FDA LIES & DENIES — CARE TO LIVE CRIES
May 25th, 2009 | Posted by CTLThe FDA blew a golden opportunity.
It took them 2 years of foot dragging to reach their decision on our CareToLive Citizens’ Petition.
They DENIED it!
The only redeeming factor in their pages of excuses, is that the FDA stated 3 times that they will process the amended Dendreon BLA expeditiously.
We at CTL feel the FDA lacks the compassion and the scientific ability to evaluate our Petition.
With the stellar Provenge survival data recently exhibited, we believe the FDA should have immediately reconsidered their death rattle.
The dysfunctional, omnipotent FDA has spoken loudly and clearly to the men with late stage prostate cancer who are out of options.
You can’t have a safe and effective immunotherapy yet.
Go home and die!
You can read the FDA’s response here >> fda-response-to-citizens-petition.pdf
Here are some of our thoughts on the FDA response. We welcome your comments.
Before addressing the specific requests in your petition, we first want to make it clear that we share your concern for men suffering from advanced prostate cancer.
Too many men continue dying a painful death while the FDA continues to stonewall the approval of Provenge by not addressing the deception that took place during the Provenge approval process.
We are committed to expeditiously reviewing the new information as soon as it is submitted.
This was the only good thing we read in their response.
PLEASE HURRY.
THIS IS AN EMERGENCY!
FDA shares the goal of approving new products, such as Provenge, as soon as they are shown to be safe and effective.
Provenge has shown all along that it is safe and effective. The Advisory Committee questions are regulatory questions.
Is it safe?
Is there substantial evidence of efficacy?
The panel voted overwhelmingly that it is safe and effective.
The FDA response tried to gloss over the conspiracy and conflict-of-interest issues, simply denying them without offering any evidence.
The agency lied when it said Provenge didn’t slow progression in either 9901 or 9902A. The correct terminology would have been “did not slow progression with statistical significance.”
We think that 11.7 weeks vs. 10.0 weeks in the 9901 trial is evidence of slowed progression.
A p value of 0.052 (Journal of Clinical Oncology number) or 0.085 (FDA number) should not be taken lightly, even if it did barely miss statistical significance.
Combine that with the survival p value of 0.01, and that’s pretty convincing evidence that 9901 was a successful trial.
It is a lie that Provenge did not slow progression in 9901, and it is a lie that there is no positive correlation between progression (91.5-94.8%) and survival (99.0%). The FDA’s progression argument is a LIE.
FDA has a long history of permitting access to investigational drugs to treat serious and immediately life-threatening diseases without adequate available therapies. Individuals can obtain access by enrolling in on-going clinical investigations of such products, including any existing expanded access protocols.
Who is going to pay for this expanded access? I can tell someone, sure, you can have a brand new Porsche, but who is going to pay for it?
Certainly a small, struggling biotechnology company cannot be expected to pay.
If Dendreon gives Provenge away prior to approval, what would ever make the FDA approve it?
They can say that anybody who wants it can get it, so what’s the problem.
The problem is that there are 30,000 men a year who are dying for Provenge that will never be able to access it without FDA approval.
Dendreon has stated that it has two other actively enrolling studies. One of these trials is a single-site trial enrolling 40 patients with localized prostate cancer who are scheduled to undergo a prostatectomy. The other trial is a multicenter trial enrolling approximately 120 patients with metastatic androgen-independent prostate cancer.
That would help 120 patients with AIPC. What happens to the other 95,880 men?
There are 96,000 men with AIPC. They need help now.
This designation does not necessarily lead to a priority review or accelerated approval. In fact, a product with this designation may not be approved at all.
The Provenge case did lead to priority review.
It is the first time the FDA went against a positive advisory committee vote for a treatment for a life-threatening disease when there are no other viable options.
Further, we believe that you have misunderstood the advisory committee process and its role with respect to the biological approval process.
We fully understand the advisory committee process.
We watched on entire advisory committee process on the internet.
The FDA violated the laws put in place for the advisory committee process.
Somebody at the FDA tampered with the second regulatory question.
Dr. Jesse Goodman stopped the vote and changed the question back.
There has never been an investigation into who altered the regulatory question and why.
