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azure, de Moivre "discovered" the concept of "normal distribution". In 1738 he published the second edition of “The Doctrine of Chances.” Pearson said it best,“ ...the normal curve is beautifully simple, and we may use it as a first approximation, particularly in theoretical investigations.
My understanding is the PPHM data presented at ASCO withstood the "null hypothesis" at the 95% confidence level. Can someone verify that? CJ? Maybe I'm remembering wrong. Tests of normality measure the chances that a given data set {x1, …, xn}, or trait(Bavi test results) comes from a normal distribution of measured traits vs. the alternate, that the measured trait distribution is arbitrary.
About 68% of values drawn from a normal distribution are within one standard deviation s > 0 away from the mean µ; about 95% of the values are within two standard deviations and about 99.7% lie within three standard deviations. This is known as the 68-95-99.7 rule, or the empirical rule, or the 3-sigma rule.
As a rule of thumb, 2 standard deviations past the mean is considered significant. That's the 95% confidence level. Scientific inquiry into biological systems presupposes flexibility because of infinite variation, but 2 standard deviations from the mean, or 95% confidence level, is acceptable to infer that there is, in the case of Bavi, biological activity. Nothing is ever completely certain, but the closer 100% is approximated, the mre certain.
The India tests on Bavi reveal that even though it is chimeric in construction, that is, has mouse protein parts rather fully human parts, and must induce some body reaction against that protein, the MAB still creates what is almost certainly a net positive when mixed in the cancer chemotherapy mix. Bavi does not reduce reduce chemotherapy efficacy, but almost certainly adds to the cancercidal effects without adding complications. Adding naked Bavi to standard chemotherapy protocols actually facilitates clean-up after chemo-kill, and probably increases survival time. The chemotherapy industry cannot be thrilled. MAB-Bavi can deliver with pinpoint accuracy a tiny dose of the same chemo agents or better--park it alongside cancer where it explodes the tumor like a suicide bomber. And a little naked Bavi in the mix helps tidy up afterward. The cancer chemo companies are accustomed to cancer patients wallowing in cytoxins taken orally or intravenously. So quantity demand for the same crowd of chemo- warhorses, cytotoxins will surely diminish in the next decade as medical science converts from gross total-body chemotherapy to specifically guided tumor-site MAB delivery systems like Bavi.
A caveat: normal distribution is a simple and convenient model to use, but sometimes researchers assume that trial data is distributed normally rather than skewed, and efforts have not been made to measure the skew. An example is assuming outcomes in Bavi would be the same between Indian castes, or caucasians, without measuring the assumption. It is said that the maturity [or immaturity] of a scientific field can be judged by the prevalence of the normality assumption in its methods.
source: Wikipedia "Normal distribution"
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lurker, you're right. I alluded to that study when ASCO results were first published. Really, the most we got from our study is that it is safe to use an anti-PS in combination with other chemo agents, and maybe (probably) as an unarmed and non-fully humanized MAB, naked Bavi has some immuno-stimulatory properties. The question is what this data allows us to skip in regulatory steps on the way to market with an armed and fully humanized Bavi.
thurly, your interpretation of the company's vision of early FDA approval seems about right. You said, "I would not be surprised if we missed stat[istical] sig[nificance] for some reason that was not clear from the earlier work."
In some ways PPHM DID miss statistical significance, by reporting data that was only good at the 05% confidence level. Any number less than that is a wasted trial. So we can say the India venture paid off handsomely. Huge! After the numbers are in, statisticians take over to determine the statistical significance of the generated numbers, and their formulae will push the confidence level as high as the numbers will permit. An order of magnitude greater than .05 would definitely do it. So would .01%. But .05% was it. No higher level of significanc was possible from that set of data. That's what they had to go public with. That's what we live with. 05% is acceptable evidence for me because I am gambling here, but it is not acceptable to the hardened realists at FDA (and BP and Wall St.).
A repeat of that number (or better) under US testing and reporting conditions would probably do it. Most important, overall survival number is not in, and as CJ and others have observed here, the longer that information takes to generate, the better it looks unless the number is known already and not divulged. If that number is spectacular the other numbers won't matter.
As mentioned here before, the DNDN denouement was actually good for PPHM because if DNDN can get Provenge approved on the piddling numbers they came up with, PPHM can get Bavi through on its results, India or no.
