Dendreon: The FDA's Commissioner Doth Protest Too Much!

In his latest The FDA this Week: Andy's Take: FDA Advisory Committees: A High Priority, April 18, 2008, FDA Commissioner Andrew von Eschenbach, MD, had the following to say:

Many of you may not be aware of the great lengths we at the FDA go to to (sic) ensure the integrity of our advisory committees—to assure that we get good information and advice. FDA carefully scrutinizes each committee member for potential conflicts of interest—we review who they work for, any contract work they’ve done, and even any investments and stock they or their family members hold. We weigh the potential for those financial holdings to bias their participation with the need for their expertise and determine whether they should participate, and issue a waiver if appropriate. When a waiver is granted, we then share this information publicly so that others know what conflict might exist.

Given the revelations surrounding the multiple conflicts of interest (COIs) that have come to light in the wake of the scandal involving certain members of the Provenge Advisory Committee meeting of March 29, 2007, one is apt to ask: Where was the commissioner back in early 2007, when the rules governing COI that now are in force were being considered for implementation?! It was clear to many, including Steve Usdin, Washington Editor of BioCentury, The Bernstein Report on BioBusiness, that certain members of the forthcoming Provenge Advisory Committee would not qualify for participation under the new rules. Writing in the March 26, 2007 edition, he said:

When FDA’s Cellular, Tissue and Gene Therapies Advisory Committee meets this week to discuss whether the agency should approve the first cancer vaccine, a product that could establish proof of principle for an important new therapeutic class, several of the votes will be cast by internationally respected experts who were invited to join the committee on an ad hoc basis because of their specific expertise.

The picture might look quite different if FDA’s new draft guidance for determining conflict of interest and eligibility for participation on its advisory committees were in force. Under the proposed policies, three of the invited experts probably would be ineligible to vote on Provenge sipuleucel-T from Dendreon Corp. (DNDN, Seattle, Wash.).

And two might be completely barred from participating in the discussions.

In particular, running test cases for the new rules on three Advisory Committee members, he concluded the following:

Dr. Maha Hussain: “The waiver notes that Hussain is the principal investigator on a research contract awarded by a competing company for a product that is not related to Provenge. Under the draft guidance this probably would not be considered a conflict. However, the fact that her husband owns stock in three competing companies, valued at $15,000-$300,000, would at minimum prevent her from voting. If the total value of the stock exceeds $50,000, Hussain wouldn’t even be at the table if the new policy were in effect.”

Dr. Howard Scher: “Under the draft guidance, Scher either would be prevented from voting or excluded from the meeting.

“He owns stock in a firm that competes with DNDN valued at $5,000-$100,000. In addition, Memorial Sloan-Kettering has a grant from a competing company valued at $100,000-$300,000 to study a licensed, approved drug in prostate cancer trials.”

Dr. Savio Lau-Ching Woo: “One standing member of the committee, Savio Lau-Ching Woo, was also granted a waiver for the Provenge meeting. Woo, professor of gene and cell medicine at Mount Sinai School of Medicine, reported that an affected company has licensed a gene therapy technology he invented. It is being studied in prostate and other cancers.

“Although Woo has received less than $15,000 from the patent license in the last 12 months, he would be prohibited from voting if the draft guidance were in effect.”

All three of the Advisory Committee members cited above voted YES on the first question (regarding Safety; the vote was 17-0 in favor of the drug being safe), and NO on the second question (regarding the drug evidencing “Substantial Efficacy,” the federal standard (the vote was 13-4 in favor of the drug evidencing substantial efficacy)).

Importantly, two of the Advisory Committee members above, Drs. Scher and Hussain, went on to write letters to the FDA, disparaging Provenge and calling for non-approval of the immunotherapy…letters that were leaked immediately upon their receipt at the agency (if not before) to the non-peer-reviewed The Cancer Letter. Who asked Dr. Scher to write his letter and what part was played by personnel at the FDA and NCI in helping Dr. Scher write his letter? (A draft of Dr. Scher’s letter (version 3) was found on the computer of a researcher at the National Cancer Institute [NCI] and at least one other NCI researcher attended a meeting at the FDA to discuss the development of Dr. Scher’s letter.) These questions never have been answered by the FDA or NCI. Nor has the person or persons responsible for leaking the letters written by Drs. Scher and Hussain (as well as a third letter written to the FDA by Dr. Thomas Fleming) to The Cancer Letter ever been identified and prosecuted.

