Replies to post #509345 on Anavex Life Sciences Corp (AVXL)

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EMA Makes Post-Hoc ABCLEAR3 Impossible:

From the EMA Subgroup Guideline:
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-subgroups-confirmatory-clinical-trials_en.pdf

1️⃣ If the primary endpoint fails ? NO confirmatory claims

“No further confirmatory conclusions are possible… where the primary null hypothesis cannot be rejected.”
(Section 5.4)

ADL failed ? ABCLEAR3 cannot be confirmatory.

2️⃣ Post-hoc subgroups require NEW TRIALS

“One or more additional trials should usually be conducted.”
(Section 5.4)

Post-hoc = new RCT required.

3️⃣ Post-hoc rescue is almost never allowed

“In rare instances… approval without additional studies…”
“…trials not feasible to repeat OR large trials where subpopulations have considerable randomized evidence.”
(Section 5.4)

This does NOT apply to Alzheimer’s.

4️⃣ Subgroup credibility requires PLAUSIBILITY + REPLICATION

“Credibility depends on biological plausibility and replication.”
(Section 4.6)

ABCLEAR3 has none of these.

This explains why EMA cannot accept ABCLEAR3 in this MAA. A new, pre-specified Phase 3 is mandatory.