NorthWest Biotherapeutics Inc (NWBO)

[Rkmatters]

The partial hold has everything to do with MANUFACTURING. The Company (NOT regulators) stopped screening patients IMHO. That went unnoticed for a short time, and then the Company was forced to address why patient screening stopped. At which time they made it clear enrollment was well above 300-patients, but did not elaborate on the partial clinical hold (screening only).

Whatever the reasoning the Company stopped screening patients. That we know as fact. We also learned that they are in the midst of a manufacturing change abroad for this Phase III trial.

OUT with the OLD manufacturer (The 2013 Protocol detailed Fraunhofer):

• Fraunhofer-Institut für Zelltherapie und Immunologie IZI will provide
manufacturing and QC services in the EU. Fraunhofer is located in Leipzig,
Germany. Immunologic Monitoring and Cellular Products Laboratory will analyze
the immune monitoring samples for all study sites.
• Translational Centre for Regenerative Medicine will provide processing and
storage of immune monitoring samples in the EU until samples are shipped for
analyses.

IN with the NEW manufacturer (CTU - once this new vendor receives the necessary clearances):
Flip found this press release, and within, it details a new vendor, CTU:

http://www.ecmcnetwork.org.uk/news/announcement/kings-college-hospital-lead-dcvas-l-study

Detailed negotiations are now underway to build on a contract (>£2M per annum) for the CTU to serve as a manufacturing hub for the production of DCVax-L and its broader use at multiple other facilities in UK and other European Centres.

More about the CTU:

https://www.cancerbrc.org/our-facilities/clinical-trials-unit

Clinical Trials Unit

The Clinical Trials Unit (CTU) provides a central coordination function for new trials across The Royal Marsden. The recently expanded team, based in the CTU at the Sutton site but also serving Chelsea, provides central support for designing, coordinating, analysing and publishing clinical trials and other well-designed studies. Investigator-initiated studies are welcomed from all clinical units, and investigators, with the support of the CTU, apply for external grant funding in order to support the additional activity.

The first trial to be run through the CTU will be the Patriot Trial, led by Professor Kevin Harrington, in collaboration with colleagues at University College London, Guy’s and St Thomas’ and Kings College London. This non-randomized, open-label, first-in-man Phase I study will examine safety and tolerability of AZD6738 as a single-agent and in combination with palliative radiation, and will provide a recommended dose for subsequent trials.

The expansion of the CTU is a significant step forward and exciting addition to the BRC’s research strategy, allowing us to fully maximise the potential for research excellence and ensure a more integrated system for research across all the units.

Researchers interested in running a trial through the CTU should contact Dr Rowena Sharpe, Assistant Director, BRC, or Sally Ellis, CTU Operations Manager.

The Company even told us though SEC statements that changes in biological manufacturing is the reason regulators keep living-cell trials on clinical hold, below. Obviously they will need the PEI and the MHRA regulators to grant CTU all the necessary approvals to act as their UK manufacturing hub. They can not screen patients without it!

"We contract out the manufacturing of our DCVax products to Cognate BioServices. Although there are many contract manufacturers for small molecule drugs and for biologics, there are only a few contract manufacturers in the U.S. and even fewer in Europe that specialize in producing living cell products and that have a track record of success with regulatory authorities. The manufacturing of living cell products is highly specialized and entirely different than production of biologics: the physical facilities and equipment are different, the types of personnel and skill sets are different, and the processes are different. The regulatory requirements relating to manufacturing of cellular products (especially personalized cellular products) are exceptionally difficult to meet and are one of the most frequent reasons for a company’s clinical trials and product development to be put on clinical hold (i.e., stopped by regulatory authorities).

What other proof do you need that Manufacturing is changing for this PHASE III study? Hopefully, none. But in case you need proof that new sites need to be QUALIFIED; and INDs are put on hold until they pass all inspections -- as they are deficient in clearance until they get all approvals -- see below:

www.ncbi.nlm.nih.gov/pmc/articles/PMC3659665/pdf/sct825.pdf

The FDA has reported [5] that some of the reasons for placing cell therapy INDs on clinical hold include dose regimen and safety monitoring deficiencies; problems with the chem- istry, manufacturing, and controls (CMC) aspect of the IND; and inadequate study design or criterion for objective assess- ment of outcomes (Table 1). The FDA has specifically and publicly stated that many INDs go on clinical hold because the sponsor does not listen to or heed the advice given by the FDA in sponsor-FDA communications. Regardless of the reason, the result is delay in development time and additional costs for the sponsor.

