Bioequivalence and Bioavailability Forum

❝ So they allow a partial replicate as well? The Same as FDA

Replicated cross-over designs may also be used, where the formulations are tested more than once in the same subjects.

• The EMA’s upper cap at CV_wR 50% (i.e., scaling ends at expanded limits of 69.84 – 143.19%) is arbitrary but at least we have some empiric evidence that it “works” since an acceptance range of 70 – 143% for C_max (only!) was used in the EU in the 1990s. I don’t think that such an AR was ever acceptable for AUC (very rarely 75 – 133%).
  
  
• Where does HC’s upper cap at CV_wR 57.40% come from? In the June 2015 proposal it was 50%. A yellow compromise somewhere in between the EMA’s and the FDA’s “implied BE limits” of 62.11 – 161.01% to get “nice” numbers for the expanded limits of 66.7 – 150.0%?
     round(100*exp(c(-1, +1)*0.76*sqrt(log(0.574^2+1))), 1)
  
  
• I don’t like HC’s strategy of less significant digits than other agencies use. Remember NTIDs? Everywhere else the AR is 90.00 – 111.11% but in Canada (for “critical dose drugs”) it is 90.0 – 112.0% (Eric Ormsby: “More convenient and easier to remember”).
  Same here: 100/0.667 ≠ 150.0.
  
  
• Hip hip hooray, a mixed effects model! Splendid, I like it.
  • By definition the cross-over design is a mixed effects model with fixed and random effects. […] If the mixed model approach is used, parameter constraints should be defined in the protocol. Higher order models must be analysed with the mixed model approach in order to estimate random effects properly.
  Partial replicate? You know what might happen! The EMA in their Q&A-document give the RTRT|TRTR and the partial replicate as examples but accept the RTR|TRT as well. HC: “Either RTR, TRR, RRT or TRTR, RTRT”. Nothing else. Good morning?
  At least no SAS-code is given. Hence, nothing speaks against using FA0(1). However, I still hold that the partial replicate is a lousy design.
  
  
• I expect an inflation of the Type I Error very similar to the EMA’s ABEL in the critical region around CV_wR 30%. Well done! Papers^1,2 published in US-journals ignored out of principle? OK, maybe only Canadian ones count? The two Lászlós reported³ for CV_wR 30% a Type I Error of 6.98% already back in 2009…

1. Wonnemann M, Frömke C, Koch A. Inflation of the Type I Error: Investigations on Regulatory Recommendations for Bioequivalence of Highly Variable Drugs. Pharm Res. 2015;32(1):135–43. doi:10.1007/s11095-014-1450-z.
   
2. Muñoz J, Alcaide D, Ocaña J. Consumer's risk in the EMA and FDA regulatory approaches for bioequivalence in highly variable drugs. Stat Med. (early view 28 Dec 2015). doi:10.1002/sim.6834.
   
3. Endrényi L, Tóthfalusi L. Regulatory Conditions for the Determination of Bioequivalence of Highly Variable Drugs. J Pharm Pharmaceut Sci. 2009;12(1):138–49.  free resource.