Bioequivalence and Bioavailability Forum

the basis of T/R in the Pro­tocol [Regulatives / Guidelines]

posted by Helmut  – Vienna, Austria, 2014-03-14 14:53 (3692 d 23:29 ago) – Posting: # 12625
Views: 5,759

Hi Mittyri,

❝ Do you state in the protocol the reasons why did you choose the exact T/R ratio …

Yes.

❝ … (not default 95% setting)?

There is no “default” of 95%. The batch release spec’s generally are ±10%. EMA wants to have less than ±5% in measured content (unless it is demonstrated that nor suitable reference batch could be found; in this case a dose-correction is accept­able). But ±5% in content does not necessarily translate into ±5% in vivo. If I have information about a larger deviation from a pilot study I use it.
The GL only mentions an “appropriate sample size calculation”, whereas the old NfG was more specific: “the expected deviation from the reference product”. No idea why EMA boiled down the detailed – and reasonable – section about sample size estimation to plain .
I also include a sensitivity analysis according to ICH-E9, showing how violations of assumptions (larger deviation and/or CV, higher drop-out rate) might affect power. I generally aim for ~90% power (best case) and try to keep power ≥70% (worst case).

For HVDs/HVDPs I use ±10% even if I have seen a smaller deviation in a pilot study. For these kinds of drugs, the ratio tends to jump around between studies. I try to be con­servative.

Note that the FDA requires for NTIDs tighter release spec’s (±5%). For NTIDs I there­fore use ±2.5%. IMHO planning a NTID-study without a reasonably sized pilot is risky.

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна! 
Helmut Schütz


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Complete thread:

• Difference between test and reference nlpati 2013-10-10 13:40 [Regulatives / Guidelines] 
  • Assayed content Helmut 2013-10-10 14:46
  • Difference between test and reference jag009 2013-10-10 15:19
    • ∆ <5% ⇒ T/R 95% Helmut 2013-10-10 16:08
      • ∆ <5% ⇒ T/R 95% nlpati 2013-10-11 04:37
      • ∆ <5% ⇒ T/R 95% jag009 2013-10-13 21:02
        • Optimism Helmut 2013-10-14 17:50
          • T/R 90% to 110% for sample size estimation kumarnaidu 2013-11-26 05:36
            • T/R 110% Helmut 2013-11-30 14:02
              • T/R 110% kumarnaidu 2013-12-02 05:35
              • the basis of T/R in the Pro­tocol mittyri 2014-03-14 08:10
                • the basis of T/R in the Pro­tocolHelmut 2014-03-14 13:53
                  • the basis of T/R in the Pro­tocol mittyri 2014-03-14 14:31
                    • the basis of T/R in the Pro­tocol Helmut 2014-03-14 15:01
                      • the basis of T/R in the Pro­tocol mittyri 2014-03-14 21:08
                        • the basis of T/R in the Pro­tocol Helmut 2014-03-14 23:02