It felt like this...Mozz & Friend ... 90 minutes style...was worth the effort, some good insights gained and further leads obtained! Big thanks to my friend and of course, Mr X.
THE QUESTIONS CONTINUED.....
QUESTION 5 How does the relationship between FDA and EMA work? Have you had any direct experience of this? I know the meetings these days are effectively Zoom calls, were they phone calls in the past or were there some face to face meetings too?
Yes there has been a lot of work to get these two agencies to work together, generally in his experience the FDA have slightly higher standards in terms of safety, the EMA does need a little more effort in terms of co-ordination (eg so many countries under its responsibility and X mentioned that approval actually needs to be requested from each individual country and while that might be just a formality, it can add some overhead in terms of time though generally it's only a few extra months).
He personally hasn't seen a drug that has passed FDA but not passed EMA. He mentioned that this alignment is particularly apparent in the case of rare disease applications and trials.
QUESTION 6 How often does a sponsor need to check in with the FDA, is it on a monthly basis or ad hoc during a phase three trial? I understand there has to be immediate (within 7 days?) if there are any noticed safety issues or AE's but I'm referring to just general checking in and general updates on how the trial is progressing etc.
X started off by saying there is hardly ANY discussion between the agency and the sponsor once the trial starts. I was a bit taken back. I was expecting him to say there is constant liaising, almost on a bi weekly basis...sometimes more... The only liaising that occurs is around safety events, if there was a safety issue that came up. He then further explained by saying that the sponsor would usually set up an independent group of clinicians known as a data safety monitoring board who are charged with the responsibility of overseeing any safety concerns and reporting these immediately back to the Sponsor.
The committee will have access to the blinding codes so somewhat like what happened in the latest AstraZenca Covid Trial, the trial can be halted while the AE is investigated. If this board observes some concerning safety event they will tell the sponsor and the sponsor must communicate with the FDA in this case. Apart from this, once the study begins, the only communication that really occurs between the sponsor and the FDA will be at the end when the study documentation has been being written up and the sponsor makes the application for approval!
He also said the FDA really only give you recommendations, they never give instructions. Prior to a drug's trial commencement they never say anything, they only say what you CAN'T do in a trial. You can never, for example, go to the FDA and say can we use XXX as an endpoint? You need to say, does the regulator have any problem if we used XXX as an endpoint? [Mozz's note: In light of this information the feedback we received from the FDA in the Pre IND was pretty encouraging].
Interestingly X mentioned that under the FDA system and what happens in the USA there is much more of a separation between payers and the agency whereas in the case of the EMA once a drug has passed at that level, each country will weigh in to determine if there is a good cost/benefit advantage for each country, from their point of view if it is of small efficacy and some benefit, is it really worth us (the country) in taking it on? In other words there is more of a meld between the countries of the EMA and the EMA itself in terms of the whole cost benefit scenario.
QUESTION 7 [Dungiven] What is the scale of groundwork required ahead of a trial beginning?
Usually a company like PAR will arrange a Contract Research Organisation (CRO) The most famous is IQvia (Used to be called Quintiles), there are others eg PAREXCEL. These are large international companies. They are experts in running clinical trials. It depends on your needs and of course your budget and timeline. They are responsible for recruiting, it can take up to 6 months to get this sort of work done. Each CRO will have expertise in certain areas. If the sponsor are more in a hurry then the trial centres could be used off the beaten track in other countries that may not have as much load/work on at the moment.
The CRO are effectively charged with the grunt work. They are expensive but particularly for smaller companies, it's overall well worth it.[Mozz's notes: Hmm so Mozza, when will PAR appoint a CRO? Well....It's already happened... huh? Where is your proof Mozz? Right under our noses and not just one...at least more than one CRO...plural...how do I know.?...Page 24...see the red box below.
CRO appointment? Check!It's another point I would've missed without "The Interview", Thanks again X !
So X mentioned that this can take 6 to 8 months, the fact that PAR have already declared this recently, I'm thinking they have had this CRO(s) lined up and in progress for weeks already. Things are happening in the background is my point here. The beauty of a CRO is that they easily maintain a full log system, every action is written down and recorded. If the FDA at any point in the future ask how this data point was achieved and request the sponsor to detail in depth the audit trial for the said point, this can easily and effortless by achieved.
