Bioequivalence and Bioavailability Forum

❝ We being a CRO in India have been exploring the possibility of conducting a BE study of the formulation both in pts and healthy human volunteers (HHVs) for a requested US submission.

1. There is no specific draft guidance, yet available from the OGD, FDA. Controlled correspondence for the purpose might take 7-8 months time to know their views!!
   
   
2. The 10 mg IR formulation requires to be tested in HHVs both under fasted & fed states as per the available guidance.
   
   
3. Very limited avaiability of elderly pts fulfilling the eligibility criteria, readiness to sustain the required blood loss, probable dropouts due to vomiting, ethical concerns, etc. are found as hindrances for a multi-dose, steady-state (SS), two-way cross-over BE study in pts.
   
   
4. Upon reviewing the literature, regulatiory guidance on modified ER formulations and BE studies, it appears that a single-dose, two-way, cross-over study in HHVs (if permissible in view of safety profile of the molecule) is expectd to give more reliable results as against a multi-dose, SS one in pt population. Moreover, the molecule has linear P/Ks. This also favours the single dose P/K assessment ruling out the compulsion for undertaking a multi-dose, SS study even from regulatoy point of view.
   
   
5. Drug like quetiapine reported to cause serious cardiac arrhythmias, noticeable giddiness, nausea, vomiting, etc. is also allowed upto 200 mg ER to study in HHVs as a single-dose, two-way, cross-over study. BE reports are accepted without asking for a separate SS study or patient based P/K evaluation (BE). It is only when the strength exceeds (raising safety concerns), i.e. 400 mg ER requires participation by patients only as per the current thinking of OGD and the resultant modified guidance draft.
   
   
6. According to me, reading with the PIL of RLD, the tolerability profile of donepezil 23 mg ER should permit us to do two single-dose, two-way, cross-over BE studies both under fasted and fed states in HHVs to suffice the regulatory requirements.
   
   
7. Since the pilot studies have already reported considerable dropouts due to vomiting, study should be performed under cover of any suitable anti-emetic like ondansetron, dimenhydrinate, etc. having no interaction with the compound.