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Thanks, cabel. Interesting weekend coming :)
On that I agree with you. I don't see any reason not to publish the meeting date. The time period to deliver meeting minutes and possible FDA responses is 30 days --> Leo seems to have enough fudge room without being coy about the meeting date.
BTW, eons ago my British educated (<-- caveat: snobbery possible) English teacher, when speaking about the proper usage of expression 'a few', defined it being more than 1 and less than 5. Where he got that one - no clue, but it has stuck.
In order to continue my tradition of being a verbose nuisance I put two tables below with these comments:
1. Numbers in the tables DO NOT present altogether fair comparison. Among differences: IPIX and Soligenix using radiation threshold of 55 Gy into oral cavity for inclusion into mITT. Galera and Amgen (palifermin) seem to have used 50 Gy. And there are others.
2. Galera has not specified what criteria was used in selecting base head counts for the reported percentages. CLEARLY IT IS NOT the number of randomized subjects (ITT) as Galera's presentation lets one to believe. As a results, head counts for Galera are too large in the tables.
3. In any case, forget Galera's GC4419, so far it has show more consistent results than Brilacidin. BTD was deserved.
4. IPIX seems to have tripped over the usual occurrence in their trials: placebo group behaving out of the norm. A trap that might have been avoided with a bit larger trial head count or maybe even doing things Galera's way - using 50 Gy threshold. That corresponds to 5 full weeks of IMRT out of max 7 and is obviously acceptable to FDA.
5. Soligenix got FDA's go ahead for phase 3 regardless of the miserable numbers with weekly cisplatin (worse than those for Brilacidin) and is recruiting, but accepting only subjects suitable to cisplatin Q3W schedule and cancer strictly in oral cavity. What might FDA think about brilacidin vs dusquetide?
Enjoy your weekend.
Placebo arms:
Treatment arms:
Sources:
Brilacidin:
http://www.ipharminc.com/new-blog/2018/9/24/brilacidin-for-oral-mucositis-at-a-glance-comparative-data-presentation-with-other-investigational-om-drugs
GC4419:
https://www.mascc.org/assets/2018_Meeting_Files/Fri29/Strauss_3/1411_Anderson_Strauss%203_Fri.pdf
Dusquetide:
WARNING: direct download of supplemental word DOC, which happens to be the only place where Soligenix gives overall SOM incidence numbers.
https://ars.els-cdn.com/content/image/1-s2.0-S0168165616315668-mmc1.docx
The careless buffoon who created the SOM incidence table in the said above supplemental doc copied head counts for ALL subject into table for subjects with cisplatin Q3W schedule. Therefore, one needs to peek at results at ClinicalTrials.gov to get the correct numbers for cisplatin Q3W subjects:
https://clinicaltrials.gov/ct2/show/results/NCT02013050?term=SGX942&rank=2
palifermin:
http://ascopubs.org/doi/full/10.1200/JCO.2010.32.4103?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed
and
http://ascopubs.org/doi/full/10.1200/JCO.2010.32.4095?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed
Maybe you should consult This EOP timeline (in image) before forming any opinions.
http://www.regardd.org/drugs/drug-development/meetings
Meeting minutes & responses ...
Maybe you were after where that 46.2 % percent came. First time I saw it was in this press release on May 26th, 2016. here:
http://www.ipharminc.com/press-release/2016/11/12/cellceutix-provides-additional-insight-into-successful-phase-2-trial-for-treating-psoriasis
If you were wondering why we don't know how PP was selected, then welcome to club. Pharma typically does not release trial protocol before applying for NDA or publishing (some periodicals do required it as a part of publication).
Otherwise, I don't have a clue what you might be after. Sorry.
I am late into the fray as usual. LR, all the additional info needed is in the presentation given in
MEDICAL DERMATOLOGY THERAPEUTIC R&D AND TECHNICAL INNOVATION, Boston, MA, 19 September 2016
source:
https://static1.squarespace.com/static/5715352e20c647639137f992/t/583f7f14bebafbe20767391b/1480556310644/Prurisol-Presentation-for-Med-Derm-RD-Workshop_19Sep2016-u.pdf
Slide 10: Per Protocol population: 20, Subjects achieving at least IGA shift 2: 7.
