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As you probably know, Amphastar stalked FDA executives (including Janet Woodcock) while lobbying members of Congress to steamroll the FDA into granting approval for Lovenox.
DewDiligence, this is, for lack of a better term, a bombastic contention. I'm not saying it isn't true, but it's not something one accepts without pretty serious evidence. Could you possibly link a source for background? I'm no skeptic regarding scumbag behavior with lobbyists and corporate favors, but this is pretty hard to believe.
Regards,
Tasty
Thanks Dew. I just missed the dead cat bounce on TSPT, and so I'm sensitized to the opportunity.
I just started following this... I gather from the traffic there are a lot of MNTA longs here.
Sucks. Been there. Too many times.
Regards,
TGW
but patents used to test/confirm the quality and purity of the generic drug during the manufacturing process.
Yes, I read it very quickly but it was clearly a "how to make it properly", not a "what it is" thing
DewDiligence, I quickly scanned the complaint...
...unless I'm missing something, the claim is that Watson must have infringed the patent simply because they were able to solve the manufacturing dilemma that MNTA solved (and patented).
It's a logical claim, rather than one based on a smoking gun (having documents that show the use of the patented process, testimony, emails, etc).
Is that right, or am I missing something?
Thanks,
TGW
what makes the MNTA-Amphastar case unusual is that one generic-drug company is suing another.
OK, here comes another naive question... how can there be a patent enfringement in a generics case? What can a company do to infringe on patents when patent protection on the original drug has expired?
iwfal, ok if I ask a naive MNTA question?
Would the FDA really approve a drug if there was serious concern about patent infringement? Are there existing examples where the FDA approved a drug and a patent infringement suit was successful shortly thereafter?
Serious question -- I'm not long MNTA right now, but I do have a "dead cat bounce" sweet tooth.
Thanks,
TGW
Sounds like a good opportunity for TSPT longs to cash out.
I wish I were one.... I was watching but never pulled the trigger!
TSPT: BTW, remember that all you are hearing is what the company is saying. The actual FDA letter could be much more clearly damaging.
I guess the actual FDA letter wasn't much more clearly damaging
Redplate, as you may know, helped design Stimuvax!
I'm hardly one of the brainiacs over there, but I don't think you need to be a biotech whiz to have a strong opinion on this one.
The publishing of the enrollment curve at a conference is the thing that permitted anyone the opportunity to model the trial, as I'm sure you know.
Now it's just courage, I think. But I'm with you... It's a lot easier to stand firm when you have a nice, low basis!
Thanks BTH! It's a nuthouse but it's fun.
I'm pot-committed on ONTY so I should just go away and keep busy until Q1 2012, but I can't pull myself away. I like trash talking too much!
bladerunner, I think we're sitting in a classic "no good choices" situation....
...and when that's the case, the last thing you want to do is create more distortions.
There is no way to avoid a certain amount of pain going forward. Deleveraging hurts. Period.
Government needs to back off, stop all the QE nonsense (how low does the freaking 10-year yield need to go, 1%?), call home the army of regulators that are choking industry and the banks into zombification, leave tax rates alone for now, repeal that stupid healthcare bill, and start working on some sensible, structural solutions on entitlements that are really just refinements on the margin but have enormous long-term spending impacts.
And for Pete's sake, can we drill a few holes in the ground?
We don't need any more freaking stimulus. We need a stable playing field. Nobody can blame businesses for hoarding cash and waiting when they have no idea what the rules are going to be.
Regards,
TGW
iwfal, I found this on O'Brien Fleming and interims, which made me wonder if the methodology is uniform:
http://realizationsinbiostatistics.blogspot.com/2007/09/my-obrien-fleming-design-is-not-same-as.html
Realizations in Biostatistics
Biostatistics, clinical trial design, critical thinking about drugs and healthcare, skepticism, the scientific process.
Wednesday, September 19, 2007
My O'Brien-Fleming design is not the same as your O'Brien-Fleming design
I know this discussion is a little technical, and nonstatisticians can probably skip this, but I hope that a statistician struggling with the O'Brien-Fleming design and its implementation in SAS/IML (notably the SEQ, SEQSHIFT, and SEQSCALE functions) can find this from a search engine and save hours of headache.
