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Here is a bit more from that article that goes in to the FDA's thinking in more detail.
Given the very low SOC for AD maybe they would apply the one study consideration. Looks to me that will depend on how clinically meaningful the AD results are.
Back in the 1970s and 1980s, the US Food and Drug Administration (FDA) made clear that at least two adequate and well-controlled studies were necessary to establish a new drug’s effectiveness, except in only the rarest of circumstances.
Then in 1997, the Food and Drug Administration Modernization Act was passed, and Congress clarified that FDA may consider “data from one adequate and well-controlled clinical investigation and confirmatory evidence” to approve a new drug.
But in guidance from 1998, FDA says that its reliance on only a single study “will generally be limited to situations in which a trial has demonstrated a clinically meaningful effect on mortality, irreversible morbidity, or prevention of a disease with potentially serious outcome and confirmation of the result in a second trial would be practically or ethically impossible.”
The agency also explains the persuasiveness of using two studies versus one.
“Whether to rely on a single adequate and well-controlled study is inevitably a matter of judgment. A conclusion based on two persuasive studies will always be more secure than a conclusion based on a single, comparably persuasive study,” the guidance notes.
I agree with your reasoning.
However your calculation ignores the large number of options that Missling has.
Missling has closer to $800,000,000 riding on the success of out Rett an AD trials. That's a boat load of money!
On the subject of timelines. Bolding is mine.
Biotechnology Innovation Organization (BIO), another industry group, analyzed 9,704 clinical development programs over the course of a decade from January 2011 to November 2020. They found that, on average, it took 10.5 years for a drug to get from Phase I to regulatory approval.
Looking at individual stages of the process, the averages were 2.3 years for Phase I, 3.6 years for Phase II, 3.3 years for Phase III, and 1.3 years between Phase III and regulatory approval. According to BIO, a drug’s disease area impacts how long it takes to get to market. While 10.5 years was the average for drugs across all disease areas, averages for specific areas ranged from 9.2 to 12.2 years. At the lower end were drugs focused on allergic, metabolic, and infectious diseases. Meanwhile, drugs focused on neurological, cardiovascular, and urologic diseases had the longest development timelines.
Good question. Here is an article I found on the subject.
Approvals Based on a Single Trial
According to a 2014 JAMA study, between 2005 and 2012, FDA approved 188 novel therapeutic agents for 206 indications, and 74 indications (36.8%) were approved on the basis of a single pivotal trial.
Most recently, IQVIA released a report finding that 25 of 59 (42%) novel drugs approved in 2018 were approved on the basis of only one trial. And one out of eight approvals relied only on Phase 1 or 2 trials, with no Phase 3 trials. But as in previous years, a large portion of the drugs relying on only one trial were new orphan and cancer drugs.
For instance, AstraZeneca’s orphan drug Lumoxiti (moxetumomab pasudotox-tdfk) was approved in September 2018 based on one trial of less than 100 patients with a rare, slow-growing blood cancer. Stemline Therapeutics also won approval in December 2018 for Elzonris (tagraxofusp-erzx) to treat a rare, rapidly progressing cancer of the bone marrow and blood after conducting one trial of 94 patients in the US.
Other cancer drugs, meanwhile, won approval after larger single trials.
Pfizer’s Vizimpro (dacomitinib), for example, was approved in September 2018 on the basis of one clinical trial of 452 patients with advanced non-small cell lung cancer in Asia. Array Biopharma’s Braftovi (encorafenib) was approved, in combination with Mektovi (binimetinib) in June 2018 on evidence from one clinical trial of 383 patients with BRAF V600 mutation-positive melanoma that was advanced or could not be removed by surgery. The trial was conducted at 162 sites in Europe, North America and elsewhere.
And Advanced Accelerator Applications’ Lutathera (lutetium 177 dotate) was approved based on one trial of 229 patients with a specific type of rare tumor at 41 sites in Belgium, France, Germany, Italy, Portugal, Spain, UK and the US.
But not all the new drugs approved in 2018 based on one clinical trial were cancer treatments. For instance, Achaogen’s Zemdri (plazomicin) was approved in June 2018 as a complicated urinary tract infection treatment based on one trial of 604 patients in Europe, the US and Mexico.
Paratek Pharmaceuticals also won approval for its antibacterial medicine Nuzyra (omadacycline) in October 2018 on the basis of a single trial of 774 patients with community acquired bacterial pneumonia at 86 sites in Asia, Europe, Israel, Latin America, South Africa and the US.
But Kesselheim said he does not think this is a recent shift to the use of one pivotal trial, and he did not know if the 42% figure from 2018 “is a sign that the number is creeping higher or just normal year to year fluctuation.”
The IQVIA report also reports a slight uptick in the number of pivotal trials in 2018 being randomized controlled trials compared to previous years and that active control arms were more common in 2018 than recent past years.
The Changing Landscape of Research and Development
© 2023 Regulatory Affairs Professionals Society.
Due to the constant personal attacks you post, you have won the coveted position of ignore #13.
