for good articles:
Wolfeman;
1. Well thought out post. FWIW, some comments follow;
2. Things are different at the FDA. The positive advisory committee votes recommending approval appear to have been totally ignored since the Committee recommendation was qualified with the requirement that 9902b become a Phase 4 post marketing approval study. The FDA letter apparently asked for additional efficacy data without being specific (per DNDN's PR), and even Dr. Rusk commented during the UBS call that specific requirements should have been included. Where else could additional efficacy data come from but 9902b? Dr Frohlich mentioned during the meeting that 9902b requires 360 events (deaths) before being opened and analyzed, meaning by my estimates a weighted average of only 28% of ITT and control patients will still be alive. While a major percentage of 9902b patients (post protocol change) may be sicker, with a 2:1 randomization and with 34% of the 9901 ITT patients surviving three years, maturing survival data will take a lot of time to accrue, especially since it is highly likely that the recent crossover rate will now be in excess of the past 9901's 75%.
3. TTP data, now a 9902b secondary endpoint, is somewhat different. See Slide 18 at:http://www.fda.gov/ohrms/dockets/ac/07/slides/2007-4291S1_1.pdf
If and a big if, the new Clinical Trial Paradigm rules are followed,the first 10 to 12 weeks post randomization where the ITT and control curves overlap would be ignored when about 50% of all patients progressed.Half of those remaining would progress in 24 to 32 weeks. Technically that data might mature by the end of this year, and putting aside arguments about whether this could be a basis for a surrogate and Accelerated Approval, and adjusted per the agreed Cox regression analysis, this would likley be statistically significant. The chances of the FDA giving Accelerated Approval on this basis would remain slim.
4. Another approach is more creative and thus, unfortunately, unlikely. Localized prostate cancer doesn't kill, metastases do. TTP measurement reflects increased metastases, and a delay should be considered a clinical benefit. A look at 9901 TTP plots clearly shows that under the new "Paradigm" TTP would have been statistically significant, if progression were censured during the time to allow an immunity rampup. Rising PSA during hormone therapy is indicative of cancer growth / metastases. It is also the beginning of AIPC/HRPC.The median time to failure of hormone therapy has been generally reported as 18 months. Enrollment of 175 patients in the P11 trial was completed 24 months ago. In November 2006, 16% of patients had already progressed with evidence of distant metastases. Provenge had already shown statistical significance in increasing PSADT. Time to distant metastases is an endpoint of the P11 trial along with survival. There are no crossovers in the control group. The ITT group are given a Provenge booster when PSA crosses 3 ng/mL, unfortunate in a way, that this differentiates the trial from 9901/9902a, but along with the P11 immunology data is strongly suggestive of clinical benefit. If 9902b's protocol is left unchanged, patients will be denied the benefit of boosters while the trial accepts the penalty of crossover confounding. If I were advising DNDN I would strongly argue with the FDA that if the P11 trial is statistically significant for PSADT and time to distant metastases, it is the second confirmatory trial that should support Accelerated Approval while waiting for 9902b to mature. It should also be the basis for allowing booster shots to all 9902b patient requesting them.
