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We may be overdue for our long established practice of management by example. I remember the story of the quality manager in an Asian refrigerator manufacturing site. The site was shipping an unacceptable number of defective devices. The story goes that the quality manager was taken out to the parking lot and executed. All defects stopped. Here, we just lock them up.
[quote I could only watch it 10-15 minutes at a time][/quote]
I had identical reaction, overwhelming. The stats are mind blowing but credible. I accept about 70% on the face presentation w/ credibility of presenters, particularly the academics. The big P stats/links w/Medical DR's are intuitively correct based on my own experience and real life. The scope and $$$value of the corruption all fits w/recent learnings from DC. I often wondered how poor boys/girls could go to DC and within years become multi-millionaires, now I get it. The synched up Amyloid moves by BP make sense when this context is provided. Tip of the iceberg...we hope.
all faults are FDA and all other pharma companies and cabal are after AVXL
This is not about blame. This about an effective problem solving process (or not) being established(developed... written)and used by the FDA. I know of many really smart/hard working FDA people. They are really usually very good at doing what they are told to do, that Is their job. Look at the historical results in CNS disease for last two decades. Look at the chart posted by Xena. Review/watch the link posted by Investor2014. This is not a friggen game.
In summary: We should not be surprised there is no effective treatment for many CNS diseases even after decades of spending/efforts. Seriously, the issue here is that Dr. M. and others like him are somehow left to their survival skills training to succeed, in spite of the millions of patients in need. Many patients are relying on the equivalent of bake sales (3rd party orgs) while BP has continued to produce stuff covered w/warning labels while they pocket zillions $$$. All while we wait for (who knows) to agree on simple IND trial plans. The process is broken.
We may never know with any level of integrity what REALLY happened in BP over the past decades of AD trial and error or other CNS failures. Somehow, we should make sure that never happens again. Science should, if nothing else, insist on integrity.
Thanks Xena...I have a question...mostly rhetorical. When I read statements like the one quoted here I ask. Just exactly WHO IS RESPONSIBLE to FIND and effective AD treatment? The FDA always says...(it ain't me) w/o actually saying that. They will say things like below, and we let them get away with it.
Susan Mayne, the director of the F.D.A.’s Center for Food Safety and Applied Nutrition, disputed this characterization, pointing out that the agency has worked to get trans fats, which increase the risk of heart disease, out of foods. She added that the F.D.A. is actively monitoring the microbiome research but the science is still in “earlier stages.”
Who really OWNS/IS RESPONSIBLE FOR finding a treatment that is effective? Who gets paid to do that? Does their job description hold them directly responsible for REAL MEASUREABLE progress?
We have lots of comments here which seem to hold Dr.M. responsible for establishing an effective process and putting it in place which will with confidence lead directly to finding an effective treatment. OK, I guess that sort of comes w/the turf. REALLY? The FDA did authorize and spend lots of resource (read tax payers money) supporting the whole Amyloid effort for decades. We have seen recently that effort is now on a back burner somewhere. Was anyone fired?
Not to start a circular debate here but does anyone REALLY understand who is responsible to fix this and other CNS diseases? B/C if it is Dr. M. he needs staff/resources/support from NIH/FDA and the established authority. If they(the regulators/politicians) are serious about this they better act like it.
The hand wringers and the observers need to get out of the way and to support/enable the people with real ideas and solutions. The current system seems to support and reward mediocracy. Precision medicine as a fight song sounds good but it must not be used as an ongoing excuse, such as...the FDA is working on it. None of us is going to live forever, if not now-WHEN? Time's up, go out and kick some ass.
If you read the paper it is CSF and PET scans detecting levels of Aß42 and the transition from CSF high levels and PET scan normal levels to CSF high levels and PET scan high levels that the authors found as indicative of early stage AD.
This was not a study discussing treatment, only early diagnosis based on biological factors.
And...
Depending on the tool suite capabilities, R&R it might prove useful in clinical testing and reverse engineering during trials even to support RWE.
It should disturb everyone, greatly, that an inept bureaucracy, that can’t even get its act together, is calling all the shots
After some study during the past couple of years I have (more or less) concluded the same thing. IMO, when this CNS treatment process finally gets cleaned up it will not be b/c of the FDA.
IMO, a learning process driven by peeling back the steps/sequence (gradual/spontaneous) by which cognition is snuffed out is critical. The reverse engineering of the whole sequence will certainly get us to the root cause. If M. is correct and the restoration of CNS cellular Homeostasis suggests cognitive health and behavioral normalcy then this kind of imagery might be used to validate such a correlation and to verify restoration. We would expect any restoration would vary from pt to pt measured over time/compared with controls of course. Using reverse engineering techniques/thinking keeps the ball on the field all the time, we expect to see the cause/effect virtually real time. If AD is progressive w/time then the reverse must/might also be true. There has been anecdotal evidence that some AD pt's recover, but what about the rest? Does partial restoration count, how is it measured? RWE/PET and cognitive testing will certainly be factors in AD future trials testing.