Dr. Scher wrote in his original emailed “leaked letter” that the question originally asked “Do the data show significant benefit.” Where did he come up with that? Later he realized his mistake and removed “significant data” in the hard copy and inserted in the exact same space “Do the data show substantial evidence”. That is not even a complete sentence. The regulatory question is “Does the data show substantial evidence of efficacy. We question if he even knew what the regulatory question was. How can he weigh in on a question on substantial evidence of efficacy, when he doesn’t even know what the question was. Why did nobody challenge him on his non sequitor?
The FDA allowed the 2 doctors with conflicts of interests onto the panel, and gave them a vote. Although the FDA usually follows the advice of the AC, they opted out in this case, and delayed an extremely safe and effective drug that would have saved thousands of lives. The FDA allowed the 2 conflicted doctors to derail the Provenge approval. 2 doctors who admitted they knew little about immunotherapy. Their main approach to evaluating a cancer treatment is to measure tumor shrinkage.
The FDA did not address the $500 million deal for Novacea, a Provenge competitor. The deal happened right after the FDA stopped Provenge licensure. Conflicted panelist Dr. Howard Scher was leading the Novacea trial. He was also advising the Proquest Investment firm at the same time. That firm had a multi million dollar investment in the Novacea Phase III trial. That is a major conflict of interet and he should have recused himself from the process.
Why wasn’t the chairman of the Provenge advisory committee at all the meetings for this committee. That is a legal requirement.
As explained below, the advisory committee is in place to provide advice to the agency and does not make the decision whether to approve a product. The agency makes this decision based upon the review of the data and science available to us.
That is not what your own employee told us. Patricia Harley, Consumer Safety Officer for the Food and Drug Administration at the Center for Biologics Evaluation and Research said:
“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.”
It appears that the minority committee members had a say and influenced the decision. They were seriously conflicted. They were not immunologists. They stated they saw the survival but would not admit that it was coming from Provenge. They said they couldn’t be sure. These two committee members who had the conflicts of interest were part of CDER’s ODAC, the FDA oncology division.
FDA has not made a final decision on whether to license Provenge.
For the Fish family, the Study family, the Ripp family, the Cassell family, the Qwick family, and all the other families who lost a dearly loved man in their lives during the past two years, the FDA decision was all too final.
We look forward to receiving this information and are committed to expeditiously reviewing the new study data upon submission.
You said it again, now be sure to do it. In fact, do it now!
CTL cannot, by means of its petition, circumvent the approval process.
We are not trying to circumvent the approval process. We are trying to show how Pazdur, Scher and Hussain, and Thomas Fleming, as FDA employees, derailed and delayed Provenge without just cause, compassion, or scientific evidence. As far as we can tell, they all circumvented the approval process.
CTL is not privy to Dendreon’s legal, business, or scientific concerns, and therefore cannot represent its interests.
We are not representing Dendreon’s interests.
We are representing the men who have died and thousands more who are dying, who have no other option.
FDA had a public meeting and we watched how FDA handled the BLA.
Then FDA went behind closed doors with Von Eschenbach, Pazdur, Scher, Hussain and Fleming, all who work for and represent FDA, and stopped Provenge for invalid reasons. It is time for FDA to correct their mistake.
Furthermore, without express authorization from Dendreon, which CTL has not provided, CTL may not step into Dendreon’s shoes, or rely on Dendreon’s data (be it proprietary or otherwise).
We are not stepping into Dendreon’s shoes.
We are walking in the patients’ shoes, whom we represent.
Dendreon didn’t tamper with the second question.
Dendreon didn’t lobby the FDA Commissioner.
Dendreon didn’t leak letters.
Dendreon didn’t allow a doctor on the panel who was leading a competitive Phase 3 trial and was advising an investment firm who was heavily invested in at least one competitior?
Dendreon didn’t allow this same doctor who was also working with other competitors, namely Cougar, Cell Genesys, Medivation and Bristol-Myers Squibb to influence the FDA decision to derail Provenge.
Many late stage prostate cancer patients are being sentenced to die sooner because of this.
Why have a Citizens’ Petition if you are then going to claim that we are stepping in the Sponsor’s shoes?
