Bioequivalence and Bioavailability Forum

Simulators,

I explored “type 1” designs derived from Potvin’s Method B (T/R 0.95, target power 80%). As posted previously Pocock’s α_adj 0.0294 is unnecessarily conservative (and might be too liberal for Method C); 0.0304 suits pretty well (largest in­fla­tion of the TIE 0.050111; n.s. >0.05). Since EMA in their Q&A-do­cu­ment (Rev.7) stated a minimum n₂ of 2¹ and sometimes Dutch regulators seemingly don’t like² interim power (for “type 2” TSDs only?), I gave it a try. I ob­tained an α_adj of 0.0310 with a maximum TIE of 0.050229 (n.s. >0.05).

Empiric TIE; I = modified Potvin 0.0304, II = EMA/NL (?) 0.0310.
           12             24             36             48             60     
CV     I      II      I      II      I      II      I      II      I      II  
0.1  0.0304 0.0409  0.0302 0.0378  0.0303 0.0366  0.0303 0.0358  0.0302 0.0352
0.2  0.0474 0.0497  0.0324 0.0387  0.0303 0.0366  0.0303 0.0358  0.0302 0.0352
0.3  0.0453 0.0455  0.0488 0.0493  0.0405 0.0423  0.0328 0.0370  0.0304 0.0353
0.4  0.0358 0.0355  0.0448 0.0449  0.0501 0.0502  0.0468 0.0471  0.0416 0.0427
0.5  0.0321 0.0322  0.0353 0.0353  0.0434 0.0434  0.0500 0.0498  0.0494 0.0493
0.6  0.0310 0.0310  0.0320 0.0321  0.0343 0.0345  0.0419 0.0417  0.0485 0.0484
0.7  0.0304 0.0304  0.0315 0.0315  0.0316 0.0316  0.0337 0.0337  0.0397 0.0397
0.8  0.0302 0.0301  0.0310 0.0310  0.0309 0.0309  0.0313 0.0313  0.0330 0.0330
0.9  0.0300 0.0300  0.0309 0.0309  0.0309 0.0309  0.0308 0.0308  0.0311 0.0311
1.0  0.0300 0.0300  0.0308 0.0308  0.0307 0.0307  0.0307 0.0307  0.0307 0.0307

Whereas TIEs of EMA’s approach are similar at high CVs, we see higher inflation of the TIE at low to mo­de­rate CVs (the main application of TSDs). Though the patient’s risk is still maintained – why all that fuzz‽

Empiric power; I = modified Potvin 0.0304, II = EMA/NL (?) 0.0310.
           12             24             36             48             60     
CV     I      II      I      II      I      II      I      II      I      II  
0.1  0.9775 0.9912  1.0000 1.0000  1.0000 1.0000  1.0000 1.0000  1.0000 1.0000
0.2  0.8411 0.8483  0.8816 0.9037  0.9571 0.9693  0.9889 0.9922  0.9975 0.9984
0.3  0.7845 0.7865  0.8306 0.8314  0.8366 0.8437  0.8551 0.8714  0.9017 0.9177
0.4  0.7520 0.7524  0.8040 0.8038  0.8227 0.8235  0.8305 0.8301  0.8303 0.8331
0.5  0.7366 0.7364  0.7824 0.7824  0.8063 0.8063  0.8194 0.8179  0.8248 0.8257
0.6  0.7287 0.7297  0.7738 0.7738  0.7908 0.7908  0.8029 0.8029  0.8153 0.8153
0.7  0.7251 0.7251  0.7695 0.7695  0.7853 0.7853  0.7930 0.7930  0.8028 0.8028
0.8  0.7233 0.7233  0.7689 0.7689  0.7830 0.7830  0.7882 0.7882  0.7963 0.7963
0.9  0.7207 0.7207  0.7672 0.7672  0.7808 0.7808  0.7874 0.7874  0.7923 0.7923
1.0  0.7191 0.7191  0.7670 0.7670  0.7802 0.7802  0.7854 0.7854  0.7924 0.7924

Slightly higher power at low to mo­de­rate CVs.

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1. Alfredo García told me that he suggested the BSWP a minimum stage 2 sample size of 12 in order “to get a good estimate of the variance“.
   
2. Deficiency letter of the MEB (2011) about Method C: “Confidence intervals were adapted based upon the power of the pharmacokinetic variable. In this case for C_max the power was below 80% and confidence intervals were adapted to 94.12%, instead of the usually applied 90%. However, adapting the confidence intervals based upon power is not acceptable and also not in accordance with the EMA guideline. Confidence intervals should be selected a priori, without evaluation of the power.”
   (my emphases)
   Bonus question: Is interim power acceptable for “type 1” TSDs?