NorthWest Biotherapeutics Inc (NWBO)

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Interestingly, it seems those three “requests for extenstion” are (I believe) from the lobbyist groups:
Pharmaceutical Research and Manufacturers of America (PhRMA),
Biotechnology Innovation Organization (BIO), and the
Alliance for Regenerative Medicine.

Perhaps some our investors here may want to consider making a comment as well, because certainly individuals are also able making their thoughts known to the FDA. This represents your chance to be actually be heard, and to have others hear you, should they choose to review the comments.

If you’re interested in commenting yourself on the actual recent FDA guidance document, then click the link below, scroll down a bit, then click the link to the left in blue, stating:

Submit Comments Online

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/demonstrating-substantial-evidence-effectiveness-human-drug-and-biological-products

… which will take you to this page:

https://www.regulations.gov/docket?D=FDA-2019-D-4964

The top listing is the FDA guidance document I’m referencing:

Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products; Draft Guidance for Industry; Availability

Hit the “Comment Now!” button to the right of it.

This will take you to the comments page, where you are allowed 5000 characters to comment directly into the comment box. I’d recommend that you draft your comment first in something like word, and then copy and paste it here.

If you prefer to be more formal, you can also attach a pdf of a letter, if you choose.

The comments section does ask for your first and last name.

It looks like you have a also choice as to whether to give your contact information.

Finally, the section asks that you identify yourself as an academic, or an individual, or industry.

This Guidance has until February 18, 2020 for comments.



Below is the link to the download button to read the actual guidance.
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/demonstrating-substantial-evidence-effectiveness-human-drug-and-biological-products

If you are interested in making a comment, I’ve listed below several topic areas that I found interesting about the guidance. You might want to browse through them and see if one or a few interest you enough to consider commenting on the guidance. I do think it would be helpful if some of us did do this, and we certainly have some time to draft what we might want to say. We often state our opinions on this board, so now there is an opportunity to state your opinion on another board.

Topic Ideas

Flexibility in Evidence
A flexibility in the rules of what is acceptable evidence will help get efficacious treatments to market sooner. If one were interested in making a comment on the Guidance, one of the more obvious subjects would be whether you think the evidence of effectiveness could stand for some more flexibility on the part of the FDA, as this guidance suggests they are willing to be. The cost of drugs is a topic that comes up daily in the media, and likely effects many of us as individuals. One of the reasons drugs are so costly is due to the methodology currently used to judge these therapies. But if a treatment or a drug is indicating it’s efficacy, AND it is safe, OR EVEN BETTER, non-toxic, relaxing these rules and speeding up the approval process would lessen the time and cost it takes to get a drug to market; hence, resulting in a lower cost to treatment for the patient.

Quantity of Evidence
Two adequate and well-controlled trials (that prove efficaciousness) has generally been what is required for an approval. Do you think that under certain circumstances (especially when safety has already been proven), the FDA should consider instead one large, multi-center trial to satisfy this requirement? Do you think it’s all right to add on confirmed evidence (obtained prior or after the investigation) to the single multi-center trial as opposed to running an additional second trial? The guidance is suggesting that when the trial is a large multi-center trial (the DCVax trial has over 80 clinical sites), the trial is less vulnerable to selection or measurement biases, and are often more consistent to the intended population across subgroups, centers and endpoints.

Additionally, multi-center trials that have multiple arms (DCVax has the info arm, the pseudo arm, the main arm, which can be divided into true control, early DCVax and late DCVax treatment, AS WELL AS the expanded access open arm trial consisting primarily of rapid and pseudo progression patients) and can often be appropriately analyzed as multiple trials within a trial.

From the guidance:
An example is a 4-arm (“2×2 factorial”) trial (placebo, drug A, drug B, and drug A + drug B) in which the effectiveness of drug A could be supported by two controlled comparisons if the combination of drug A + drug B is superior to drug B alone and drug A is superior to placebo.

I wonder, could DCVax Early be seen as a Drug A, and could DCVax Late be seen as a drug B?

Externally Controlled Trials
An externally controlled trial is where the treatment group is compared with a group of patients external to the study. In the case of DCVax, this would mean comparing the treatment arm (either all those who received DCVax late or early, or splitting them) with another set of patients external to the trial who reflected the same characteristics (age, scores, complete resection, etc.). This type of trial is usually reserved for those diseases with high and predictable mortality or progressive morbidity.

This FDA guidance is suggesting that when the external control population is very similar to that of the treatment group AND the natural history of the disease is well-defined, such a trial could overcome challenges associated with this type of design IF the outcome is markedly superior to the well-established natural history of the disease.

