Bioequivalence and Bioavailability Forum • Sequences of BE study under both fasting and fed studies

A.Shtaiwi
☆

Jordan,
2025-09-03 14:40
(279 d 19:16 ago)

Posting: # 24437
Views: 4,420

Sequences of BE study under both fasting and fed studies [Design Issues]

Hi everyone,

I’m working on the design of a study that needs to be done under both fasting and fed conditions. Normally these would be two separate studies, but to save time we’re thinking of running them together in a single 4-period study.

My question is: would it be acceptable to give all subjects the fasting treatments first (Periods 1–2) and then the fed treatments (Periods 3–4)? Or do we need to randomize subjects so that fasting and fed are mixed across periods?

For example:

A = Test, fasting
B = Reference, fasting
C = Test, fed
D = Reference, fed

Possible randomization options I’m considering:

Option 1:
S1: A → B → C → D
S2: B → C → D → A
S3: C → D → A → B
S4: D → A → B → C

Option 2:
S1: A → B → C → D
S2: B → A → D → C
S3: A → B → D → C
S4: B → A → C → D

Option 3:
S1: A → B → C → D
S2: B → A → D → C

Which approach would regulators (e.g. EMA) accept?

Also, would the same logic apply to studies of orally inhaled products where we compare “with charcoal” vs “without charcoal” (instead of fasting vs fed)?

Thanks in advance!

Edit: Category changed; see also this post #1. [Helmut]

ElMaestro
★★★

Denmark,
2025-09-04 10:05
(278 d 23:52 ago)

@ A.Shtaiwi
Posting: # 24438
Views: 3,735

Sequences of BE study under both fasting and fed studies

Post reply

Hi A. Shtaiwi,

❝ Which approach would regulators (e.g. EMA) accept?

In my experience option 2 has been rather commonly used and accepted.
The others may be as well but I don't have a lot of experience.

❝ Also, would the same logic apply to studies of orally inhaled products where we compare “with charcoal” vs “without charcoal” (instead of fasting vs fed)?

In my experience, yes. But I think companies tend to start with the "without charcoal" matter first.

There could be national preferences. I mean, if you approach DE and SE for sc. advice then they might not have exactly the same opinion or preference.

—
Pass or fail!
ElMaestro

A.Shtaiwi ☆ Jordan, 2025-09-07 07:52 (276 d 02:05 ago) @ ElMaestro Posting: # 24440 Views: 3,519	Sequences of BE study under both fasting and fed studies Post reply
	Thanks a lot ElMaestro and Helmut for your feedback

Helmut
★★★

Vienna, Austria,
2025-09-04 10:26
(278 d 23:31 ago)

@ A.Shtaiwi
Posting: # 24439
Views: 3,768

Fed → fasting

Post reply

Hi A.Shtaiwi,

❝ […] would it be acceptable to give all subjects the fasting treatments first (Periods 1–2) and then the fed treatments (Periods 3–4)?

Acceptable, yes. However, IMHO, not optimal (see below).

❝ Or do we need to randomize subjects so that fasting and fed are mixed across periods?

No.

❝ A = Test, fasting

❝ B = Reference, fasting

❝ C = Test, fed

❝ D = Reference, fed

I suggest to reverse the order of your option 3 and go with

S1: C → D → A → B
S2: D → C → B → A

Why? In many cases it is more difficult to demonstrate BE in fed state than in fasting state. If you have prior information about the respective variabilities, you could include more subjects for periods 1–2. You could also opt for a sequential design in each of the parts. For details see this presentation.

To consider:

Don’t perform an ANOVA of pooled data. Not only the variances of the parts will be different but very likely the estimates will be biased as well. Evaluate the fed and fasting parts separately. This is also recommended in ICH M13A:
- In studies with more than two treatment arms, e.g., a four-period study examining fasting and fed conditions […], the analysis for each comparison should be conducted excluding the data from the treatment arms that are not relevant for the comparison in question.
The assessment of food effects of test (C/A) and reference (D/B) is only ‘nice to know’. Exclude the respective other conditions to get incomplete block designs and evaluate them as paired groups (assuming equal period effects).

❝ Which approach would regulators (e.g. EMA) accept?

Likely any. As of today ICH M13A is implemented by Swissmedic (Switzerland), the FDA (US), the EMA (EEA), the MHRA (UK), the JFDA (Jordan), and will be implemented by Health Canada in December 2025. See there for the current implementation status.

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

The quality of responses received is directly proportional to the quality of the question asked. 🚮
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mittyri
★★

Russia,
2025-09-22 13:01
(260 d 20:55 ago)

@ Helmut
Posting: # 24445
Views: 2,592

Fed (failed) → fasting (succeeded)

Post reply

Hi Helmut and all,

Could I sanity-check a downside case
Suppose the Sponsor uses the sequences (S1: C -> D -> A -> B; S2: D -> C -> B -> A) and the Fed part fails to show BE while the fasted part passes.
If the sponsor decides to reformulate, my understanding is that this would require starting over, since a new formulation would invalidate both the fed and fasted data. Is that correct?

Alternatively, if the Sponsor believes the fed miss was a play of chance in a study powered at 80%, he can run another fed study with a larger sample while retaining the original fasted results for submission.
How are reviewers likely to view the initial fed failure alongside a clean fasted outcome? Would submitting both studies make the package look problematic, or is this generally acceptable provided the second fed study succeeds?

—
Kind regards,
Mittyri

Helmut
★★★

Vienna, Austria,
2025-09-23 17:35
(259 d 16:22 ago)

@ mittyri
Posting: # 24446
Views: 2,543

Fed (failed) → fasting (succeeded)

Post reply

Hi Mittyri,

❝ Suppose the Sponsor uses the sequences (S1: C -> D -> A -> B; S2: D -> C -> B -> A) and the Fed part fails to show BE while the fasted part passes.

❝ If the sponsor decides to reformulate, my understanding is that this would require starting over, since a new formulation would invalidate both the fed and fasted data. Is that correct?

Yes, it is.

❝ Alternatively, if the Sponsor believes the fed miss was a play of chance in a study powered at 80%, he can run another fed study with a larger sample while retaining the original fasted results for submission.

Makes sense to me.

❝ How are reviewers likely to view the initial fed failure alongside a clean fasted outcome?

If the fed part was underpowered, I don’t see a problem.

❝ Would submitting both studies make the package look problematic, or is this generally acceptable provided the second fed study succeeds?

I don’t think so. You have to submit the synopsis of the fed part anyway. If an assessor wants to dig deeper, you have to submit the complete report. However, the second – properly powered – study overrules the fed part of the first.

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

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes