Bioequivalence and Bioavailability Forum • Sample Size Benefits of Replicate Design with ABE

Sereng
☆

USA,
2023-05-24 17:41
(509 d 16:34 ago)

Posting: # 23566
Views: 2,328

Sample Size Benefits of Replicate Design with ABE [Power / Sample Size]

Folks, I have three questions:

(1) If you conduct a full replicate crossover design BE study (T x 2, R x 2, e.g., TRTR|RTRT) is there any sample size efficiency (fewer patients required) with ABE analysis or is it no different (in terms of sample size) than a non-replicate crossover design BE study (T x1, R x 1) with ABE analysis.

(2) For demonstrably HVD (WSV >30%), why do some product specific guidance for ANDA suggest (or allow) full replicate designs and others do not mention this approach?

(3) For demonstrably HVD (WSV >30%), why do some Clinical Divisions object to use of full replicate design studies in 505(b)(2) NDAs?

Any input would be appreciated!

—
Biostatistically Challenged CEO

dshah
★★

India,
2023-05-25 11:56
(508 d 22:19 ago)

@ Sereng
Posting: # 23569
Views: 1,882

Sample Size Benefits of Replicate Design with ABE

Post reply

HI Sereng!

❝ (1) If you conduct a full replicate crossover design BE study (T x 2, R x 2, e.g., TRTR|RTRT) is there any sample size efficiency (fewer patients required) with ABE analysis or is it no different (in terms of sample size) than a non-replicate crossover design BE study (T x1, R x 1) with ABE analysis.

The number of observations will be same but the sample size will be half in fully replicate design compared to standard CO study.

❝ (2) For demonstrably HVD (WSV >30%), why do some product specific guidance for ANDA suggest (or allow) full replicate designs and others do not mention this approach?

For HVD, the fully replicate/partial replicate can be helpful for widening of 90% CI limit based on regulatory agency for particular PK parameters. Ethically, due to widening of 90% CI, the sample size will be less than if it has be to standard limit of 80-125%.

❝ (3) For demonstrably HVD (WSV >30%), why do some Clinical Divisions object to use of full replicate design studies in 505(b)(2) NDAs?

Not aware of any. Can you share the link?

Regards,
Divyen

Helmut
★★★

Vienna, Austria,
2023-05-25 18:27
(508 d 15:48 ago)

@ Sereng
Posting: # 23570
Views: 1,911

Dropouts less problematic

Post reply

Hi Sereng,

I agree with Divyen’s post.
Maybe this article helps as well. Furthermore, if in a TRTR|RTRT-design a subject drops out in period 3 or 4, he/she can be kept in the analysis – and would not be completely lost like a dropout in period 2 of a 2×2×2 Xover.

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

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