I declare as a volunteer for the continuous frat boy control branch of the trial.
Sponsors must give the Agency adequate information to thoroughly critique the SPA and decide if it addresses the key scientific concerns. Therefore, any potentially problematic features of the study protocol should be addressed with sufficient information for the FDA to come to a consensus.
Despite the provided justification, the FDA does not always agree that the submitted protocol will satisfy all questions. Subsequently, a nonagreement letter can be issued. When a nonagreement letter is reached, the Sponsor has three general options. They can initiate the clinical trial without an agreed upon SPA, send a written response to the FDA regarding the nonagreement letter, or request a meeting to discuss the nonagreement letter. To ensure the most effective utilization of resources, reaching an agreed upon SPA is recommended before initiating the clinical trial. Depending on how many outstanding protocol issues are presented, a meeting or written response may be preferred.
The significance of the RETT trials continues to grow every day. No wonder they kept going w/the amyloid plaque trials even though a child could see they went no where. Powerful AI and strong intervention skills will be needed here.
[quoteBiogen just adapted their amyloid drug study by adding more patients ][/quote]
Thanks doc. Like the man said. "Tip of the iceberg". Very much appreciate your contribution I understand you to say that this is going to take a while and there is no, "one size fits all" solution.
At some point the science must be tested*. When that happens (* tested means under established controlled conditions ) the smoke will begin to clear. On days like today I am actually happy I do not have the level of scientific knowledge of Falconer/Doc and others. I used to tell a brilliant friend and 820 product sterilization expert that I was happy I did not know what he knew b/c I could not sleep at night if I did.(we all assume that products labeled STERILE have been correctly processed) Again longs were compelled to be civil while being attacked. I remain thankful for the 15# post limit on iHub.
Better days are ahead for certain, baseball season has begun, the Red Sox are going to kick the NYY ass all season and eventually little Rett patients will get a shot at a better life. All the best.
In fact bio investment (waiting for trials) pass/fail bungee investor reflex will be gone. IND trial agreements/starts will eventually be equivalent to strong P2/3 results if not more. B/C of the new scrutiny done by sponsors and regulatory. Will not be same ole FDA guidance. All this work will migrate to the sponsors process left where it should have been all along. IMO you are correct. If RWE IND patient comm. gets hacked then we will see SP chaos. Less (maybe no) emphasis on long term massive statistical models which accomplished nothing till now except cover some committee hacks ass.
BUT, if AVXL IS worth what clinical evidence indicates is possible then the SP will reflex faster than the hackers can anticipate. IMO. But, it WILL drive SP chaos for sure.
T-38...thx again for all you have done and for your over the horizon insights.
We must appreciate the scope of the AVXL task. We are presented with either one massive binary event (a true OMG moment) leading to effective treatments or an old school BP/WS CFIT. All the best.
Doc...thanks for grounding all of us in the reality of dealing w/regulatory bodies during times of change. Can you say ,in this context, how the new "precision Medicine" trials rules are being developed/applied. Are these guidance or are they requirements being applied to the first trials and how is RWE being treated? If new learning occurs which change the trial plans, do they stop/go back and restart or evolve as they go? TIA
How does an enterprise establish a IND protocol with these process controls in place?
Type B meetings are as follows:4
• Pre-investigational new drug application (pre-IND) meetings (21 CFR 312.82)
• Certain end-of-phase 1 meetings (21 CFR 312.82)
• End-of-phase 2 and pre-phase 3 meetings (21 CFR 312.47)
• Pre-new drug application/biologics license application meetings (21 CFR 312.47)
Type B meetings should be scheduled to occur within 60 days of FDA receipt of the written meeting request. If a sponsor or applicant requests a meeting date that is beyond 60 days from the date of request receipt, we will work with the sponsor or applicant to determine the earliest agreeable date.
To promote efficient management of formal meetings, the requestor should try to anticipate future needs and, to the extent practical, combine product development issues into the fewest possible meetings. Generally, we will not grant more than one of each of the Type B meetings
[quote“As clinical trials become more virtual, sponsors will be able to ‘dial in’ what capabilities they want virtualized,” he said. “This new Apple feature will enable new capabilities that were not possible before.”]
Can you imagine trying to do a config mgmnt validation to comply w/part 11 under on the fly/cloud based clinical system?
Are Apple iPhones a key to the progress of our future trials?
On the other hand this results path is absolutely consistent w/RWE concepts. Who will own/validate trials results? How will FDA use this trials data to do pass/fail? What could go wrong?
The reported conversation with IR on IND status is very encouraging news. Some of us have suggested a scenario similar to the one described by IR. A study of what has been published by the FDA on new IND-Precision Medicine protocols also indicates we are doing what was expected working with the FDA. We could not predict how much time would be required to do the back-forth planning/critique but months(not weeks) are to be expected. Anyone with any FDA interface experience can see what is being done. Extreme caution must be exercised at the trials expectation/RWE/PR-news interface. The work must be done well and it must be reproducible. Expense and time must be forecasted while day to day conflicts are resolved. Conflicts galore.
