Replies to post #438361 on NorthWest Biotherapeutics Inc (NWBO)

[highwayman4life]

DMB2~

I am in complete agreement with ATL on the ethical consideration aspect of placebo patients.

A placebo-controlled, double-blind, randomized clinical trial is the historical gold standard for clinical research, and is fundamental to the development of evidence-based medicine. Apcalisz.com research has shown that placebos produce strong, genuine psychobiological effects in both laboratory and clinical settings. Although the approach is scientifically sound, ethical concerns still arise in some cases which outweigh the benefits of this trial design.

According to the critics of placebo-controlled trials (PCTs), if a proven, effective therapy exists, a placebo should not be used. They further stress clause 33 of the Declaration of Helsinki, which states that, “The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best proven intervention(s).”{1} It goes on to stress that, “In any medical study, every patient should be assured of the best proven diagnostic and therapeutic methods and no patient should suffer from unnecessary pain.”

I believe that given there were no safety issues (2% SAE's for ITT patients) noted in the trial, for ethical reasons given the severity of GBM and its outcome, further placebo patients were restricted IMO.

WRT to an IA being performed and Exwannabe's assertion of a efficacy trial failure during this time, see the Company's PR as well as input from Dr Furberg (DMC head): https://nwbio.com/nw-bio-corrects-ongoing-false-claims-by-feuerstein-about-phase-iii-trail-of-dcvax-l-and-interim-analysis/

[ATLnsider]

I believe it is this FDA steering this DCVax-L review and approval ship (via Project Orbis). The DCVax-L clinical trial IND was first approved by the FDA and started in the US in 2006, and all the DCVax-L clinical trial sites were initially only in the US. The trial sites were later expanded to Germany and the UK in 2012, and then to Canada in 2015.

The FDA has been and will always be the lead regulatory agency for the DCVax-L Phase III clinical trial. In order for DCVax-L to become part of the new SOC to treat ndGBM and rGBM, the FDA will have to take the leadership role in this effort. The UK is too small (population 67 million) to create a new global SOC. The world needs the US (population 329 million) to lead this effort. The FDA and Dr. Pazdur know this.

Here is another “oldie but goodie” post from May 2021:

https://investorshub.advfn.com/boards/read_msg.aspx?message_id=164085000

The FDA held a Project Orbis Grand Rounds presentation on May 13, 2021, along with Health Canada and Swissmedic, to discuss how Project Orbis works, and the benefits of having concurrent submission, review, and almost simultaneous approval of NDAs, sNDAs, BLAs and sBLAs in up to 6 different countries.

This presentation was very interesting and informative. In particular, it was noteworthy what Dr. Richard Pazdur says around the 30:45 minute mark, regarding the reasons why the FDA started Project Orbis, and the benefits of establishing a new global standard of care (SOC), especially for a “truly important Breakthrough therapy drug”.

https://collaboration.fda.gov/pbq6126oijaa/

I still believe that NWBio will utilize the FDA Real-Time Oncology Review (RTOR) and the Project Orbis programs to get expedited global regulatory approvals for DCVax-L. These programs will also help establish DCVax-L as the global SOC for ndGBM and rGBM, and will help pave the way for future global combination trials for DCVax-L, along with global trials for DCVax-L and DCVax Direct to treat other solid tumor cancers.

[biosectinvestor]

I do not believe the FDA did the partial halt, but the rules are, in a global trial if any of the regulators do a halt, the FDA also adheres to that halt. I expect all the regulators behave similarly.

The FDA is far more transparent. I believe some of the issues related to this trial involve complex issues that happen when you have conflicting policies and rules involving a trial in multiple countries under multiple regulators. Inevitably there can often be some issue that arises that is substantially different in one country than another and I personally believe, and have since my first post in this board, which was deleted, said that I believe the Germans are particularly uncomfortable with anything they perceive as unethical human experimentation. I believe they felt the placebo arm was getting clearly inferior care and felt that it was an ethical concern to maintain the placebo. The partial halt happened not long after the trial started in Germany and also not long after they got the Hospital Exemption, which is an extremely thorough process of review.

I do not think the FDA had any issues with the placebo arm, I believe they insisted on the placebo. So that is the jurisdictional difference I am suggesting could be one of the reasons for the complexity here and also for the mystery.

So while the FDA is the primary regulator, they can’t tell a regulator in another country not to do what they think is ethical, and the regulations require that a trial that is halted in one country, is also halted in US. In this case it it was a “partial” halt and only the final count of the placebo patients was affected. I believe the company indicated that they were not told the reason, which together with no public discussion of any safety failings or stopping of the deliveries of DCVax, including for compassionate use, or for patients outside of the trial, just lots of indicators to me suggest it was not at all related to DCVax itself as a “product”. Nor is there a suggestion by the facts that it was dictated by any worries about the drawing of blood to get the dendritic cells. There is absolutely nothing to suggest that treated patients were in any danger or risk for their safety.

So in my opinion, it was for ethics, but not a determination of efficacy because the trial’s entire premise was based on having a placebo, as per the original FDA insistence. Again, jurisdictional differences in my opinion.

So you get a kind of complicated muddle out of that and I think everyone likely knows this looks to be a really wonderful potential new treatment, IMHO, and I believe that is another reason why it seems to me the FDA is bending over backwards to do what it can to help get this over the finish line including addressing the external control guidance. I just think they go slow when reforming themselves.

Everything in terms of regulation in a global endeavor like this is it going to be “clear”, because that is the nature of multilateral cooperation, that there is often ambiguity. Regulators learn to work together to address these things often, and sometimes they are individually stubborn. The FDA seems to me to be doing its best to accommodate, but they are just very slow with this kind of change, particularly so in a pandemic.’

https://www.thestreet.com/.amp/investing/stocks/northwest-bio-forced-to-temporarily-halt-study-of-brain-tumor-vaccine-13263780

“ Investors picked up on the temporary halt of the DCVax-L study before trading opened Friday from a notice posted on the European Union Clinical Trials Register web site. Northwest Bio didn't acknowledge the halt publicly until late Friday afternoon, but by then, the damage was done. Northwest Bio shares closed Friday down 22% to $6.96.”

https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-001977-13/DE

“ Summary
EudraCT Number: 2011-001977-13
Sponsor's Protocol Code Number: 020221
National Competent Authority: Germany - PEI
Clinical Trial Type: EEA CTA
Trial Status: Temporarily Halted
Date on which this record was first entered in the EudraCT database: 2013-02-11”