Replies to post #560630 on NorthWest Biotherapeutics Inc (NWBO)

[hoffmann6383]

NWBO's trial was certainly not a well-controlled or designed trial.

Appreciate your often repeated opinion but the RA authorities that matter, i.e. the MHRA, recently approved a pediatric trial using the same trial design.

Have a good one Gro!

[CherryTree1]

When you allege:

NWBO's trial was certainly not a well-controlled or designed trial.

according to who's measure.

and when you further allege:

Post hoc tossing out the primary endpoint and totally redesign the protocol, endpoints, comparator and SAP after the trial is virtually complete.

We have been through this before several times in the past few days be here it is again.
Updating the SAP later in the trial is standard practive.
Here again in my post on this from October
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=170236939
The protocol NWBO is following has been standard practice for some time. Here is information from 2010
http://onbiostatistics.blogspot.com/2010/04/when-to-finalize-statistical-analysis.html

When to Finalize the Statistical Analysis Plan (SAP)?
"The statistical analysis plan may be written as a separate document to be completed after finalizing the protocol. In this document, a more technical and detailed elaboration of the principal features stated in the protocol may be included. The plan may include detailed procedures for executing the statistical analysis of the primary and secondary variables and other data. The plan should be reviewed and possibly updated as a result of the blind review of the data (see 7.1 for definition) and should be finalised before breaking the blind. Formal records should be kept of when the statistical analysis plan was finalised as well as when the blind was subsequently broken.
If the blind review suggests changes to the principal features stated in the protocol, these should be documented in a protocol amendment. Otherwise, it will suffice to update the statistical analysis plan with the considerations suggested from the blind review. Only results from analyses envisaged in the protocol (including amendments) can be regarded as confirmatory."
This indicated that the ICH principal is followed as long as the statistical analysis plan is finalized or signed off prior to the study unblinding (or database lock if it is open label study). I believe this is the common practice in industry.

. . . so again do we believe you or the ICH . . . I know how I would vote.

and when you allege:

The treatment bias is complete starting with cherry-picked, healthy nGBM patients,

Here is the patient selection criteria

Inclusion Criteria:

All patients must meet the following inclusion criteria. All tests and eligibility criteria must be completed within four weeks of completion of radiation and chemotherapy, following surgery.

Patients must have sufficient tumor lysate protein that was generated from the surgically obtained tumor material. Patients must also have sufficient DCVax-L product available after manufacturing. These determinations will be made by Cognate BioServices, Inc. (Cognate) and communicated to the clinical site through the Sponsor, or its designee.
Patients with newly diagnosed, unilateral GBM (Grade IV) are eligible for this protocol. An independent neuropathologist will review this diagnosis during the enrollment process.
Subjects ≥18 and ≤70 years of age at surgery who are capable of informed consent. Patients must be able to understand and sign the informed consent documents indicating that they are aware of the investigational nature of this study.
Patients must have a life expectancy of >8 weeks.
Patients must have a KPS rating of ≥70 at the baseline visit (Visit 3).
Primary therapy must consist of surgical resection with the intent for a gross or near total resection of the contrast-enhancing tumor mass, followed by conventional external beam radiation therapy and concurrent Temodar chemotherapy. Patients having a biopsy only will be excluded. These primary treatments must be completed at least two weeks prior to first immunization.
Patients may have received steroid therapy as part of their primary treatment. Steroid treatment must be stopped at least 10 days prior to leukapheresis.
Patients must not have progressive disease at completion of radiation therapy. Patients with suspected pseudoprogression will be enrolled and analyzed separately.
Patients must be willing to forego cytotoxic anti-tumor therapies except temozolomide essentially according to the schedule of the Stupp Protocol (Stupp et al. N Engl J Med 352: 987-96, 2005) while being treated with DCVax-L. DCVax-L treatment must be given as described and temozolomide/Temodar treatment schedules must be given essentially according to the Stupp Protocol.
Patients must have adequate bone marrow function (e.g., hemoglobin >10 g/dl, white blood count 3600-11,000mm3, absolute granulocyte count ≥1,500/mm3, absolute lymphocyte count ≥1,000/mm3, and platelet count ≥100K/mm3. Eligibility level of hemoglobin can be reached by transfusion.
Adequate liver function (SGPT, SGOT, and alkaline phosphatase ≤1.5 times upper limits of normals (ULN) and total bilirubin ≤1.5mg/dl), and adequate renal function (BUN or creatinine ≤1.5 times ULN) prior to starting therapy.

https://clinicaltrials.gov/ct2/show/NCT00045968
If you take the time to get your head around this you will realize they were mainly ensuring the patients had adequate immune system function in the patient selection. Doesn't that make sense to the most casual observers since the are testing how dendritic cells can marshal the patients immune system to attack the tumor.
and when allege:

confounded the results by multiple doses of DCVax-L

Who cares how many doses they get? Give them triple or quadruple doses of DCVAX if that is what it take to be effective. The trial was set up so that the patient got many does over multiple months/years.

When you further allege:

statistically manipulated the OS to try to compensate, picking external comparators that don't do either.

I don't even know what that means. They had an independent impartial company determine what were the best external comparisons to use and then further censored the data to make the results look worse to ensure fairness. Even with that the result are eyepoppingly fantastic. Just read them and weep.