Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
It sure is a legitimate question. Unfortunately the answer is not that helpful: It depends on the CRO in question. Some, smaller, do provide only site management and clinical investigators, some offer more, up to and including FDA NDA related services. In IPIX case, the CRO(w) is supposed to be the leader in clinical dermatology services - my guess is that it provides a full plate of services.
kfcyahoo is correct. We tend to think prurisol p2b as a small trial, which it is when compared to phase 3 trials. But for phase 2 it is sizable. Anecdote: look for NCT00954915 in ClinicalTrials.gov. It is p2 psoriasis trial by MacroGenics and Lilly.
kfcyahoo, welcome to lunatic fringe. My spreadsheet has now over 110 p2 and p3 psoriasis trials with results, and it does not include NCT00954915. A person has to have some principles. Besides, that trial did not report PASI75 and sPGA 0/1 percentages which are my inclusion criteria. Did not expect this - there must be some 500 or more psoriasis trials between US and EU registries. I WANT MY SANITY BACK --- Which brings this idea up: I just invented swallowable mouthwash: menthol and zantac infused vodka. I call it BANG: Start your days with BANG! End your days with BANG!
I doubt that 'normal' thinking about standard deviations applies here -duration distribution probably has a 'fat' tail on the longer duration side.
Nice BS. My admiration, JT.
Nope, just including subjects already in screening. One has to take care of one's reputation. It's a faux pas trying to be a snobby biotech before you can afford being one.
Interesting, scottsmith. I take you mean that Leo is volunteering information, material or not, and not just answering to 'favored' questioners. Most biotech biggies do have their favorites. Just ask Adam Feuerstein. He should be able to provide examples both ways. Legality of it depends on the information divulged, as you know. I doubt you can legally nail Leo for explaining why there was not interim analysis when there should not have been one in the first place. That is a though one.
Thanks for clarification, KMBJN. I take Leo is not a statistical expert - any interim analysis affects alpha and risks investigator bias. It is not clear to me exactly how they were planning to do the analysis (was there specific portion of population at 6 weeks or all), but it seems like due to slide in the trial schedule they ever not able to hit their own requirements for analysis until it was very late in the trial. A blessing in disguise, I say.
Have noticed that you can register for emails at IPIX website. How nefarious is that? Unless there is another group of recipients, of course.
What you say, Daubers, is very possible and would be refreshing confirmation of sanity by IPIX. It still annoys me that they were even considering an interim analysis. Try find an interim analysis for a blinded, time-limited (efficacy at less than 20 weeks), interventional psoriasis trial. They don't make sense. But on this board any sign of corporate sanity (however late acquired) is treated with suspicion.
If the 'interim' analysis was in the trial protocol submitted to FDA then it means it got FDA's sign-off. I can't stop wondering why FDA would do that, just for fun or to see if the IPIX bunch is really stupid enough to follow thru? Snapshot in mid-treatment and 10 weeks before the trial is guaranteed to be completed is, as far as I can tell, a sizeable waste of money plus, also, a very unusual interim analysis design in a time limited, blinded, interventional psoriasis trial. It does not have any cost savings or patient benefit value as futility stop measure and a limited value as a predictor for the significance of the final outcome.
Yes, IPIX may have run the analysis anyway. I doubt if seeing the results told them a thing beyond prurisol not being in the class of biologics and that fact was known already. Still, it may have been enough to silence Leo.
Oh, just a minor thing. That 68 days average for building and releasing a trial database had associated standard deviation of 32.8 days. I asked. Nice people at Tufts Center for the Study of Drug Development answered.
I leave the interpretation of this bit of data to others with these words of warning: one probably can't assume normal distribution of durations in this case.
Yeah, probably, and the qualifier stays until I see the trial protocol for prurisol p2b. I should have used the term 'planned interim analysis' i.e. specified in the trial protocol. But wording doesn't really matter - useless and stupid analysis in any case.
Can you see any sense of unblinding and then again bliding a trial 10 weeks before it is over and done for the sake of first of its kind interim report in the history of blinded psoriasis trials? I don't. Open label trials are a different thing, there this stuff comes naturally.
TIAB, I have only two conclusions
1. There probably was a plan to do an interim report. But that report was not a typical interim report, more like an initial final report when all subjects had been 6 weeks in treatment.