CTL objects to FDA’s denying immediate approval of Provenge even though the advisory committee voted 17-0 that Provenge was safe and 13-4 that there was evidence of efficacy.
You’re darn right we object and why did you leave out the word SUBSTANTIAL? The advisory committee voted 17-0 that Provenge was safe and 13-4 that there was SUBSTANTIAL evidence of efficacy.
The BLA must include, among other things, data derived from non-clinical laboratory tests as well as clinical studies demonstrating that the product is safe, pure, and potent, 42 U.S.C. 262(a)(2)(C)(i)(I)
Richard Pazdur stated publicly that he has regulatory flexibility.
Rick Pazdur said he felt sorry for breast cancer patients when he approved Avastin, even though it did not prolong survival.
Are we to surmise that he does not feel sorry for prostate cancer patients.
Dendreon, the sponsor of Provenge, submitted its BLA in late 2006, and FDA considered it to be filed in January 2007. As part of its review, FDA sought the advice of its Cellular, Tissue and Gene Therapies (CTGT) Advisory Committee (see section V.B. for additional information). After reviewing Dendreon’s BLA, FDA determined there were deficiencies in the BLA that precluded approval and on May 8, 2007, sent Dendreon a Complete Response Letter declining to approve the BLA as filed, and requesting additional information.
Dendreon submitted its Biologics License Application (BLA) for Provenge in January 2007.
FDA granted it Priority Review on Januuary 16, 2007.
On March 1, 2007, FDA decided to call for an Advisory Committee, at a taxpayer cost of hundreds of thousands of dollars, to advise them concerning an approval license for Provenge.
The Advisory Committee was overwhelmingly favorable.
Why did FDA waste our tax dollars and call for an advisory committee AFTER carefully reviewing the information in the submitted BLA prior to calling an advisory committee, thereby acknowledging that the data available was sufficient to grant or deny a license.
As explained more fully below, although FDA takes advisory committee recommendations under advisement; only the agency can make the decision to approve a drug or biologics application. In addition, members of an advisory committee are thoroughly screened for compliance with rules governing conflicts of interest and may be granted waivers when appropriate.
Patricia Harley said the conflicted doctors influenced the decision. How can you say Dr. Scher was carefully screened on his conflict of interest waiver and on his SGE application. He only listed a few of his conflicts on his waiver. We know of at least six other conflicts he had, all of which were in competition with Provenge.
At the time of the advisory committee meeting addressing Provenge, 21 U.S.C. 355(n)(4) (since rescinded and superceded) required each member of an advisory committee reviewing drug or biologics applications to disclose all conflicts of interest the member may have had with the work to be undertaken by the committee, and prohibited the member from voting on any matter where he or his immediate family could gain financially from the advice given to the FDA.
You omitted the part that Scher’s did not disclose that his employer, Proquest Investments, could gain financially from his advisement to the FDA.
Novacea gained financially by Scher’s deliberate sabotage of Provenge.
As far as we are concerned, Scher lied on his applications, and the FDA did nothing about it. The FDA deliberately chose not to properly screen him.
Since that time, the Food and Drug Administration Amendments Act of 2007 amended the FDCA by adding new section 712, codified at 21 U.S.C. 379d-1, which now governs conflicts of interest for FDA advisory committee members.
CTL was instrumental in getting this Act amended. To us, this was an admission of guilt on the part of those conflicted doctors, and of the FDA not properly screening them in regards to the Provenge BLA.
Although FDA carefully considers the advice and recommendations of its advisory committees as part of the overall review process, such advice is not binding, and decisions, such as whether to approve a BLA, are made by FDA alone. See 21 CFR 14.5 (the purpose of an advisory committee is “to conduct public hearings on matters of importance that come before FDA, to review the issues involved, and to provide advice and recommendations to the Commissioner;” however, “[t]he Commissioner has sole discretion concerning action to be taken and policy to be expressed on any matter considered by an advisory committee.”).
Former FDA Commissioner Andy Von Eschenbach’s ties to Michael Milkens Prostate Cancer Foundation, as well as Howard Scher’s, and Maha Hussain’s ties to the PCF ruled out objectivity on their part. The government is supposed to steer clear of these kind of conflicts.