FDA was mightily swayed by Merck Germany's trials of Erbitux, but probably learned a lesson on that one. I don't think Bavi results in India were impressive enough for that. The results were good, but a lot of questions remain. Bavi's role reported at ASCO as an immunological stimulant is a quirky result discovered on the pathway to developing fully humanized Bavi which carries a payload. The Indian trials render a verdict rather more on the entire anti-PS platform's potential going forward. If a non-human form of naked bavi is safe, and its also effective stand-alone against cancer, what will be the results of a fully-humanized and fully-armed Bavi carrying a payload of known anticancer agents with known side-effects when adminstered systemically rather than locally? Slam-dunk IMO. Anti-PS is here to stay. They're just jockeying for the bucks right now.
Moby, the statement,"...the FDA and bigfinance respond only to sufficiently large, randomized trials..." is erroneous. There ARE other avenues to FDA approval, many.
In regard to; "Where [what] is the threshold for a sufficiently large, randomized trial publicly documented?"
No documentation exists as such, but the parameters driving test- subject size is related to statistical method. That is, at what "confidence interval" are you comfortable.
The "numbers" generated in India PPHM trials reported at ASCO were said to be good to the .05 confidence level. Thus the observed results for Bavi in India, if they had occured from chance, could have only done so 5 times in a hundred. The .05% confidence limit is not generally considered good enough, but a barometer, and an easily duplicable number, and duplication is the name of the science game. Bavi has earned undisputed right to confirm its numbers in this country, a great leap forward. So pick your "confidence level," and given the same numbers generated in India, a statistician can tell you the patient trial cohort size.
Does Peregrine's "flagship gold-standard" (AKA repeat phase II) trials exceed that threshold?
swingtrader, good article on SKG Avandia. Side-effects causing its demise. But hey, Avandia is competing with insulin, and diabetes is a chronic disease now, with better prognosis than cancer or AIDS. Poorly reported side-effects may bounce an otherwise good pharmaceutical off the retail shelf, witness thalidomide. But AIDS and cancer is where PPHM is, and little PPHM has great science aimed that direction.
drontole2,someone forgot to shut down the computer for the weekend?
weekly PPHM recap. The bottom arrived with a ten cent bounce which almost tranquelized shell-shocked PPHM retail stockholders fearing the worst. However, moments of light peeked through, such as when one poster wrote that PPHM's wholly owned subsidiary, Avid, an FDA certified manufacturer of the most brill and complex monoclonal antibodies, alone is worth the float.
Until the,uh,boardroom bulls gain enough maneuvering room to divvy up the gazillions, retail stockholders pray they're hangin' onto the right coattails and have enough voice to shout what they thimpk about ten cent turn-arounds. Another idea a poster here had, that this might be a "quiet time,"--can't remember his penname, the one who posts a photo of himself: happy-looking; in cover-alls; and smoking a corn cob pipe. He postulated the company silence might be mandated by a soon-to-be-announced take-over announcement.
Retail stockholders are so shell-shocked at this point most would agree with a low multiple to par buy-out, as if it would be a blessing. A takeover at this point makes sense. A charade usually ends when everyone is in on it, and the value of PPHM intellectual properties remains inestimable. Roche/DNA are stymied, resorting to a conjugate of Herceptin now. Be real. Herceptin, Avastin, ERbitox,and that ilk are old, and now ineffective warriors. Let them retire with dignity. I agree with those posters here who decry the inhumane delays...no matter what spoke they are in the wheel. Roche does not appear to be the winner here. BMY just bought a fully humanized EGF MAB to replace erbitux. Got it right. It must be Merck. International clout. Getting PPHM would be the coup of the century.
Unpath, thanks. The newest HIV discovery does not work in humans.
jgal, thanks. Primacy is important, and the Roche/DNA announcement is an attention getter. Their conjugate will probably work better than Herceptin. However, any reasonable person would choose Bavi's exclusive -PS docking site over Herceptin's since Bavi is much more widely applicable. There is every advantage in the world to Roche/DNA seeing to it that PPHM stock price and prospects remain low, whether because of an intended buy-out, PPHM going it alone, or a proxy-skirmish with another big pharma with a winking understanding with PPHM for the future. There is no question that fully armed and fully humanized Bavi- is a viable anti-cancer weapons system, and probably the best one out there (along with BMY's fully humaninzed anti-EGF). But proof remains, and the game is getting tighter. The strategy is how to get that system to the marketplace. It already has credibility for safety and efficacy. PPHM has no financing problem if its science is sound.
anyone think Roche/DNA has anything to gain by gaming PPHM stock?
Not to mention its credibility. The MAB-conjugate is the obvious place to be, and guess why we're not there yet. Another eloquent attestation to realities of the marketplace.
A Phase II trial evaluating T-DM1 for this use has completed patient enrollment, with interim data expected to be reported at the European Society of Medical Oncology (ESMO) meeting being held Oct. 8-12, 2010 in Milan, Italy. This trial compares T-DM1, given as a single agent, to Herceptinâ (trastuzumab) plus Taxotereâ (docetaxel).
thurly, nice find. We would be there too with armed Bavi if we had the $$$ Roche has.
