## NTI drug Bioequivalence study Statistical approach [Study As­sess­ment]

This is regarding NTI drug Bio equivalence study Statistical approach.
As per regulatory,
1. Primary pharmacokinetic parameter(s) for the 90% confidence interval of the geometric least square means must fall within 80.00% to 125.00% (both inclusive).
2. Reference Scaled Average Bioequivalence:
The 95% upper confidence bound for (μT-μR)2-θ*S2WR must be ≤ 0.
The point estimate of the Test/Reference geometric mean ratio must fall within [0.80, 1.25]
3. The within-subject standard deviation of test and reference products will be compared, and the upper limit of the 90% confidence interval for the test-to-reference ratio of the within-subject variability should be ≤ 2.5.
Observations during study:

All the above criteria has been met except 90% confidence interval for the test-to-reference ratio of the within-subject variability ≤ 2.5 were not meet the criteria for all PK variables (Cmax, AUCt and inf).

Exercises, Observations and Analysis:
1. We have taken subjects who have completed at least 2R or 2T in Reference Scaled Average Bio equivalence calculation (existing study).
2. We have done the exercise who have completed all four treatments and did the statistical calculation- still failing on the same criteria marginally(90% confidence interval for the test-to-reference ratio of the within-subject variability should be ≤ 2.5).
3. It was observed that if the “SWT” value should be closed to SWR value or lower, then 90% CI for the test-to-reference ratio of the within-subject variability ≤ 2.5 will meet the criteria.
Seeking help on:
1. Which Reference Scaled Average Bioequivalence approach is acceptable in regulatory?
Approach 1: Subject completed at least two test product will consider for SWT calculation and subject who completed at least two reference will consider for SWR calculation.
Approach 2: Subjects who completed four period will be consider for SWR & SWT calculation.
or both.
2. which are the factors adding variability to SWT?
3. Whether same formulation can be taken for the repeat bio-study with some clinical restrictions? If yes then what are the clinical factor to be considered?

Kindly respond.