In fairness to Doc, Jin is operating with full information available to him. Doc and the rest of us are operating with very limited information from which to draw conclusions.
So the fact the the two come to different conclusions is not a big surprise to me.
I'll go with the person that has the full information.
According to the company the increase in the n was at the suggestion of the FDA. They wanted additional subjects so they could analyze the results within age sub groups.
His job was to check out that statistical presentation in the NDA and verify that it showed what the NDA claimed.
He didn't make the decision to approve it.
That decision was made at higher paygrades.
Anavex says this about Dr Jin.
Dr. Jin will draw on his extensive experience, including recently as the Statistical Team Leader at the U.S. Food and Drug Administration (FDA).
STFU Georgejjl
Guys arguing over P3 or P4 is meaningless.
Guys arguing over P3 or P4 is meaningless. If Anvex receives AA approval there will be a confirmatory trial. If that trial is started before AA is granted it will be labeled a P3 trial. If it is started after AA is granted it will be labeled a P4 trial. Either way there will be a confirmatory trial.
If Anavex is granted traditional approval there will still be a P4 trial, the requirements of that trial will be dictated by the FDA at that time. All approved drugs have some degree of a P4 trial. That P4 can range from just setting up tracking program for large number of patients to a full on controlled trial.
What you are arguing over is a label.
Two things. What you are referring to is the SAP Statistical Analysis Plan not the SPA which is a different thing entirely. Schmiggins has a good post on the differences. https://investorshub.advfn.com/boards/read_msg.aspx?message_id=172866337&txt2find=spa
Next is Rett will be the first NDA and the first approval. Rett will have a major impact on the company and most likely the share price before AD does. So, focusing on AD is to miss the important events on the calendar.
I took your suggestion today and sold 2,580 sh AVXL in my Roth and bought 17,800 sh NWBO. No loss of long term cap gains in a Roth.
I view this as a short term trade and plan to roll whatever funds I have from NWBO back into AVXL.
OS for NWBO is 1.1 billion shares which limits the up side considerably. Even so there is still 50% to 200% up side still possible with NWBO.
We shall see if that was a wise decision in the next few weeks.
Real time trade info for those keeping track.
AD is a year or more off. Rett is the item on the current agenda and it is looking very good.
You might want to consider that in your doom and gloom forecast.
Wow. You should be giving writing advice to AF.
Turns out the primary purpose of this board is to discuss and learn about Anavex and its drug trials.
Evaluating the various posters based on their postings and pontificating about them not so much..
The full answer to your question needs to know about how the two primary endpoints met their endpoints.
As I understand it, if both primary endpoints met the P<0.05 standard then choosing the more demanding 0.025 for one endpoint and the secondary endpoint would seem to be more stringent requirement indicating more efficacy.
If one end point didn't make the P<0.05 standard and the other primary endpoint did make the p<0.025 and the secondary made the P<0.025 standard then the results are just as strong i.e. the trial met endpoints.
As I see it, it's like this. Plan A met all endpoints and they chose Plan B which was more demanding to show efficacy. Or Plan A didn't quite make it and Plan B does meet the criterion for success so they went with Plan B.
I'm not really concerned about AD at this point.
AD approval is a minimum of 1 year away.
Pediatric Rett is THE important item on the list at this point in time.
The Rett NDA will be filed first.
Rett will generate revenues first.
Rett approval will move the AD partnering process along and increase the negotiating leverage Missling has.
You are out of your ever lovin' mind.
How long do you think it takes to write an NDA for a drug with a new MOA?
First, the company has plenty of money in the bank. More than enough to get "a very large P3 AD trial" started.
Second, trial costs are not paid up front, the costs ramp up over a considerable time frame.
Third, Missling is much better money manager than what you are suggesting. If he decided to raise more money he would do it over a period of time so not to drive the share price down.
Forth, most bio techs were down today. Sava was down almost as much on a percentage basis as Anavex.
I think you can read a bit more into Missling's choice on how to deal with that option situation.
He waited to exercise those options until he was forced to by the expiration date.
He could have exercised earlier when the share price was higher but chose not to.
Why he made that choice is an open question.
All the bio tech indexes I follow are down more than the usual down day. All the bio tech stocks I follow are down today with the exception of NWBO. which is up 10.98% at the moment in anticipation of an NDA filing.
SAVA down 5.75% AVXL down 5.81%
Looks like it is bio tech's day in the barrel.
P value of 0.025 implies stronger results than a of P 0.05.
Extend that to the secondary endpoints and it becomes a stronger case for efficacy.
There is a distinction between the various classes of biomarkers.
Simple Methods for Evaluating 4 Types of Biomarkers: Surrogate Endpoint, Prognostic, Predictive, and Cancer Screening
approximately 16,700,000 shares are shorted. That short position has unlimited risk if the SP goes up a lot.
Let's say the share price doubles on great news. That is certainly not out of the question. That would create over $120,000,000 liability for that short position.