X mentioned that academics generally are hopeless at maintaining such diligence and it is vastly in the interests of shareholders in a public company to have a CRO in place, it is particularly an acute requirement for smaller companies in Mozz's mind! If it is a smaller study and the sponsor have a good regulatory team then it is more plausible that the sponsor may undertake such an assignment on their own. It is also possible that again if it is a small study then the hospital itself that is involved could over-see some of this functioning as well X mentioned that the standard of clinical trial settings is at least as onerous if not more than the GMP templates applied, want more information about what a GMP is and what is involved? See the following links for some more info ----- >
QUESTION 8 [Dungiven] What milestones should we look out for (i.e. securing trial sites, recruiting participants, any regulatory ticks reqd etc)
Well here is a checklist of sorts based exclusively off what X said:
Appearance on Clincialtrials.gov
Appointment of CRO
Once the study kicks off, recruitment rates are important and should be consistent
Inclusion/Exclusion criteria shouldn't change though it can be common for one or two changes though be wary of these. Your drug should be optimised for the best group but usually this isn't changed for the better. If it does change and more than once it might be because they are trying to get this recruitment rate up and it can be a warning. [Mozz's notes, this shouldn't really be a factor/issue for us as we know that there was a high demand for us in the SAS program, bad news leaks out...and this wasn't the case for us so far.]
No change in Endpoints is a good sign. The trial should largely proceed as planned.
AE's...look out for these, if there are a lot, it is a warning.
QUESTION 9 [Dungiven] And how long could that process typically take for a multi-site trial of several hundred people (i.e. the pre-trial groundwork, not the trial itself)?
Approx 4 to 5 months is typical.
QUESTION 10 [Jerund] One thing I'd be interested to know would be to show him PAR's Phase 2b results and ask him in the past whether he has seen a company fail phase 3, given such phase 2b results, given the tight range that we had, and the significance of the results etc. And if he has seen failures before, for what reasons did they fail?
We did indirectly mention the results but OA wasn't his field of expertise, but he appreciated the check points my friend and I ticked off including such things as GMP, patents, difficult to copy in terms of manufacturing as evidences by mass spectrometry and FDA sanctioning only the Bene material/product to be utilised in trials.
There can be many reasons for failure but the common ones are of course failing to meet the endpoint, too many AE's and safety concerns along with the sponsor sometimes running out of cash!
QUESTION 11 After Trial is read out what is next step and how long does it take…Marketing labelling, registration? Can it take up to 1 year?
Once the trail is over the Advisory committee will meet with the FDA along with the academic experts, they will review the data and put the data through the hoops, the statistician will check the data and it is appropriately analysed with a fine tooth comb, it gets audited. The FDA have 90 days to respond. Once it is accepted then the authority to sell the drug can be granted.
The next step is to write the label. Every word is fought over. Typically the sponsor wants as broad classification as possible...."Zilousul can be taken for pain", we want a broad leaflet, "Treatment with Zilosul is appropriate in knee pain from ages of 18 to 90"...But the committee/FDA will review this.
An example of a drug label and accompanying leaflet, hmm... what better example than a sister drug!
ADDITIONAL NOTES/COMMENTS
X also mentioned that pain is a fundamentally tricky thing to rate...yes WOMAC is a recognised scale but at the end of the day it is still subjective. Your 7 out of 10 may not be anywhere near mine. There can be regional differences, gender differences, language and cultural differences that can lay on the effects of drugs. Your threshold could be a lot more. This is important when our entire PRIMARY endpoint is pain... [Mozz view - thus it is also good that we have other empirical data to back us up such as MRI data in BML volume and measurement].
A lot of errors can be minimised in the trial design itself. The help of a statistician with loads of experience in this field can help a lot and it's a advantage that this person has now been appointed in an official capacity by Par. The goal for any clinical trial is to remove the noise and retain the signal. Noise is the error, the misunderstanding of the Womac rating sheet and thus the patient incorrectly fills in the wrong answer as an example. The signal is the drug effect. Companies such as X's company can help in such data points and removing errors. This is a very important part which we know as data cleaning before the Database gets locked. X's real speciality is minimisation of error in the data and this plays an important role just before the final data is submitted after the clinical part of the trial is over.
X also commented that we have had it quite smooth so far, sometimes there can be hurdles like absorption (of the drug) problems, and more than one phase 2 trials required etc.
I always thought MPS was a biological condition primarily centred on the cells lacking the enzymes to remove waste. I learnt for the first time that it is also neurological condition and this manifests particularly in MPS III. X mentioned it in the interview and I made a note to look that up. Check this fact out:1"MPS III is marked by severe neurological symptoms that include progressive dementia, aggressive behaviour, hyperactivity, seizures, some deafness and vision loss, and an inability to sleep for more than a few hours at a time."
