NorthWest Biotherapeutics Inc (NWBO)

[ae kusterer]

Larry Smith responds to the question posed in 437257 with peceptive intelligence.

https://smithonstocks.com/northwest-biotherapeutics-fda-statement-regarding-use-of-external-controls-in-clinical-trials-is-a-huge-positive/

Northwest Biotherapeutics: FDA Statement Regarding Use of External Controls in Clinical Trials is a Huge Positive
POSTED by LARRY SMITH on JAN 21, 2022 • (0)

((https://www.annalsofoncology.org/article/S0923-7534(22)00006-0/fulltext#%20)

I put out a blog last week alerting subscribers that I am writing an update on Northwest Biotherapeutics. I continue to work on this report and hope to have it out soon, but I am compelled to address some late breaking news beforehand. As the report stood yesterday, I was highlighting as a major uncertainty one aspect of the Statistical Analysis Plan (SAP). Northwest has specified in the SAP that it will compare results of DCVax-L plus standard of care (SOC) from the phase 3 trial in newly diagnosed glioblastoma ndGBM to SOC results from other phase 3 trials in ndGBM that were conducted in the same time frame as the DCVax-L trial. This use of external controls was unthinkable some years ago as statistical purity demanded that patients enrolled in a trial be randomized so that some patients were randomized to active drug added to SOC and others to just SOC. Cross trial comparisons were unthinkable.

This aversion to use of external control has been eroding in recent years as the FDA began to consider that use could speed development of breakthrough drugs. As an example, the CAR-T drugs were initially approved on the basis of phase 2 trials that had no control arm and essentially relied on external controls. However, the FDA had not taken a formal position on external controls. Short sellers have stridently maintained that the FDA would not even consider the phase 3 trial of DCVax-L because it uses external controls so that the trial was doomed.

Based on the example of the CAR-T drugs, I was reasonably certain that the FDA would accept external controls. My confidence was also buoyed by action by the MHRA, the UK equivalent of the FDA. On its website, it indicated that it would accept NWBO's SAP use of external controls. Still, there was no clear signal from the FDA on whether it agreed with the MHRA decision. Yesterday, it issued a statement that clarifies its position on the use of external control arms in oncology trials. I include the statement from FDA at the tail end of this note. It makes clear that for the first time that I am aware of that the FDA will consider and probably allow the use external controls to evaluate the DCVax-L trial. It was signed by 13 FDA officials including Richard Pazdur. He is key player at the FDA as shown by a brief FDA bio which is also shown in the back of this note.

This is an extremely encouraging development for Northwest that comes on the heels of an equally exciting announcement that the MHRA had GMP certified the Company’s Sawston, UK plant for production of DCVax-L for compassionate use. It is clear from the FDA statement that any company using external controls in a regulatory submission will have to rigorously address issues about the external controls. In the case of DCVax-L, Northwest will have to address numerous issues in the external control arm such as methylation status, IDH mutations, degree of surgical resection and so on. It will have to convince the FDA that patients in the external control arm are medically comparable to patients treated with DCVax-L plus SOC in the phase 3 trial. This is a difficult challenge for NWBO and I suspect that gathering this information has been a major factor for the Company not yet releasing topline data from the phase 3 trial in which the data lock occurred on October 5, 2022.

FDA Statement on External Control Arms in Oncology: Current Use and Future Directions

S. Mishra-Kalyani
Amiri Kordestani
R. Rivera
Singh
Ibrahim
A. DeClaro
Shen
Tang
Sridhara
G. Kluetz
Concato
Pazdur
A. Beaver
If tumor response cannot be reasonably measured due to disease characteristics (such as in certain neuro-oncologic tumors) or there is interest in estimating a comparative treatment effect within the population of interest, approaches have been explored to supplement single arm data with data external to the clinical trial, also referred to as an external control arm.

A fit-for-purpose assessment is necessary as data source quality and granularity varies. Best practices for study design and statistical analysis plans are not yet defined and challenges exist. Despite these challenges, marketing applications in oncology have included trial designs with external control comparator arm(s). The adequacy of the external control data has been variable based on the quality and it being fit-for-purpose in a comparative analysis.

