Bioequivalence and Bioavailability Forum

Dear kamblpa1!

❝ During subject analysis of Antipsychotic drug in BE studies, three subject were showing concentration more than 5 % of Cmax value in the predose samples of period 1. Please let me know whether these three subjects should be included in statistical analysis or should be excluded?

Counter-question: Which procedure have you stated in the protocol?

❝ since ANVISA guideline does not say regarding the inclusion & exclusion for the above issue,

Do you have a current on-line reference? ANVISA’s website is a mess – I have given up keeping it up-to-date.

❝ whereas USFDA & EMEA guideline says that,

❝

❝ If the predose concentration is ≤ 5 percent of Cmax value in that subject, the subject’s data without any adjustments can be included in all pharmacokinetic measurements and calculations. We recommend that if the predose value is > than 5 percent of Cmax, the subject be dropped from all BE study evaluations.

Note that:

• This is a quote from FDA’s guidance (2003). It’s unclear whether you have to state the procedure for exclusion in the protocol or it is sufficient to make a general statement like ‘The study will be evaluated according to the recommendations of )’.
  
• EMA (2010) is a little bit more specific:
  “[…] the decision to exclude a subject from the statistical analysis must be made before bioanalysis.*
  In principle any reason for exclusion is valid provided it is specified in the protocol and the decision to exclude is made before bioanalysis. However the exclusion of data should be avoided, as the power of the study will be reduced and a minimum of 12 evaluable subjects is required.
  The permitted reasons for exclusion must be pre-specified in the protocol.
  Exclusion of data cannot be accepted on the basis of statistical analysis or for pharmacokinetic reasons alone, because it is impossible to distinguish the formulation effects from other effects influencing the pharmacokinetics.
  The exceptions to this are:
  2) Subjects with non-zero baseline concentrations > 5% of C_max. Such data should be excluded from bioequivalence calculation (see carry-over effects below).
  If there are any subjects for whom the pre-dose concentration is greater than 5 percent of the C_max value for the subject in that period, the statistical analysis should be performed with the data from that subject for that period excluded. In a 2-period trial this will result in the subject being removed from the analysis. The trial will no longer be considered acceptable if these exclusions result in fewer than 12 subjects being evaluable. This approach does not apply to endogenous drugs.”
  Leasons learned: Subjects should be excluded, procedure must be stated in the protocol, final sample size ≥12.
  
• ANVISA is very proud about their guidelines; I would expect that they don’t care too much about FDA’s and EMA’s.

❝ Since above study is for ANVISA scope,

Ask them: bioequivalenciaanvisa.gov.br

If you don’t want to wait, my suggestion:

• If you have a statement about exclusion already in the protocol, fine. Exclude the subjects. If you want to be on the safe side present a secondary analysis of the full data set.
  
• If you have nothing in the protocol don’t be tempted to start the evaluation before you have prepared an amendment to the statistical analysis plan. Smells like cherry-picking and could in the worst case even trigger an inspection.

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• Note the “must”. Of course only applicable to emesis, etc. – not to pre-dose values (how could we know before bioanalysis? Fortune-telling?).