Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
Error in FDA Briefing Docs regarding 9902a
Per slide 33:
No. of bone metastases/subject
Provenge Placebo
N = 61 N = 32
0 5 (8.2%) 4 (8.9%)
1-5 19 (31.1%) 11 (34.4%)
6-10 6 (9.8%) 2 (6.3%)
>10 31 (50.8%) 12 (37.5%)
Last time I took division in the 2nd grade 4 divided by 32 is 12.5%. Since this guy is still learning to speak english as well, you have to wonder about the details of the rest of his statistical analysis.
http://www.fda.gov/ohrms/dockets/ac/07/slides/2007-4291S1_3_files/frame.htm
Interesting article quoting Dr. Mule:
http://www.medicineatmichigan.org/magazine/2003/spring/cancer%2Dvac/
I guess this is where we disagree. I do not think it is "rare" in this country. You can have the last word. I would rather be discussing or learning about the odds of Provenge hitting on the interim and final or any looming competitive threats.
I was poking fun at the Chinese system, although I wish ours actually enforced its rules equally for the financial elite and the little guy.
China Takes Lead in Cleaning Up Their FDA
http://news.yahoo.com/s/afp/20070710/wl_afp/chinapolitics_070710152113
8K
10-Jul-2007
Other Events
Item 8.01. Other Events.
On July 2, 2007, Dendreon's Board of Directors received a letter dated June 28, 2007 from counsel for Harriet Goldstein IRA, a Dendreon stockholder claiming damage to the Company from alleged wrongful disclosure and insider trading and demanding that the Board investigate and take legal action against certain Dendreon officers and directors. The wrongful disclosure allegations stem from Dendreon's disclosures surrounding correspondence with the FDA during the first half of 2007 pertaining to the Company's Biologics License Application filed with the FDA for Provenge. This potential claim is not against the Company. The Company's Board of Directors will be evaluating a response to the letter. On July 9, 2007, Dendreon Corporation (the "Company") received a letter from the New York Regional Office of the Securities and Exchange Commission (the "SEC") dated July 3, 2007, notifying the Company of an informal inquiry related to the Company's clinical trials for Provenge®, the Company's Biologics License Application for Provenge filed with the U.S. Food and Drug Administration ("FDA"), and the FDA's review of Provenge and related correspondence to and from the Company, from January 1, 2007 through the present. The SEC's letter notes that the request should not be construed as any indication by the SEC or its staff that a violation of the federal securities laws has occurred nor should it be considered a reflection upon any person, entity or security.
The Company intends to cooperate fully with the SEC staff and respond to the staff's request for information. The Company does not intend to comment on any aspect of the inquiry or possible outcomes until the inquiry is completed.
Front Page of Today's Washington Post (MSNBC.com as well)
FDA Delay In Cancer Therapy Is Attacked
By Rob Stein
Washington Post Staff Writer
Friday, July 6, 2007; A01
Oncologists do not usually need bodyguards when they present scientific data at a medical symposium.
But when Howard I. Scher of the Memorial Sloan-Kettering Cancer Center and Maha Hussain of the University of Michigan spoke at the recent meeting of the American Society of Clinical Oncology, they were in fear for their safety.
The two doctors have been at the center of an unusually bitter debate over an experimental therapy for prostate cancer, ever since they helped persuade the Food and Drug Administration to delay approving it, enraging both patients and investors. The first-of-its-kind therapy, called Provenge, is a "vaccine" designed to extend the lives of patients with advanced prostate cancer by stimulating their immune systems.
The debate over Provenge illustrates the highly charged atmosphere that often surrounds new treatments as the desperation of deathly ill patients increasingly converges with the high-stakes intensity of biotech investing in the anything-goes forum of the Internet. The result in this case has been anonymous threats, accusations of conflicts of interest, Capitol Hill protests, congressional lobbying and vitriolic postings on blogs, Web sites and MySpace pages.
"This case may be different and all the more controversial because it's at the intersection of patient advocacy and the nervous world of biotech investors," said Daniel P. Carpenter, who studies the politics of health care at Harvard University. "It makes for a much more volatile politics."
A panel of experts recommended in March that the FDA approve Provenge. But in May, the agency instead asked for more evidence that the vaccine works after specialists, including Scher and Hussain, questioned its effectiveness.
Scher and Hussain told the FDA that Dendreon Corp., the small Seattle biotech company that developed Provenge, submitted a study to win approval for the drug that was so small that the apparent benefit it showed could have been the result of chance.
