Replies to post #401971 on NorthWest Biotherapeutics Inc (NWBO)

[sukus]

Thanks ATLnsider for the info. I believe NWBO can provide the support documents asked by the peer reviewers for journal publication. And one of them is what you just mentioned here.

[Doc logic]

ATLnsider,

I think you might be right now but I also think the German response to trial data during a safety check pushed FDA out of their slumber with and submission to the status quo. Best wishes.

[flipper44]

Right. Here is my post from a while back.

https://investorshub.advfn.com/boards/read_msg.aspx?message_id=161819435&txt2find=Synthetic

flipper44 Member Level Sunday, 02/14/21 08:55:54 AM

Pardon me for repeating this post. I just think it is highly relevant, because the DCVax-l phase III trial is an RCT with a (now) 2.3 to 1 ratio of treatment to control that was recently “augmented” by introducing concurrent/historical/synthetic control comparisons, probably because continuing the placebo randomization back in 2015 would have been unethical. In essence, getting the best from both control paradigms. (Aka: two heads are better than one)

[External controls] are more common today. This 2019 article is comprehensive https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218288/.

I found this excerpt helpful.

First, external data can be used to augment the precision of a concurrent control group in a randomized clinical trial (eg, using 4:1 randomization between treatment and control). Second, they can be used to create a stand-alone control group solely from external data. The latter is more common for rare diseases where single-arm trials predominate and randomizing to control is unethical, infeasible or highly inefficient.

Synthetic controls used to augment the precision of a concurrent control group generally have higher validity since they can be validated with the control arm in the performed RCT. Particularly control data from similar RCTs are valuable in this setting. Even if pertinent RCTs are not highly identical, much strength can still be gained.25 Where it is either unethical or infeasible to enroll patients to a control intervention, external data should be selected from the best possible source of data and synthetic controls can be used as a substitute for an absent control arm. In this setting (often a rare disease setting), pertinent RCTs are typically not available. There are many examples where various types of historical data, but increasingly data from prospectively recruiting patient registries as well as subsets from commercial real-world databases are being used. The scientific validity of these depend on the accuracy of the match. N-of-1 data, where each enrolled patient has at least several months of historical data on SOC, are ideal, but often not available. Data from similar medical centers from similar geographical regions to the target trial of interest can also improve validity. Of course, the more recent the higher validity, although a few months’ buffer should be allowed for full data curation processes (including quality assurance) to be finalized. Aggregate estimates from published cohort studies or case series may also be considered, either to validate primary sources of external data or as a substitute in the absence of individual-level patient-level data. Aggregate estimates from published studies nonetheless face limitations as detailed reporting on patient demographics, and clinical settings can be relatively sparse, and as such, similarity can be difficult to validate.

[biosectinvestor]

Agreed ATL and Flipper.

The ethical reasoning is clear and I have been saying for a long time that 1) I believed the halt was ethical, for the benefit of the PLACEBO arm, not the patients receiving DCVax- (Purely speculation on my part); 2) that unfortunately it was likely that the problem with the judgment that the placebo arm was not getting the best care at that point was that they could not stop the trial for efficacy because you still need to prove efficacy and they did not have what they needed yet; 3) the FDA recognized the regulatory unreasonableness of the circumstance and would likely address this ultimately because you can't really tell applicants to do one thing, then to do another thing (the opposite thing), and then tell them they are not approved because they did not keep doing the first thing which you told them to stop doing (it's actually the law, regulators can't be that irrational); 4) when the updated guidance on external controls came out, I explained that their keenness about it suggested to me that this was the FDA's likely guided fix to the circumstance, which they recognized was a real issue for treatments that should be likely approved but might face unnecessary regulatory hurdles.

That's the quick way of saying that the FDA would not want to fail a product that is obviously efficacious (despite a challenge in the trial due to regulatory hurdles that were not well crafted to achieve the regulator's primary end), but where the regulatory process itself got in the way of fully proving what had become obvious from the facts. The regulatory process had to be reformed (which they are doing with the 21st Century Cures Act), to allow for reasonable scientific evidence to be introduced. Dr. Liau had been talking about historical evidence for some time before the FDA guidance was updated. That does not just happen, that is likely the result of a long conversation between the FDA and many researchers over years, and then the acuteness of this particular trial seems maybe to have gotten the FDA to act (as well as the authorization of the 21st Century Cures Act). I do not think this is the only trial to have issues with a placebo arm and the treatment arm being so divergent, for such a difficult disease, but I do think it was likely more acute.

Now this is all me guessing, deductive reasoning and a lot of experience with regulators in the past and I don't naturally distrust every regulator I see. I am not going to quote the regulators, or the FDA, I've done it in the past. In my own experience, I've been in communication with regulators over the years working through issues and challenges and worked through how to address what otherwise might be a regulatory challenge and make it a win-win for all stakeholders. Primary regulators, in my experience, tend to like parties that are working with them to solve problems. It is actually the positive side of their job.

This is the lens through which I have viewed many events, and I could very well be wrong on some of it. But, I'm pretty sure the FDA guided them on the external controls and updating their SAP, in my opinion. The reality is that parties seek to discuss many things at different levels of formality and informality with regulators. It might be a formal call, a submission, there are lines for counsel to call on matters that are questions with no assurances of course, and regulators do appear at conferences and events where questions can be asked and they can be queried on their mindsets. There are many ways that lawyers and parties can get into the minds of regulators though I expect these steps came with direct communications mostly.