NorthWest Biotherapeutics Inc (NWBO)

[sentiment_stocks]

You reference the FDA guidance on the use of external controls for clinical trials dated February 2023 and titled: Considerations for the Design and Conduct of Externally Controlled Trials for Drug and Biological Products Guidance for Industry (which we should note is still a draft guidance).
https://www.fda.gov/media/164960/download

But when the Statistical Analysis Plan (SAP) for the External Control Arm (ECA) was being designed, this guidance had not been published by FDA. As noted by the company in their 2018 Annual Report (dated April 2, 2019) on page 2:

As previously reported, the Company is now moving forward with the several stages of work that are needed to reach completion of this trial. These include finalizing the Statistical Analysis Plan, conducting the final data collection, data validation and data lock, and then unblinding and analyzing the data.
https://www.sec.gov/Archives/edgar/data/1072379/000114420419017803/tv517288_10k.htm

And from the guidance you cited in your earlier post, please note that it states on line 26, it states,

Although various sources of data can serve as the control arm in an externally controlled trial, this guidance focuses on the use of patient-level data from other clinical trials or from real-world data (RWD) sources, such as registries as well as electronic health records (EHRs) and medical claims. 7 This guidance does not address other types of external controls, such as using summary-level estimates instead of patient-level data. This guidance does not discuss details of the design and analysis of a natural history study8 nor the reliability and relevance of various sources of RWD9 that could be used in an externally controlled trial.

Footnote 8 from the February 2023 guidance:

8 See the draft guidance for industry Rare Diseases: Natural History Studies for Drug Development (March 2019). When final, this guidance will represent FDA’s current thinking on this topic. Natural history studies can be used for purposes such as identifying a study population, developing clinical outcome assessments or biomarkers, and serving as a comparator group in an externally controlled trial.

So since the FDA footnoted the FDA’s Rare Diseases: Natural History Studies for Drug Development Guidance for Industry (dated March 19 and referenced in the footnote from the guidance you cited) be looked at, let's do that. And please remember, this guidance was released while Northwest was preparing their SAP for the ECA.
https://www.fda.gov/media/122425/download

Now everyone will agree that GBM is a rare disease.

You probably are thinking, though, that the DCVax-L trial was not a Natural History Study. But, on line 63, the guidance does suggest that natural history can be used as an external control (and I'll note, for the record, that the ECA in the DCVax-L trial was more than a historical control... it was a concurrent control:

It also touches briefly on the potential use of natural history data as an external 6 control in a clinical trial, but not as the primary focus of this guidance.

And as the footnote 6 indicates, a historical control is a subset of an external control.

6 The regulation at 21 CFR 314.126 uses the term historical control, which is a subset of external control. An externally controlled trial compares a group of subjects receiving the test treatment with a group of patients external to the trial, rather than to an internal control group consisting of patients from the same population assigned to a different treatment. The external control can be a group of patients treated at an earlier time (historical control) or a group treated during the same time period but in another setting. See the ICH guidance for industry E10 Choice of Control Group and Related Issues in Clinical Trials (May 2001). This guidance uses the term external control,except when referring to section 314.126.

Furthermore, at line 132, the guidance indicates this regarding using this type of historical data for marketing approval:

4. Design of Externally Controlled Studies: Use of Natural History Study Data
To qualify for marketing approval, an application submitted under section 505(b) of FD&C Act must, among other things, be supported by investigations showing the drug to be safe and effective under the conditions prescribed, recommended, or suggested in the product labeling and demonstrate a favorable benefit-risk profile in the specified patient population.8 To demonstrate effectiveness, sponsors must provide substantial evidence from adequate and well-controlled investigations, including clinical investigations,9 that include (among other factors) a valid comparison to a control.10

Footnote 10 cites:

10 The characteristics of an adequate and well-controlled investigation are detailed under FDA regulations at 21 CFR 314.126.

Now while you’ll likely argue that the trial is not designed to be adequate and well-controlled, it certainly was as the trial was quadruple blinded, randomized (despite the portion of the placebo arm who received treatment having been turned into a treatment arm and living longer) and was conducted during its duration as a randomized trial, eliminating many biases that might have been applied had the trial never been randomized (which is also one of the main reasons for randomizing a trial).

The guidance also addresses the issue of bias as it might apply to the use of Natural History Study Data when it states the following, which could be argued covers GBM (a rare disease) almost exactly.

However, bias may be mitigated in certain situations where the disease course is predictable and the treatment effect dramatic. In some cases where the natural history data exist and are part of the general medical knowledge of the disease course, a baseline control study design can be used because the pathophysiology is well understood (e.g., tumors do not shrink in the absence of treatment; tumors are known to have a high probability of progression in a defined time period). In other cases, data and information from a natural history study may provide an untreated, external control group for use as the comparator to the treatment group(s) in an investigational drug trial.

and

Regardless of external control type, even for diseases with relatively predictable progression, an external control is most interpretable when a treatment effect:
(1) is large in comparison to potential biases and the known variability in progression,17
(2) is not affected by patient or investigator motivation or choice of subjects for treatment,18
(3) can be objectively measured,
(4) is measured in a manner that reasonably manages and minimizes bias,
(5) has a strong temporal association with administration of the investigational drug, and
(6) is consistent with expected pharmacological activity based on the target and perhaps shown in animal models.

In closing, I would just like to remind you that this rare diseases guidance was made available at the time Northwest was assembling their ECA (the other guidance you cited did not exist at that time) which offers more latitude on the subject of using an ECA for marketing approval.