Also problematic is this statement made in Dr. von Eschenbach’s latest “Fireside Chat”: Each year the US Food and Drug Administration expends considerable resources convening over 60 advisory committee meetings. This is part of our commitment to engage a wide range of scientific expertise to inform our regulatory decision making process. This is the right thing to do for we must keep up-to-date with the rapidly-changing world of science related to the products we regulate. [emphasis added]

The majority of those on the Provenge Advisory Committee were immunologists…they were the ones who were “…most up-to-date with the rapidly-changing world of science related…” to Provenge and immunotherapy. Contrary to Dr. von Eschenbach’s assertion above, however, the FDA did not listen to these experts. Instead, for reasons known only to those within the FDA, the agency, in the case of Provenge, let itself by swayed by the minority. If you want proof of that statement, the FDA admitted as much in an e-mail the agency sent to Mr. Stephen D. Study after he questioned it, on behalf of his father (who passed away from prostate cancer on March 27, 2008, almost one year to the day from the date of Provenge Advisory Committee meeting) when the FDA refused to approve Provenge on May 8, 2007. Here's that text of that e-mail:

To Stephen D. Study:

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. [emphasis added]

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

It often is said that the true measure of a person (or in this case, an agency) is how they behave when the “policeman” is not around. Dr. von Eschenbach and the personnel involved in the submittal, review, and approval of waivers for Drs. Scher, Hussain, and Woo, among others, knew well the COI rules that were being considered at the time. In good conscience, they should have refused to approve all three of these waiver requests. That they did not speaks volumes regarding the bankrupt ethics of the Federal agency charged with the health and welfare of the American People. Unfortunately, more than 28,000 men with prostate cancer, many of whom could have been helped by Provenge, have paid the ultimate price for the FDA’s incompetence since the agency sent Dendreon a “Complete Response” (“Approvable”) on May 8, 2007.

In many other countries of the world, given the FDA’s handling of the Provenge application described above, a person in Dr. von Eschenbach’s position would have resigned in disgrace long ago.

Disclosure: The writer owns shares of Dendreon (DNDN).

Comments

[Been There]

The tax paying and insurance paying public wants to be paying for safe and effective medicine. Provenge failed to prove effectiveness several years ago, but did show an apparent activity in a subset of patients. Dendreon then did a second phase III trial in the subset as requested by the FDA. Recently Provenge failed to show efficacy in that subset, but apparently did show efficacy in a subset of the subset. The FDA should now require a third phase III trial to prove that Provenge actually works in the subset of the subset. I would suggest that Dendreon find a biomarker for the subset of the subset of patients, because if they can not identify the subset of the subset of the patients that walk into a doctors office, then their patients will not be able to be identified and I suspect the responsive patient numbers will be under ~10% of the total patient population and Provenge will not be approved. The patients may be unhappy, but there is a background of cancer patients who will actually survive without chemotherapy or immunotherapy, again a group who can not, as yet, be identified, prospectively. So, at the moment, Provenge does not seem to be any better than no treatment or at least the standard treatment, which is not very good either. The author own no cancer vaccine stocks, but does agree that committee members with the stock ownership indicated should not be on the committee for this compound. However, I also think the last advisory committee was incompetent to judge Provenge and I am happy the FDA stuck to their principles.

[pharma]

FDA oncology division is a total disgrace. It chief Dr. Pazdur has done everything in his power to kill cancer drug Erbitux which with huge time delay has been approved in colorectal and head & neck cancer applications as well as on its way to be approved in lung and other cancers. This year, ASCO 2008, the most prestigious international oncology conference, will feature Erbitux as a drug that is changing oncology paradigm. The drug not only prolongs lives of cancer patients and improves their quality of life but also cures good many of cancer patients.

Dr. Pazdur was very instrumental in FDA decision even to deny Erbitux consideration for an approval. He leaked confidential FDA information [he himself admitted it at the congressional hearing].

The Provenge saga is very much similar to Erbitux's FDA adventure. IMO, FDA oncology group is directly responsible for endless cancer patients suffering and deaths.

[echotoall]

Been There, you can use the word 'failed' because of poor trial design and lack of understanding the mechanism of action, but the survivablilty aspect of provenge is hard to argue.

also... 13-4 people industry experts basically said it works. And 3 of those 4 were not voting with their head, but instead with their wallets. So yeah... tone down the whole 'failure' argument.

At the very least, this treatment should have been allowed via tight label to those with no other option while the current trial goes forward.

