Posted by unregistered user at 4/17/08 12:44 p.m.

I think it is becoming clear that the FDA's CRL regarding approval of the Provenge NDA was never about ‘good science.' It was, and remains a story about FDA politics and money.

And it also casts a shadow of guilt on Congress, all Americans and our media for having allowed the FDA to conduct "real meetings" in secret and AC panel meetings in public. We got what we deserved in today's FDA and Kerry Donahue nailed it in his CTL/FDA lawsuit:

"Its not meaningful if the public AC hearing is merely a sham and the "real meeting" occurs behind closed doors in ignorance that this is The United States of America where operating in secrecy in a non- democratic manner is frowned upon. The decision to take the "due" out of due process was a deliberate wrongdoing and more than just run of the mill negligent conduct…"

What is needed now –in addition to Provenge approval, is complete access by the public to FDA records to find out who calls for the "real meetings"; who attends the "real" meetings; and transcripts of all arguments, notes and votes of those who attend the "real meetings."
Does the FDA really expect Americans to sit with doltish reverence begging "our FDA" to tell us that life and death decisions are not being made with "winks & nods" but with serious discussion and debate?

Apologies to the FDA, but this is America.

And yes, it is time for America's Fourth Estate, and our legislators to be as equally outraged as Provenge advocates because taking the "due" out of "due process" was not just a ‘deliberate wrongdoing' regarding Provenge –it shreds the entire fabric of this Republic.

Thank you The Life Sciences Blog for covering this story!

Posted by unregistered user at 4/17/08 12:58 p.m.

Joe,

Thank you for continuing to cover this story and your attendance at the Bothell FDA protest on May 30, 2008.

Posted by unregistered user at 4/17/08 1:47 p.m.

User response #118629 probably is Kyto27 who spouted this same rant on Pharmalot Blog and added more recycled exaggerations and part truths from CaretoLive. There is failure to acknowledge what looks like a poor job by Dendreon with the data they went after for approval (time to progress increase) was not there when they submitted and more critical data on demonstration of survival extension was not yet sufficient (by design and maturity of study). The Advisory Committee was willing to look well beyond this in making a majority recommendation on efficacy as limited options for these patients however FDA does have procedures to follow and under circumstances the scientific justification was missing so they requested more data (a not unusual event). Weren't there also some manufacturing issues also that needed resolution? I don't know details since have not been elaborated but that alone could have caused similar delay. The hand wringing and accusations don't really contribute to a solution (beyond heightened awareness of problems) and add pressure to a overstressed system at FDA who largely do a difficult job well and certainty are more reliable than legislators and aggressive advocacy groups is evaluating drugs.

Posted by unregistered user at 4/17/08 2:05 p.m.

Glad to hear Joe. I contacted the coordinator for this event and told I will be there rain or shine.
Wish I could her beforehand but too damn busy.

Scott

Posted by unregistered user at 4/17/08 3:10 p.m.

Here's how the Provenge decision was made...

The e-mail below was sent to the son of a man dying of prostate cancer in August, 2007; the son had written the FDA to ask why Provenge was not approved on May 8, 2007:

"Thank you for your recent email to FDA's Center for Biologics Evaluation and Research (CBER) regarding Provenge. CBER is one of six centers within FDA, responsible for the regulation of biologically-derived products, including blood intended for transfusion, blood components and derivatives, vaccines, allergenic extracts, tissue, and cell and gene therapy products.

"I share with you the goal of safe and effective treatment choices for all cancer patients and FDA does this in the context of being a science-based regulatory agency whose mission is to both promote and protect the public health. In reviewing marketing applications for new medical products, our medical and scientific experts objectively evaluate all the data submitted and base their decisions on the available scientific evidence. Often we call upon independent outside experts for their advice. In this instance, we sought the advice of an FDA advisory committee. The majority of the advisory committee members indicated that the data submitted for Provenge supported its effectiveness; however, several members expressed significant concerns about the strength of these data. FDA factored the advisory committee discussions into its decision regarding this application. As noted by Dendreon, the manufacturer of Provenge, FDA determined that additional scientific data is required before a definitive decision can be made. The public and patients we serve deserve such a rigorous and disciplined effort to both protect and promote their health. FDA is committed to working with Dendreon to quickly obtain and review new information as it becomes available.

"You can contact Dendreon directly for any clinical trials using Provenge [www.dendreon.com].