Jonny...."The researchers also found that VRC01 did not bind to human cells — a characteristic that might lead to its elimination from the body and lack of efficacy."
this morning's trading data is an eloquent testament to who is in charge...
joev2,welcome.we need your insightfulness.
jess, enjoyed the retail trader article, thanks
good post moby. interesting articles.
an up/good day, only lost about $500.
lafont, you've fingered the problem: nobody has any cash.
geo, good point. We all form patterns in our minds created in part by connecting dots of data, and although the information is only a pattern (except to patients who are cured or who live a few extra weeks), it is enough in this case to form a strong inference. Thales asked if the data would have created a bigger pps ripple if the studies had been double-blinded placebo controlled. At PII level? Questionable. Such trial designs help decrease observer/experimenter/patient bias, and should be done, but it actually makes more sense to do it the way PPHM did it. Why? What if the results had been worse? We got a huge amount of information at much less cost than if the trials had been done in the US.
jess and thales, strong inferences may safely be drawn from the data which attains statistical significance at the 95% confidence level (if memory serves me), which means that such data would only be generated by chance 5 times out of 100, odds I am comfortable in gambling with. The trial established that Bavi is safe enough and has enough anti-cancer activity to continue trials, and has garnered considerable interest in the scientific community, the details of which we don't need to detail again. Without management's huge gamble to take trials offshore we would have almost no data and correspondingly less hope.
and thales, about SK wanting to have FDA product approved within 2-5 years.... "and taking into account slippage and we are talking 7.." Time to production will shorten in the future, and in some cases, dramatically. The public will not be fooled long, and the demand is obvious for safe cancercidal agents with unique MOAs, witness Cotara and Bavi-both with definite therapeutic utility--proven utility IMO. We are witnessing a bewildering denouement of huge proportions. Interesting to see who gets the most money out of it.
agree with this. SK's stated aim for this year (according to a conference webcast) was to get some licensing deal in place.
Thales, the glass is half-full, believe me. Read my lips. A WRITTEN deal hasn't happened. Period. You said the market swoon makes a deal more difficult. Maybe easier. The public needs to believe in sumpin' right now, and imo it might as well be Bavi-.
You said, "the trial data isn't good enough." That's not true. If the data stands on repeating, the data speaks, and its good enough to warrant the market and continued development. And Bavi data will get even better. The gold standard to establishing drug efficacy is double-blind randomized trials. True. That's where PPHM and Bavi- are heading, and if an investor cannot abide throwing off some extra ball-ast in this race, they should enter another, or watch from the sidelines. You said, "All [the bavi/cotara] studies are - from the point of view of professional investors - not worth jack s**t." Utter nonsense.
The science behind bavi IS magnificent, agreed. IF(?)they [PPHM] can raise money for a double blind randomized trial? Done. Results? About the same as those conducted in India, a country of medical genius and integrity, trying harder because they are an "underdeveloped country."
You said, "as it stands [PPHM] has a drug pipeline that' never produced a product in ... 20 years or so." Correct. But PPHM got it right this time. Probably an accident, but they got the science right. Imagine the pressure. PPHM has been totally ethical on the science. It is what it is. And it will only get better.
According to SK he wanted to have either one or both products approved within 2-5 years. I was optimistic before and thought it could be done in 2 but this was just exuberance. 2 years is the time to get the phase 2bs completed. If nothing is approved after that then they need phase 3's and it will be more like 5. Take into account slippage and we are talking 7
nysemover indeed. The prodigal son. What IS up? Which boards ya'l be hauntin'? Weird timing. Still workin' for the same folks?
OMG old bloggers reappear out of the mist of time....
have anti-PS prospects changed/worsened in the past two weeks, or only the pps? help me on this one. if you're fund that must buy PPHM shares on the open market this is a good way to do it. wonder who bought that quarter of a million shares? wonder who's going to step into this hyena attack to give succor to the wonded beast? its a jungle out there and we're only a couple paces inside the canopy with no deep pocket defender. interesting and painful stuff. for the 4th time, does anyone have any memory of what happened last time PPHM was fortunate enough to be included in the Russell? and who was it here that said we simply have to be part of that crowd? maybe it as simple as we aren't grown up enough to run with that crowd yet. someone has made (and lost) some BIG bucks as a result.
mojojo, most posts about DNDN here, and the great article on the white collar crime/criminals surrounding that story, miss one important point: Provenge approval is a huge plus for PPHM because it reinforced a much lower bar to be surmounted for efficacy and approval of any new drug. Skeptics and shorters of DNDN stock had a valid point of view. It truly IS a weak sister (IMO). I got involved short-term in DNDN at about $18 just before the FDA declined to approve it, and saw it go to $8, and I had bought against all scientific fact and logic, betting that the public hoopla would carry the day. DNDN is an interesting story, but not because Provenge is any great shakes. PPHM and Bavi- have much more potential.
thanks CJ. Great analysis. PPHM needs DTRA?