Yeah. There are people trying to protect that liability.
There isn't a "broad category of approval". Each indication gets a trial. There are basket trials where a single trial protocol is run for several different but related indications simultaniously. Even so, each indication has it own trial population.
The FDA doesn't design trials. That is the job of the trial sponsor. Part of the trial design is the statistical analysis package (SAP). All of that is submitted to the agency for approval prior to trial start.
The SAP details the statistical analyses that will be performed on the data. The trial design specifies what types of data will be gathered from the trial and the frequency that it will be taken. The SAP is not an immutable document. It can be changed under certain conditions. It may be changed prior to data lock for example. There are certain circumstances where it can be changed after data lock although that is unusual and can compromise the validity of the trial.
The point of this is, the required checklist of required data points and analysis is specified by the trial documents and approved by the agency.
Much of the discussion about stat analysis is because we haven't had access to the SAP. As I understand it most SAPs are not made public so that is not a "red flag".
Dr. Jin does have access to the SAP and also knows the various ways that the FDA is willing to see the data analysis based on the SAP.
The FDA can request the raw data and perform its own analysis of the data using whatever techniques it sees ae appropriate without regard to the SAP. Again, as I understand it, that is not done most of the time but if the FDA sees something it doesn't like or thinks there is a better approach it can do so.
I hope this is helpful.
Good post.
I suspect the grouping into 30 and 50mg groups was, for lack of a better word, smeared as a result of the titration. Some didn't make it up to the target dose and some got down titrated. Hence the LMS approach.
I would very much like to the see the data in graph form to see what is really going on. Hopefully peer review paper will give that to us.
I don't suppose that you want to mention why he sold those shares would you?
Something about expiring options? Or how that options was exercised and how the total of the shares was handled?
Would that interfere with your narrative?
You wouldn't want to tell the whole story would you?
I have been re-watching the Dec 5th web presentation. They do repeatedly claim that the data they were presenting is designed to show improvement over baseline. They also discuss the Odds Ratio as being in the sap. They do present the OR for both primary endpoints. Then they discus the mean of the ADSL-COG along with the OR data. ADSC-ADL mean is not given. That has been pointed out since the day this presentation was posted.
The time frame the George mentioned at 45 min with Roy was about CRD sum of boxes. Which also had mean info given.
No matter how we rehash this there is insufficient information available.
The recent PR shows the data in an format that Jin says represents what the FDA wants to see and with criteria that the FDA finds acceptable for trial evaluation.
Apparently there is more than one way to analyze data to show trial success. Of course part of that has to do with what is specified in the SAP which we have no knowledge of. Jin has seen that of course.
So the bottom line is we are pissing in the wind* trying to come to conclusions based on insufficient information.
In defense of some of the more critical posters on the board that look for every possible weakness in the data and the company's performance, I would say I appreciate seeing what they have to say. It causes me to take a deeper look than I might otherwise do. Most of the time when I take that deeper look I don't agree with their interpretation of the information. Interpretation is a key word here. We all take information and place it in our own world view i.e. interpret what meaning it has.
As investors we take what information we can get and build a story out of it. That story informs our investing decisions. In general the critical posters strengthen my opinion of what Anavex will do at the same time they tell me what I need to paying attention to or not as the case may be.
* I live in Texas. Jerry Jeff Walker is very well known in these parts.
Odds ratio was reported in the DEC PR. The PR DID NOT SAY the odds ratio was in place of means. That is a conclusion that has been jumped to by several posters.
If Anavex has said that the Odds Ratio was in place of means endpoints no one has posted that on the board.
I'm more interested in what his source is for "Is there any other case FDA rejected a foreign trial protocol but accepted a post-hoc SAP proposed for a completed foreign trial?."
Where does he come up with the Post Hoc SAP proposal?
People seem to forget that the plan was to have Rett done and approve long before AD trials were completed. Unfortunetly Covid delayed that pediatric Rett trial by one year + and put Anavex in the situation where Pedi Rett and AD are now close together.
Missling had to make a choice about the $100,000,000 value voucher and decided that the delay was worth it.
The question in now how much of a delay to AD approval is really caused by waiting on Pediatric Rett? An honest look at the timelines tells me it is not much of a delay for the reasons I laid out.
I am reminded of a line I heard on a football game today. The questions was " What is the best place to play Quarterback?" The answer was "200 feet in the air in the broadcast booth."
You never showed where the company claimed the Odds Ratio was an endpoint, mostly because the company never claimed it was. That is your made up conclusion.
And then you have the audacity to clime that others are misleading.
The ADCS-ADL endpoint was by odds risk. And your first sentence is misleading.
You do realize that the peer review acceptance and publishing schedule is not under the control of Anavex, right?
We shall see.
We will have to disagree on this. For example, a few super responders could have actually gained brain volume and that would have moved the mean enough to get a very low P value.
I'm not suggesting that the numbers are anything other than good. I'm just not willing to extrapolate that P value the way you are to everyone.
I'd say that was just mean.