2. The interim report as planned was about the most futile I have seen.
So, the report was to be at 6 weeks of treatment. The only way this makes any statistical [1] or any other kind of sense is if it was for all subjects. IPIX would have gotten the report no earlier than Nov 15th 2017, more likely about the same time when last subjects were finishing the treatment. Somebody wiser, please, tell me what's the utility of that kind of report, because I see none. I can't even see how one would estimate the effect of this interim analysis on final Type I error rate, but, then, I am not a professional statistician.
And a personal conclusion: If I had been the person responsible of putting in this interim/initial report and the absolute futility of my creation would have eventually dawned on me - I would have denied everything: "Wha? There never was ... Show me where it says... Oh, that's a typo. I am a bad typist, you know". The uselessness of it is on that scale. But that is what little vain PP would have done. Others, smarter ones, may disagree.
Because nobody else will move off their lazy asses and check things I moved and checked.
ClinicalTrials.gov is a funny site. It even lets you check change history. Here is an interesting timeline for IPIX prurisol 2b trial.
Nov 9, 2016 changes
Study is now recruiting
Primary completion date is set to July 2017
Study completion date as set to June 2017
...
and so it stays until
July 16, 2017
Primary completion date is changed to December 2017
Study completion date is changed to December 2017.
Meanwhile, things were percolating in IPIX PR stream:
Dec 19, 2016 - A sunny projection with important tidbit
'Interim analysis of 6-week data with readout is anticipated in 2Q2017, with full study top-line results in 3Q2017'
May 9, 2017 - Reality starts to set in
'Recruitment trended slower than projected due to competition from other companies also testing psoriasis drugs. To expedite enrollment, the Company has added additional investigator sites, with a total of 28 sites now actively recruiting patients, and expects interim analysis, with top-line results, to be completed in 3Q2017.'
May 11, 2017 - Important milestone regarding enrollment (and viability of interim report, if you know how to think).
'An already started Phase 2b clinical trial of Prurisol as a treatment for moderate-to-severe chronic plaque psoriasis has recruited more than 70 percent of the 189 participants that researchers hoped for.
The therapy’s developer, Cellceutix Corporation, said it expects to release the trial’s initial results during the third quarter of 2017.'
August 28, 2017 - Full enrollment
'Innovation Pharmaceuticals Inc., (OTCQB:IPIX) (“the Company”), a clinical stage biopharmaceutical company, today announces that it has met the goal of 189 patients enrolled in its ongoing Phase 2b clinical study of Prurisol for the treatment of moderate-to-severe psoriasis. The final number of patients will be up to 199, including those awaiting final screening test results through the end of this week (September 1). Based upon the protocol for 12 weeks of Prurisol treatment and additional patient follow-up for 4 weeks, the study is expected to be completed in Q4 2017, with results to follow thereafter. Prurisol is being developed as a novel, non-biologic, orally-delivered psoriasis drug candidate.'
Feel free to ponder, embellish and distort according how you have set your mind. It may take some effort to fit the above into rigid frame - but I trust you are capable. I already know what I think.
Cheers.
Dr Reddy isn't the only Indian pharma in deep doo with FDA. Sun Pharma's approved mee-too psoriasis drug tildrakizumab is probably delayed for similar reason, Halol plant is currently non-compliant with FDA's GMP.
We would know if IPIX was really planning for interim report, or just spreading PR pixie dust, if trial protocols were made public before the trial begins. FDA should do us that service. There are no trade secrets in those documents, only some borderline cheats and those would probably fade off if protocols were made public before trials - an additional benefit. So why not?
I think AA would be very iffy. Efficacy in UP might be good enough i.e. astounding, I can't say the same about efficacy in OM - it's good, but by current reading it is not significantly superior to other candidates. Also, probably only Polymedix trials for ABSSSI have a size to satisfy FDA about risk being acceptable. What little I know about accelerated approval is that it still takes evidence from sizeable trial ~ headcount > 100.
Touche, and that hurt :) My meaning was to point out that maybe Dr Reddy as IPIX previous and tentative future CMO could be an issue in the eyes for FDA and potential partner. Therefore contract with Evonik.
