Bioequivalence and Bioavailability Forum

Dear KR!

❝ statistical analysis of highly variable drug like lansoprazole

I guess you are referring to FDA's drafted product-specific guideline from Oct 2008.
For details of the design and evaluation see the guideline itself and the quoted paper:
Haidar SH, Davit B, Chen M-L, Conner D, Lee LM, Li QH, Lionberger R, Makhlouf F, Patel D, Schuirmann DJ, and LX Yu
Bioequivalence Approaches for Highly Variable Drugs and Drug Products
Pharmaceutical Research 25/1, 237-241 (2008, DOI: 10.1007/s11095-007-9434-x)
free online resource

❝ 1. Sample size: how can we calculate sample size as we do not have any in-house study data of partial/full replicate data? Can anyone suggest me the procedure for sample size for highly variable drug (HVD) using reference scale approach.

See [msg]this post[/msg] from David Dubins. Essentially in the proposed RSABE procedure it’s not necessary to perfom studies in more than 34 subjects in a 3-period replicate design regardless the variability.

❝ Can we use the data of two way crossover for sample size calculation in such case?

No, these studies give you just a hint of high variability. But you may justify RSABE by such studies. If FDA is of concern, two guidelines have been published so far – for other drugs/drug products you should contact FDA's review staff beforehand. In the EU RSABE is not acceptable anyhow.

❝ 2. Bioequivalence criteria: How and when to decide bioequivalence limits of HVD using reference scale for a new study? i.e after statistical analysis of the study or should be pre-defined in the protocol. How to mention the criteria in the protocol?

It's the aim of RSABE to scale the acceptance range according to the intra-subject variability of the reference (therefore, you have to use a replicated design). Since the acceptance limits are scaled based on the variability obtained in the actual study, you cannot set them beforehand.

❝ 3. Statistical analysis: How to do statistical analysis using reference scale?

First you have to have suitable software (SAS, WinNonlin,…) which will give you CV_intra of the reference. Then follow Method C2 given in Haidar et al. to calculate to scaled BE limits. You may download David's FARTSSIE.xls, activate Macros, navigate to the Scaled BE - HVD-tab and enjoy. But remember: FARTSSIE.xls comes “as-is” (Excel is not a statistical software); therefore you should set up the method in your preferred software and validate it there.

Procedure: if you have sigma²WR (the intra-subject variance of the reference formulation) already, fine; if not, calculate it from CVintra,R:
  sigma²WR = ln(CVintra,R²+1)
FDA's goalpost for scaling (sigmaW0) is 0.2936; i.e., the limit corresponds to 30% CV (that's the commonly accepted limit for a HVDP):
  0.2936 = sqrt(ln(0.3²+1)).
Next calculate the scaling parameter thetas:
  thetas = ln(1.25)²/sigma²W0
The scaled BE-limits in ln-scale are:
  ±sqrt(thetas×sigma²WR)

Your CI should lie within the scaled BE limits and the point estimate - in FDA-speak the GMR (geometric mean ratio) - should lie within 0.80-1.25.

For example:
CVintra,R | BE-limits (lin)
--------+-----------------
 0.3924 | 0.7500 - 1.3333
 0.4    | 0.7462 - 1.3402
 0.4964 | 0.7000 - 1.4286
 0.5    | 0.6984 - 1.4319
 0.6    | 0.6561 - 1.5242
 0.7    | 0.6188 - 1.6160
 0.8    | 0.5859 - 1.7067
 0.9    | 0.5569 - 1.7958
 1      | 0.5311 - 1.8828
 1.1    | 0.5082 - 1.9676
 1.1390 | 0.5000 - 2.0000