Ventz et al considered the use of data from both previously conducted clinical trials as well as RWD for an externally controlled trial to understand treatment effect on OS in glioblastoma multiforme (GBM). The authors advocate for the use of several sources of external data to assess and potentially reduce potential bias, provide complete time-to-event data, and retain sufficient power when comparing to traditional randomized control trial designs.

Additionally, the 21st Century Cures Act has led FDA to develop a framework for evaluating the quality and relevance, also referred to as fit-for-purpose, of real-world evidence (RWE), such that it may be incorporated into regulatory decision making.

Potential applications may include a study design for a clinical question where the natural history, morbidity, or mortality of the disease is well characterized, highly predictable, the expected effect size of the investigational treatment is high, and the outcome precisely measured.

It is important that selection of data eligible for an external control arm is transparent and traceable with an audit trail available for FDA inspection.

A pre-specified statistical analysis plan for any study that incorporates external control data increases the integrity of the data analysis and results. The analysis plan should include statistical methods to account for various types of potential bias, including major threats from lack of randomization (e.g., selection bias) and confounding amongst others. An assessment of the similarity of the patient populations in each arm using pre-specified criteria to measure balance [16, 17], before and after any statistical procedures or adjustments could further minimize the concern of bias. These comparisons of the populations of interest before and after analytical adjustments to account for bias and confounding are ideally conducted prior to the analysis of any outcome data.

To date, no primary efficacy analysis of a study used to support approval of a marketing application in oncology has included a formal comparison to an external control arm.

In the future, it is possible that formal analyses for comparative treatment effect between an investigational therapy and an external control arm would provide the primary evidence of efficacy to support a regulatory approval in oncology, particularly for a disease type with a highly predictable natural history and the precisely measurable treatment effect.

Importantly, the granularity of the data with respect to measurement or categorization of important variables is not trivial, and must be similar between experimental arm and external control data to ensure comparative analyses.

Bio for FDA’s Richard Pazdur

Richard Pazdur, M.D. is the director of the FDA's Oncology Center of Excellence (OCE), which leverages the combined skills of the FDA's regulatory scientists and reviewers with expertise in drugs, biologics and devices to expedite the development of novel cancer products. In his role as director of the OCE, Pazdur is responsible for leading the effort to develop and execute an integrated regulatory approach to enhance the cross-center coordination of oncology product clinical review.

Pazdur previously served as the director of the Office of Hematology and Oncology Products (OHOP) in the FDA’s Center for Drug Evaluation and Research and will continue to serve in OHOP as acting director. This Office was formed in 2005 to consolidate the review of drugs and therapeutic biologics for the diagnosis, treatment, and prevention of cancer, as well as the review of drugs and therapeutic biologics for hematologic diseases and for medical imaging. As director of OHOP, Pazdur facilitated coordination of oncology activities across all FDA Centers and ensured an ongoing outreach and collaboration between the FDA, the National Cancer Institute, and other cancer-related organizations within and outside of the government. Pazdur was the director of the Division of Oncology Drug Products from September 1999 to May 2005.






Tagged as Northwest Biotherapeutics Inc. + Categorized as Company Reports, LinkedIn
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ae kusterer Thursday, 01/20/22 09:38:45 PM
Re: None 0
Post #
437257
of 437335
Corrected copy.


ATLnsider: Is ((https://www.annalsofoncology.org/article/S0923-7534(22)00006-0/fulltext#%20) the first time that the FDA has issued an official edict that "external controls" can be used in trials such as NWBO's P3/331 patients/ GBM to calculate whether control versus drug achieved statistical significance in meeting the endpoints ?

I think it's possible that NWBO's supporting parties wanted to be sure that Linda Liau's slide showing 7 failed GBM trials averaging 16.3 months MOS would be accepted by:investment bankers , the major journal, global regulators, health care payers, etc.

Now that (https://www.annalsofoncology.org/article/S0923-7534(22)00006-0/fulltext#%20) has been published , the building blocks of a big company can get accomplished: journal, BLAs, combo trial partnerships, manufacturing contracts with CRL, $1 billion financing (at above $8.00 oer share), etc.