Slide 12 Right hand chart:
IGA 3 at start: 65 % --> 0.65 * 20 = 13
IGA 2 at start: 35 % --> 0.35 * 20 = 7
Because there seems to be widespread misunderstanding about Intent to Treat and Per Protocol groups, at least in terms of validity, I am going say a bit about them here.
Intent to Treat: all subjects that were randomized for a trial.
What one expects a "real world" experience with a treatment to be. Intent to Treat is preferred because using it eliminates one source of bias. But it is also generally considered that ITT analysis has a tendency to underestimate treatment effect.
Per Protocol: all subjects that completed a trial without (major) protocol violation.
What one expects the effect of a drug to be with perfectly executed treatment regimen and perfectly behaving patients. Eliminating subjects introduces the possibility of an adding bias and underestimating adverse effects. Usually regarded as too optimistic.
The "truth" is out there somewhere in between ITT and PP.
There is occasionally some "fudging" with ITT, trial runners may eliminate subjects that never received any treatment and like. There is a much bigger problem with PP - what constitutes Per Protocol group is not well defined and varies from trial to trial. I, personally, don't use PP data in my evaluations UNLESS it is crystal clear to me what got eliminated from Per Protocol group.
In this case I stick with ITT analysis until IPIX tells me why 8 subjects (original size 28 not 27 as in the table on slide 10) from prurisol 200 mg group and 12 subject from placebo group got eliminated for PP. Reasons could be valid and benign, I just don't know.
BTW: It is not true that FDA abhors PP analysis. FDA official position is that they will consider results from reasonable PP analysis as long as it is accompanied with ITT analysis. If my rotten memory serves me correctly FDA has approved at least one rheumatoid arthritis drug based mostly on results from PP analysis.
some sources
ICH
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E9/Step4/E9_Guideline.pdf
FDA
https://www.fda.gov/downloads/Drugs/.../Guidances/UCM071665.pdf
SPIRIT 2013 Statement for Trial Protocols:
http://annals.org/aim/fullarticle/1556168/spirit-2013-statement-defining-standard-protocol-items-clinical-trials
interesting commentary at the end of a short article:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4936074/
And what should I do with Roche?
DaubersUP, your example manages to demonstrate two important things at the same time.
1. Significance of early BTD to companies working with substitute endpoints. In this case it is known that Hepatic venous pressure gradient (HVPG) does correlate with the stage of liver fibrosis. What is obviously not well known is what change in HVPG does constitute reliable indication of clinically meaningful change in NASH fibrosis. At least that seems to be FDA's view. Therefore, Galectin would have benefitted from applying for BTD as soon as possible i.e. before the start of p2 trial - they might have even managed to soften up FDA's requirements for meaningful change in HVPG with closer contact during the design of p2 trial.
2. Good example of what FDA requires for approval of BTD - reasonable clarity is good way of putting it.
TIAB, I don't disagree with you on not getting BTD being bad news. I just disagree about how bad.
At the stage Brilacidin is currently (past p2 according to IPIX, some may disagree) breakthrough designation has nary development benefits left - phase 3 is approval trial, BTD does not alter or speed up approval process nor approval trial design and conduct - only accelerated review or priority review do. But, if IPIX comes out of EOP2 meeting with FDA recommendation for additional p2 trial before p3, then BTD might have some benefits. As I see it: currently it is EOP2 meeting that is crucial to IPIX, not BTD.
As to why FDA may not have granted BTD I can offer two reasonable explanation, both from FDA guidelines:
1. In general, the preliminary clinical evidence should show a clear advantage over available therapy.
2. In all cases, preliminary clinical evidence demonstrating that the drug may represent a substantial improvement over available therapy should involve a sufficient number of patients to be considered credible.
source:
https://www.fda.gov/downloads/Drugs/Guidances/UCM358301.pdf
IPIX may have gone for blanket coverage in SOM and FDA may have concluded (as I would have) that IPIX has not demonstrate credible or sufficient benefit in weekly cisplatin group.
Does this possible stance by FDA have any effect on EOP2 outcome? It probably will. I don't see drug safety being an issue which in my mind would be the major obstacle of getting FDA approval for p3. FDA may 'advise" to conduct a trial that is either limited in scope to cisplatin Q3W or a trial with large enough population to address conclusively the uncertainty with cisplatin Q1W. I hope that will be the outcome. Unfortunately I can't completely rule out of possibility that FDA wants an additional phase 2 study to address weekly cisplatin question. We'll see.
