NorthWest Biotherapeutics Inc (NWBO)

[hyperopia]

No hank it’s not the kiss of death. I think its important to remember that Glioblastoma is a severely debilitating, rare disease, and one of the deadliest, and most difficult to treat cancers, with very limited treatment options and mortality rates little changed in the past 20 years, when many other cancers have seen huge advances. The naysayers here want everyone to believe that this is the same old rigid FDA of years past, but it is not. The FDA understands that gene and cell therapies represent a new medical treatment paradigm that requires new methods for trials and new ways to evaluate them. The FDA’s really wants to approve more treatment options for rare diseases like GBM, and there is growing political pressure to do so. One of the primary concerns of the FDA when making a Benefit Risk Assessment during the approval process of a new molecular entity, is safety. Well guess what? DCVax is extremely safe, and especially so when compared to chemotherapy, or even other immunotherapies like the checkpoint inhibitors, or the hot CAR-T’s, which the FDA has been falling over to approve.

Have you read the Congressional Glioblastoma Awareness Day Resolution? Here’s the highlights:
https://mast.house.gov/_cache/files/b/7/b75c3380-6809-495c-b634-340e9e51cdfa/047DE2899DD53E6E51082C01FBE9C238.glioblastoma-awareness-resolution.pdf

Whereas there is a need for greater public awareness of glioblastoma, including awareness of both—
1) the urgent unmet medical needs of glioblastoma patients; and
(2) the opportunities for research and treatment advances for glioblastoma: Now, therefore, be it

Resolved, That the House of Representatives—?(1) supports the designation of ‘‘Glioblastoma Awareness Day’’;
?(2) encourages increased public awareness of glioblastoma;
?(3) honors the individuals who have lost their lives to glioblastoma, a devastating disease, or are currently living with it;

(4) supports efforts to develop better treatments for glioblastoma that will improve the long- term prognosis of individuals diagnosed with glioblastoma;

(5) expresses its support for the individuals who are battling brain tumors, as well as the families, friends, and caregivers of those individuals; and

(6) urges a collaborative approach to brain tumor research, which is a promising means of advancing the understanding and treatment of glioblastoma.



More importantly, have your read the FDA’s most recent guidance on Demonstrating Substantial Evidence Of Effectiveness? Here is an especially critical part:

https://www.fda.gov/media/133660/download


EXAMPLES OF CLINICAL CIRCUMSTANCES WHERE ADDITIONAL FLEXIBILITY MAY BE WARRANTED:

A. When the disease is life-threatening or severely debilitating with an unmet medical need

Subpart E regulations promulgated in 1988 call for FDA to exercise its broad scientific judgment in applying the evidentiary approval standards to drugs for life-threatening and severely debilitating diseases, especially where there is no satisfactory alternative therapy. . . Below are considerations for drugs developed for life-threatening and severely debilitating diseases. ?
1. Trial design
2. Trial endpoints
3. Number of trials

4. Statistical considerations
. A typical criterion for concluding that a trial is positive (showed an effect) is a p value of < 0.05  (two sided). A lower p value, for example, would often be expected for reliance on a single trial. For a serious disease with no available therapy or a rare disease where sample size might be limited, as discussed further below, a somewhat higher p value – if prespecified and appropriately justified – might be acceptable.

B. When the disease is rare

By statutory definition, a rare disease – including a genetically defined subset of a disease – affects fewer than 200,000 people in the U.S.; . . . In addition, many rare disorders are life-threatening or severely debilitating diseases with no approved treatments, leaving substantial unmet medical needs for patients. ?

Do you remember Linda Powers’ comments on this document regarding statistical considerations? Here’s a little reminder:

“In regard to p value… professional statisticians and other professionals involved in data modeling and evaluation have been calling for years for the drug approval process to stop using a rigid cutoff of p ≤ 0.05 for determination of statistical significance. A group of 800 such statisticians and professions published a paper making compelling case as to why such a rigid cutoff is inappropriate and fails to give an accurate picture of the real efficacy (or lack of efficacy) of a new medicine. See, e.g., https://www.nature.com/articles/d41586-019-00857-9?utm_source=twt_nnc&utm_medium=social&utm_campaign=naturenews&sf209700813=1 Other similar papers have been published by professional statisticians as well.

It is not fair to patients for a potentially helpful new medicine to be blocked from approval by the rigid application of p value measures that even professional statisticians oppose. In addition – as with the rejection of sub-groups – the rigid application of p values to refuse product approvals is something that the healthcare system simply cannot afford. Each time a new medicine is rejected on this basis, it adds enormous development costs. It also prevents new competition by the new medicine. All of these factors are leading to the skyrocketing drug prices.

Accordingly, we urge that the Agency add to the Draft Guidance express flexibility in regard to p values, along the lines proposed by such a large number of professional statisticians.”


No one (except maybe ex or AVII) knows the shortcomings of this trial better than Linda Powers, or the best ways to overcome them. I probably don’t need to remind anyone that it took nearly eleven months of “the most labor-intensive work with independent statisticians” (and 1 PhD from Merck) to complete the draft SAP. It’s clear that it was not simply “finalizing the SAP” as they indicated in November 2018, but instead, composing a completely new “phonebook size” SAP that spells out multiple pathways to approval, and is based on the most optimal methods of analyzing an immunotherapy with a potential delayed vaccine effect, crossover, and a long survival tail, and incorporating feedback from the very regulators who want to approve a new (safe) treatment. It wouldn’t surprise me at all if the endpoints were modified, or alpha adjusted if it would benefit the OS endpoint to achieve statistical significance.