Replies to post #40574 on NorthWest Biotherapeutics Inc (NWBO)

[sentiment_stocks]

Could this be why the clinical trial.gov site still shows 300 and not 348? Perhaps the remaining 48 were/are intended to be in the confirmatory trial?

Posting later... I guess you answered my question. I'm making my way up the posts. :)

[Dan88]

You have stretched too much but your efforts are appreciated. Agreed the stubbornly fixed number of 300 and the final data collection day of September 2015 appeared in the clinical trial site might mean something although the site is famous for its unreliability: while all other trivial has been updated regularly , why not the total enrolment number and the final data collection day if there were some changes?

As far as the most positive scenario is concerned, DMC by seeing the unexpectedly good data (unblinded)can decided to have a look (interim analysis) before full enrolment. No rules have prohibited that. And if the results confirm, it can recommend stop and the company can file AA application to FDA if the results are significant good enough (for instance, more than 6 months or more PFS advantage over standard of care compared to the target 4 months). Of course, before the filing, there must first have some consultation with FDA for direction.

If FDA not buy it, the company may just issue a release saying the temporary screen halt has been lifted as the 1st interim analysis has been conducted, and the trial will continue according to the protocol.

[maverick_1]

For others and worthy reminder:
It should be clear from CEO Linda Powers remarks Aug 2014 about why the DC VAX L Ph3 was redesigned and expanded and to be HIGHER powered to SUCCEED:

Excerpted from NWBO PR Aug 2014:

The changes relate to the statistical analyses that will be done at the end of the trial, and do not affect the treatment protocol, dosing, randomization of patients or other such aspects. The changes were driven solely by external factors — particularly research reports about a newly discovered variable which has been found to significantly affect GBM patients’ survival times, and which the Company recognized could significantly skew the clinical trial results if the trial’s statistical analyses did not control for it. The Company’s Phase III trial design and statistical analyses already controlled for key variables known at the time when the trial was designed, such as a particular genetic factor (referred to as MGMT methylation), the extent of tumor removal, and others.

The new variable involves the level of certain white blood cells in GBM patients when they finish the 6 weeks of daily radiation to the brain which is part of the current standard of care treatment. Important recent research has found that as many as 40% of GBM patients have such severely depressed white blood cell counts following radiation that their level is comparable to the level at which AIDs patients are put on continuous antibiotic treatments, prophylactically. Further, this research has found that these GBM patients’ white blood cell counts do not recover with the passage of time. See, for example: Grossman et al., 2011: Clin Cancer Res 17(16):5473-80; Ellsworth et al. 2014: Oncoimmunology 3(1):e27357. Epub 2014 Jan 3.

Most importantly, the recent research has identified a major impact on these GBM patients’ Overall Survival (OS): the variable relating to severe depression of white blood cell counts can make a difference of 6 months in OS. As a comparison, the standard of care drug for GBM, Temodar, only makes a difference of 10 weeks in OS. If the statistical analysis of GBM trial results does not take account of such a major variable, the overall trial results could be significantly skewed.

Under the enhancements to NW Bio’s Phase III trial, the statistical analyses of the trial results will be modified to take account of, and control for, this important new variable.

Also under the enhancements, the threshold for satisfying the primary endpoint of the Phase III trial (which is Progression Free Survival, or PFS) will be lowered from requiring a 6-month difference to requiring only a 4-month difference between the PFS of the patients treated with DCVax-L and the PFS of patients in the control arm of the trial.

The bases for reducing the threshold from 6 months to 4 months difference in PFS include increasing the total number of patients in the trial from 312 to 348, and increasing the number of “events” that will be counted in the statistical analyses at the end of the trial. An “event” is a tumor recurrence or a patient death.

The current trial plan involves counting 110 “events” from among the 312 total patients in the trial to evaluate whether the primary endpoint is met.Under the enhancements of the trial, 248 “events” will be counted from the 348 total patients in the trial to evaluate whether the PFS primary endpoint is met.

