Bioequivalence and Bioavailability Forum

joyjac ★ Philippines, 2006-01-27 01:58 (7046 d 03:38 ago) Posting: # 64 Views: 10,258	Replicate Designs for Average Bioequivalence [Design Issues] Post reply
	Dear colleagues, Can you enlighten me on replicate designs, its pros and cons for ABE? Is this analogous to doing individual bioequivalence? Thanks!

H_Rotter
★

Germany,
2006-01-27 13:15
(7045 d 16:21 ago)

@ joyjac
Posting: # 67
Views: 8,518

Replicate Designs for Average Bioequivalence

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Dear joyjac!

Whereas the standard 2×2×2 cross-over design (two treatments, two sequences, two periods) gives us the inter-subject- (between subjects) and intra-subject- (within subjects) variability, replicate designs (or sometimes called 'higher-order' or 'optimal' cross-over designs ) give us the additional information on the variability of treatments.

The most simple form is the two-sequence dual (two sequence, two treatment, three period) design [1] (sometimes called 'extra-reference' design):

S1: T R R

S2: R T R

A more sophisticiated design is the two-sequence, four-period design [2]:

S1: T R R T

S2: R T T R

Designs [1] and [2] are given in FDA's guidance; others (e.g. Balaam's design and the four-sequence, four-period design) are discussed in the literature, but to my knowledge rarely used.

Pros:

desirable statistical properties (i.e. allow for the estimation of treatment variability)
reference-scaled average BE may protects against a unreasonable high sample size in 2×2×2 based on a 'bad' reference product; recommended for highly variable drugs (CV>30%) in various guidelines (e.g. ANVISA)
it may give protection against outliers based on product failure (distinguishes from subject-by-formulation interaction)

Cons:

errors in the randomization procedure are more likely
additional periods are time-consuming
there is a higher chance of drop-outs
the number of blood-samples per subject may be rather high

So if you are dealing with an HVD, it may be a better option to go for a reference-scaled ABE in a conventional 2×2×2 design (Tothfalusi, L. and L. Endrenyi; Limits for the scaled average bioequivalence of highly variable drugs and drug products. Pharm Res 20(3), 382-389, 2003). You will find some slides at FDA's website. If you want to be protected against outliers caused by product failure of the reference, you may go for a replicate design (prefereably [1]).

regards
Hermann Rotter

Edit: Link corrected for FDA’s new site. [Helmut]

joyjac ★ Philippines, 2006-01-31 07:41 (7041 d 21:56 ago) @ H_Rotter Posting: # 70 Views: 8,310	Replicate Designs Post reply
	Thank you very much for the knowledge sharing. I would truly appreciate advice on what would be the best method of calculating CI based on replicate design. Clarification: Is this design approach similar to individual bioequivalence?

joyjac
★

Philippines,
2006-08-23 11:47
(6837 d 18:50 ago)

@ H_Rotter
Posting: # 237
Views: 8,254

Replicate Design/Scaled ABE approach

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Can we revert to the average BE approach if within subject variances obtained from a replicate design/scaled ABE (TRTR) show that the drug is NOT highly variable, or can we apply the usual BE assessment criteria of 90% CI (80-125%) using data from periods I & II? The reason for conducting a replicate design was that a high CV estimated from the ANOVA model was obtained in a previous ABE study, an indicator for high within subject variability and data from published literature. The intention for using replicate design and for turning back to the average BE approach (if the drug is not highly variable), would be stated in the protocol.

I would appreciate your thoughts/comments on the above. Thanks.

H_Rotter
★

Germany,
2006-08-23 14:09
(6837 d 16:28 ago)

@ joyjac
Posting: # 240
Views: 8,122

Replicate Design/Scaled ABE approach

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Dear joyjac!

❝ Can we revert to the average BE approach if within subject variances obtained from a replicate design/scaled ABE (TRTR) show that the drug is NOT highly variable, or can we apply the usual BE assessment criteria of 90% CI (80-125%) using data from periods I & II?

Assuming suitable software available (e.g., WinNonlin ≥4.x), it’s possible to obtain the standard average BE evaluation from any replicate design as well.
The point estimate is simply the same, with the additional information of the CI.
I would not 'throw away' half of the data obtained in the study. ;-)

❝ […] The intention for using replicate design and for turning back to the average BE approach (if the drug is not highly variable), would be stated in the protocol.

IMHO this should be possible.

regards,
Hermann Rotter

Replicate Designs for Average Bioequivalence [Design Issues]

Replicate Designs for Average Bioequivalence

Replicate Designs

Replicate Design/Scaled ABE approach

Replicate Design/Scaled ABE approach