There are two ways of designing an O'Brien-Fleming design, a popular design for conducting interim analyses of clinical trials. The first method is to use an error (or alpha) spending function, which essentially gives you a "budget" of error you can spend at each interim analysis. The second is to realize that, if you are looking at cumulative sums in the trial, the O'Brien-Fleming design terminates if you cross a constant threshhold. In the popular design programs LD98 and PASS 2007, the spending function approach is used. In the book Analysis of Clinical Trials using SAS, (a book I highly recommend, by the way), the cumulative sum approach is used at the design stage (the spending function is used at the monitoring stage). When interim analyses are equally spaced, the two approaches give the same answer. When interim analyses are not equally spaced, the two approaches seem to give different answers. What's more, the spending function for O'Brien-Fleming as implemented in LD98 and PASS are different from what they show you in the books. They use:
4 - 4*PHI(z(1-alpha/4)/sqrt(tau))
for two-sided designs.
They don't tell you these things in school. Or in the books.
iwfal, I think I would agree with all of that, except...
There was talk on YMB last fall about the interims being based on O'Brien Fleming around a .001 threshold, and I don't know what that translates to. Clearly there are a range of interim practices and no single convention on what "O'Brien Fleming" means.
It is also possible, given the oddities of this trial (viz. the halt), that the DMC was more conservative in its recommendation, especially since full enrollment hadn't been reached at the 1st interim. FDA guidelines about interim stoppages talk about this kind of stuff. (I'm not saying this DID happen, of course.)
Also, most of the estimates I have seen are based on constant hazard rates (monthly) that would not be appropriate if Stimuvax were working the way that the trial sponsors think it will -- that is to say, that since it's immunotherapy, it takes awhile to "kick in". That would result in the KM curves separating later than you would see in many other trials.
Given that the 1st interim event trigger (presumably) was hit in late summer or early fall of 2010, the weighted average duration of enrollees in the trial at that point was less than 2 years. If I model the curves with later separation and declining hazard rates (esp for Stimuvax), I get an HR right around the level you quoted (.725).
I would agree that, if you are skeptical about Stimuvax, and don't believe the immunotherapy story, then you'd stick with a more traditional approach to the modeling, and end up with the MST estimates in the mid-20's or higher, as you say.
I actually think the control arm is performing well. I think more common use of concurrent chemo-radio is producing good results. I wouldn't be surprised if the control MST came out in the 23 to 25 month range. But given the Merck Germany guidance on 2nd interim timing (and they have regular event count updates), you can't make the math work and have Stimuvax fail.
For me, it's an Occam's Razor situation. Is it more likely that chemo-radio is taking a "great leap forward", or is it more likely that Stimuvax is matching its performance in the two earlier Phase II trials. That's a subjective judgment, of course.
I would point out -- and this is something many didn't note, or may still poo-poo after it is noted -- that the MST in the Phase IIB for Stimuvax was one patient short of being around 47 months. The 47-month survival was 49%. Again, I'm not saying this is an enormous trump card, but it's important data. I think we'd be having a very different discussion, at very different price levels, if that statistic had been 51% instead of 49%.
Regards,
TGW
iwfal, mind if I ask for a clarification of a point you made in an earlier ONTY post?
Please don't use the Phase 2 subgroup results or 3-year pvalue, since that is all post-hoc analysis.
Translation: Please don't use data or arguments that are in your favor. You must ignore all facts that support your belief that Stimuvax is effective.
I'm all for a balanced discussion of what to expect in the START trial, but you have two Phase 2 trials with breathtaking results, and some basic math (enrollment curve x survival rates) that put the onus on a short to explain how that's possible.
Do you have an explanation of how radio-chemo suddenly is producing MST in Stage III NSCLC patients of over 30 months? If you don't, what's your logic for shorting arithmetic? Do you think the rules of arithmetic have changed? That multiplication doesn't work the way it used to?
I can explain how Stimuvax is different from Theratope. Stimuvax had 11 out of 22 Stage III NSCLC patients living longer than 6 years. That makes it different from Theratope, and everything else.
I get a blended median survival of about 9.5 months if you assume:
iwfal:
I concede that, using your assumptions below, and also assuming basically linear PFS (i.e. increasing hazard rates), I get approx identified 310 events at the end of September.
This, of course, is the aggregation of a number of conservative assumptions (esp. LTFU of 14% given crossover offer to progressors, and AVEO guidance of Q4 "at the earliest"), decked against a worst case control arm median PFS based on one trial with healthier entry requirements.
