Part 2 of 2
Quality-by-design is a science and risk-based approach to pharmaceutical development and manufacturing. It involves designing and developing pharmaceutical formulations and manufacturing processes to help ensure product quality; these concepts are described in the international guidelines ICH Q8, Q9, Q10 and Q11.
The document published today focuses on ‘design space verification’, a demonstration that the combination of the process parameters and material attributes established at pilot scale during pharmaceutical development are capable of delivering a product of appropriate quality on a commercial scale.
In March 2011, the EMA and US FDA launched a three-year pilot programme for the parallel assessment of certain quality or chemistry manufacturing and control (CMC) sections of applications that are relevant to quality-by-design. With the agreement of the applicants, experts from the Japanese (PMDA) participate as observers in the programme.
The objective of the parallel assessment is to share knowledge, facilitate a consistent implementation of the international guidelines on the implementation of the quality-by-design concept and promote the availability of medicines of consistent quality throughout the European Union (EU) and the USA.
The question-and-answer document published today reflects the conclusions reached by the EU and US regulators on the specific topic of design space verification as part of their parallel assessment.
The EMA and the US FDA will publish further conclusions on other quality-by-design-related topics as the pilot programme continues and more parallel assessments are conducted.
The pilot programme is open to selected procedures, including applications for initial marketing authorisations, type-II variations and scientific advice.
Participation in the pilot is voluntary. Interested applicants and sponsors should notify both agencies three months prior to submission of an application.
Good night all
Part 1 of 2
European Medicines Agency and US Food and Drug Administration release further guidance on quality-by-design approach
The (EMA) and the US FDA) have published a second joint question and answers document that provides guidance on the quality-by-design concept.
You will find this wording below “The pilot programme is open to selected procedures, including applications for initial marketing authorisations, type-II variations and scientific advice”
You may also recall that I have posted about the EMA variations in the past. If you cannot recall the same the EMA variation system is basically an indication add on path way using the original approved drug data. One of our competitors drugs Memantine recently used this route in a speedy manner to gain approval for further indications in relatively rapid order.
I have only just got wind of the update so I have not studied it in depth, never a less I’m greatly encouraged that the EMA and the FDA are working close on this aspect ( Note Japan are now sitting in). With the future developments of Avanir in mind as mentioned in the recent investors day one would hope that the collaboration will be of great benefit to our growing company.
IMO Avanir are sitting pretty, a little bit of controversy for you just in case you have forgotten. When thinking of a Partner outside of the USA refer to the original CNS agreement regarding royalties, I have seen nothing that tells me they do not stand, I would like some clarification on that situation. Oh they will look after Richard Smith MD IMO. I do not think the lengthy time that has passed regarding a possible partner is detrimental at all, surely it has given AVNR time to pull more together on such matters as DNP using DDM and increasing the bargaining power generally with the whole scope of things.
Once again there was a lot of information in that presentation if you were to divide into 3 it is still huge numbers.
The tea is brewing nicely.
Enjoy your day.
I read another little snippet this morning; correction I read a good number of snippets this morning regarding NMDA. One of these being, articles and discussions amongst scientists in respect of NMDA are increasing in number more and more each week.
Amazingly in N we have a drug that is proven to work for PBA, but it is not known exactly how it works.
FWIW IMO the jury is out in respect of Tourette’s and the possibilities remain. I think it would be prudent to mention, as far as I’m aware Tourette’s is mainly associated with the young, this probably is restrictive to N at the present time pending paediatric study data.
Very best regards.
Good morning Onlyfacts.
Thank you for your additional comments, much appreciated. I had a quick search this morning typing in NMDA for Tourette’s. One of the articles that I came across is as follows. There were other articles that I need to go back to as they were heavy reading for me.
Glutamatergic drugs exacerbate symptomatic behavior in a transgenic model of comorbid Tourette's syndrome and obsessive-compulsive disorder
Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church St. S.E., Minneapolis, MN 55455, USA.