The FDA's surprise decision unleashed a spasm of criticism by prostate-cancer patients, advocacy groups and investors in Dendreon.
After the price of Dendreon's stock quadrupled and then plummeted, irate investors wrote hundreds of letters to the FDA and Congress, posted blistering critiques in Internet chat rooms, and created Web sites and MySpace pages denouncing the FDA, Hussain and Scher. They alleged various motives for the decision, including internecine rivalries within the FDA and pressure from larger rival drug companies.
"Why else would they object?" said Ray Vestal, a Huntsville, Ala., investor. His "Approve Provenge Now" MySpace page asks, "Hey, Hey, FDA, How Many Dads Did You Kill Today?" as images of Hussain and Scher flash across a backdrop of crooked crosses and Mozart's "Requiem" plays. "Perhaps there's something else behind the scenes," he said.
Patients and advocacy groups, meanwhile, borrowing strategies from AIDS activists and breast-cancer advocates, mounted an orchestrated lobbying effort. They launched their own letter-writing campaign and Web sites, staged a Capitol Hill rally June 4, and demanded and got a meeting with FDA Commissioner Andrew C. von Eschenbach the same day. They began lobbying to amend FDA legislation moving through Congress to allow easier access to experimental treatments.
"The prostate-cancer community has probably been awakened for the first time. We're clearly upset about what has happened," said Thomas A. Farrington of the Prostate Health Education Network, which created the ProvengeNow.org Web site. "The true victims are the prostate-cancer patients whose lives could be saved. We're talking about terminally ill men, many of whom have no other options."
Scher and Hussain, meanwhile, began receiving anonymous e-mails, phone calls and letters attacking and sometimes threatening them.
"We have been harassed and trashed for giving our opinion in an area of our expertise," Hussain said. "It's been a nightmare, to say the least."
The pair requested and received extra security at the cancer meeting in Chicago after they heard that Provenge supporters were planning a protest June 3.
"This was concerning, especially since I was scheduled for a podium presentation that day," said Hussain, who has wondered whether to continue as an FDA adviser.
"When this sort of thing interferes with my patients and/or family, I might have to say 'sorry' and pull out," she said. "Right now, I believe I have an obligation to my patients to stay and continue to do the right thing, no matter how difficult it might be."
A handful of protesters did try to enter the meeting, but they left peacefully after being turned away by guards.
Farrington and other patient advocates, and several vocal investors, including Vestal, dispute Hussain and Scher's arguments but deny any involvement in the threats.
"I don't believe terminally ill men are getting up off their beds to threaten anyone," Farrington said.
Dendreon CEO Mitchell Gold said that the company has not orchestrated or financed any of the efforts by patients or investors. He also condemned the attacks.
"We don't condone those kinds of threats," he said. "But we morally support what the patients and advocates are going through and their desire to live longer and better lives."
The FDA said the agency continues to work with the company as it completes more research on Provenge.
"Additional scientific data is required before a definitive decision can be made," spokeswoman Kristine B. Mejia wrote in an e-mail.
The campaign for Provenge has been seized on by other groups who want to make it easier for patients to get experimental therapies.
"It's certainly glaring proof of what we've been talking about and the need for change," said Frank Burroughs of the Abigail Alliance, which is suing the FDA in federal court. "What we're saying is that when you have a drug like Provenge, you should let people have access to it who have run out of options."
But that argument worries those who say the FDA needs to be more vigilant, not less, about ensuring the safety and effectiveness of new treatments in order to avoid another Vioxx debacle.
"I certainly understand the desperation that patients feel," said Nancy Davenport-Ennis of the National Patient Advocate Foundation. "But at the end of the day, our society is protected through the system that we have and the process that assures us that when a drug is approved by the FDA, adequate testing has been completed to assure safety and efficacy."
The Provenge controversy comes amid revelations that a widely used diabetes drug, Avandia, may increase the risk of heart attacks. That triggered a similarly intense debate, including angry criticism of cardiologist Steven Nissen of the Cleveland Clinic, who sounded the alarm about the drug.
The stakes can be especially high for small biotech companies, because their future is often riding on a handful of products -- and sometimes just one. At the same time, patient groups are vying more for scarce research dollars, experts say.
"Something has changed," said Marie Hojnacki, who studies patient advocate groups at Penn State University. "It's become an increasingly competitive atmosphere, and both patient advocacy groups and others, including pharmaceutical companies, are doing what they feel like they need to do, which means being very aggressive about getting what they want."
http://www.washingtonpost.com/
Clark
When you have had a chance to run your simulations on the interim on 9920b could you share them with the board - no rush as we have plenty of time. Your work on these have been so helpful to us on determining the odds on the interim.