So if literally everything goes against us, it could be non-stat-sig. I'll take the risk.
But I appreciate that you focused on this and actually modeled it.
Regards,
TGW
Well you have to look at the K-M curve for Nexavar out beyond the median to do this right - don't recall if it flattens out or not.
I did at one point. In the examples I looked at, it was very modestly concave, meaning, it flattened out very modestly.
Reiterating regarding the AVEO 310 event count
I got a confirmatory email from AVEO IR
Re the comment on percentages, it's a PFS trial, so they probably assume a pretty high LTFU rate, maybe not as high as some trials though, because there's a cross-over feature in this one.
If you're skeptical, you could really easily just send them an email and ask them. They responded to me quickly, and were very polite and cheerful about my interest in the company and TIVO-1.
Regards,
TGW
AVEO 310 events
I first learned about it on Yahoo
http://messages.finance.yahoo.com/Business_%26_Finance/Investments/Stocks_%28A_to_Z%29/Stocks_A/threadview?bn=106901&tid=288&mid=290
Confirmed it after with AVEO IR
Regards,
TGW
AVEO trial and math
Here's the exact enrollment curve, which you don't get most of the time for a trial:
http://aveopharma.com/product_candidates/tivo-1/
I've done a ton of homework on the control arm in this trial, and 6 months is pretty conservative for median PFS... 7 months would be a big outperform...
It's a 1:1 trial.
If you now assume that the event count for completing the trial (310 PFS events), it's a pretty simple matter to make a reasonable estimate of the median PFS of the tx arm given the hitting of those events on different dates, yes?
They just guided that we'll get a readout no earlier than Q4 2011.... back off three months to July and run the numbers.... my spreadsheet leaves me with a big smiley face
Regards,
TGW
To folks here who have sent PMs welcoming me!
Thanks so much, and don't misinterpret the fact I haven't PM'ed back yet. I have to have a paid membership to do it, and I haven't decided yet what level of commitment to make.
This place is cool, but it ain't cheap!!!
biomaven re AVEO:
Another interesting thing I noticed about this trial is that it's open label, so everyone knows who is getting what.
I assumed that the guidance on trial results timing was a function of AVEO mgmt knowing more or less how things were going based on monthly event reports AND know how much Tivozanib was going out the door for the trial.
Is that naive?
TSPT company spin
I get your point exwannabe. I guess what we have to handicap is whether through dosage differentiation, weight/gender?/other factor differentiation, and overt labeling, they could get the paranoid FDA over the hump.
Clearly the company thinks this will be a long haul as they've cut expenses drastically in anticipation of a long repositioning effort.
TSPT -- rough road, I hear you, but....
I think you have to read the whole press release to get a feel for how rough the road is. It felt walkable to me, albeit it'll take time -- and these guys have a TON of cash:
POINT RICHMOND, Calif., July 14, 2011 /PRNewswire/ -- Transcept Pharmaceuticals, Inc. (Nasdaq:TSPT - News) announced today that it has received a Complete Response Letter from the U.S. Food and Drug Administration (FDA) regarding the resubmitted New Drug Application (NDA) for Intermezzo® (zolpidem tartrate sublingual tablet).
In the Complete Response Letter, the FDA confirmed that Transcept has adequately demonstrated that Intermezzo® is efficacious for use as needed in the treatment of insomnia when a middle-of-the-night awakening is followed by difficulty returning to sleep. However, the FDA stated that it cannot conclude that Intermezzo® can be used safely based on the information in the Intermezzo® NDA.
The proposed label for Intermezzo® indicates that Intermezzo® should only be taken when patients have at least four hours of bedtime remaining before being active again. In the original, October 2009 Complete Response Letter, the FDA indicated that Transcept must demonstrate that Intermezzo®, when taken as directed, would not unacceptably impair next-morning driving ability.
To address FDA concerns raised in the October 2009 Complete Response Letter, Transcept and FDA agreed that a highway driving study conducted to assess the effect of Intermezzo® on subjects' next-day driving ability would provide a reasonable approach to characterize the safety profile of Intermezzo®. As previously announced, in the four-hour treatment condition of this highway driving study, the primary analysis used to determine the capacity of Intermezzo® to impair driving showed no statistically significant difference between Intermezzo® and placebo. In a secondary analysis, the mean effect on driving ability four hours after dosing was statistically different from placebo, but below the level considered in the literature to define the threshold of potential driving impairment.
