Bioequivalence and Bioavailability Forum

Hi Manesh,

1. Recommended (read: mandatory). You need a fully replicated design in order to assess 2.III. below.
   
2. No. See the tacrolimus guidance and the SAS-code given in the guidance for warfarin. In order to pass BE, all of the following three conditions must be fulfilled:
   1. Upper 95% CL for (Y_T – Y_R)² – θ·s²_WR ≤0,
      
   2. 90% CI ⊂ [80.00–125.00%],
      
   3. Upper 95% CL of σ_WT/σ_WR ≤2.5.
   For the statistical background see this presentation.

❝ […] what’s about other NTI drugs like Sirolimus, Everolimus etc.

Note that the guidances for sirolimus (10/2010) and everolimus (06/2012) were published before the first NTID-RSABE guidance (warfarin 12/2012). I would expect the same conditions as for tacro­li­mus to be applicable nowadays (these guidances are simply not updated yet). For everolimus see also this thread. If in doubt, ask the OGD.
BTW, don’t forget that the FDA requires tighter limits of actual content (batch-release) for NTIDs.

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So far the EMA classified tacrolimus (Q&A document Ref. 2, 07/2010) and sirolimus (Product-Spe­ci­fic Bioequivalence Guidance, 11/2013) as NTIDs. Both are also classified as Critical dose drugs by Health Canada’s HPFP/TGD (02/2012).