TIAB, it all depends on the structure of a deal. These are typical
1. Total process takeover by a partner --> IPIX hands over development and commercialization.
2. IPIX responsible for development up to and including marketing application. Partner takes over at commercialization stage and may provide expert support for development and marketing application.
3. Partner takes over development and future commercialization but IPIX supplies the drug for development phase and possibly for early commercialization
I have seen mostly cases 1 and 2, some rare cases of 3. In cases 2 and 3 a sane partner would require FDA approved and trouble free CMO for manufacturing before signing the deal and Dr Reddy, for certain, is not it.
If there is a partnership deal in the works it would probably be something like case 2. I am basing the guess on the current activity by IPIX. If there is no deal to be had and Leo's has decided to go alone IPIX would still need to address Dr Reddy's non-compliance situation ie. get trusted CMO. FDA will inspect plans and possibly facilities for manufacture, storage, distribution and administration of an experimental drug before giving a go ahead for a P3 trial - Dr Reddy might make FDA to balk.
I think you mean accelerated approval which is a possible but not automatic for drugs with fast track designation. With accelerated approval applicant gets marketing approval conditional to approval confirming study results (P3) at later date.
Ffrol, and you think Dr. Reddy (IPIX's previous CMO) doing manufacturing would not be cause of concern. It seems that Mezzion and FDA strongly disagree.
Indeed! I second that.
Since 2014 Dr Reddy's manufacturing sites at Medak, Miryalaguda, Bachupally and Srikakulam have failed FDA inspections. Dr Reddy has been forced to withdraw over 600000 famotidine tablets from US market. And Mezzion is currently suing Dr Reddy for damages claiming that Dr Reddy's non-compliance with FDA regulations was the sole reason given by FDA for denying NDA for udenafil. Maybe that explains why IPIX's CMO is now Evonik.
ffrol, sufficient manufacturing capacity meeting FDA GMP specs may have been an issue, if IPIX is pursuing partnership where it is responsible for development until marketing approval or even if IPIX is supposed to provide just brilacidin. A potential partner would not sign a deal and hand over upfront payment unless there were sufficient guarantees that IPIX is able to handle manufacturing.
Evonik has close collaboration with Lilly. They actually bought a plant from Lilly and are using it to supply Lilly. Besides, Novartis is probably eyeing Galera. GC4419 would be a nice fit to their cancer business.
Biodoc, does the company name happen to start with C and the name of the drug in question with A and the cancer subject whose death was the cause of of the clinical hold was having acidosis with is a no-no with A?
JTORENCE, it is also quite customary to construct partnership deals as follows:
Company A, the license holder is responsible for development up to and including filing marketing application with FDA.
Company B, the licensee will be responsible for the commercialization of the drug. Company B agrees to pay company A certain $$$ as upfront payment and additional $$$ per milestone (typically successful P3 trial(s) and successful marketing application) plus possible expert support with dealing with FDA.,
There is a simple reason for this deal structure: time. Company A usually has some sort clinical trial team (contract or not) possibly including kilo scale manufacturing in place, while company B would have to build one. Even the BIGGEST PHARMA does not have idle clinical trial staff lounging around office corners.
Yes, the deal is obvious. When the manufacturing and paying for it starts is not, assuming, of course, that it was not a retainer they signed.
Ah, TheDane, and how it would explain Aspire? You might want to refresh your take on 'specialty pharmaceutical company'.
Although I must admit that I do find this passage in the article somewhat offputting. But, well, maybe it explains the so-called delays with prurisol. Soo bad t...
'Specialty pharma often has a small research and development (R&D) organization and contracts out animal and human tastings to CRO...'
It would be very helpful to know the associated standard deviation, average alone is not that helpful.
is it 68 +- stdev of 12 days
or is it 68 +- stdev of 36 days
or something else
Yes, planned as being pre-specified regarding its statistical power and hence its timing plus being spelled out in the trial protocol i.e. communicated to FDA. Any other kind would very likely prevent the use of p2b trial in application support beyond safety evaluation.
biodoc, I like to add this:
Considering Leo's, let's say gregarious nature I find it baffling that if there was a planned interim analysis for p2b the exact timing of it never came up. Leo would have counted subjects down to take off in his communications.
Ffrol, I think this may ease your worries about vanishing interim report for prurisol.