Good point. Maybe you can provide the answer. I honestly admit that I don't have clue how get THAT INFO.
LR, you are absolutely right that my table does not address the whole picture. It was not intended to. I intended it to point out that not getting BTD is not end of the world for IPIX. Bad news, YES.
About those statistics you were asking. Here are some:
Fast Track Designation, Cumulative from March 1 1998 to June 30, 2018
Applied: 424
Granted: 283 (6 applications pending)
Designation approval percentage: 66.7 (pending applications assumed to be denied)
NDA/BLA Granted: ?
Marketing approval percentage: ?
Breakthrough Designation, Cumulative from 2012 to November 14 2018
Applied: 724
Granted: 264
Designation approval percentage: 36.5
NDA/BLA Granted: 125
Marketing approval percentage: 17.3
Unfortunately I could not find NDA/BLA percentages for fast track, my guess is that it is markedly lower than for BTD. Otherwise, numbers do confirm your contention, BTD is more difficult to obtain.
I am bit surprised with the differences in application numbers. It would be interesting to get breakdown by applicant size and business stage (development stage co, or not). That info might explain at least some of the difference in numbers.
Sources:
FTD
https://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cber/ucm122932.htm
BTD
https://www.focr.org/breakthrough-therapies
I noticed that there has been number of messages about how crucial breakthrough designation (BTD) is for the future of B-OM and hence survival of IPIX. Here is some historical background for that discussion.
Currently Brilacidin has Fast Track designation (FTD) but not Breakthrough designation (BTD) and it looks like BTD is not coming.
Last year (2017) FDA approved 46 novel drugs.
18 of the approved drugs had FTD.
17 of the approved drugs had BTD.
9 of the approved drugs had both FTD and BTD.
28 of the approved drugs had FDA granted Priority Review for NDA/BLA application.
Here is the interesting part. One might assume that BTD would results in FDA granting more Priority Reviews for drugs with BTD than for drugs with just FTD (BTD being so 'crucial'). Not so, as one can figure out from the above table. ALL approved drugs with FTD had also priority review, so did ALL approved drugs with BTD.
In case someone asks - Priority Review is not automatic consequence of either FTD or BTD. (can't help it, but I do sound like discussing about some disease)
Helluva good questions Karin!
We know that FDA and NIH are putting renewed pressure on companies to publish trial results, but what can they do if a co keeps a trial in not completed state for years. Probably nothing.
As to competitive advantage: not updating early stage clinical failure might keep competition chasing possibly wrong target or formulation a bit longer. Much harder to see what benefits there would be for not announcing success.
LR, about the last paragraph in our post: Probably so and about time.
The question is "Why?"
The PR shows up at the bottom if one filters for 2016. So, take your pick
a. bad data entry
b. sloppy filter code
c. Leo's nefarious plan to hide certain PR:s
By my experiences with the filter at IPIX website I lean towards a+b as the most likely culprit. Others can go with more outrageous reasons if they feel compelled.
What I meant was: Depressing number of pharmaceutical companies treat trial registry as nuisance and in violation of regulations do report very little or nothing. And why not: as far as I know before 2017 FDA had not issued single fine for violations.
I, for one, hope the new rules in effect since January 2017 will improve situation. May be futile, thou.
current trial registration regulations:
https://www.ecfr.gov/cgi-bin/text-idx?SID=e617ec4da22678f934787ed565bbaa5a&mc=true&node=pt42.1.11&rgn=div5
Trial protocol is THE DOCUMENT that specifies ALL outcome measures in a given trial. It must be approved by FDA before a trial can commence if the drug is intended for sale in USA. So FDA does know, very often we don't.
I noticed the same thing. So I peeked what Galera did in phase 2 (still ongoing). Cancer survival is there. I assume that Galera's filing is a sort of placeholder and will be fattened up soon.