[Tony F]

Mr. Cohen accurately describes exactly how poorly and unethically the FDA is operating, particularly regarding the Provenge situation.

To aid those not up-to-speed on exactly how badly the Scher Conflict of Interest situation appears to be in the FDA Provenge Advisory Committee meeting, take a look at these alleged COI for Dr. Howard Isadore Scher of Sloan Kettering.

In order to sit in judgment of Provenge, Scher certified to the FDA that he had 3 Conflict of Interests. These 17 (SEVENTEEN) have been found on the internet for Scher.

NOTE particularly items 1 & 17

1. NOVACEA: grants & research support; STUDY CHAIR of DN-101 ;

…. and DIRECT COMPETITOR to Provenge

2. GPB BIOTECH: financial conflict of interest per Scher in MedPage

3. PHARMION: financial conflict of interest per Scher in MedPage

4. SANOFI-AVENTIS: grants & research support

5. BRISTOL MYERSSQUIBB: consultant, grants & research

6. MILLENNIUM PHARMCEUTICALS: grant of research support

7. COUGAR BIOTECHNOLOGY: principal investigator; advisory board;

8. INNOVIVE PHARMACEUTICALS: principal investigator

9. INFINITY PHARMACEUTICALS: principal investigator

10. BIOGEN-IDEC: jointly held stock with spouse

11. PFIZER: jointly held stock with spouse

12. GENTA: scientific advisory board (as of Mar 6, 07; since removed but cached)

13. CONFOMA THERAPEUTICS: scientific advisory board

14. DEPARTMENT of DEFENSE: Principal Investigator PC Clinical Trials-P1 and P2

15. AMBRILIABIOPHARMA INC: Principal Investigator PCK3145, Phase I/II

16. MEDIVATION, INC: principal investigator MDV3100

17. PROQUEST INVESTMENTS, Board of Directors, Advisor. Novacea Investor

Despite the above being reported to the Health & Human Services investigate office and the FDA investiative office, nothing has been done for almost a year to investigate these allegations that Scher may have violated the law by his apparently failure to disclose ALL his COI.

However, when two individuals sent flowers to the Commissioner of the FDA several weeks ago, the FDA sent 2 investigators--within 1 business day--to the florist who delivered the flowers in order to get the names and other information about who sent Dr. Andy flowers.

Now, that's genuine justice, isn't it?

Finally, remember that Provenge is a treatment for TERMINAL prostate cancer victims... it's not about an aspirin or an OTC supplement... this is about life and death.

83 men die daily from prostate cancer and some 28,801 have died just since last May 9th when the FDA postponed Approval/Conditional Approval for Provenge... a treatment all AC members voted to be "safe" by a 17-0 ballot.

Approve Provenge NOW and, Dr. Andy, fulfill your duties of office or resign.

Tony F

[paidher]

March 29th marked the 1 year anniversary where an overwhelming majority of FDA experts convened and confirmed that Provenge met the safety and efficacy criteria for marketing approval. Yet, the science and normal process at the FDA was overturned by a small group of people with inordinate influence. After the overwhelming panel vote, Dr. Scher even lobbied the FDA Commissioner himself to withhold Provenge. Dr. Francesco Marincola, who himself participated in the Provenge AC, stated that his role as a member of the advisory board was “to express his opinion during the meeting but it would be ill advised to influence the FDA decision beyond that point.”

A fiduciary duty is the highest standard of care imposed by law. As an employee of the FDA, Dr. Scher has a fiduciary duty up hold to all Americans and is expected to be loyal to and act in the best interests of all Americans. As such, Dr. Scher must put aside his own personal interests and must not profit from his position. The foundation of Dr. Scher’s position is based upon good faith, loyalty, and trust. A fiduciary must not put themselves in a position where their interest and duty conflict.

As a Board Member to ProQuest Investments, a $1 billion venture capital fund, whose largest single investment was in Novacea, and whose lead product, Asentar, is in direct competition with Provenge, Dr Scher’s fiduciary duty at the FDA conflicted with his fiduciary duty to promote the interests of ProQuest and its investment in Novacea. This is like a lawyer representing both the plaintiff and the defendant in the same legal matter. The lawyer cannot make either the plaintiff or the defendant’s interes ts a top priority if both the plaintiff and the defendant’s interests are diametrically opposed. Dr. Scher should have recused himself from the Provenge Advisory Committee.