"Sincerely,

"Patricia H. Harley

"Consumer Safety Officer

"Food and Drug Administration

"Center for Biologics Evaluation and Research

"Office of Communication, Training and Manufacturers Assistance

"Division of Communication and Consumer Affairs"

Let me translate the critical section of this e-mail for you: We had 17 experts on the Provenge Advisory Committee. All voted (17-0) that the drug was safe. As regards evidence of substantial efficacy, 13 voted YES; they, primarily, were immunologists; 4 voted NO, including Drs. Scher and Hussain, who work in the field of chemotherapy. The latter two provided additional information after the AC was concluded that we felt was much more important that whatever was provided by the people who really know this field, so we decided not to approve the drug.

By the way, the man whose son wrote the letter to the FDA, questioning their actions regarding approval, died of PCa on March 17, 2008, almost a year to the day following the Provenge Advisory Committee meeting. You can read the tragic story of his death at the URL below:

http://www.pharmalot.com/2008/04/provenge-protest-planned-for-asco-meeting/

Posted by unregistered user at 4/17/08 4:23 p.m.

The War on Cancer is a scam. Drug companies are all about the money. If they happen upon a blockbuster treatment for Cancer, all the better, but that is secondary. The only thing that has proven to have a significant effect is widespread protest as with HIV and Breast Cancer which have made tremendous strides relative to other terminal disease as a result. In this respect, advocacy groups are really little more than support groups for education and screening which are very important in and of themselves. Lack of activism from support groups, in my opinion, stems from the fact that much if not most of their funding comes from entities such as drug companies that benefit most from the status quo.

A classic example is Michael Milken's Prostate Cancer Foundation(PCF). A billionaire ex-felon convicted of securities fraud, he is barred for life from securities investing and is also a Prostate Cancer Survivor himself. But through his financial conglomerate he is heavily invested in both drug companies that specialize in cancer as well as his "advocacy" organization PCF. Both PCF and his financial conglomerate are run by the same individuals. You can look at Proquest Investments, one of his investment vehicles that invests primarily in cancer drug companies and see their board of directors is a who's who list of the same folks who run PCF and even some who work for the FDA regulating New Cancer Drugs. Dr Howard Scher comes to mind. His significant roles at Milken's Proquest Investments and the FDA regulating Prostate and Breast Cancer vaccines is all too revealing.

Again, the point of this is that these very powerful individuals/companies drive cancer treatment development. In this example, if one of Milken's companies happens upon a breakthrough, great! But if it's some other small innovative go-it-alone company, they will literally try to destroy or at least delay as long as possible their competitor's breakthrough treatment(as in the case of Dr Howard Scher and Cancer vaccines). It really is and will be all about the money unless people get fed up.

Posted by unregistered user at 4/17/08 5:39 p.m.

Hey Poster #118650,

Here's a clue:

Scher was protecting the advancement of Novcea's Asentar and Cell Genesys's GVAX.

That is why this statement of his at the Advisory Panel hearing is so telling (Page 322 of the transcript):

"So I say well, what if we think that this (Provenge) really should be available, start thinking about the number of agents (Asentar and GVAX) that are currently under development."

Note: He didn't say Provenge shouldn't be approved, he was just worried about other drugs he &/or his friends were invested in.

Next he followed that up with "his" letter to the FDA and then Dr. Thomas Fleming reiterated the main point:

"Reportedly, Scher felt motivated to write the letter after being kept awake the night following the March 29, 2007, FDA Cellular, Tissue and Gene Therapies Advisory Committee by the thought that if Sipuluecel-T were approved, patients may well forego more effective treatment alternatives."

What alternatives? Asentar? GVAX?

So is this why Howard Scher had to lobby the FDA Commissioner after the Advisory Panel Hearing?

And is this why Richard Pazdur had to leak letters to
The Cancer Letter?

And why won't Richard Pazdur turn over documents
requested under the Freedom of Information Act?

If it is all about science, there should be nothing to hide. Right?

Posted by inhumane fda at 4/17/08 6:04 p.m.

In response to the above comment that says the FDA commonly asks for more data: The reason they commonly ask for more data rather than to just deny an application is to avoid oversight. It is purely a legal mechanism thought out by a huge FDA legal team (it works as Dingell bought it hook line and sinker).

By requesting "more data" rather than "denying" which operates functionally the same way, they can say its an ongoing process, which is just baloney and nobody can then challenge for being capricious.

In other words they take away everyones due process rights away by the mechanism they created called a CR letter. The CR letter is what hey use to request more date. Its a disguised denial...the result is the same to the rights of Dendreon and the patients.

It is absolutely an effort to avoid review and oversight...its done for purely legal reasons and has nothing to do with the science.

