The MHRA draft guideline is very clear on its flexibility regarding trial design, specifically by embracing augmented control designs and making concessions for when a fully randomized controlled trial (RCT) isn't feasible.
1. Augmenting a Randomized Control Arm
The guideline explicitly prefers a design that incorporates an ECA while retaining an internal, randomized control. (See further below regarding possible DCVax-l MAA possibility)
Augmented Control Arm: The guideline covers the use of an ECA to augment a randomised internal control arm. This design is preferred over a single-arm trial with only an ECA because it "allows for better control of potential biases."
Purpose of Augmentation: The external data is used to supplement or enhance the evidence from an internal, randomized control, which could be underpowered on its own. The internal randomized arm acts as a 'bridge' or consistency check, increasing confidence in the comparison between the investigational arm and the combined (internal + external) control data.
2. Situations Allowing ECAs Over RCTs (Flexibility)
The draft guideline accepts that a trial design can be changed from the preferred full RCT to an ECA design under specific, justified circumstances. This constitutes a change in the ideal trial design to one that is practically and ethically feasible.
The use of an ECA is more likely to be accepted in situations where conducting an adequately powered RCT is:
Unethical or not Feasible: For example, in rare diseases or where there is no existing standard of care, or for a severe condition where assigning patients to a placebo/suboptimal care arm is not ethical.
Result in a Significant Delay: If a full RCT would take too long, impeding patient access to a promising therapy.
Expected Large Treatment Effect: Where the effect of the intervention is so large that it is expected to allow for the interpretation of the study results despite the potential for bias inherent in an ECA.
In these circumstances, the trial design essentially changes from the Gold Standard RCT to an Externally Controlled Single-Arm Trial or an Augmented RCT. The decision is ultimately based on whether the data is "sufficiently convincing," even if a different approach "may have ideally been preferred."
Flexibility on Pre-Specification: While the general principle is to pre-specify the ECA in the trial protocol, the guideline acknowledges that an appropriate external dataset might not be available when the trial is initially designed. In this case, sponsors can amend the protocol to justify the inclusion of an ECA after the trial has started, provided they demonstrate that this was not done in a "results-driven" manner. This is a significant change to the standard strict adherence to the initial protocol.
Moreover, the DCVax-l trial also completed collecting its randomized data on December 31, 2024. It is certainly not unlikely this mature internal control arm data was both significant and folded into the MAA.
Additionally, a likely more patient specific trial control arm, from Survaxm 2b (collected Aug 18 or earlier) could have been added and compared to the DCVax-l MAA.
I’d say GZ’s response that NWBO/mhra maa interactions didn’t really pick up until 2025 is in line with this thinking.
LP’s recent expectation of increased DCVax-l demand and action thereon, and yes, even your own perplexity as to why she folded Advent into NWBO seems to indicate progress on the MAA front.
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