Thanks
Steve
The MD. in the piece (with the beard) is Dr. Berger. He is treating my uncle for PC and has enrolled more patients in Provenge trials than any other MD. in the country.
Opened over $12. Great advice from David Miller on this one. "Shot first and ask questions later."
This whole thing is making me sick. DNDN releases expected news that 9902b is required and the stock is up 30%. Of course I got out on 5/9.
So let me get this straight - Scher is on the Scientific Advisory Board for a ProQuest a healthcare VC firm, where Jay Moorin is partner, and Jay Moorin sits on the Board at Novacea. Novacea is running trials for the same pc target population as Provenge targets. Scher also Chairs one of these competing trials (Ascent-2). Novacea inks a deal three weeks after Provenge's complete response letter worth up to several hundred million dollars in precommercializion milestones. Novacea common stock is up 86% today because of this deal. How in the world could he be given a conflict of interest waiver and be afforded the opportunity to provide any advice whatsover to the FDA on the Provenge BLA?
http://www.proquestvc.com/investment_team_moorin.asp
Example of What a CR Letter Looks Like
LaJolla CR from a few years back (source: SEC Edgar).
EXHIBIT 99.2
[United States Food and Drug Administration Letterhead]
La Jolla Pharmaceutical Company
Attention: Lisa I. Koch
6455 Nancy Ridge Drive
San Diego, CA 92121
Dear Ms. Koch:
Please refer to your new drug application (NDA) dated December 14, 2003,
received December 16, 2003, submitted under section 505(b) of the Federal Food,
Drug, and Cosmetic Act for Riquent (abetimus sodium) 50 mg/ml Injection.
We acknowledge receipt of your submissions dated December 14, 2003 and January
8, 22, February 6, March 2, 15 (two), 19, 24, 30, April 2, 5 (two), 9, 13 (two),
15, 28, May 28, June 8, 11, 15, 17, 24 (two), 25, 29, 30, July 6, 13, 20, 21
(two), 22, August 2, 4 (two), 11 (two), 12, 13, 18, 19 (two), 20 (three), 31,
(two), September 9, 10, 27, and October 1, 2004.
We have completed our review of this application, as amended, and it is
approvable. Before the application may be approved, however, it will be
necessary for you to address the following concerns:
Your study 90-05 was designed to show a clinical benefit (delayed time to
renal flare) associated with treatment, but it failed to do so. An unplanned
analysis of patients with high affinity antibodies to dsDNA appeared to show
benefit, leading to study 90-09, designed to study benefit in that high
affinity subgroup. Study 90-09 also failed to show benefit, thus failing to
support the hypothesis raised by the subgroup analysis in study 90-05.
Whether these results indicate that the hypothesis that lowering anti-dsDNA
antibodies slows disease progression is wrong or that the effect was too
small to affect disease progression cannot yet be known. Only another, better
powered outcome trial, perhaps with a larger dose, will resolve this issue.
The combined analysis of the high affinity subgroup of study 90-05 and study
90-09 is not a credible analysis as it is driven by the retrospective
analysis of study 90-05.
To gain approval, you will need to conduct a further randomized, double-blind
study that successfully distinguishes abetimus from placebo on an endpoint of
clinical benefit, such as time to renal flare. Your ongoing clinical study
(90-14) would appear to satisfy this requirement, although we think that it
could be valuable to learn more about the dose-response for the effect of
abetimus on antibody titer before carrying out a large clinical trial of long
duration.
Because a description of the drug's effects and proper use are yet to be
determined, at this time, we are deferring comments on labeling.
In addition, we have the following request:
<PAGE>
We remind you that before we can establish a definitive expiration dating
period for the drug product, you should develop a more sensitive stability
indicating analytical method for the drug product.
Within 10 days after the date of this letter, you are required to amend this
application, notify us of your intent to file an amendment, or follow one of
your other options under 21 CFR 314.110. If you do not follow one of these
options, we will consider your lack of response a request to withdraw the
application under 21 CFR 314.65. Any amendment should respond to all the
deficiencies listed. We will not process a partial reply as a major amendment
nor will the review clock be reactivated until all deficiencies have been
addressed.
Under 21 CFR 314.102(d), you may request an informal meeting or telephone
conference with this division, the Division of Cardio-Renal Drug Products, to
discuss what steps need to be taken before the application may be approved.
The drug product may not be legally marketed until you have been notified in
writing that this application is approved.
