Bioequivalence and Bioavailability Forum

Hi BRB,

❝ […] the recent EUFEPS/AAPS Harmonization initiative conference…

Was great fun.

❝ I would be curious to get feedback from those who were there as to what you thought of what was discussed.

My impression was that the EMA in some parts will have to move towards the other jurisdictions:

• When it comes to acceptance of Adaptive Two-Stage Designs based on simulations, and
  
• the overly “conservative” approach of dealing with outliers, irregular profiles, etc.

It was refreshing to see how open-minded and flexible the American regulators (of the FDA, HC, ANVISA, Mexico’s Secretaría de Salud, and Chile’s ANAMED) were. Different from the EMA’s…

❝ I found the discussion regarding the attempts to harmonize the use of scaled BE between the FDA, EMA and Canada quite interesting (i.e. AUC and Cmax for FDA, whereas EMA only allows for Cmax).

Actually:

FDA: AUC and C_max by RSABE – without a clinical justification. The fact that the reference product – despite its high variability – is on the market for years without safety / efficacy issues proofs already the applicability of reference-scaling.
EMA: C_max (and for MR-products C_ss,min, C_ss,τ, partial AUCs) by ABEL (capped at CV_wR 50%) – with a clinical justification. Doesn’t make sense to me. There are classes of drugs / formulations (PPIs, bisphosphonates, locally acting MR,…) which show high variability in AUC as well. Remember the example I was talking about at the panel? Details here (slide 17).
HC: Only AUC by ABEL (but capping at CV_wR 57.4%)* – with a clinical justification.

For all scaling-methods at higher CVs (say ≥50%) the GMR-restriction leads the decision to a good part. Inflation of the consumer risk might be substantial (even if ABE is used since the CV_wR observed in the study was <30%).

❝ However, there seemed to be no overall conclusion made, unfortunately.

IMHO, László’s presentation gave a good summary of the open issues. It will be a long way to harmonize the requirements. My personal order of importance and difficulties we are facing:

1. Which PK metrics qualify for reference scaling?
   
2. Different statistical models (RSABE for the FDA; ABEL for EMA, HC, ANVISA, and jurisdictions following the WHO-GL).
   1. The FDA’s code for ABE (if RSABE is not applicable since s_wR <0.294) sometimes fails to converge for the partial replicate design. Study done, computer says no.
      
   2. The EMA’s implementation of ABEL is crippled. Assumes equal variances of test and reference!
3. Upper caps (none for the FDA; 50% for EMA, ANVISA, and the WHO; 57.4% for HC).
   
4. Inflation of the Type I Error. Most critical in all methods close to the switching CV_wR of 30%.
   
5. Bias in the estimate.

Statistically the GMR-restriction makes no sense indeed but I guess it will stay for a long time due to political reasons. As Charlie DiLiberti said: “Ask 100% physicians for the definition of bioequivalence and 99 of them will get it wrong.” I would add: 50 of them believe that the common acceptance range means that generics may differ in their effect [sic] by 45%. Oh dear.

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• Seems that HC prefers “nice” numbers. in many countries for NTIDs the narrower acceptance range is based on a clinically not relevant difference of 10%. That leads to an AR of 90.00–111.11%. In Canada the nicer looking upper limit of 112.0% is used. I guess the cap of 57.4% was introduced because the upper scaled limit of 150.0% looks nicer than the EMA’s of 143.19%…