X also specifically mentioned that the co-ordinators at the FDA, the case reviewers, are particularly sympathetic to the sufferers of rare disease and will guide sponsors through and are more lenient and accommodating to possible remedies and solutions by the way of drugs that show efficacy in these areas. Again this is great news for us Paradigmers, to hear this from someone in the industry that has vast experience.
From a commercial perspective, X also mentioned in isolation of anything else, it is once the data starts coming back and it is shown to be efficacious and safe, that's when the share price will lift significantly.
We chatted a bit more about Rare and X stated that the companies that do Rare diseases well are the ones that form a good liaison with advocacy groups, they will speak to the docs, they will go to the seminars. Paradigmers...this is us....We have attended the seminars in Orlando...we have set up working groups with patients and their guardians...Remember, even Scott Williams travelled with PAR and reported on his experience. We are that good corporate citizen and this all comes into play either directly or indirectly on our standing with the community and the patient network. This building up of a good relationship will only enhance what our drug does for the patient.
He also reiterated the fact that the Orphan pathway is so much quicker, recruitment is much quicker, it's a close knit community, there is no buy in that needs to be done or to the same extent. The advocacy groups and networks are much stronger and there are usually dedicated medical centres set up for these patients or known centres. This coupled with a different perspective and attitude on behalf of the FDA makes this story a totally different one to a regular drug pathway.
X also suggested that pricing in the drug industry is like a lot of industries, finally price dictates a lot and it's not always necessarily based on only the merits of the drug particularly in the regular pathway. Finally what can be charged to the patient can also play a factor in the success of a drug under the normal pathway such as OA. To some extent the fact that the Apple phone is priced quite highly, there is extra perceived value of it's working and features. However, this is different in the Rare pathway...the big pharmas aren't as well represented here and competition is so much less, another reason why the FDA deliberately adds extra incentives for sponsors to develop drugs for this under-served market.
X stated that the Docs that work in the rare disease industry are generally of a different nature, they are more protective of their patient and want to see good drugs that work and don't have nasty side effects that can do more damage to their patients. It's all about improving their quality of life, another reason why the PGIC will be come more important to us in this area. See this link for more on this concept ---->PGIC
No wonder X stated that it is particularly in the Rare field where drug development does shine and usually works at it's best. I do believe we are very fortunate to have a drug that will do a lot of good to a lot of people that currently suffer terribly with not just one or two mild symptoms but many and severe symptoms.. This will become a priority in my view as the FDA gets a better sense of what is being presented to them. X mentioned that the number of sites involved does drive up the costs, in an ideal situation all recruitment would happen at the one site, it would be a lot cheaper and easier. However, in Covid times this cannot be achieved, in fact more clinical sites spread across geographical areas will mitigate some of the risk in my view. Yes this will have an overhead of cost and time but will de risk the chance of a longer delays due to clinical trial site shutdown if an outbreak were to occur.
EDITOR'S NOTE:
My friend and I were very impressed with X and we have decided to split the cost of a nice bottle of Red for his valuable time and candid information. It was fun bringing you a different sources of info...it all adds to our overall picture that we can form...we have a stack of info coming and the two big trials are set to start very very soon...we are making good progress behind the scenes...our time in the sun is coming....
ACKNOWLEDGEMENTS
Dungiven/Jerund , thanks for your questions, it educated me ! This is the beauty of HC....we exchange questions and answers and you know what? It benefits us all... As I say...WE are the educated and empowered investors, this should NOT be a PASSIVE investment for YOU that are reading this...it is an ACTIVE investment...think of questions for yourself, do not be shy we will not burn you down no matter what you ask...for in answering, we too may just get a further education ourselves. I am patient...hey, I've been waiting 5 full years...I can wait some more...the times of share consolidation are boring....the times between PAR announcements are dull...but I find myself furiously busy in research...I do not have enough time to cover the material I want to cover, is this not a sign of just how compelling a company we have invested in?
I wish to publicly thank my friend for the beautiful lead and what led to some great information that adds more weight to an already compelling story.
DISCLAIMERS
My views here throughout this post, while I do my best to bring good quality, independent information as well as unique data and in this case interview information, you must always do your own research, do not rely on anything I say, formulate your own conclusions and never invest too much in one thing no matter how good it smells and sounds.
It's another point I would've missed without "The Interview", Thanks again X !
(20min delay)