can relax the acceptance range. In this case, the acceptance range can be as broad as 69.84% ~ 143.19%. To relax the acceptance range, the bioequivalence test must be a replicate design to demonstrate that the [variability of the] reference drug in the study [is] >30%.
Applicants should state the reason that the calculated variance within the subject is a reliable estimate, rather than the result of an outlier. The request for relaxation must be specified in the study protocol.
According to the possibility of variability in the subject, the acceptance limit is not applicable to AUC, and its acceptance is maintained at 80.00% ~ 125.00%, regardless of variation.
In a repeat trial design, it is acceptable to use a three- or four-period crossover design.

In short, that’s the EMA’s approach:

• Intention to expand the BE-limits has to be stated in the protocol.
  
• Justification that widening the acceptance range is clinically not relevant.
  
• C_max only.
  
• Leveling off at 69.84–143.19% (upper cap).
  
• Outlier check.
  
• The GMR-restriction of 80.00–125.00% (mandatory in all other jurisdictions) is not mentioned. Forgotten?