We can agree that interim report is not produced at a whim, especially in trials destined for marketing application support. That means: if there ever was a planned interim report for prurisol phase 2b then it must have been specified in the trial protocol (which we don't have) and specified to be performed by CRO at pre-specified number of pre-specified events.
My guess is for interim prurisol report the pre-specified events were the count of subjects that had completed the trial. In order to make many statistical sense in terms of statistical power the count should have been above 60 % of enrolled subjects.
It turns out that p2b schedule was slipping from the get go; first the interim results was due Q2 2017 then Q3 2017. After that it vanished. The filings at ClinicalTrials.gov indicate that the trial may have become significantly back loaded - until June 2017 IPXI/CRO still believed that they can complete the trial during Q32017. In July they knew the could not. Also, between May 2017 and June 2017 they added 4 new trial sites, each in large population center (2 in LA, 1 in Vegas and 1 in Savannah) - enrollment rate should have picked up a lot after May 2017.
The evidence suggest that if there ever was a planned interim report specfied time for it may have eventually been so close to the end of trial that the report became superfluous. That is, if there ever was a planned interim report; IPIX never published subject/event requirement for it. Why?
See this for evidence .
We are Keystone Cops company with a reputation of shooting our toes off.
I guess you meant the words above. I am all for it.
yes, it could.
Does not apply to prurisol. Prurisol is developed for a different indication than indication(s) for abacavir, but is allowed to use 505b2 pathway related to abacavir because the long lasting metabolite just happens to be abacavir. No generic competition.
Infinity, you are not going to like this. Did you read Barron4664's message?
That message made me realize that I had absolutely forgotten 2 important things.
1. Prurisol has FDA 505b2 approval pathway
2. FDA trial database rules.
The first one means that IPIX does not need 2 large trials to get FDA's approval for prurisol. One is enough and possibly FDA is willing to accept p2b as such. That would explain why the trial is stuffed up with all those questionnaires - they need to be there in a trial supporting marketing application.
And that brings us to the point 2; FDA clinical trial database rules. If IPIX is going to use p2b for approval support then it must submit a copy of the locked trial database to FDA. FDA has this nasty policy: when a trial database is locked and unblinded it stays locked - no later data submitted by applicant approved. Only exception I know are protocol specified and FDA pre-approved interim test done by data monitoring committee (a sort of exception - multiple locked versions of database) or data request from FDA during its application review process. I am not sure how things go with running application, but IPIX does not have that in the pocket, not yet at least.
Conclusion: IPIX must get the trial database as complete as it can before locking and unblinding. That includes, obviously, all those weekly questionnaires.
As to Leo being silent. I am not so sure if Leo considers the trial report even being delayed. But, do you really think it would help IPIX share price if Leo would put out a press release detailing delays in data collection, even if it relates only to perceived 'How are you feeling today' kind of stuff? I mean it is IPIX we are talking here. That puny Keystone Cops company that has a reputation of shooting it's corporate toes off.
You may be right. I wish you are.
Thanks. Excellent remark. I had forgotten about 505b2. And I had also forgotten trial database rules, shame on me (I claim obviously rampaging dementia as my defence). I repeat the database rules here:
data entered in database --> database as complete as is timely possible -->
database locked --> data unblinded --> analyse and report.
The point is: A clinical trial database is not like Starbuck's toilet door which gets unlocked and locked at request. When clinical trial database is locked it stays locked. Only exception I remember is predefined interim analysis and that is typical for long duration trials like cancer trials, where interim analysis for OS is performed typically at the same time as the nominal final analysis for PFS.
in our case here: all conceivable data must be in before any analysis. There is no separate lock date for topline data and for the rest of the stuff. That is my understanding, but it can be faulty understanding. Please advice.
Post trial questionnaire about the trial probably is, but not weekly questionnaires how is the condition of subject's skin, itch etc...
Oh. My mistake. That might explain. IPIX/CRO could write a report about questionnaires separately, but database would have to be as complete as it can be and locked before unblinding and any reporting.
Trial reporting order is: enter data --> all data in --> lock data --> unblind -->analyze and report. It is possible they have been forced to wait resolution for last questionnaire items and therefore delayed data lock.
Dizzying.