Bioequivalence and Bioavailability Forum

Dear Ken!

❝ ❝ • Perform a pilot study which will (after drop-outs) > the minimum sample size in your regulation (Malaysia: 12). State in the protocol that if you are able to show BE already in the pilot the study will act as the pivotal study.

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❝ Do you mean if we use 20 subjects (>12) and able to show BE although the power is less than 80%, we can switch from pilot to pivotal ? How to justify to the regulatory agency on this ?

The sample size should be as large that after excluding drop-outs you have still 12 evaluable subjects. In how many you actually start depends on the AE-profile of the drug. I would consider it unethical to perform a pivotal study when you have already shown BE in the pilot. Of course your intention to do so has to be stated in the protocol.

❝ ❝ • Perform a Two-Stage Sequential Design (see e.g., this presentation). Ask your authority whether such a design is acceptable. The Malaysian GL from 2000 of course does not cover such a design.

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❝ Yes, the new ASEAN guideline addresses this.

Do you have a reference? The newest version I know is the 2004 ‘final draft’. BTW, the 2009 Q&A-document v2 is in error:

Q: How is the required number of subjects determined?
A: The number of subjects required is determined by:

1. the intra-subject coefficient of variation of the drug to be studied either estimated from a pilot study, results of previous clinical studies or from published literature.
   
2. the significance level desired (α=0.05)
   
3. the expected deviation from the reference product compatible with bioequivalence (delta, ie percentage difference from 100% ie. ±20%)
   
4. the required power should be at least 80%

The clinical and analytical standards imposed may also influence the statistically determined number of subjects. However, generally the minimum number of subjects should not be smaller than 12.

If one expects a deviation of ±20% (c) the samples size has to be infinity even for a CV of zero. Should read “ie ±5%”.