5. Getting back to the Advisory Committee process, if the FDA action is not cleared up in the near future, it makes a farce of the whole quasi judicial Advisory Committee process, especially in the absence of a detailed and reasoned explanation of why its recommendations were not followed. The statute actually states that the Advisory Committees are the only officially sanctioned source of advice wrt to FDA approvals. The published letters from Hussein, Scher and Fleming, if considered at all, are breaches of that statute. The FDA approval of Gemzar as a salvage therapy in ovarioan cancer in spite of a 7-3 ODAC recommendation for rejection of Gemzar reportedly came as a result of Lilly providing further data from the completed trial, and not from post ODAC third party advice. My WAG here, unfortunately, is that Scher, Hussein, Fleming and unidentified third parties' opinions counted more than the Advisory Committee. If DNDN, its patients, shareholders, employees and others are to be screwed by a demand for data only available years from now, the whole process should get a thorough dose of sunshine and hearing before the same Federal Court system now deciding whether the FDA can withhold experimental therapies from dying cancer patients.Whatever people think about the Federal judicial system, the trial court success of the Abigail Alliance in making the FDA show cause as to whu dying patients should not be free to consider experimental medicines, indicates that there is a genuine aversion to unfairness especially wrt to dying patients. Even that cold hearted witch, Maha Hussein endorsed that at the Advisory Committee with her inside joke that DNDN provide Provenge at no cost to all patients asking for it from now until 2010. Let her explain to a judge what difference it should make if DNDN gets paid for Provenge in deciding whether a dying patient should have access to it. It could even be possible for patients and other impacted parties to bring a derivative class action should the company decline to do so itself.
6. Where to from here? IMHO, there would be no question that if SNY, PFE, Roche or Novartis asked Drs. Petrylak, Small and von Andrian of Harvard to detail the M of A and opine whether Provenge works, the answer would be a strong yes. Suggestions that any of these companies might enter into a near term ROW agrement with a large upfront payment must be balanced against the possibility that they could take everything, now and for the future, with an offer at least 50% above the market price to force DNDN to the offer to shareholders. IMHO, there is a great likelihood of this occurring in the relatively near future. DNDN would have little ability to mount what ultimately would be a futile defense. Patients would benefit since these valuable vaccines would eventually be available. The present management would largely be replaced, but would be financially protected with their change of control employment agreement provisions. Whenever the next CC is held, Gold should be asked whether or not DNDN would entertain or even encourage a fair acquisition offer if the issue with the FDA cannot be settled within months, as opposed to years. If the FDA issues cannot be resolved promptly, the answer should be yes, even if Gold's opionion would ultimately be rendered irrelevant.
Sad days for cancer patients,and the transparency and integrity of the FDA. Good luck to all DNDN patients and investors.
Wolfeman;
1. Well thought out post. FWIW, some comments follow;
2. Things are different at the FDA. The positive advisory committee votes recommending approval appear to have been totally ignored since the Committee recommendation was qualified with the requirement that 9902b become a Phase 4 post marketing approval study. The FDA letter apparently asked for additional efficacy data without being specific (per DNDN's PR), and even Dr. Rusk commented during the UBS call that specific requirements should have been included. Where else could additional efficacy data come from but 9902b? Dr Frohlich mentioned during the meeting that 9902b requires 360 events (deaths) before being opened and analyzed, meaning by my estimates a weighted average of only 28% of ITT and control patients will still be alive. While a major percentage of 9902b patients (post protocol change) may be sicker, with a 2:1 randomization and with 34% of the 9901 ITT patients surviving three years, maturing survival data will take a lot of time to accrue, especially since it is highly likely that the recent crossover rate will now be in excess of the past 9901's 75%.
3. TTP data, now a 9902b secondary endpoint, is somewhat different. See Slide 18 at:http://www.fda.gov/ohrms/dockets/ac/07/slides/2007-4291S1_1.pdf
If and a big if, the new Clinical Trial Paradigm rules are followed,the first 10 to 12 weeks post randomization where the ITT and control curves overlap would be ignored when about 50% of all patients progressed.Half of those remaining would progress in 24 to 32 weeks. Technically that data might mature by the end of this year, and putting aside arguments about whether this could be a basis for a surrogate and Accelerated Approval, and adjusted per the agreed Cox regression analysis, this would likley be statistically significant. The chances of the FDA giving Accelerated Approval on this basis would remain slim.
