Bioequivalence and Bioavailability Forum

Hi Sukalpa,

❝ For NTI product of ANVISA studies,

❝ 1. if 95% CI need to be ensured within 80-125, then can we prefer doing 2WCstudies(ISCV<30%)?

Calculating a 95% CI (instead of the common 90% CI) was dropped a while ago and for good reasons. It does not decrease the patient’s risk. That was a misconception by the ANVISA. Only a narrower acceptance range (EMA and most other agencies) or reference scaling acc. to the method of the FDA does.

See the draft of 27 Dec 2019 (in Portuguese). Inofficial Translation:

Chapter VI, Section V, Narrow therapeutic index drugs (NTID)
Article 82. In specific cases of narrow therapeutic index drugs, the acceptance range for AUC should be adjusted to 90.00 –  111.11%; the same can happen with C_max where safety, efficacy or drug level monitoring is of particular importance.

❝ 2. If ISCV>30%, can we go for full replicate/partial replicate design? If yes then what will be the statistical approach?

It is extremely unlikely that an NTID shows high variability. The only ones I know are dagibatran and rivaroxaban. Whether you opt for a 2×2×2 or a replicate design, up to you. The evaluation has to be done for ABE. If you expect AEs in healthy volunteers and a high dropout rate, I would avoid a replicate design.

❝ 3. Is it necessary to get the statistical approach approved from ANVISA regulatory prior initiation of the study.

The protocol has to be approved by the ANVISA anyway. It is up to you to give a clinical justification for the limits (C_max, AUC, both). Examples from the EMA’s product-specific guidances:

• Colchicine
  AUC 90.00–111.11%, C_max 80.00–125.00%
  
• Everolimus
  Both 80.00–125.00% (oncologic-only indication, 2-10 mg)
  AUC 90.00–111.11%, C_max 80.00–125.00% (transplant-only indication, 0.1–1 mg)
  
• Sirolimus
  AUC 90.00–111.11%, C_max 80.00–125.00%
  
• Tacrolimus
  AUC 90.00–111.11%, C_max 80.00–125.00%