If you have questions, please contact:
Dianne C. Paraoan
Regulatory Health Project Manager
(301) 594-5308
Sincerely,
/s/ Robert Temple, M.D.
Robert Temple, M.D.
Director
Office of Drug Evaluation I
Center for Drug Evaluation and Research
Clark - What do you think the p-values might be if you used more real world assumptions, i.e curves similar to combined 9901/9902a, at the interim analysis (assuming 180 deaths) and the final analysis? Thanks
Hi Wall - do you think .02 would be enough at the interim and why? Also any thoughts on the HBK 7.7% acquisition of DNDN stock. Thanks.
Thanks Wall, Clark and Ocyan for your responses to my questions. So, I guess the consensus at this time, assuming an interim at 180 deaths and a p value of .01 to .015, that the odds of the interim coming in significant are low (as we quess the SPA stands now), and the final at 360 death are probably good. This is the result of realtively immature survival data and the slow ramp up of enrollment. Is my understanding correct?
As an aside, attached is a dated article about Dr. No. Boy, does he talk out of both sides of his mouth. I can't stand him.
http://www.communityoncology.net/journal/articles/0201095.pdf
Questions for the Board relating to 9902B hitting requiried results. What factors led to the relatively poor results of 9902A? How much of the shortfall in log rank p-value and HR is attributable to smaller size? trial imbalances favoring placebo, etc? Why should the results of 9902B look much more like 9901 than 9902A at the interim and final? If 9902B mirrors the combined 9901/9902A results, what might the results of 9902B using the SPA prespecified cox analysis look like at the interim and final? Do you feel that the combined 9901/9902A results could serve as a proxy for 9902B? How much of a margin of error is involved? Could the results of a few patients sway the results one way or the other if we roughly mirrored the combined 9901 and 9902A results? How might the relatively sicker patient population effect the results? How might slow ramp up on enrollment of 9902B affect the results at the interim and final for an event given trial? How do long-term survivors factor into the results of an event driven trial? Just trying to get a handle on some of these questions, as we have plenty of time to discuss. Thanks for your thoughts.
OT Dew - I justed wanted to apologize for snide backgammon comment after the AC vote. I had found over the years that some of your posts on IV were a bit too abrasive at times. I could not resist the temptation to snip back at the time. I know have come to the conclusion that your posts were not meant with malice, but were more your style of debate. Best wishes.
I second that. Wall is a class act.
More UBS BS
Thanks to CMH-760 on IV
UBS - Latest research note
AACR 2007 Highlights
Dendreon (Reduce 2 Rated)
In a poster presentation, Dendreon shared immune monitoring data from its
ongoing P-11 trial for Provenge, a novel active cellular immunotherapy now
pending FDA approval (PDUFA is May 15) for use in hormone-refractory
prostate cancer (HRPC). P-11 evaluates the potential of Provenge in “upstream”
use for hormone-sensitive prostate cancer (HSPC), a much larger market
opportunity (company estimates there are roughly 56,000 patients with HRPC,
but ~380,000 with HSPC).
The data were very much similar to that found in the abstract made available
prior to the conference, and confirm previously announced data from other
Provenge trials. In essence, the data suggested that Provenge could elicit a
prolonged immune response in patients with HSPC in that: 1) the change in
PA2024-specific proliferative responses from baseline to weeks 4 and 13 were
significant for Provenge across three different antigen concentrations compared
to placebo (p<0.0001); and 2) at the time of the booster infusion (ranged from 4-
33 months), the immune response was still significantly higher for the Provenge
arm than the placebo arm.
While the data are supportive of potential use of Provenge in the HSPC setting,
we note that P-11 is a non-registrational Phase III trial, for which Dendreon
is not likely to be able to file with FDA as proof of efficacy should it wish to
pursue this indication. Dendreon is still collecting data from P-11 (enrollment
was complete in 2005), and we await results on PSA doubling times and timeto-
bone metastases in order to better assess the potential of Provenge in HSPC.
While it remains difficult to estimate when final data will be available (survival
data won’t be available for several years), we believe additional data may be
presented at the upcoming AUA and ASCO meetings (May 19-24 and June 1-5,
respectively).
KOL Feedback on Provenge’s Potential Approval was Very Cautious
Attendance at the AACR meeting gave us a unique opportunity to gather
feedback from various experts in the fields of immunotherapy and prostate
cancer on their general thoughts on Provenge and their views on whether
Provenge should be approved on May 15.