Mngmt. understands the uncertainty of government contracts.
Govmt work is frosting, hardly the meat of corporate financial planning.
If the PeoplesrepublicArmy is "into" Cotara, and
anti-PS therapy is a "go", and it is, ...combined with Avid
potential for rabid growth, and present cash position...hmm.
PPHM survived a tough year in the marketplace.
Looking back, was survival a serious question?
Transitional times are uncertain, and
Politics and cold reality still determine
Health resources for the "small people".
Stockholder satisfaction is a corporate asset,
And PPHM's decreases as the science strengthens.
I shudder when thinking of my PPHM stock account...
Where all that money could have gone.
Stockholders sentiment is not.
Some token...at least...seems in order.
Thus far PPHM science has not faltered, but progressed.
Let's continue to protect our investment in the ultimate commercial applicaton of PPHM technology.
wonder where the Russell people can get their shares cheaply...
cj, most common reason is "lost to follow-up." Amazing how many people drop out of trials or do not return for follow-up visits, and cannot be reached, yada.
Sunstar, correct. That's why I'm here. "The many" will wish they had been here too. Remember, it's still the jungle out there, and monkey see, monkey do.
wildhorse,you asked, "...if you'd just had several rounds of radiation, would you rather have Avastin or Bavi as a last chance shot?" At this point I would rather have Bavi in combination with irradiation. Wonder when that trial is going to happen. And in the near future, Bavi and/or Cotara actually armed with the irradiation agent.
a history buff query...What hounds took the PPHM share price down after last PPHM admission to(and drop from) Russell index? Failure to ban naked shorts? When is that supposed to happen? More people lookin' this time than last, that's for sure. Maybe that's a good thing. Whew, what a boat ride. We've paid dearly for in the past month. Nobody promised those of us in PPHM steerage the ride would be easy or cheap. Sail on.
mojojojo, I've thought Roche/DNA have been running this company for some time...years
Best of the cancer meetings after dust settles? The widening approval of MABs in the cancer treatment mix...the ability of MABs to carry a payload and deposit it selectively at specific disease sites. Why did PPHM progress notes pass muster with the oncology treatment specialists and researchers? It starts with the dreams and thoughts of a scientist totally in touch with the latest in his field...one who knows how to build a better MAb,a veritable intravenous rocket. From the inventor's brain to the pharmacy shelf is the journey we're on, and PPHM appears to have a good product and smoothly functioning team. Good work!
bungler thanks. int'restin...you old scholar, you.
dia, Hear. hear. Nice.
dia, nice post. Agreed,sounds like Bavi.
co3aii. yes, last two ASCO trading days bode well for PPHM credibility. Not ONE slip. No false note of undeserved optimism. ASCO is enormously hype-conscious, and tries not to suffer fools lightly. Yes!! We stockholders can say. Not ONE negative comment or serious question about the science. (And if you've heard one, please share.) With the hefty albeit tacit nod of approval at ASCO, there really is no question of future financing. Despite the shirt-waving it ceased being a problem some time ago. Commodities as precious as Bavi- and Cotara are financed, and the funds a source of greedful manipulation. Are MABs the delivery system of the future? Site specific humanized MAB-missiles capable of carying cancercidal payload directly to cancer vasculature, surface, and necrotic core. Nano-particles and smaller might work too. Will MABs carry small-particles? Anything, actually. And dump a load of poison only at the worksite My IV rocket? a designer MAB that goes directly to cancer. Cuts to the core. Releases total death for millimeters all around. It isn't pretty. Meanwhile on the surface of cancer? Anti-EGFs, Anti-VEGF, and Anti-PS. In the past we said, "When full human Bavi- is here.... Fully human Bavi- IS here. The question is how best to proceed. If ThePeoplesRepublicArmedForces is interested in TNT-MAB (Cotara) technology, and the USDD in Bavituximab, Cotara profits will probably come out of China initially, so that dance is going on. Why China? That country understands Cotara's worth. Meanwhile PPHM management has lined up the gris iminences of the biotech world to help move Bavi- forward. Should be smooth sailing if the India numbers are solid, and betting money inside a 95% confidence level works for me.