Replies to post #68773 on Biotech Values

[north40000]

GNVC: I found this analysis interesting and persuasive.
What is wrong with it?

http://www.investorvillage.com/smbd.asp?mb=1195&mn=1834&pt=msg&mid=6144414

>> Recs: 5 Yahoo Poster Tamuvet2002: PACT Interim look in SIMPLE terms
Apparently considerable confusion about "median" and 24 months.
Hence, hereby I have copied the posting of Yahoo poster TamuVet providing a decent explanation.
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1. 50% of Locally Advanced Pancreatic Cancer patients are going to die by 10 months, no matter what you do at this point with all available treatments, including TNFerade.

2. However, most of the remaining (SOC only) patients seem to be barely hanging on at that point (10 months) because only 22% are alive 2 months later. Which means 78% of (SOC only) patients are deceased by 12 months. It seems 28% (!!!) of all SOC patients die between 10 and 12 months.

3. To contrast, the vast majority of those remaining 50% of (SOC + TNFerade) patients are going strong at 12 months. Only another 10% or so die between 10 and 12 months.

4. At the 12 month mark, 40% of the total (SOC + TNFerade) patients are alive, while only 20% of the (SOC only) patients are alive.

5. It gets even better between 12 and 18 months. Of the remaining (SOC only) pts at the 12 month mark, only half of them (50%) make it to 18 months. However, of the remaining (SOC + TNFerade) pts alive at the 12 month mark, a full 82% of them will make it to 18 months...so 33% of the total (TNFerade + SOC) pts are alive at 18 months, compared to only 11% of the (SOC only) group. This is the most compelling and significant data, IMO.

6. As many have stated, with the starting date of enrollment and the minimal number of patients enrolled 24 months prior to the 92nd event, the 24 month survival data cannot be at all relevent yet.
n=not nearly enough to draw ANY conclusions yet.

I wish the press release had included something stating that the n was so low at 24 months that the data cannot be interpreted with any degree of confidence yet.

It is unfortunate that many seemed to have looked only at median survival and panicked, when it is obvious from the data that the real benefit of TNFerade comes in the 12-18 month period. And maybe beyond that. There's just not enough data now to know how long some of the TNFerade pts will survive.

Even if 24 month survival turns out to be similar to SOC, any drug that keeps 3 times as many people alive for 6 extra months is destined for approval...With current treatments and prognosis for pancan patients, 6 extra months is HUGE! <<

[DewDiligence]

>GNVC – Can the endpoint "overall survival with a P<0.245" be met when there is no difference in median survival?<

In theory, yes. Median survival is simply the intersection of the K-M curve with a horizontal line drawn at a height of 50% on the y-axis. There is no magical power to this 50% number — it’s merely a convention to report data that way.

The observed hazard ratio is—to a first-order approximation that’s accurate enough for this discussion—the ratio of the area under the K-M curve for the control arm to the area under the K-M curve for the treatment arm.

In this case, where HR=0.75 at the interim look, there is roughly 75% as much area under the K-M curve for the control arm as there is under the K-M curve for the treatment arm. However, the difference in the areas under the respective K-M curves comes almost entirely from the interval between 12 and 18 months on the x-axis. This is a bizarre finding that suggests the HR=0.75 result is a fluke and it will not hold up at the final analysis.

>If so, how strong does hazard ratio have to be [to achieve statistical significance]?<

The HR per se does not have to improve to achieve a statsig outcome; however, the 95% confidence interval on the HR needs to shrink considerably. GNVC reported that the 95% CI at the just-completed interim look was [0.49-1.15]; a statsig outcome at the final analysis will require that the upper bound of this interval be <1.0. (Actually, it will have to be slightly lower than that because a small amount of alpha [the “penalty” you referred to] gets expended on the interim looks; however, this is a minor consideration in the overall scheme of things.)

All told, I don’t think this trial is even remotely promising and it certainly would not induce me to seek a license for the drug if I were in the business development department of a Big Pharma. Regards, Dew