Go look at what the FDA has already released on the topic (we have posted the links here a while back with discussion). The FDA has established a structure/framework of the trial design with required checkpoint with emphasis on what not how and RWE-patient interface-takeaways. It all reads to me like they expect tp rely heavily on pts/RWE and being as flexible as possible in interpretation. Nothing at all like conventional FDA trials. What would be unknown at this point is what clinical/pts evaluations must be done, at what point in the protocol, what will/must be measured and when, what pass/fail acceptance criteria (if any) will be used and when applied.
We must keep in mind that these CNS diseases have NEVER been effectively treated. Even though pre trial information establishes basic expectations no one has ever been here before. Not only do we need results to be precise and meaningful but we better not make an error b/c the entire pharma world has just had it's collective ass handed to it. We can intuit that something very important will eventually come from this molecules testing. Let's hope it is soon but sadly we have no way of knowing when or what. I do believe that some very exciting science is about to demonstrated.
Varian Medical Systems has projected that by 2022, approximately 15 million patients will be affected by metastatic brain cancer. According to DeSantis CE’s cancer treatment and survivorship statistics for 2014, 20%–40% of those total cancer patients have brain metastases. These factors highlight a growing demand for stereotactic radiosurgery solutions for treating brain metastases. That, in turn, is expected to accelerate the buying of new and the replacement of older radiotherapy systems that will be fitted with the HyperArc solution. Additionally, upgradations of the company’s large TrueBeam Eclipse installed base are expected to be a key driver in increasing the adoption of the HyperArc solution. The company has projected the market opportunity for HyperArc to be $300 million by 2022.
...ever been to Singapore? YYYUUUUHHGGGE wealth and it is 80%+ Chinese. Don't look now but the Chinese ALREADY OWN just about everything. They just let us think we own anything. IMO, the "T" man get's it.
Xena..cannot do PM. Would expect Si3N4 -silicon nitride body of knowledge to be extensive (semiconductor guys have been all over the physics for decades) compared to CNS. Should be much lower risk than AVXL. Looks very solid.
Discovery of new levels of scientific knowledge that change the trial structure is not a "miss".
IMO, this point you make helps explain some/most of any back-forth between sponsor(AVXL) and FDA on Rett IND. We may never know for certain but we can speculate that the "Precision" process is doing what it should be doing, it is raising the bar. Another important consideration is no one has ever done this before. The term "Untreatable" is applied in the CNS disease space every day. The FDA and all BP have failed completely to after decades of their "best" efforts, etc.. The risks do not get any higher in investment.
References in other posts have been made here to quotes from famous martial arts leaders-poets. A favorite of mine is from Musashi, "Walk as a dead Man." As a samurai, fight as though you were already dead. The risk is so extreme you should assume your investment is already gone.
I think all the preclinical data being revealed as to sigma 1 r agonism restoring cell function and achieving homeostasis in a multitude of indications is a warning bomb and a big stick. I think the absence of data contradicting this or showing adverse effects means the big stick is made of strong wood which won’t splinter easily...when the time comes to use it
think all the preclinical data being revealed as to sigma 1 r agonism restoring cell function and achieving homeostasis in a multitude of indications is a warning bomb and a big stick. I think the absence of data contradicting this or showing adverse effects means the big stick is made of strong wood which won’t splinter easily...when the time comes to use it.
Bios...thanks for an excellent leadership post. The key points for me are as far as we know the science is real. There is still no contradictory scientific thesis. You make the point that Dr. M. cannot provide details b/c the size and strength of the opposition is too much to defeat head on. I had not considered that before and it is a legitimate point. Avoiding death in the military varies day to day but you better act like it is constant ,"act like a dead man".
He had a duty to "take his time" and get it right the first time, to assess the needs to get it right, to assess the pitfalls of the FDA, to submit a clean IND, and to get trials on the timeline HE set. He failed.
Name ANY organization that has filed IND since new FDA "precision medicine" requirements have been set.
Not an apology for M just trying to establish a meaningful context for this comment. Increased "precision" infers a more detailed factual assessment process. Looks to me like the rules/protocols are being rewritten. If any examples/facts exist it would be helpful to review them and in fact any relevant example could add credibility to your statements.
Got this from a site specific Google search use "m4 site:anavex.com":
Good effort, thanks. Still possible, still no contradictions. Can only imagine what the parents and caregivers for these little girls go through night and day. Makes one feel a little guilty for whining about lack of news/movement/progress/validation/verification/trials/test results ...anything that is not negative.
All we need is a solid-fact based set of objective evidence that the science has been validated again in some CNS context. Substantial but no need to be massive(would be great but), I'll go w/substantial and not a PR Puff piece only.
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