Overall sentiment on Provenge’s chances of being approved next month
was negative, with no particular bias between immunotherapy and prostate
cancer key opinion leaders (KOLs). On the positive side, despite the setbacks of
previous immunotherapies, KOLs were still enthusiastic on the potential of
immunotherapy in treating cancer, and while it was likely that Provenge might
not be approved on time, sentiment was best summarized by comments by a
thought leader from Memorial Sloan-Kettering Cancer Center (New York) who
said it was “important not to throw the baby out with the bathwater.” Provenge
P-11 data is supportive of Provenge’s
potential in hormone-sensitive prostate
cancer, but more data is needed
KOL feedback reinforce our view that
an approvable letter for Provenge is
likely on May 15
US Small/Mid Cap Biotechnology 23 April 2007
UBS 3
was viewed as an important advance, with additional efforts and investment
necessary and warranted, but it might be some time before definitive proof on
Provenge might be available.
KOLs we spoke with felt that while the data were encouraging, one
problem with Provenge was that they still didn’t know enough about the
therapy itself to feel comfortable.
Issues and concerns raised by thought leaders about Provenge included the
following:
■ Uncertainty surrounding Provenge’s exact mechanism of action by which it
mediates an anti-cancer effect.
■ Lack of proof that Provenge has any direct effect at all on the cancer/tumor.
■ Immune responses seen to date appear to be directed towards the PA2024
PAP fusion protein, not the native PAP prostate antigen itself (a response
directed towards the latter is much preferred).
■ It remains unclear whether the benefit being attributed to Provenge could
simply be attributed to GM-CSF (which is an important component in
Provenge).
■ To date, Dendreon has shown that the Provenge immune response is more of
a CD4+-mediated effect, when ideally a CD8+-mediated response (direct
killing of tumor cells) is preferred.
■ Other adjuvants besides dendritic cells would be preferred.
■ The clinical trial program would have been more ideal if the company had
generated more meaningful and more easily interpreted/understood Phase I/II
data before moving into Phase III.
As it relates to approvability on May 15, the KOLs felt that there just
wasn’t enough conclusive evidence at the current time to prove Provenge’s
efficacy, and that more clinical data were required before potential FDA
approval. Comments were:
■ All “serious medical oncologists” do not believe the efficacy data presented
are robust enough to allow FDA to approve Provenge.
■ While it may be difficult politically speaking, at the end of the day, the FDA
will have to go against the advice of the advisory panel (remember, the vote
by the advisory committee is only a recommendation).
■ Many oncologists agreed with the negative contents of a recent letter written
by Dr. Howard Scher (Memorial Sloan-Kettering Cancer Center) to FDA on
the flaws in the Provenge clinical data. (Dr. Scher is a leading authority in
prostate cancer, and he was one of four who voted “no” on the efficacy
question for Provenge at the March 29 advisory committee meeting.)
We believe this provides additional support behind our cautious view on the
Provenge BLA filing, where we continue to believe that the existing clinical
Provenge still a mystery to many
thought leaders
KOLs don’t see an approval likely as
more conclusive data are needed
US Small/Mid Cap Biotechnology 23 April 2007
UBS 4
data available data for Provenge, while suggestive of efficacy, are not robust
enough to warrant FDA approval on May 15.
Thus, we reiterate our view that Provenge will be the subject of an
approvable letter from FDA by or on Provenge’s May 15 PDUFA, and that
Dendreon will need to submit additional clinical trial data (from the
ongoing IMPACT/D9902B study) before ultimate FDA approval can be
secured.
Understood. MEDI was trading in the high 20s to low 30s over this past winter. It has moved up on Ichan sell out pressures.
Medimune Deal
The AZN - MEDI deal looks good for MEDI shareholders. At a transaction value $15.6 billion this would imply a control premium of 37% over MEDI's mkt cap of $11.4 billion. It also implies a transaction value-to-LTM sales of 12.2x, TV-to-E2007 sales of 10.7x, and TV-to-E2008 sales of 9.3x. Can't be bad for the sector.
Steve
Thanks io. Just trying to stir the debate. Let's hope for a good week after next.
Yes, I am very well aware of the problems with Allos' subgroups analyses. My desire was not to bring these up here again. According to Allos, the cox was significant for surival for the entire ITT as well. My desire was to bring up a quote I found by an FDA reviewer said cox should not be considered a substitute for a failed log rank. Wall's response on IV that this quote should be probably best applied to a pivotal trial (like ALTH's) and not a supportive trial like 9902a makes sense to me. Hopefully, it will to the FDA as well.
