Bioequivalence and Bioavailability Forum

Hi VSL,

I agree with all of what ElMaestro wrote. Hence, only some more remarks.

❝ 1. Half-life: Is half life independent of formulation effect? I mean, IR vs. MR products of the same substance.

Without IV data and after a PO dose we can only assume that the apparent half-life = the intrinsic half-life (elimination). This assumption is reasonable for IR products (k_a > k_e). When you slow down the absorption process you will reach k_a = k_e or “flip-flop PK”. If you go further (k_a < k_e) the apparent half-life (now the slowest phase) is no more the intrinsic half-life but absorption. That’s why the EMA (in contrary to IR) for MR products additionally to AUC_0–t requires AUC_0–∞ and does not allow using a truncated AUC.

❝ 2. High variable drug substance vs. High variable drug products, Is there is any demarcation for protocol design aspects?

No, but you have to know the drug and your formulation. If the high variability is a property of the drug (HVD) you can design the study as usual (but taking the high CV into account and possibly opt for reference-scaling). If you have to deal with a HVDP it depends. F.i., gastric resistant formulations exhibit a wide range of t_max-values (due to variability in t_lag caused by the interplay of the formulation with gastric transit). In such a case you should increase the number of samples in order to “catch” C_max.

❝ 5. For endogenous substances, how many and for how much time duration (-48 hours etc.) baseline samples should be collected?

As ElMaestro wrote: No rule rulez. There is a wide range of options.

• Best case:
  If you know that the baseline is stable it might be sufficient to collect just three samples within one hour before the administration and subtract the mean (I prefer the median) from the profile.
  
• Worst case:
  Circadian rhythm and levels of the endogenous compound depend on food. Have a run-in period where you standardize food. Sample an entire “blank” profile before administration and subtract concentrations at corresponding time points.

❝ 6. Why passing ratio is high for BE studies (especially pivotal studies) …

I have heard that pilot studies never fail. The CROs want to perform the pivotal ones as well.

❝ … conducted in India compared to foreign countries? Is there any geographical/ethnic/staff expertise/deliberate effect?

Fabricated data, plain fraud, etc. Sorry to say.
One of my clients (her boss’ decision) started to perform studies in India (before mainly in Canada, Central, and Eastern Europe). The company always powered studies to 90%. Since the sample size estimation is based on assumptions and with 90% power one can expect that 10% will fail by pure chance – and that was essentially what she observed in the past. In two years none (!) of the studies performed in India failed. Every study was monitored. No obvious explanation. She was concerned and called me up. Given the number of studies the chance that none failed (Fisher’s exact test) was not significant but scratching the limit.

Absence of evidence is not evidence of absence.    Carl Sagan