We previously created a transgenic mouse model of comorbid Tourette's syndrome and obsessive-compulsive disorder (TS+OCD), by expressing a neuropotentiating cholera toxin (CT) transgene in a subset of dopamine D1 receptor-expressing (D1+) neurons thought to induce cortical and amygdalar glutamate output. To test glutamate's role in the TS+OCD-like disorder of these transgenic mice (D1CT-7 line), the effects of glutamate receptor-binding drugs on their behavior were examined. MK-801, a non-competitive NMDA receptor antagonist that indirectly stimulates cortical-limbic glutamate output, aggravated a transgene-dependent abnormal behavior (repetitive climbing and leaping) in the D1CT-7 mice at doses insufficient to induce stereotypies, and more readily induced stereotypies and limbic seizure behaviors at high doses. NBQX, a seizure-inhibiting AMPA receptor antagonist, reduced only the MK-801-dependent stereotypic and limbic seizure behavior of D1CT-7 mice, but not their transgene-dependent behaviors. These data imply that TS+OCD-like behavior is mediated by cortical-limbic glutamate, but that AMPA glutamate receptors are not an essential part of this behavioral circuit. Our findings lead to the prediction that the symptoms of human Tourette's syndrome and obsessive-compulsive disorder are elicited by excessive forebrain glutamate output.
PMID: 10980239 [PubMed - indexed for MEDLINE]
Hello Fred – You are welcome.
“This board is getting weirder by the day”
That may well be the case, however think of the entertainment value, you would normally have to pay to witness such goings on. As a side line/additional block buster, I hear on the grapevine that our message board has been looked at as a soap opera, you know the sort of thing Downton Abbey or is it Faulty Towers with a twist.
Enjoy this week’s episode ;-)
Hi DM – Good to hear from you.
That is what I thought. I have been trying to get a better understanding of the mechanism of N for many years, I would just like to add and show my appreciation to Onlyfacts who has helped me tremendously over time on our message board in this respect. To have Avanir present so much additional information was a delight.
I have a good friend who suffers with Tourette’s and other apparent mood conditions. He is a very good singer in a local rock band that was until late. Sadly my friend can not always control his condition and was asked to leave the band. If I recall correctly we had a little look in to this in the past, I have just checked back, OFP came up with a relative brief article unfortunately the link no longer works my end. I’m with you and hope that an interested party will wish to look at this aspect further. Certainly will keep the fingers crossed.
Very best regards.
Now look at this, this has four of these. So now you understand why we’re so enthusiastic with the future prospects of developments at Avanir.
Very best regards
Hello Sarge - I do hope you are having a pleasant weekend and thank you for this weeks round up and your thoughts.
What an interesting week it was for us. I was over the moon with Joao Siffert comments during the Investors Day presentation. Sarge my friend if you do nothing else this weekend and have not done so already read Joao statements on the transcripts not once but at least twice .
Avanir and others have talked to you about NUEDEXTA pharmacology dextromethorphan with pharmacology which is the dextromethorphan as being the CNS active compound of this drug combination as being a NMDA weak antagonist, and I’ll come back to that in a minute to then the Sigma-1 agonist. But we have not talked or look to invest very much until most recently is the fact that dextromethorphan also is a strong inhibitor in serotonin reuptake with a moderately to high affinity and also a moderate affinity norepinephrine reuptake inhibitor. These are well known receptors in CNS pharmacology that round out the dextromethorphan pharmacology. So, imagine the drug that has four of these binding sites in both the standard SSRI, SNRI and NRI pharmacology. And on top of that you have a receptor that modulates the expression of Glutamate. Why is that important? Glutamate is an important excitatory amino acid which has enrolled in multiple CNS disorders ranging from neuro degeneration to pain and mostly recently we’ve learnt has an important role in management of depression.
And on top of that, it works with the Sigma-1 agonist and what does that do. For Sigma-1 is a receptor that modulates multiple other neurochemical systems downstream. It helps modulate glutamate by combining with the -- not combine itself but modulate in addition to the NMDA modulation and also help modulate the monoamines which includes serotonin, dopamine and norepinephrine.
So if you look at these receptors here and if I have a drug that had one of these receptor binding I’ll be enthusiastic about developing
Hi Ray Thank you for getting back to me. I thought as much they subject matter had been discussed here before.
Your initial statement “When shorts cover, the price goes up” is the subject matter which I commented on. I gave examples of this not being the case.