At the time of the advisory committee meeting addressing Provenge, 21 U.S.C. 355(n)(4) (since rescinded and superceded) required each member of an advisory committee reviewing drug or biologics applications to disclose all conflicts of interest the member may have had with the work to be undertaken by the committee, and prohibited the member from voting on any matter where he or his immediate family could gain financially from the advice given to the FDA.
If Advisory Committees are to be taken lightly, why all the laws regulating them? Note that the regulation says “to disclose all conflicts of interest.”
Also, at CBER’s request, Dr. Pazdur from FDA’s Office of Oncology Drug Products (OODP), Center for Drug Evaluation and Research (CDER) participated in the advisory committee meeting. Dr. Pazdur has extensive experience in OODP evaluating other prostate cancer therapies. On March 29, 2007, the CTGT Advisory Committee held a public meeting to discuss the safety and efficacy data submitted by Dendreon. Prior to the meeting, FDA screened all participants, including Drs. Scher and Hussain, for conflicts and granted waivers in accordance with 18 U.S.C. 208(b)(3) and 21 U.S.C. 355(n)(4).
If Dr. Richard Pazdur was invited to be a participant in the Provenge regulatory proceedings, why wasn’t Pazdur introduced at the meeting when Drs. Wonnacott, Liu and Zhen were all introduced?
Why wasn’t he made to stand up and wave like all the FDA media contacts?
Why did Pazdur recently claim in his sworn Freedom of Information testimony (see below) that he deleted his e-mails and shredded documents because he wasn’t involved with the Provenge BLA? He said they “it did not require a response from me.”
Why didn’t Pazdur receive the Fleming letter, if he was asked to participate due to his extensive knowledge in evaluating other prostate cancer therapies. Where is further FDA documentation of his participation?
Richard Pazdur’s FOIA documents: “I declare under penalty of perjury that the foregoing is true and correct.
In part:
1.At the request of CDER’s Division of Information Disclosure Policy (“DIDP”), I searched both my paper and computer files, and I was unable to locate any documents that were responsive to Plaintiff’s request.
2.I recall receiving both hard copies and electronic copies of these letters in April 2007. However, as these letters related to a specific regulatory application conducted by a different FDA Center (CBER), did not fall under my direct regulatory supervision, and did not require a response from me, I shredded my hard copies of these letters and deleted any electronic copies. The documents were shredded and deleted within a month of receipt.
11.I never received a copy of a letter from Dr. Thomas Fleming to the FDA regarding Provenge.
5/18/2009 Freedom of Information Act (FOIA) documents received:
Declaration of Richard Pazdur >> ctlpoaz29exbd-5.pdf
Defendant FDA’s Motion for Summary Judgment >> ctlsj29-1a.pdf
Declaration of Fredrick J. Sadler >> exba.pdf
Declaration of Nancy B. Sager >> ctlexhibitc3.pdf
Declaration of Beth Brockner-Ryan >> ctlryanexhibitb.pdf
Where is the proof Scher and Hussain were properly screened?
Dendreon presented post hoc analyses of the data from the first study. According to Dendreon’s interpretation, that data showed a statistically significant difference (approximately 4.5 months) in a different endpoint, survival, in patients treated with Provenge as compared to placebo. Transcript, at 37, 42, 151, 169; FDA Clinical Briefing Document, at 37. By contrast, the second study did not show a statistically significant difference in survival. Transcript at 151, 164, 169; FDA Clinical Briefing Document, at 35, 37. Moreover, neither study was designed prospectively to measure survival as an endpoint, see FDA Clinical Briefing Document, at 14 (noting statement in Dendreon’s protocol that “[t]this study is not powered to show a survival effect”), and, as FDA staff observed, the survival analyses had limitations that affected their reliability. Transcript, at 170-71; FDA Clinical Briefing Document, at 4 (”doubts remain about the persuasiveness of the efficacy data’).
Specifically, FDA staff noted that the survival analyses were post hoc, making the results difficult to interpret, that the studies had small sample sizes (even the first study had only 127 patients), and that a statistically significant survival difference was seen in only one of the two studies. Transcript, at 151, 170-71, 177-182.
You knew all of this before the Advisory Committee was called! Explain why you called for an Advisory Committee if Dendreon did not have the proper data.