I don't think the cox analysis on 9902a will be of benefit to the BLA in the FDA's eyes. If the log rank is not significant, I don't think they pay much attention to the cox analysis (see FDA quote below). I really hope they consider the 3-year survival numbers as supportive enough.
"The sponsor used the Cox multiple regression model to adjust for potential imbalances within the two treatment arms. A reference is given to Akazawa et al. (6), highlighting the regression model’s ability to adjust for the imbalance of prognostic factors between two treatment groups. Such a strategy is not intended to be used as a substitute when the primary analysis has failed according to the log-rank test."
This is from the ALTH clinical review in the briefing documents.
See right below Table 24:
http://www.fda.gov/ohrms/dockets/ac/04/briefing/4037B1_04_B-FDA-Clinical%20Review-RSR13.htm
Those words of wisdom deserve to be posted a third time:
>The new prediction of the Chinese fortune teller that , the drug will be definitely agreed in May . but the process is thought-provoking, those biological scientist which have notlearned to statistics opposes this agreement, however, FDA's heads strongly welcome the drug. Wall Street is following these dubious biologists,so the price is fluctuating overly before this may. the drugs agreement process surpasses biology itself . the price will be climbing to 50 by the end of 2007.<
Nice find Stuck - Thanks
Wall
What do you think the probability of a scenario involving a negative briefing doc on Thursday morning March 29th (ie., 9901 missing on TTP, 9902 on missing TTP and log rank surival) with resultant stock crashing, followed by a thumbs up on Friday March 30th from the advisory panel that hopefully looks through the statistical weaknesses to see clinical benefit, while trading is halted for the day, followed with the stock really taking off on Monday April 2nd? It could be a real roller coaster over those 4 days.
Thanks for your thoughts
Steve
The following are tidbits I cut and paste from the FDA guidance document Skcotswonki posted earlier on IV. Having read it, I still think the decision will come down to how supportive the FDA views 9902a (as Wall has suggested many times in the past). It really is a judgment call. The log rank p value of .33 is very weak, but the trial was not adequately powered, had a high crossover rate and was imbalanced in favor of control. Based on log rank alone, 9902a hurts much more than it helps. However, the FDA should recognize these confounding factors, but how much reliance can we place on that? How much weight will the FDA place on Cox? Where the statistical protocols strictly followed in the Cox analysis? Could 9901 and 9902a be effectively treated as one integrated highly significant study? I wish I could get clear in my mind the answers to these questions and other questions. I welcome and appreciate all well reasoned thoughts on these issues from members of this Board.
Guidance for Industry
Providing Clinical Evidence of
Effectiveness for Human Drug and
Biological Products
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
May 1998
www.fda.gov/CDER/GUIDANCE/1397fnl.pdf
“Nevertheless, FDA has been flexible within the limits imposed by the congressional scheme, broadly interpreting the statutory requirements to the extent possible where the data on a particular drug were convincing. In some cases, FDA has relied on pertinent information from other adequate and well-controlled studies of a drug, such as studies of other doses and regimens, of other dosage forms, in other stages of disease, in other populations, and of different endpoints, to support a single adequate and well-controlled study demonstrating effectiveness of a new use. In these cases, although there is only one study of the exact new use, there are, in fact, multiple studies supporting the new use, and
expert judgment could conclude that the studies together represent substantial evidence of effectiveness. In other cases, FDA has relied on only a single adequate and well controlled efficacy study to support approval — generally only in cases in which a single multicenter study of excellent design provided highly reliable and statistically strong
evidence of an important clinical benefit, such as an effect on survival, and a confirmatory study would have been difficult to conduct on ethical grounds.
…
The inherent variability in biological systems may produce a positive trial result by chance alone. This possibility is acknowledged, and quantified to some extent, in
the statistical evaluation of the result of a single efficacy trial. It should be noted, however, that hundreds of randomized clinical efficacy trials are conducted each year with the intent of submitting favorable results to FDA. Even if all drugs tested in such trials were ineffective, one would expect one in forty of those trials to “demonstrate” efficacy by chance alone at conventional levels of statistical significance. It is probable, therefore, that false positive findings (i.e., the chance appearance of efficacy with an ineffective drug) will occur and be submitted to FDA as evidence of effectiveness. Independent substantiation of a favorable result protects against the possibility that a chance occurrence in a single study will lead to an erroneous conclusion that a treatment is effective. Results obtained in a single center may be dependent on site or investigator specific factors (e.g., disease definition, concomitant treatment, diet). In such cases, the results, although correct, may not be generalizable to the intended population. This possibility is the primary basis for emphasizing the need for independence in substantiating studies.