In the Complete Response Letter received today, the FDA stated that during its review of the Intermezzo® NDA resubmission it became concerned that those patients with higher zolpidem blood levels from Intermezzo® could be at risk of unacceptable next-day impairment. The FDA further hypothesized that such patients may belong to distinct and identifiable demographic groups.
During the review cycle, the FDA requested, and Transcept submitted, analyses of all Intermezzo® studies seeking to identify patient sub-populations that may be at risk for elevated blood levels or next-day residual effects. In these analyses, demographic groups that exhibited higher blood levels were identified, but these blood levels did not correlate with an increase in next-day residual effects as measured by Digit Symbol Substitution Test (DSST), a standard cognitive function test employed by Transcept throughout its development program. In the Complete Response Letter received today, the FDA expressed the opinion that DSST may not be able to adequately distinguish possible adverse effects of zolpidem on driving ability.
In its October 2009 Complete Response Letter, the FDA asked Transcept to demonstrate that inadvertent Intermezzo® dosing errors could be adequately minimized, or that the potential adverse effects of such dosing errors on driving safety could be shown to be acceptable. Potential dosing errors cited by FDA as concerns include inadvertent dosing with less than four hours of bedtime remaining and inadvertent re-dosing in a single night. FDA expressed concern that such errors could lead to higher next-day blood levels that could present an unacceptable risk to next-day driving ability.
In the Complete Response Letter received today, the FDA confirmed that the proposed single unit dose pouch packaging adequately addressed the risk of inadvertent re-dosing of Intermezzo® in a single night. However, the FDA remains concerned that some portion of patients will dose with less than four hours remaining in bed, despite proposed packaging and instructions that the FDA viewed as clearly communicating this dosing restriction.
The FDA further expressed the view that, while a patient use study to define dosing error rates might be capable of detecting high rates of misuse, such a study would not be required. To address the risk of inadvertent mis-dosing with less than four hours remaining in bed, the FDA believes that driving performance at 3 to 3.5 hours after dosing should be considered as part of the safety review of Intermezzo®.
To characterize the risk profile of Intermezzo® on next-day residual effects if Intermezzo® were inadvertently mis-dosed, Transcept assessed subjects' driving ability in a highway driving study beginning at three hours after dosing Intermezzo® in the middle of the night. As previously announced, in drives that started three hours after dosing, Intermezzo® was associated with statistically significant effects in the primary analysis, and one drive was discontinued due to excessive driver drowsiness. In a secondary analysis, mean effects on driving ability three hours after dosing were also statistically different from placebo, but were below the level considered in the literature to define the threshold of potential driving impairment. In the Complete Response Letter received today, the FDA stated that these results suggested clinically meaningful impairment.
As a possible path forward, the FDA suggested that Transcept further investigate whether body weight and demographic factors contribute to differentially elevated blood levels the morning after dosing Intermezzo®, develop strategies to decrease next-morning zolpidem levels, and, after mitigation strategies are implemented, demonstrate that next-morning blood levels do not present an unacceptable risk of next-day impairment, which may include the conduct of an additional driving study.
Transcept plans to meet with the FDA to discuss the potential paths forward, and will provide further updates as appropriate.
Anybody here follow AVEO?
I took a position a few months back and am thinking about adding.
The recent earnings report included news about the results of the TIVO-1 trial being delayed until next year. I think it's pretty easy, from the enrollment curve on their website, some reasonable presumptions about the control arm, and about LTFU given they have a crossover feature in this trial, to reach some optimistic conclusions about the likely outcome of the trial.
Anybody here done any homework on that?
Man, this is a great board!
I spent the better part of the evening reading through the posts, lots of great stuff.
Looking forward to following this regularly!!!
Regards,
TGW
Hey guys, did you read the press release from TSPT about the letter from the FDA? It seemed like a pretty solvable problem, albeit it will take some time.
The cash load is enough for years for these guys. It feels like a good risk, but with no short-term catalyst, is there any necessity to dive in now?
Would appreciate any input on TSPT.
Regards,
TGW
pcrutch:
I guess you don't trust these data either, which were from another Phase II trial including Stage IIIA and B patients, and where the MST, as far as I know, exceeds 5 years.
http://ir.oncothyreon.com/releasedetail.cfm?ReleaseID=515788