“Again, you can't look at a change of only 0.7 million shares in the short position over a two week period of time and say the stock price is dictated by the covering of shorts” Please re phrase that I have not said anything other than show examples of the pps dropping in tandem with the short position decrease.
rayonman1 • Jul 16, 2011 1:46 PM
“Shorts absolutely have no chance to cover at any reasonable price. They are not covering today because they can't, simple as that. Any covering will make the price zoom to the moon. The best these losers can do now ---"
It is true that the short position is so large that they can not all cover at once in the face of some good news but they can cover over time without the price going up much. I've followed stocks with large short positions expecting the price to rise as the shorts covered.
But the short positions over time were decreased and the price did not rise.
The stock price scoreboard says shorts have been the clear "winners" not the "losers". Longs like us have been the clear "losers."
rayonman1 • Jul 21, 2011 10:39 PM
Not an expert but my understanding is you need a large short position and then you need news that suddenly drives the price up.
Shorts try to cover but there aren't enough shares to buy and the stock price goes up a lot, more than commensurate with the importance of the news.
I think it is important to note that you need a sudden event to cause a short squeeze.
A large short position can cover over time without driving the price up much.
Your thoughts on the subject? (Since you brought it up)
Good morning Winkles - Trust all is well, and another fine post from your good self.
Re : Observations:
1) Yes agree that a good number of us do that. The investment length of time IMO is some what in proportion to the emoting, which in turn is/should be in proportion to the factual information gained in order not to cloud ones mind ;-)
2) Agree business as usual.
3) “The fraudulent Gravity report” agree on that as well. With the edition of, those that wish to hide behind the curtain IMO are of no substance and simply not worth the time of day. Having said that it worked again.
4) With out doubt.
Re : Information - Thank you for sharing.
Have a very pleasant weekend my friend.
PS Red Thumbs
Do not be surprised to see more of the same in the recent past, present or future.
We shall see how this recent fiasco comes out.
Oh yes Holding on with both hands despite their best efforts.
Cheers for now.
Good morning Red Thumbs.
Please find below a closer range example of the Shares Short covered in tandem with the PPS dropping. Please feel free to comment in order that wee may discuss the matter further if you so wish.
7/29/2011 Shares Short 35,392,914 PPS at Close 3.75
8/15/2011 Shares Short 34,677,841 PPS at Close 2.99
In above period Short Shares Covered 715,073 with a decrease in the PPS of 76 cents.
Hi Ray Thank you for the reply.
With all due respect, as you can see I was referring to your statement “When shorts cover, the price goes up”. Before we proceed into further matters I’m sure you will agree, from the records I have provided regarding AVNR this is not the case.
Hello Friend Horcents.
I’m some what stunned and saddened on hearing your news at the same time I’m heartened by your positive and up beat attitude. I shall continue thinking of you my friend and wishing you well.
Very best to you Horcents.
Regarding your statement below.
“When shorts cover, the price goes up”.
That would be the case where the game is played with a straight bat.
Here are some facts regarding AVNR
07/29/11 Shares short at peak 35,392,914 PPS 4.05
06/15/12 Shares short 23,008,015 PPS 3.06
In the Range above I make it 12,384,899 short shares covered with a decrease in the PPS of almost a dollar. There are a number of examples where the pps has declined with short covering in respect of AVNR. I guess the next question is was that played with a straight bat, I say No but they get away with it.
Hi Greatday – glad you found the post.
Rest assured Nuedexta is eagerly awaited, I have been reading articles over here on the subject matter for what must be at least 4 years now. The publications have gradually increased over time.
Just a reminder on one of the EMA conditions of approval.
“In addition, the company that makes Nuedexta must ensure that all healthcare professionals who are expected to use Nuedexta receive an information pack”
Just imagine, just one pack to each EU member country health authority for internal distribution will reach more people than you can wave a stick at. Forget the expense of your large sales force, key people with the right knowledge of access is the thing here.
Hey see what you can do to get another indication or two data out, better still get N changed over to DDM as a matter of urgency. We shall talk about the latter another day.
Very best regards.
Hello Robert – Good to hear from you.
We have discussed amongst our selves the potential for further indications. I was so pleased to have seen substantiated information direct from Avanir during the presentation.
All the very best to you.
Hello Greatday hope you got to see my note to your good self
All the best.