We are still waiting for the FDA to say why they could not have granted at least conditonal approval subject to the ongoing trials, which would have been the same result the FDA has now ACCEPT THAT THE PATIENTS COULD BE GETTING PROVENGE NOW as the confirmatory trials continue.

Posted by unregistered user at 4/17/08 6:23 p.m.

The FDA's request for more data was an excuse, not a reason. As the FDA's own statisticians said at the Advisory Committee hearing "survival is not a post hoc analysis". As Dr. Pazdur said himself, "survival is the gold standard".

The chances that the number of Provenge treated patients on the combined 9901 and 9902a trials survived 36 months or longer being a fluke are on the order of 80:1 - much lower than the 20:1 which is used by the FDA to approve new drugs. Since the survival measurement is the gold standard and is not considered by the FDA to be post hoc analysis, why on earth would the FDA refuse at the very least a conditional approval?

The FDA's great failing is its lack of empathy for terminally ill patients. That the decision was made in secret when billions of dollars were on the line is ludicrous and reeks of corruption and foul play. Investors, patients and patient advocates should shout it from the rooftops.

Posted by unregistered user at 4/17/08 9:42 p.m.

116892 no translation necessary when you read "FDA determined that additional scientific data is required before a definitive decision can be made. The public and patients we serve deserve such a rigorous and disciplined effort to both protect and promote their health. FDA is committed to working with Dendreon to quickly obtain and review new information as it becomes available." Didn't we just hear that Dendreon may now have or are close to the data necessary? All fingers are pointed at the FDA but there appears to have been missteps by Dendreon including possibly creating expections not (yet) fully supported by their studies.

The reasoning on chemotherapy could be reversed to suggest that immunologist would vote in favor because it enhances their field (which I do not believe is true either)

I can't argue that an approvable request for data can often be a delay and/or legal tactic but does not mean there is no scientific basis involved. My understanding is that unlike Europe there is no such mechanism for a conditional approval and I do wish more empathy for terminal patients could be factored more that it is now. Those are changes that should be promoted as lessons from this episode.

Posted by unregistered user at 4/18/08 12:09 a.m.

118650--

With regard to Provenge, the real question before the FDA is not whether the agency has the right to study this drug further, but whether immunotherapy treatments need to be judged by a different standard than chemotherapy treatments?

And sadly, the FDA already knows the answer is yes —as they were told just that at the NIH/NCI workshop they hosted in February 2007:

"Therapeutic cancer vaccines pose the possibility of a delayed onset of activity. This is based on the time required to mount an effective immune response
and the time for that response to be translated into an observable clinical effect. As such, patients may experience early tumor progression before eventual tumor
regression. If the conventional definition of DFS or time-to-progression (TTP) is used, there is a possibility for premature treatment discontinuation in a patient who could ultimately experience benefit from a cancer vaccine. This might be avoided by modifying the definition of progression requiring confirmation on at least 2 observations or by not considering early progression within a prospectively defined time-interval (eg, 3mo from therapy start).

And from ‘Rational approaches to human cancer immunotherapy' in the Journal of Leukocyte Biology

In the case of immunotherapy, often tumors will progress before a response is seen [83 ], as an effective immune response (if it occurs) may take several months to become apparent. If effectiveness were measured by response rate alone at conventional time points, then these agents would be thought to fail even if they could ultimately lead to a cure of the disease.

http://www.jleukbio.org/cgi/content/full/73/1/3

And yet the FDA went blindly ahead overuling the conclusions of its own workshop and its own Provenge Advisory Committee where every single member of the AC who had recognized expertise in immunotherapy (and they were from Moffit, MD Anderson, NIH, Harvard, Stanford, UCLA, Duke, U WA) voted 13-4 that there was "substantial evidence" of effectiveness and unanimously (17-0) that there were no safety issues. Not one of the "no" voters on the panel had recognized expertise in immunotherapy. The drug in question was an immunotherapeutic agent.

With all due respect, CMC, if all the FDA wants to continue to study is why a round ball will not fit into a square hole, the inner workings of the FDA process appear to be seriously flawed – as was Dr Richard Pazdur's decision to include Drs Maha Hussein and Howard Scher on the AC panel given their very real conflicts of interest. Not to mention their over-the-top crusade in The Cancer Letter.

At the end of the day, the FDA needs to answer this question:

In the FDA's pursuit of statistical absolute certainty, is there no room for assurance sufficient for the purposes of human life? Especially in terminal illnesses like advanced prostate cancer, the FDA's Provenge decision blurs to the extreme the distinction between statistical and practical significance.