Appreciate the discussion. Let’s walk through this carefully, because several recent claims misapply FDA guidance and ignore how DCVax-L was actually designed and analyzed.
The FDA’s August 2023 RWD guidance does not apply to the DCVax-L Phase III trial. That document addresses non-interventional observational studies using routine clinical data (EHRs, claims, registries). DCVax-L, by contrast, was a randomized, double-blind, placebo-controlled interventional trial.
Below is the full breakdown, including references and direct quotes from both the FDA and Dr. Linda Liau:
🔹 What the 2023 FDA Guidance Actually Covers
The guidance in question, titled:
📄 “Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drug and Biological Products” Link: https://www.fda.gov/media/171667/download
➡️ focuses specifically on non-interventional studies that rely on RWD such as: • Electronic Health Records (EHRs) • Insurance claims data • Patient registries • Other routine clinical care data
The FDA defines non-interventional studies as those in which “patients receive the medical product during routine medical practice, rather than being assigned by protocol.”
In these cases, when a sponsor attempts to construct an External Control Arm (ECA) using RWD, the FDA explicitly states:
“The ability to match patients across studies at the patient level is critical when using RWD to construct an external control arm.” —FDA, August 2023, p. 11
In other words, patient-level data is mandatory when real-world data is being used to generate comparative effectiveness or support trial conclusions.
🔹 DCVax-L Was Not a Non-Interventional Study
The DCVax-L Phase III trial was a prospective, randomized, double-blind, placebo-controlled interventional clinical trial, not an observational study.
Patients were enrolled under a formal protocol, screened, and randomly assigned to receive either DCVax-L or placebo, with cross-over permitted at progression. That design places the study squarely outside the scope of the 2023 RWD guidance.
Dr. Linda Liau, Principal Investigator and Chair of Neurosurgery at UCLA, confirmed that NWBio initially considered using RWD to build the ECA. But the data quality wasn’t sufficient.
Her exact quote:
“As we pursued the databases that were out there, which is kind of surprising to us, there is not enough data to match these individual patients.” —Dr. Linda Liau, public forum interview
This is a direct reference to real-world datasets from commercial or registry sources lacking patient-level resolution.
As a result, NWBio and the trial team made a critical strategic decision: They did not use RWD to construct their ECA.
Instead, they used data from contemporaneous, peer-reviewed randomized controlled trials (RCTs) that had already been submitted to and reviewed by global regulators. These were formal trials, not observational datasets.
✅ Why That Matters
This decision accomplished three things: • ✅ It bypassed the need for patient-level RWD, because no RWD was used • ✅ It aligned with FDA and EMA expectations for scientific rigor and contemporaneity • ✅ It preserved the regulatory defensibility of the external control arm
To be clear: This is not a workaround. This is exactly how regulators advise sponsors to proceed when RWD is insufficient.
🔹 What Guidance Does Apply to DCVax-L?
For those seeking the correct framework for evaluating external control arms built from published trials or other study-level data, the relevant FDA document is the December 2018 Draft Guidance:
This guidance outlines how real-world evidence, including ECAs, may be used to support effectiveness, especially for single-arm trials, and describes when patient-level data is necessary.
It is the 2018 guidance, not the 2023 one, that addresses these cases, and it reinforces the validity of NWBio’s approach, since their control group came from contemporaneous RCTs, not uncontrolled real-world datasets.
This is not a gray area: • The 2023 RWD guidance is not applicable to DCVax-L because the trial did not use RWD. • DCVax-L was a randomized interventional trial, not an observational study. • NWBio constructed its ECA from published RCTs, not from real-world clinical records. • The FDA’s requirement for patient-level data in RWD-derived ECAs was avoided by design, because no RWD was used.
When critics cite the wrong guidance and ignore the actual structure of the DCVax-L trial, they are misrepresenting both the science and the regulatory context.
This isn’t speculation. It’s documented fact.
Let’s be precise, because precision matters.
To clarify: Real-world data (RWD) is defined consistently across global regulators. That consistency is essential for multi-national trials like DCVax-L and programs like Project Orbis, which rely on a shared understanding of what RWD is—data collected outside traditional clinical trials, such as from EHRs, claims, or registries.
But while the definition of RWD is harmonized, the way it’s used in regulatory decision-making varies. Some agencies may require patient-level RWD for external control arms; others may emphasize different standards depending on the product type or approval pathway.
In the case of $NWBO, the distinction doesn’t even apply. They did not use RWD or RWE in their external control arm. Instead, they used contemporaneous randomized trial data—the gold standard—eliminating the need for patient-level RWD entirely.
And importantly, it is the MHRA, not the FDA, currently reviewing DCVax-L. The MHRA is operating under the UK’s evolving ATMP framework, including SI 87, which reflects a different legal and regulatory structure. Applying FDA-specific requirements here is a basic misread of jurisdiction and process.
It’s also important to understand the structural and procedural differences between the U.S. FDA and the UK’s MHRA, as these often contribute to regulatory misunderstandings. The FDA (Food and Drug Administration) operates under a risk-based, precedent-driven framework that places strong emphasis on randomized controlled trials (RCTs), and typically applies narrower definitions for real-world evidence (RWE), especially when it comes to external control arms, requiring patient-level data if RWD is used. In contrast, the MHRA (Medicines and Healthcare products Regulatory Agency) has historically shown greater flexibility in accepting context-specific evidence, especially under its “Specials” and “Exceptional Circumstances” pathways, and more recently under post-Brexit reforms aimed at accelerating access to advanced therapies. While both agencies recognize RWD and external controls, their thresholds for evidence quality, patient-level matching, and trial classification can differ, especially in cases involving rare diseases or unmet needs. This divergence can lead to confusion when critics attempt to apply FDA-specific definitions, such as those outlined in the 2023 RWD guidance, to submissions or access models operating under UK law, particularly when the MHRA has already reviewed and accepted the methodology. Understanding this regulatory asymmetry is crucial to avoiding flawed comparisons.
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