Yes, all outcome measure should be in the registry at clinicaltrials.gov. In practise companies do have much leeway when and what do they provide.
see: https://www.statnews.com/2017/01/17/clinical-trial-reporting-new-rule/
And no, I don't expect B-OM phase 3 to have cancer survival component. Galera's interest is a results of some studies showing hydrogen peroxide inhibiting tumor growth. GC4419 presumably converts radiation produced super oxides (oxygen diatom with one electron knocked off by radiation, I guess) to hydrogen peroxide. Hence Galera's interest. Also, Galera had survival analysis included in the protocol of GC4419 phase 2 trial, which is still ongoing.
see: https://clinicaltrials.gov/ct2/show/NCT02508389?term=GC4419&rank=3
Brilacidin has not (yet ??) shown similar effect on cancer as far as I know.
Can someone explain what is done between the Primary and Study Completion Dates that takes 4 years to do?
The time difference is usually due to secondary measures. Galera probably wants to see if GC4419 inhibits tumor growth and hence improves survival time and has included survival analysis in secondary measures. Waiting sufficient number of people to die takes a long time. Cancer study part does not prevent Galera from filing for SOM after SOM related studies are done.
There are ways. All uncommon, but these come to mind.
Outright denial of phase 3.
FDA tells to applicant that additional phase 2 studies are needed before proceeding to phase 3. Admittedly very rare, FDA rather rejects the request for EOP2 meeting than wastes its time with a futile meeting, but it is possible that information revealed only in EOP2 meeting does not leave FDA any other choice.
Giving the applicant a tough task.
a. FDA advises to have a such trial size (or number of trials) that the applicant may not be financially ready to undertake the studies (CTIX/IPIX, AVEO)
b. FDA advises using trial design which may cause the applicant to conclude that successful phase 3 is not achievable (GSK).
c. FDA advises on indication restrictions that may cause the applicant to reconsider the market potential of the drug and make the market to re-evaluate the applicant's value even if the applicant decides to proceed.
In some cases the applicant may choose to ignore FDA's 'advice' and go ahead anyway, but that usually comes and haunts them on approval filing. Both AVEO and GSK did ignore FDA advice and went ahead. Only the bigger one got 'lucky'.
Thanks, Karin. Enlightening.
Nice problem. I give it first a probability treatment to see if any other explanation is really needed.
We have 17 subject out which 6 have median enema retention time less than one hour. 4 of these short retention (SR) subjects are found in cohort B which has 6 subject. How likely this is if subjects are otherwise similar?
This is called k combination out of set N problem.
There are 12376 unordered ways to take 6 subjects out of 17 (cohort B out of all subjects) or
Factorial(17) / [Factorial(6)*Factorial(17-6)] = 12376
There are 15 unordered ways to take 4 subjects out of 6 (4 out of SR subjects to cohort B) or
Factorial(6) / [Factorial(4)*Factorial(6-4)] = 15
There are 55 unordered ways to take 2 subjects out of 11 (2 out of non-SR subjects) or
Factorial(11) / [Factorial(2)*Factorial(11-2)] = 55
Probability that cohort B would have exactly 4 short retention subjects is:
(15*55)/12376 ~ 0.0666.
The result would not cut the threshold for significance, but, still, does ask for some explanation. Can we find one? According to my reading of the poster the trial was open label dose escalation study with retention time evaluation based on patient diary during outpatient visits. No mention of any randomization (possibly none) which will keep us in the dark how subjects were distributed among cohorts. So ...
I tend to agree with Karin and LilKahuna - there are several benign ways how the results could have happened especially in an open label phase 1 study using evaluation performed by patients - could be differences in enema administration times, overall physical activity, eating times, overall health etc...
But let's stay with probabilities for a while.
It seems that subjects had mild to moderate UP/UPS. It is possible that cohort B just had more moderate subjects than other groups. For instance, assuming that there were 8 moderate and 9 mild subjects and no randomization based on disease severity then the probability that cohort B had at least half of the moderate subjects is about 25 % - not impossible occurrence.
Thanks, ffrol. Let's see if you get an answer.
"don't we need that space"
IPIX seems to be set to use CROs whenever possible. They probably can do what is needed in near future with relatively small staff:
- a md and possibly a biologist to oversee safety and formulation work
- a md clinical project manager and a statistician to oversee clinical work and data analysis.
