NorthWest Biotherapeutics Inc (NWBO)

[AVII77]

Now, what is your theory regarding the , now 8 month long, screening halt and submission of documents to regs?

I have several theories.

But lacking further disclosure it is difficult to connect all the dots.

It is far easier though to dismiss the popular theory here: that the hold was self imposed and the documents submitted were related to a BLA filing based on results of the interim analysis.

BLA's take many months to prepare even for Big Pharma; the disclosure from the company in August was that the documents would be submitted in weeks.

Results from IA's are inherently suspect; efficacy is systematically overestimated. That is true for hard endpoints like OS and even more so for subjective endpoints like PFS. Evidence of treatment benefit that comes from a truncated trial is less likely to be accepted by regulators and adopted by the medical community (and reimbursed by payors). These limitations are well understood by trialists's and particularly well developed in the cardiac trials. Dr. Furberg, the Chairman of the DSMB, has a strong background and understanding of these issues as he comes from this community.

For the above reason, I noted in IV post 2911 that if the current "hold" were related to a successful interim then OS would have been Stat sig also. (and I went on there to note that the regulatory submittal would be an Expanded Access request allowing control patients to cross prior to progression. That is a requirement for an IND, it is not required for an already approved drug being tested in a new population)

The recent failure of RTOG's GBM trial and the AVAGLio trial to demonstrate that OS benefit is associated with PFS benefit further brings into question the advisability of stopping a trial based on an interim finding of a PFS benefit in the nGBM population.

Furthermore, the FDA has a long history of discouraging claims of efficacy based on an interim finding of PFS benefit, especially so when such findings are from a single trial.

Furthermore, the FDA has a long history of discouraging interim analysis of a surrogate endpoint (read: trial designed to seek AA by continuing to follow already enrolled patients to confirm clinical benefit - OS) prior to full enrollment because if the surrogate results suggest benefit it makes it ethically difficult to continue to enroll the req'd confirmatory trial; the trial would be "stuck" as insufficiently powered.

For that reason it makes no sense to halt enrollment while such a process occurs. (and yes, I understand the Bull argument is that the pipeline contained sufficient patients - but that is not consistent with the "temporary" nature of the enrollment pause).

It is also important to consider just "who" imposed the hold. The Bull argument is that it was sponsor imposed; had it been imposed by the regulators it would have been a material event requiring disclosure.

I would note that there was a disclosure:

The Company’s lead program is a 348-patient Phase III trial in newly diagnosed Glioblastoma multiforme (GBM), which is on a partial clinical hold in regard to new screening of patients.

That meets the bare minimum threshold of the req'd disclosure. (and the rules for SEC filings are apparently different for LP than anyone else: where is Cognates Form 4 disclosing the 8 million shares issued 4 months ago?).

The "disclosure" still leaves open though the question of just who imposed the hold.

As I said above; it would be foolish for a sponsor to stop enrolling prior to being assured they were sufficiently powered to demonstrate clinical benefit.

And if it is not the sponsors then why would the regulators impose a partial clinical hold? The reasons are defined in the regulations. If you dismiss investigator misconduct (as I do despite the coincidental timing of the MHRA finding that NWBO advertised an unlicensed medicine - do IHubers know this?) we are left with ethical reasons and safety reasons (both inter-related).

The primary ethical reason would be that the consent form is no longer valid.

The primary safety reason (here at least because treatment continues) would be related to either manufacturing issues or (and this is related) leukerpheresis issues. We have many patient accounts of multiple leukerpheresis's required.

Regarding Manufacturing we have some interesting insight. For 3 years in a row NWBO's 10K stated:

"Moreover, the Company believes, based upon information provided by Cognate, that no client of Cognate has been put on clinical hold in connection with its product."

The 10k issued in March 2015 no longer has this statement.

But March 2015 is admittedly before the current hold. What to make of that? I'm not sure. Perhaps whatever issue that locked them down in August had arisen before and was previously handled quickly - but with more focus going forward. And in August that focus became clearer and the FDA imposed a partial clinical hold.

Regarding futility, a popular bear argument, I have some thoughts also.

(Anyone reading who doesn't understand the difference between futility and harm should stop reading and go to google.)

I've given this a lot of thought. Stopping a trial for futility based on a PFS interim has many of the same issues as stopping for efficacy at a PFS interim. While there are ethical arguments against enrolling patients into a futile trial we have to remember that no patient is denied SOC. If the drug is safe, and although futile, some as yet unknown subgroup of patients may benefit, and if those consenting did so with the intent of benefiting science (helping those similarly afflicted who will later be diagnosed with GBM), it may be ethical to continue an apparently futile trial. It may even be ethical to continue enrolling appropriately consented patients. It may even be ethical not to perform a futility analysis at all. The sections of the leaked protocol I've seen posted online indicate a DSMB stop for harm is possible, I saw nothing about futility.

So, my theory?

1. Safety (manufacturing) issue. No interim has been performed because they haven't yet reached full enrollment. If it is a manufacturing issue LP would be extra guarded to not damage Cognates reputation (someone should check the confidentiality clause in the Cognate Agreements, I have not).

It is also likely that when they changed the trial at the "enhancements" they did away with the PFS interims. The interim LP spoke of may have been the interim of OS which accompanies the final analysis of PFS (by far and away, this is the way these PFS => OS trials are usually conducted).

The trial is likely still blinded. Awaiting resolution of the hold and completion of enrollment.

That's the way is should work.

And yes, I know LP said something to the effect that the interim would happen in 2015 followed by full enrollment. But she also said the 66th event happened and the IA was underway in Dec 2013, we know that wasn't correct. (and recall the bull theory at that time was that a BLA was being filed in secret also).

You asked for my theory, there you have it.

It is, of course, subject to change as more information is available.


Below are a few supporting items I just grabbed these from my prior posts on IV in 2014 - the last time a BLA was being secretly filed for DCVax.

PFS is an acceptable end point for approval if it is measured properly and of sufficient magnitude to provide a favorable benefit-to-risk analysis. However, survival should also be measured to ensure that a new therapy does not lead to survival decrement. Interim analyses of PFS are discouraged, because they may result in a trial being stopped before accrual is complete, provide an overestimate of the treatment effect, or be underpowered to detect a survival difference. Early discussion with the FDA on the appropriate setting in which to use PFS is encouraged during trial design.

Consider also:
CLSN disclosed the following about their PFS interim, in additiion to 190 events (50%) they needed “the statistical plan for the Phase III ThermoDox trial also incorporates a pre-planned interim efficacy analysis by the DMC after patient enrollment is complete”

Ariad’s protocol for ridaforolimus notes the following statement tied into their PFS interim: “Of note, a decision to terminate the trial due to a beneficial treatment effect will only be considered after all planned patient accrual has been completed.”