Anavex Life Sciences Corp (AVXL)

[Investor2014]

Adaptive Trial Design - what is it and did it apply to the A2-73 P2a trial?

Adaptive Design Clinical Trials for Drugs and Biologics (PDF - 423KB)

II. BACKGROUND
There is great interest in the possibility that clinical trials can be designed with adaptive features (i.e., changes in design or analyses guided by examination of the accumulated data at an interim point in the trial) that may make the studies more efficient (e.g., shorter duration, fewer patients), more likely to demonstrate an effect of the drug if one exists, or more informative (e.g., by providing broader dose-response information).

The bit in bold "e.g., by providing broader dose-response information", is what Anavex has been doing in their P2a trial in AD.

We have witnessed the dose switching adaptive design in Part A. The data from Part A was then used for further adapting the 4 oral dose level groups that patients were assigned throughout Part B. We have since witnessed the results of this pre-planned (as opposed to post hoc) analysis by feeding all this Part A and Part B dose level information for each patient along with other individual patient data (age, baseline, sex, ethnicity, other medication e.g DPZ etc.) into KEM Analysis for it to discover the network of connections contained in this data matrix.

From this we have learned more about dose response and combination factors that a conventional trial design without multiple and adapted dosing groups could NOT tell us. Yet some people continue to argue that a conventional trial such as dose vs placebo or even High, low and placebo arms in a much larger study would have been much preferred.

Others can deny that the Anavex P2a AD trial was not adaptive and claim it was poorly designed as much as they like, but what I have written here is how it is, period.

On clinicaltrials.gov we see that Part A was declared as an adaptive design.

This is a Phase 2a study consisting of two parts, PART A and PART B. The first part (PART A) is a simple randomised, open-label, 2-period, cross-over, adaptive design study lasting for each participant up to 36 days.

According to the Guidance doc usually adaptive designs are for confirmatory trials, but Anavex wanted to get as much information as possible out of a small P2 trial.

The greatest interest in adaptive design clinical trials has been in the adequate and well controlled study setting intended to support marketing a drug.

The P2/3 trial in AD will, as far as I can tell, also be an adaptive design that transitions from the P2 to the confirmatory P3 stage with pre-planned adaptations learned from P2 and in agreement with the FDA.

Time will tell!

Note also that this FDA Guidance was issued 02/26/10 Eight Years Ago and is still in draft, but yet trial designs compliant with the guidance have been approved for Anavex and others.

The Guidance document is well worth a read, an other quotes:

For the purposes of this guidance, an adaptive design clinical study is defined as a study that includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data (usually interim data) from subjects in the study. Analyses of the accumulating study data are performed at prospectively planned timepoints within the study, can be performed in a fully blinded manner or in an unblinded manner, and can occur with or without formal statistical hypothesis testing.