- shared associate or two for office work
As to what clinical work is planned... anybody's guess. However, even if IPIX manages to get a business partner it is my opinion that the above persons/positions are good to have for working contact with BP.
ffrol, I agree with your take. However, it does not follow that when CRO gets paid the results are immediately out. My reading of the situation is that analysis is not done, and probably was not supposed to be done by CRO. That would also imply that nobody knows the results yet. Just my reading.
Nice point. I have been wondering why certain people seem so eager to forget that one.
It depends to what you compare. Most antibiotics do have shorter plasma half lives than Brilacidin, granted. So does aspirin, acetaminophen, ibuprofen even caffeine. But have you taken a look at half lives of some biologicals? Psoriasis medication secukinumab has half life about 27 days. Human serum albumin has half life about 20 days. I think ffrol's intended point was that B. gets eliminated in relatively short time.
Amatuer17, Re your point 5:
BEVERLY, MA – October 9, 2018 (GLOBE NEWSWIRE) Innovation Pharmaceuticals, (OTCQB:IPIX) (“the Company”), a clinical stage biopharmaceutical company, is pleased to report that it has secured new financing for up to $10 million from one multi-family office focused on healthcare and life sciences, including an initial net placement of approximately $2.2 million over the first 30 days. These funds will be used to continue to advance the Company’s pipeline of first-in-class drug candidates: Brilacidin for Oral Mucositis, Kevetrin for Ovarian Cancer and Prurisol for Psoriasis.
Emphasis mine.
Great and concise summary!
I agree, but I still want to point out that the impact of BTD on Brilacidin development time would be modest and dependent on how co-operative IPIX?BP would be with FDA about the design of phase 3 trial. They have no benefit from earlier close work with FDA and there might be some kinks to be smoothed out before proceeding. After the design is agreed upon FDA has no choice but become the traditional uninvolved gatekeeper.
Brilacidin is like most other drugs -large doses, cumulative or instantaneous, will increase the likelihood of unwanted effects. Brilacidin single dose limit due to increased incidence of hypertension is probably around 0.8 mg/kg. Others may know better.
Funny. I did not mean that. With BTD FDA will assign persons to advisory functions for the duration of development process, but these persons do not do the development work themselves.
LR, BTD was intended to speed up the early clinical stages of drug development without changing drug approval requirements. The last step where FDA can and will help a sponsor with BTD is the design of phase 3 trial. After that FDA is back to its usual gatekeeper duty.
Yes it does.
I agree in this sense: at this stage BTD would tell a possible partner a lot about FDA's attitude towards brilacidin in OM. BTD itself probably would have only a minor effect on phase 3 trial design. For that phase design rules tend to be ironclad.
Main difference is FDA's deeper involvement during early (p1 and p2) development plus FDA provides dedicated resources for development under BTD.
Dangerous to rely on wikipedia alone. BTD does not mean priority review. FDA does not say so. BTD's scope of effect stops at the start of phase 3. Priority review's scope of effect start after phase 3. I pilfered the below useful table from JAMA article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5820715/
Thanks, LR. Now, funny, that you mention the end of phase two meeting, or, more precisely, the lack of exact date for it. I was looking into it when I noticed your response. Here is what I found:
"If a meeting request is granted, the FDA will notify the requester in writing according to the timelines described in Table 1. For face-to-face and teleconference/videoconference meetings, the FDA’s letter will include the date, time, conferencing arrangements and/or location of the meeting, as well as expected FDA participants."
You have it correctly. IPIX should know the exact date. Why not divulge it? No clue.
Hey MX. this is from FDA guidance:
"For example, a meeting can be denied because it is premature for the stage of product development or because the meeting package does not provide an adequate basis for the meeting discussion"
I guess the PR has little more meaning than you waking up breathing this morning.
Loanranger, how do you know that the meeting happened over two and a half years ago? Yes, results for Kevetrin phase 1 were announced in February 2016, but when was meeting date announced? And if it ever was what was the date?
Maybe the difficulties in recruiting subjects had something to do with the fact that patients with relapsed platinum resistant ovarian cancer (meaning a really nasty cancer) were asked to wait a minimum of 3 weeks with mere BIOMARKER study BEFORE commencing salvage therapy.
I would hate to be in the recruiting doctor's shoes. And my hat goes high off for those unselfish individuals willing to shorten their already meager life-expectancies for science.