Common manufacturing reasons for hold
• Deficiencies in starting materials, e.g., donor screening and testing, master cell/viral bank qualification, vector construction/ qualification
• Facility deficiencies?• Quality system deficiencies?• Deficiencies in reagents, e.g., human- derived, nonbiologic, biologic-derived, animal-derived?• Deficiencies in manufacturing, e.g., tracking
and labeling of patient-specific products, process, final formulation, justification of irradiation dose, segregation and prevention of cross-contamination
• Deficiencies in testing, e.g., sterility, endotoxin, mycoplasma, viability, adventitious agents, replication-competent virus
• Deficiencies in stability, no shipping data, handling/manipulation at clinical site, action plan to mitigate manufacturing concerns, quality assurance/quality control, cross- referencing to files that have manufacturing concerns
• Product preparation or formulation inadequately described, lack of adequate product description

UNTIL DCVAX-L new manufacturing vendor (CTU (really the BRC)) is qualified and validated by regulators -- for both the trial and compassionate use -- the Company will NOT be able to screen additional patients. The Company may have elected to stop screening on their own, but the clinical trial will technically need regulatory approval to LIFT the clinical hold and begin screening again. IT IS THAT SIMPLE!

One last thing. Sure, I suspect that the new manufacturing hub will be cleared in their new TFF patented method "enriched leukocytes". But that doesn't mean I think the study officially stopped recruiting over PATENTS. Instead I see that the Company likely elected to stop screening in Europe, just shy of enrollment completion, to reserve a few patients to enroll months later. They pursued the patents, while they were simultaneously trying to get a new manufacturing hub approved. Fraunhofer IZI likely does not have the capacity to remain DCVax-L supplier for manufacture scale-up testing or for any subsequent clinical testing. That manufacturing space is not dedicated in any way to DCVax-L, as evident by their SEC statements:

In addition to the rigorous regulatory requirements, our DCVax programs involve a particularly challenging operational and business requirement: our programs require a large amount of capacity in these specialized manufacturing facilities, and require that the large capacity be dedicated exclusively to our programs. Most medical products, including cellular products, are made in batches on a campaign basis. The same manufacturing suites are used for a number of companies’ products, at designated times scheduled in advance. In contrast, our products are fully personalized and can only be made in individual personalized batches, not large-scale batches of standardized products, and our products are made on demand, on an ongoing basis. So, the manufacturing suites must be dedicated entirely to NW Bio’s products. Among the few specialized contract manufacturers for cellular products, even fewer have the necessary capacity that can be dedicated exclusively to NW Bio.
 

Cognate BioServices’ manufacturing facility for clinical-grade cell products is located in Memphis, Tennessee, a major air shipping hub for both Federal Express and UPS. Cognate BioServices' facility is approximately 80,000 square feet and contains substantial expansion space in addition to the portions currently built out and in use. The current manufacturing facilities are sufficient to produce DCVax for at least several thousand patients per year - an amount well in excess of what is needed for the Phase III clinical trial under way. The expansion space will also allow us to procure significantly increasing capacity as we scale-up towards many more patients for commercialization. The facility planned for the U.K. will similarly allow for scale-up there.
 

We have entered into an agreement with King’s College London to manufacture DCVax for our clinical trial and our compassionate use cases. Cognate BioServices will manage and supervise the processing in London. In addition, in Germany our partner, Fraunhofer IZI Institute in Germany, has received approval and certification from the regional and national regulatory agencies in Germany for the manufacture of DCVax for GBM. Fraunhofer IZI also received the necessary regulatory approvals to supply DCVax-L products to the U.K. for our clinical trial there. We anticipate that the manufacturing facilities in the U.K. will eventually obtain the necessary approvals, and that the German and U.K. facilities’ will be able to supply DCVax products for anywhere in Europe; however, this may not turn out to be feasible, for regulatory, operational and/or logistical reasons.

Therefore, it makes sense for the Company to finalize negotiations with a new MANUFACTURING HUB. CTU facilities have state of the art genome testing and a tissue biobank; and CTU being a relatively young trial manufacturing hub, they probably can provide more dedicated space to the DCVax platform.

In my view it would be a strategic pursuit to attempt to make the manufacturing change, while also simultaneously pursing the patent appeals process. If timing worked out, why not try to get them finished around the same time and then reserve a few patients to test it on? I know I would. Their new TFF patented methods are said to reduce their manufacturing cost. And since cost plays a big factor in payor reimbursement negotiations, it would be a smart move for the Company to get the method okayed for use in all DCVax-L patients ahead of HE roll-out. Those last few enrolled Phase III patients (of the 348-patients needed) will probably not even affect the study outcome in any way. However, once enrollment is officially complete, the Company will only be allowed to treat those compassionate patients via methods that were cleared for the Phase III trial. Anyway, I can’t seem to understand why some find this hypothesis so far fetched. But, I guess I should be used to it by now. I particularly wanted to make it clear that I never said the study was stopped over "patents". I stated they elected to stop shy of enrollment completion to reserve some patients to be enrolled using this TFF manufacturing methods if they could get it approved somehow. Hopefully my posts around "patents" will no longer be construed out of context but somehow I doubt that. GLTA