FDA Clinical Briefing Document, at 30; see also FDA Statistical Briefing Document, at sections 3.1.1, 3.2 (”The key efficacy evidence (difference between the two arms in overall survival) for this BLA is based on post-hoc analyses and the efficacy evidence is not substantial from a statistical perspective.”)
Again, why did you call for the Advisory Committee?
With respect to safety, FDA staff noted that there was a higher incidence of cerebral vascular accident (CVA) events (strokes) in Provenge, as compared to placebo. Transcript, at 166; FDA Clinical Briefing Document, at 3 (”approximately three times as many subject experienced CVA’s in the treatment group compared with controls”). Although the FDA staff members recognized that the difference was not statistically significant, they indicated that the data showed a potential safety signal.
All the panelists considered this, and even Dr. Gunter, voted it safe. Not one panelist voted it unsafe! A conditional approval would have sufficed in this case. And note what Dr. Chappell says in regards to this safety issue:
DR. CHAPPELL: Certainly seems to be safe in the context of disease commonly treated with radiation and cytotoxic chemotherapy.
This is from the latest data that Dendreon just presented. (Thanks Brian)
Incidence of Cerebrovascular events in IMPACT:
Provenge Arm= 1.8% (N=338) Placebo Arm= 1.8% (N=168) The Difference was nil. Just another distraction that Howard Scher cooked up in his leaked letter, after voting it safe at the advisory committee.
Although the Advisory Committee voted favorably on the questions of safety and efficacy, such votes were simply advisory in nature.
They were more than that. They were regulatory questions. And Patricia Harley alluded to them being part of the decision. If they were not important, why would Scher and Hussain and Fleming, all FDA employees, get upset and go completely overboard, with the help of some folks at NCI, by composing letters and then leaking them to the public?
That Advisory Committee vote meant something very convincing to these FDA employees. They were scared Provenge would be approved and they wanted to stop it. If this was simply a vote, this wouldn’t have been necessary. You want to talk about all your regulations, why aren’t you concerned with these violations?
Moreover, the FDA staff members’ clinical briefing documents, along with the advisory committee transcript, show shortcomings of Dendreon’s data, including the failure of both of Dendreon’s studies to meet their intended endpoints, the post hoc nature of Dendreon’s survival analysis, the inconsistency of survival results between Dendreon’s two studies, the small size of the studies, and the potential safety signal related to strokes.
You knew this already going into the Advisory Committee hearing. The Spokesperson for that hearing, Dr. Celia Witten, told the panel they were there because of the survival! Read pages 185-186 of the transcript. And on page 320, look at what Scher said:
DR. SCHER: Unfortunately it didn’t meet the primary endpoint and then three years later a survival analysis is reported, it is observed and there’s no question that this is the gold standard by which we live.
And on page 307, Hussain said:
DR. HUSSAIN: And as I read this, it is clear that there is a survival difference, so we’re not disagreeing on that.
These documents provide ample support for FDA’s decision not to grant approval at the time and to request more data.
And these documents provide ample support for FDA to approve Provenge, at the least conditionally, especially considering the overwhelming panel vote.
Dr. Hussain’s and Dr. Scher’s agreement with the FDA staff members’ analysis, as expressed at the advisory committee meeting and in letter to FDA afterward, does not provide evidence of a conspiracy.
One person writing a letter is understandable. Three people writing and leaking letters is a conspiracy.
CTL has not-and cannot-reasonably allege the violation of any constitutional right.
The collusion of a select few to deny thousands of men their right to life and a decent quality of life is a denial of their rights.
You hurt so many people.
How appropriate that today is Memorial Day and many of our members who were denied Provenge fought for this country and for the freedom you used to express the stupid FDA arguments you put forth in this response.
Scher clearly says it right in regards to survival, “there’s no question that this is the gold standard by which we live.” Over 61,000 men have died since the day he made that statement.
Shame on the FDA!
FDA APPROVE PROVENGE NOW!
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Tags: Andrew Von Eschenbach, CareToLive, FDA, Howard Scher, maha hussain, Michael Milken, Prostate Cancer, Prostate Cancer Foundation, Richard Pazdur, survival, Thomas Fleming