…
It should also be appreciated that reliance on a single study of a given use, whether alone or with substantiation from related trial data, leaves little room for study imperfections or contradictory (nonsupportive) information. In all cases, it is presumed that the single study has been appropriately designed, that the possibility of bias due to baseline
imbalance, unblinding, post-hoc changes in analysis, or other factors is judged to be minimal, and that the results reflect a clear prior hypothesis documented in the protocol.
Moreover, a single favorable study among several similar attempts that failed to support a finding of effectiveness would not constitute persuasive support for a product use unless
there were a strong argument for discounting the outcomes in the studies that failed to show effectiveness (e.g., study obviously inadequately powered or lack of assay sensitivity as demonstrated in a three-arm study by failure of the study to show efficacy of a known active agent).
…
Whether to rely on a single adequate and well-controlled study is inevitably a matter of judgment. A conclusion based on two persuasive studies will always be more secure than a conclusion based on a single, comparably persuasive study. For this reason, reliance on only a single study will generally be limited to situations in which a trial has demonstrated a clinically meaningful effect on mortality, irreversible morbidity, or prevention of a disease with potentially serious
outcome and confirmation of the result in a second trial would be practically or ethically impossible.
…
Although an unexplained failure to substantiate the results of a favorable study in a second controlled trial is not proof that the favorable study was in error — studies of
effective agents can fail to show efficacy for a variety of reasons — it is oftenreason not to rely on the single favorable study.”
Panel Question:
Wall: How long prior to the advisory panel meeting is the panel composition typically announced? and how is the panel composition announced to the public?
Thanks
Steve
Dew and PGS - DNDN P11 Look Good:
Press Release Source: Dendreon Corporation
Dendreon Announces Preliminary Results From PROTECT (P-11) Study
Wednesday November 8, 9:00 am ET
PROVENGE Prolongs PSA Doubling Time in Patients with Early Stage Prostate Cancer
SEATTLE, Nov. 8 /PRNewswire-FirstCall/ -- Dendreon Corporation (Nasdaq: DNDN - News) today announced preliminary results from its ongoing PROTECT (P-11) clinical trial for PROVENGE® (sipuleucel-T) in patients with non- metastatic androgen-dependent (hormone sensitive) prostate cancer. The study was designed to explore the biologic activity of PROVENGE in patients with recurrent prostate cancer prior to the development of metastatic disease. The study results demonstrate a prolongation in prostate-specific antigen (PSA) doubling time (PSADT) for patients who received PROVENGE compared to placebo. PSADT is currently considered to be one of the best predictors of clinical outcome in patients with PSA recurrence following primary therapy. Dendreon plans to submit the data for presentation at a future upcoming medical meeting.
ADVERTISEMENT
Study Design:
The study, known as PROTECT (PROvenge Treatment and Early Cancer Treatment) or P-11, is a randomized, double-blind, placebo-controlled trial designed to evaluate the safety and biologic activity of PROVENGE in men with non-metastatic androgen-dependent prostate cancer who have had a PSA recurrence following surgical removal of the prostate. A total of 176 patients at 19 sites in the United States were randomized 2:1 to receive PROVENGE or placebo following a 3-month course of hormonal therapy. Patients were then followed with serial PSA measurements to evaluate the impact of PROVENGE on PSA and PSADT. At the time of biochemical progression, defined as a PSA of 3 ng/mL or greater, men became eligible for one booster infusion of either PROVENGE or placebo in accordance with the treatment arm to which they were randomized. Patients continue to be followed for the clinical endpoints of time to distant failure, which typically would be the appearance of a positive bone scan, and for overall survival.
Preliminary Study Results:
-- Biochemical Endpoints: As specified in the protocol, an analysis of
PSADT calculated from 90 days following randomization until biochemical
progression or the initiation of systemic therapy demonstrated that
patients randomized to receive PROVENGE had a 35 percent increase in
their PSADT compared to patients randomized to receive placebo (p-value
= 0.046). To adjust for potential variations in the rate of
testosterone recovery following hormonal therapy, the PSADT was also
calculated after a patient's testosterone returned to baseline levels.
This analysis demonstrated that patients randomized to receive PROVENGE
had a 49 percent increase in their PSADT compared to patients
randomized to receive placebo (p-value = 0.038). In addition, although
not statistically significant, there was a positive trend in the
overall delay in the time to reach a PSA level of 3.0 ng/ml for
patients in the PROVENGE arm compared to patients in the placebo arm.
