NorthWest Biotherapeutics Inc (NWBO)

[MolBiol]

Being that DCVax-L trial has an adaptive character, it probably follows the adaptive design guidelines provided by the FDA. You can find those by searching for the following:
"fda guidance adaptive clinical trials"

I don't think I've heard anyone discussing these guidelines on this board so I thought I would share the information. If I missed a post then my apologies. If this comes off as condescending or talking down to anyone then my apologies, especially to you "Top 20".

Along those same lines there are very good peer reviewed articles out there (some from the FDA) that go into great detail on the structure of adaptive design trials and the logistics. Here is one of particular interest to me that lays out the firewalls between the different entities:

Adaptive design clinical trials and trial logistics models in CNS drug development?
Sue-Jane Wang a,?, H.M. James Hung b, Robert O'Neill a

And another:

Adaptive design methods in clinical trials – a review
Shein-Chung Chow*1 and Mark Chang2

There are others as well.

I found some contradictions in the literature regarding sample size adjustment. The contradictions are around the use of blinded vs unblinded data to make the changes to sample size if needed. I've found that generally the view is that unblinded is more accurate and if an independent organization is used (I viewed that as a CRO (ISAC) or DMC) then the type I error can be controlled.

Here are some excerpts from the papers:

5.2. Models involving data monitoring committee

The model established for the group sequential designed clinical trials (U.S. FDA Guidance for Clinical Trial Sponsors, 2006), the data safety monitoring board or data monitoring committee (DMC) model, is still more commonly proposed, particularly when safety monitoring is needed. Under the DMC model, the DMC members could be given additional responsibility to evaluate semi-blinded or unblinded interim efficacy data and to make recommendation about the adaptation decision, e.g., to select the treatment dose, to increase the sample size, to continue enrollment only in the selected patient subpopulation or to early terminate the study. Sometimes, the sponsor provides an unblinded statistician for interaction regarding the DMC interim analysis reports. The DMC model is mostly seen in adaptive group sequential trials where formal interim analyses are performed in addition to potentially conducting informal interim analyses for adaptation decision alone.
A more rigorous model we have seen involves three parties, the sponsor, the ISAC and the DMC. This model is referred to as combination model. Both the DMC model and the combination model involve the DSMB or DMC. As shown in Fig. 1, there are multiple interaction flows. One communication flow defines the interaction between the external ISAC unblinded team to provide the DMC with unblinded safety data analysis results. Another communication flow is from the DMC to the sponsor, then, to the steering committee (SC) on issues identified from safety monitoring. One other type of communication flow is the interaction between the external ISAC blinded and unblinded teams to the sponsor on blinded summary data and interim efficacy or safety adaptation related matters. We have seen a few such models proposed when more than one design parameter is considered for adaptation, e.g., two-stage patient subset selection allowing for sample size re-estimation.

And also this:

Adaptive seamless phase II/III design

An adaptive seamless phase II/III trial design is referred to a program that addresses within single trial objectives that are normally achieved through separate trials in phase IIb and phase III of clinical development. An adaptive seamless phase II/III design (Figure 3) is an adaptive seamless phase II/III trial design that would use data from patients enrolled before and after the adaptation in the final anal- ysis[42,43].AnadaptiveseamlessphaseII/IIIdesignisa two-stage design consisting of a so-called learning stage (phase IIb) and a confirmatory stage (phase III). A typical approach is to power the study for the phase III confirmatory phase and obtain valuable information with certain assurance using confidence interval approach at the phase II learning stage. Its validity and efficiency, however, has been challenged [44]. Moreover, it is not clear how to per- form a combined analysis if the study objectives (or end- points) are similar but different at different phases [45]. More research is needed.

AND this:

To maintain the validity and integrity of an adaptive design with compli- cated adaptations, it is strongly suggested that an inde- pendent data monitoring committee (IDMC) should be established. In practice, IDMC has been widely used in group sequential design with adaptations of stopping a trial early and sample size re-estimation. The role and responsibility of an IDMC for a clinical trial using adap- tive design should clearly defined. IDMC usually convey very limited information to investigators or sponsors about treatment effects, procedural conventions, and sta- tistical methods with recommendations in order to main- tain the validity and integrity of the study.