3 period full replicate [RSABE / ABEL]

posted by Helmut Homepage – Vienna, Austria, 2015-06-24 20:00 (3250 d 19:36 ago) – Posting: # 14979
Views: 29,495

Dear Dan et alii,

❝ I think the question is whether a replication in only half of ntotal is sufficient in order to scale or ???

Yes it is. Sometimes (!) you’ll need (slightly) more subjects.

 CV    n   power   n   power
0.30  27  0.8257  26  0.8191
0.35  30  0.8381  28  0.8037
0.40  27  0.8004  30  0.8156
0.45  30  0.8430  30  0.8064
0.50  30  0.8260  32  0.8174
0.60  36  0.8192  36  0.8013
0.70  45  0.8113  46  0.8187
0.80  57  0.8223  56  0.8155
1.00  78  0.8137  76  0.8025

Note that the partial replicate is a crappy design and sample size estimations are approximate at its best. For details see Detlew’s tractatus in your R-installion folder
See also this thread.

❝ in a former statement the "leading European regulatory authority" had no problem with full replicate design (=4 periods and 6 possible sequences)…

Four periods and six sequences? Common are two (RTRT|TRTR). Four were explored in the dark ages of PBE/IBE (RTRT|TRTR|RTTR|TRRT). The analysis was tricky. Of course you could go even beyond that: RTRT|TRTR|RTTR|TRRT|RRTT|TTRR. Have you really done that?

❝ … and half replicate designs (3 periods and 3 sequences).

Sure. That’s what they seem to believe to be the only possible one.

❝ A full replicate 3-period design would not work according to their argumentation since a 3 period design implicity needs 3 sequences.


❝ I do not know why.

You are not alone.

❝ Maybe you have an idea?

Maybe because the TRT|RTR is not mentioned in the Q&A? Probably the “leading European regulatory authority” didn’t realize that the two designs given there are nothing more than examples.

To illustrate [sic] these approaches, […] data from a four-period unbalanced study […] and data from a three-period balanced study […] were analysed.

BTW, I disagree with our Captn’s arguments.

❝ ❝ From the perspective of the trial subject the burden associated with the fully replicated design is higher.

Only if we compare a 4-period design to 3-period designs. The burden of particular subjects in the partial replicate and the fully replicated 3-period is identical. Given the table above there are cases where less subjects are required in the fully replicated if compared to the partial replicate.

❝ ❝ Since the additional information obtained in a fully replicated trial does not contribute towards the average bioequivalence conclusion […] it is contended that the fully replicate design is associated with added risk but not additional bene­fit. In accordance with GCP clause 2.2 the fully replicated design therefore has no obvious merit.

Well, that would imply:

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