4. Another approach is more creative and thus, unfortunately, unlikely. Localized prostate cancer doesn't kill, metastases do. TTP measurement reflects increased metastases, and a delay should be considered a clinical benefit. A look at 9901 TTP plots clearly shows that under the new "Paradigm" TTP would have been statistically significant, if progression were censured during the time to allow an immunity rampup. Rising PSA during hormone therapy is indicative of cancer growth / metastases. It is also the beginning of AIPC/HRPC.The median time to failure of hormone therapy has been generally reported as 18 months. Enrollment of 175 patients in the P11 trial was completed 24 months ago. In November 2006, 16% of patients had already progressed with evidence of distant metastases. Provenge had already shown statistical significance in increasing PSADT. Time to distant metastases is an endpoint of the P11 trial along with survival. There are no crossovers in the control group. The ITT group are given a Provenge booster when PSA crosses 3 ng/mL, unfortunate in a way, that this differentiates the trial from 9901/9902a, but along with the P11 immunology data is strongly suggestive of clinical benefit. If 9902b's protocol is left unchanged, patients will be denied the benefit of boosters while the trial accepts the penalty of crossover confounding. If I were advising DNDN I would strongly argue with the FDA that if the P11 trial is statistically significant for PSADT and time to distant metastases, it is the second confirmatory trial that should support Accelerated Approval while waiting for 9902b to mature. It should also be the basis for allowing booster shots to all 9902b patient requesting them.
5. Getting back to the Advisory Committee process, if the FDA action is not cleared up in the near future, it makes a farce of the whole quasi judicial Advisory Committee process, especially in the absence of a detailed and reasoned explanation of why its recommendations were not followed. The statute actually states that the Advisory Committees are the only officially sanctioned source of advice wrt to FDA approvals. The published letters from Hussein, Scher and Fleming, if considered at all, are breaches of that statute. The FDA approval of Gemzar as a salvage therapy in ovarioan cancer in spite of a 7-3 ODAC recommendation for rejection of Gemzar reportedly came as a result of Lilly providing further data from the completed trial, and not from post ODAC third party advice. My WAG here, unfortunately, is that Scher, Hussein, Fleming and unidentified third parties' opinions counted more than the Advisory Committee. If DNDN, its patients, shareholders, employees and others are to be screwed by a demand for data only available years from now, the whole process should get a thorough dose of sunshine and hearing before the same Federal Court system now deciding whether the FDA can withhold experimental therapies from dying cancer patients.Whatever people think about the Federal judicial system, the trial court success of the Abigail Alliance in making the FDA show cause as to whu dying patients should not be free to consider experimental medicines, indicates that there is a genuine aversion to unfairness especially wrt to dying patients. Even that cold hearted witch, Maha Hussein endorsed that at the Advisory Committee with her inside joke that DNDN provide Provenge at no cost to all patients asking for it from now until 2010. Let her explain to a judge what difference it should make if DNDN gets paid for Provenge in deciding whether a dying patient should have access to it. It could even be possible for patients and other impacted parties to bring a derivative class action should the company decline to do so itself.
6. Where to from here? IMHO, there would be no question that if SNY, PFE, Roche or Novartis asked Drs. Petrylak, Small and von Andrian of Harvard to detail the M of A and opine whether Provenge works, the answer would be a strong yes. Suggestions that any of these companies might enter into a near term ROW agrement with a large upfront payment must be balanced against the possibility that they could take everything, now and for the future, with an offer at least 50% above the market price to force DNDN to the offer to shareholders. IMHO, there is a great likelihood of this occurring in the relatively near future. DNDN would have little ability to mount what ultimately would be a futile defense. Patients would benefit since these valuable vaccines would eventually be available. The present management would largely be replaced, but would be financially protected with their change of control employment agreement provisions. Whenever the next CC is held, Gold should be asked whether or not DNDN would entertain or even encourage a fair acquisition offer if the issue with the FDA cannot be settled within months, as opposed to years. If the FDA issues cannot be resolved promptly, the answer should be yes, even if Gold's opionion would ultimately be rendered irrelevant.
Sad days for cancer patients,and the transparency and integrity of the FDA. Good luck to all DNDN patients and investors.
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