My operative efficacy assumption for DC Vax L in the P3 trial is that MOS will be 25 months or more, and Dr.Ashkan's 1/3 of those dosed living 7 to 8 year will be corroborated.



https://clinicaltrials.gov/ct2/show/NCT00045968?term=northwest+biotherapeutics&draw=2&rank=3


https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-001977-13/DE
https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-001977-13/GB (UK)
clinicaltrialsregister.eu



ae kusterer Thursday, 01/20/22 08:21:16 AM
Re: None 0
Post #
436886
of 437254

TOPIC:(https://www.annalsofoncology.org/article/S0923-7534(22)00006-0/fulltext#%20)






ae kusterer Wednesday, 01/19/22 10:57:37 PM
Re: ATLnsider post# 436826 0
Post #
436840
of 436887
ATLnsider:Corollary question: Could it be that NWBO management wanted to see today's FDA paper on external controls
(https://www.annalsofoncology.org/article/S0923-7534(22)00006-0/fulltext#%20)
published before the publication of the DC VAX L phase 3 trial's scientific paper ?



ATLnsider Wednesday, 01/19/22 11:17:24 PM
Re: ae kusterer post# 436840 0
Post #
436842
of 436886
ae kusterer, I don’t think that NWBio was waiting for this article, because I believe that NWBio has been having direct discussions with the FDA in 2018, 2019 and 2020, about the DCVax-L Phase IIII trial interim results, and the fact that about 86% of all of the trial participants (treatment group & the control group) received DCVax-L.

I believe that the DCVax-L Phase III trial revised SAP and new Primary and Secondary endpoints were drafted as a result of NWBio’s discussions with the FDA, and guidance given by the FDA.


ATLnsider Wednesday, 01/19/22 10:11:03 PM
Re: ae kusterer post# 436773 0
Post #
436826
of 436885
Yes, in fact, I believe that because of the crossover issue, and the fact that it was unethical (lack of clinical equipoise) to continue randomizing GBM patients to the control group, it was Dr. Pazdur and the FDA who suggested to Dr. Linda Liau and to NWBio that they use external control arms (ECAs) in the revised SAP for the DCVax-L Phase III trial, in addition to the randomized control group in the trial.

I also believe that the FDA was the first regulatory authority to give NWBio buy-in on the new SAP that revised the Primary endpoint to compare the DCVax-L trial treatment group OS, to the OS of ECAs. I believe NWBio was waiting for the UK, and Germany (EMA) to buy-in to the revised SAP and the use of ECAs.

NWBio announced data-lock on October 5, 2020 which indicated that NWBio had finally gotten buy-in to the use ECAs from all 4 regulatory authorities. Then on October 8, 2020 (3 days later) we discovered that the clinical trial registry in the EU (for the UK) had been updated to show the revised Primary and Secondary endpoints.



biosectinvestor Member Level Thursday, 01/20/22 02:25:58 AM
Re: ATLnsider post# 436826 0
Post #
436853
of 436885
I have also generally believed the same ATL, that The FDA likely made the suggestions re external data, likely from consultations. I believe that the issue was an ethical one in regards to the control group, and also a cross jurisdictional regulatory issue that the Germans likely initially raised in terms of the ethics of the control arm. I believe they also likely were taking the FDA's suggestions regarding external control arms but I also seem to be finding that the FDA is behind the UK on implementing new reforms intended to make a lot of this much easier and in fact the MHRA seems a bit ahead on using real world data, in terms of final guidelines and finalizing their external data guidelines.

But I agree that the FDA is their primary regulator and likely all of their efforts to change things broadly have come directly from discussions with the FDA. That is my experience in a global context where multiple national regulatory agencies are involved and the largest market and biggest regulatory hurdles are in the US for reaching a given market.

That totally makes sense to me. The company seems to be giving lots of hints though to others, I do not typically talk to anyone because I think it can blur clear vision on my investments, but the hints seem to suggest that they may go with UK first. Certainly situating their manufacturing there and focusing as much as they are on the compassionate use program, it is suggestive.

But my general view, absent consideration of what people are telling us that the company is saying, and my recent review of UK regulation (which was quite favorable), would be that the FDA would be the primary regulator and focus for a company in NWBO's circumstances. But the new reforms plug in even at MHRA into Project Orbis, and extend the approvals even beyond Project Orbias via the UK's relationships. So it will be interesting to see where the focus and where it all is going right now. The potential there in the UK, if results are as many of us expect and hope, is for potentially very fast approval, and hopefully the same is true for the FDA.

All IMHO. Not advice, just my own opinions.