The MHRA recognizes the potential use of external control arms in clinical trials, particularly when traditional randomized controlled trials (RCTs) are not feasible or ethical. This approach is notably applicable in the context of rare diseases or situations where patient recruitment for a control group is challenging. Exactly this case. Granted, this is all new, and same for their coordination with the FDA and EMA on adopting these policies in collaborative effort.
The MHRA also provides guidance on using real-world data (RWD) to support regulatory decisions, which includes the consideration of external control arms derived from sources such as historical clinical trials, electronic health records, or registries. Their focus is on ensuring that these external data sources are of high quality and appropriately matched to the trial population to minimize bias and ensure reliable results. NWBO went to great lengths and provided statistical and other data in spades to ensure this will be the case. Plus they have lots and lots of other data, side arms, clinical data from compassionate use and lots of supporting data.
Additionally, Health Technology Assessment (HTA) bodies across Europe, including the MHRA, increasingly accept evidence from single-arm trials complemented by external control arms. These studies also must employ rigorous analytical methods to address potential confounding factors and ensure the robustness of the evidence. Again, not really an issue in this case and they all consider historical data and this is contemporaneous data from the most important trials in this space. The individual patient data from THOSE trials is understandably, at this time, hard to come by and so the additional statistical comparisons and other work address that failing. And then remember, they hired a completely blind, external mathematical and epidemiological consulting firm filled with experts to match and provide all of this data. It is, in my opinion, very, very unlikely that besides possibly some questions, which is the job of regulators, they should find the various sources of evidence including NWBO’s scientific study on method of action, very satisfactory, compared to the other drugs previously approved in this space, most of which were in a far worse position and had no survival benefits to demonstrate.
Cool your horses.
Obviously there is never certainty with any of these trials, but there should be at least as much as with any of the other troubled trials that seemed to never bother any of the shorts before. Just their focus on this one that literally blows that old stuff out of the water in terms of the clinical evidence from numerous sources. There is even the UCLA Nature paper and UPenn confirmatory paper on scanning and measurement of results also confirming what NWBO said in its Phase 3 JAMA Oncology publication and what now everyone knows with a fair degree of comfort about immunotherapies, that they can cause pseudoprogression and also that patients do not want to join placebo trials when they have as certain a disease as GBM in terms of mortality. No one likes to be a Guinea Pig and there are more than enough Phase I and II trials these days that they do not need to be.
And let me close with this basic bit of information. It is no mystery to any doctor or patient or regulator in the field how fatal GBM is, how rapidly it kills and that the results seen in these trials is outstanding. While no doubt there could be formalists using formalism to hide their partisan and economic interests in any body, there should be no rational reason this is not ultimately approved, IMHO.
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