A single arm trial that utilizes a cross-over trial, depending upon the circumstances, can be considered an appropriate option as a trial design when paired with an external control, especially when the treatment is intended for rare disease.

Interestingly, this guidance seems to suggest that sponsor design their first-in-human trials to be adequate and well-controlled with THE POTENTIAL, depending upon the trial results, to provide part of the substantial evidence of effectiveness to support a marketing application. In other words, should the Mayo Clinic Direct trial in cancer metastasis to the brain demonstrate substantial evidence of both safety and efficacy… perhaps that data would support a marketing application.

643 Sponsors of drugs intended for rare diseases should consider designing their first-in-human to be an adequate and well-controlled clinical investigation that has the potential, depending on
the trial results, to provide part of the substantial evidence of effectiveness to support a marketing application.33

Confirmatory Evidence
Is one adequate and well-controlled trial PLUS confirmatory evidence sufficient to establish effectiveness? The FDA is suggesting they will consider factors such as the persuasiveness of the single trial, the robustness of the confirmatory evidence, the seriousness of the disease (especially where there is an unmet need), the size of the patient population, and whether it is ethical and practicable to conduct yet another adequate and well-controlled clinical investigation.

Confirmatory evidence could include:

• adequate and well-controlled clinical investigations in a related disease area

• certain types of real world evidence (like extensive data on outcomes that provide further support for the lack of effect seen in the control groupie the randomized trial)

• compelling mechanistic evidence in the setting of well-understood disease pathophysiology (note: pseudo progression is a pathophysiology; unfortunately, in past years, it’s not been particularly well-understood; however, I’d suggest that it’s becoming much more understood),

• well-documented natural history of the disease

• scientific knowledge about the effectiveness of other drugs in the same pharmacological class (it’s doubtful that this would apply to DCVax due to the legal issues and reliance on the owner of the other pharmaceuticals allowing use of their data - see the footnote on page 12 of the guidance).

From the guidance regarding the well-documented natural history of the disease:

In certain circumstances, FDA accepts one adequate and well-controlled clinical investigation that has generated compelling results as the basis to demonstrate effectiveness, when the single trial is supported by additional data from the natural history of the disease that reinforce the very persuasive finding. For example, a single trial showing marked improvement in survival compared to a control group, either external to the trial or concurrent, could be supported by data from separate sources (e.g., a natural history study, case report forms, or registries) that demonstrate a very limited median survival time or other clinically highly important outcome without treatment. In this case, the natural history data would represent confirmatory evidence.

If you think that using confirmatory evidence is an appealing idea, especially in the case of a brutal cancer like GBM being treated with a safe, non-toxic such as GBM, this natural history of the disease as confirmatory evidence may represents a topic of the guidance you might want to consider commenting on.

P Values
If a trial is for a serious disease with no available therapy, or a rare disease (less than 200k in the US) where sample size might be limited, a somewhat higher p value, if pre-specified and appropriately justified (perhaps in an SAP?) might be acceptable to the FDA.

Allocation to Placebo
Equal allocation is considered generally the most efficient to measure effectiveness, however, an unequal allocation where more patients receive the new drug than the control thereby providing additional safety experience and reduction of placebo.

So if you feel so inclined to comment to on the Guidance to the FDA, again, you may want to consider doing so. If you think that this would help GBM patients receive a safe treatment like DCVax more quickly, this represents an opportunity for your voice to be heard at the FDA.

It’s difficult to know what or how the lobbyists representing other pharmaceutical companies who are requesting additional time to respond might eventually come back and comment. Will they let this guidance slip through, especially if they aren’t given more time to respond? Could they consider some of the suggested flexibilities reflected in this guidance are actually good for them as well?

Anyhow, I’ve tried to cover most of the topics I found appealing and possibly relevant to DCVax in this guidance in this post. Of course, if you’re interested in commenting on the guidance, you should pick the topic(s) that most interests you, and comment on it as you see fit. If you know of someone who has had or has GBM, or another type of cancer (say that L or Direct could help with), you may want to remark on how this guidance appeals (or doesn’t) to you on a more personal basis.

Anyhow, your post made me want to respond in this manner, and to make the suggestion that some of us may want to take this opportunity to comment on the FDA site about the guidance.

If enough of us are interested in writing supportive comments, and actually follow through on that interest, it certainly will help to inform the FDA that there are plenty of people who support them in their efforts to be more flexible in their consideration of what is appropriate evidence as they've indicated with this particular guidance.