-- Clinical Endpoints: There was a delay of approximately 27 percent (HR =
0.73) in the time to distant metastasis for patients randomized to
receive PROVENGE compared to patients randomized to receive placebo.
Because only 16 percent of patients in the study had a distant failure
event at the time of this analysis, it is not yet powered to evaluate
statistical significance. Per protocol, patients will continue to be
followed for the clinical endpoints of distant failure and overall
survival.
-- Immunology Data: In a subset of patients the immune response against
the recombinant antigen PA2024 was measured at baseline (before dosing
with PROVENGE or placebo) and at 4 and 13 weeks following randomization
(after dosing). PA2024 is a fusion protein composed of prostatic acid
phosphatase (PAP), and a cytokine, GM-CSF. T-cell responses were
monitored by measuring T-cell proliferation by recording the
stimulation index (SI) and by measuring the number of T-cells that
secrete interferon gamma by ELISPOT. By both methods, and at both the 4
and 13 week time points, significant responses were seen in the
PROVENGE treated patients, but not in the patients assigned to receive
placebo. For example, at 13 weeks, the median SI was 118.5 in the
PROVENGE arm compared to 2.3 in the placebo arm (p-value <0.0001). The
immune response was also monitored at the time of boosting to assess
the durability and persistence of the immune response. These analyses,
conducted at a median time of 21 months following randomization,
demonstrated that the immune response continued to persist at
significant levels (p-value <0.0001) in the PROVENGE arm compared to
the placebo arm. The median SI observed in the PROVENGE arm prior to
boosting was 93.7 and 13 weeks following a single boosting infusion of
PROVENGE, the median SI was 221.8, suggesting that the immune response
can be boosted to even higher levels.
-- Safety: Consistent with the Company's other studies conducted to date,
treatment with PROVENGE was generally well tolerated. The most common
adverse reactions associated with PROVENGE were chills, fever,
headache, fatigue and vomiting. These events were primarily low grade
events, with a short duration lasting 1 to 2 days following infusion.
"The initial results from this randomized study suggest a potential role for PROVENGE early in the natural evolution of prostate cancer," said Mark Frohlich, M.D., vice president of clinical affairs at Dendreon. "We are encouraged by the effect of PROVENGE on PSA doubling time, an important predictor of clinical outcome in this patient population. We plan on following these patients for the clinical endpoints of overall survival and time to distant failure. More importantly in the near term, the data from the patients in this study will supplement our overall safety database for PROVENGE as part of our current BLA submission for men with advanced androgen-independent prostate cancer."
Wall:
That video is funny - thanks.
Steve
Hi Wall:
Glad to hear that after all these years you finally purchased a little Allos. We will see how it turns out pretty soon. At least there is a somewhat of a fallback now with PDX starting a pivotal P2.
Thanks Preciouslife EOM
Thanks Wall. You know this relates to ALTH. Just trying to figure out why we have not heard anything yet. #4 just relates to what are typical time intervals between an SPA event trigger (ie. 188th death) and when we as investors hear what happened. Hoping its good news as with P-11.
Steve
Question - How does it work with interim looks, Data Monitoring Commitees timing, Press Releases, etc. If a trial is designed to have 2 interim looks based on the number of deaths in the total trial population - 1) is there a lag in time before the DMC looks at the data?, 2) is the Company obligated to make a PR stating that the interim death number was reached and the results so far indicate that the trial should continue or be halted?, 3) is it cut and dry - the trial achieves specific results dictated by an SPA - is the trial halted or does the DMC ordinarily side on caution and recommend that trial continue to the end?, and 4) are there lag times in when an interim look is expected and co. PRs or DMC meetings? Thanks for any insight you can provide.
Question - How does it work with interim looks, Data Monitoring Commitees timing, Press Releases, etc. If a trial is designed to have 2 interim looks based on the number of deaths in the total trial population - 1) is there a lag in time before the DMC looks at the data?, 2) is the Company obligated to make a PR stating that the interim death number was reached and the results so far indicate that the trial should continue or be halted?, 3) is it cut and dry - the trial achieves specific results dictated by an SPA - is the trial halted or does the DMC ordinarily side on caution and recommend that trial continue to the end?, and 4) are there lag times in when an interim look is expected and co. PRs or DMC meetings? Thanks for any insight you can provide.
And MLNM, VRTX and SEPR have a combined market cap over $12 billion. Interesting industry. I guess it says something about market expectations for the future profitability of the biotech industry.
No way the combined TTP p vales are sig. with a near miss on 9901 and a big miss on 9902a, IMO.