By increasing the number of “events” counted, the statistical basis of the trial, which is already quite strong, will be further strengthened. As a result, it is anticipated that a 4-month difference in PFS will be sufficient to reach the strong “p value” planned in the trial (0.02), and it will not be necessary to show a 6-month difference in PFS. (“p value” is a measure of statistical significance – the probability that trial results are due to chance, rather than the effects of the treatment. So, the smaller p value, the stronger the significance. Regulatory authorities generally require that the p value of trial results be 0.05 or lower for product approvals.)

The Company has obtained approval from the US FDA and the UK Medicines and Healthcare Products Regulatory Agency (MHRA) and conditional approval from the German regulatory authority (the Paul Ehrlich Institute, or PEI). The Company is now working toward the final approval from the PEI.

The trial enhancements will also have to go through Institutional Review Board (IRB) review and approval at each of the clinical trial sites. There are currently over 50 trial sites in operation in the US and a number of sites in operation in the UK and Germany. There will also be certain other requirements for implementation of the changes, modified documentation and procedures.

Taking into account the time required for these approvals and implementation steps, and the 36-patient increase in the trial, as well as the gradual ramp-up of the trial in Europe, the Company currently anticipates that enrollment will be completed in approximately Q3 of next year, and the primary endpoint of the trial will be reached about 3-5 months after full enrollment or by around year-end next year.

“We are grateful to the regulatory agencies for allowing us to take account of important new research findings in our ongoing Phase III trial, to control for a variable that could have significantly and artificially distorted the trial results, and we are grateful to be able to maximize the number of “events” to be counted from the patients in our trial,” commented Linda Powers, CEO of NW Bio. “Although it has been a long process to obtain approvals from three different regulators for these enhancements of our trial, we believe that achieving approval for these changes will be of great value to the ultimate results of the trial and to the building of shareholder value.”

Moreove all of this was under the auspices of Max Bosch and herein is part of his responsibilities from NWBO website

Dr. Bosch led the process of designing the protocols, and managed the successful preparation and submission of our Investigational New Drug (IND) applications for FDA approval to conduct clinical trials for prostate cancer, brain cancer, ovarian cancer and multiple other cancers. He also led the processes for other regulatory submissions in both the U.S. and abroad (including the successful applications for orphan drug status in both the U.S. and Europe for DCVax-L for brain cancer).

Also as it relates to current clinical site issues:

For others, good to know that CEO relies upon:

Anthony Maida, Ph.D.(also from latest Proxy)

Sr VP, Clinical Research

Dr. Maida joined our company in June 2011, as Chief Operating Officer and brings more than 20 years’ experience in building oncology companies, with expertise in the business, financial, clinical and regulatory aspects of and the underlying science of oncology business. Over these two decades, Dr. Maida has held positions as Chairman, CEO, COO, CSO, CFO and VP Business Development. Among these experiences, he served as CEO of CancerVax Corporation, an early leader in cancer vaccines. In that role, he was responsible for conducting multi-hundred patient, multi-center clinical trials with the company’s cancer vaccines. Prior to joining us, Dr. Maida was serving as global head of oncology for a leading contract research organization that manages clinical trials in the U.S. and internationally.

AND when money gets TIGHT what happened in 2013 as copied and pasted from the last proxy statement filed last Nov 2014 is most likely what may be in effect:

In July 2013, we received a short-term loan of $0.6 million from Cognate. The short-term loan was paid-in-full during the third quarter of 2013. In October and November 2013, we received short-term loans of $0.6 million from Cognate. These short-term loans were paid-in-full during December of 2013.

In March 2013, we received a short-term loan of $0.2 million from Toucan Capital. The short-term loan was paid-in-full during the second quarter of 2013. Linda Powers, our Chief Executive Officer and a director, is a principal of Toucan Capital, which also is a substantial stockholder.

In March 2013, we received a short-term loan of $0.2 million from Leslie Goldman, our Senior Vice President, Business Development. The short-term loan was paid-in-full during the second quarter of 2013.