I am unaware of any action by the FDA to investigate and correct the obvious conflicts of interest that surround Dr. Scher's participation. Justice delayed is justice denied. This principle is the basis of the right to a speedy trial. The FDA has acted too slowly in investigating this issue. Even in responding to FOIA (Freedom of Information Act) requests, the FDA has stated that they can not reply timely because it is overburdened!

Dr. Scher should have recused himself from the Provenge advisory committee. He had a fiduciary duty to do so. Furthermore, it was inappropriate for Dr. Scher to lobby Dr. von Eschenbach personally to delay Provenge after the advisory committee meeting. And the leaking of letters from Dr. Scher, Dr. Maha Hussain and Dr. Thomas Fleming to the public was inappropriate, inimical to Provenge approval and dastardly. What is going on at the FDA to ignore these obvious attempts to sabotage a non-toxic treatment for terminal cancer?

[Been There]

I agree with you "echotoall," concerning the tight label. My concern is that we can not identify those who would qualify for treatment as defined by a tight label. I offer a way for Dendreon to identify those patients. By the way it may not be a "biomarker" in the vein of Her2 for Herceptin, it may be a clinical profile. With profile or biomarker(s), the patients who may benefit would be treated, while Dendreon is working on supplemental trial in that subset of a subset of patients. The trial would show if Provenge is actually providing the survival advantage versus the group of patients who would have survived without treatment or the standard treatment.

As for comparing ERBITUX with Provenge, they are not even in the same ball park, but there is one thing that would have been extremely helpful for ERBITUX and that would be having a driven CEO like the one in charge of Dendreon or even Genta. I think their talents and drive are being wasted on compounds destine not be approved, whereas if either had been in charge of ERBITUX, it would have kept the six month lead on Avastin and would have been approved before Avastin and would now be a multi billion dollar drug like Avastin. Not the FDA's falt. It was very poor management at ImClone and even the guys at BMS could not fix the problem even with all their influence, mostly because they did not become of aware of the issues until late in the process. All public information around the time of Martha and her problems.

[kelatious]

Been There-
After 3 years, 33% of Provenge patients were alive while only 11% of "placebo" patients were alive......how is this a subset?

[Been There]

kelatious-

Are these data from the first phase III or second phase III trial? Were these two percentage statistically different. 33% appears bigger than 11%, but one needs to know the number of patients. I can not remember the exact data, so if you answer these two questions and I will attempt explain subset and why this is so difficult. Thank you.

[gaucho]

Hey Been There and LIED HERE

I think that you must provide your credentials that prove that your are better equipped to judge the efficacy of Provenge. If 13 members of 17 voted for efficacy and the 3 who voted against were severely conflicted I would say that the vote was virtually unanimous. But since you are the GOD of immunology and look down upon those poor mortal experts in the field please perform a miracle so we can all believe. Say how about stopping the war in IRAQ and make everyone put down their hatred.

Can't do that? Then how about listing you credentials, or better yet the Hedge fund that you are connected with.

[in4thelonghaul]

FDA Commissioner Andy is obviously a shill and a liar to boot.

Provenge has demonstrated repeatedly that it is both far far safer and has superior efficacy over any FDA approved treatment for end-stage prostate cancer.

Yet the FDA claims that Overall Survival is the Gold Standard!!

Andy...you are a contemptable disgrace. You will stand before your Creator with the blood of the innocent staining your conscience and those same souls will condemn you for what you have wrought.

You had the power to speak for those who had no acceptable alternative; instead you allowed their last hope to be stolen.

Sooner or later, probably when Dendreon gets a CEO with some vision, Provenge will be approved...if not in the U.S., then in Europe. Its efficacy will be evident to the world soon thereafter.

[kyoto27]

Not so fast Mr Been There.

The insanity of the FDA's decision is that
Scher-Hussein would have the world believe that
because the 9901 Phase III trial had a p-value of p=0.052 when a p-value of p=0.05 is considered statistically significant…that the stellar Provenge survival log-rank p = .01 for D9901 had to also be thrown out!? And let's remember, the p=.01 was on the entire trial, not some subgroup (and the final Cox model improved D9901 from log-rank .01 to Cox .002!).

It cannot be overly stressed that eight years ago, the sponsors of the Provenge trial chose time to progression as the primary endpoint. They nominally hit it for one trial and missed it with another. If they instead had chosen survival as that single item, then Dr. Scher would not likely have written his letter and Provenge would likely already be on the market.

As a matter of fact, it was Dr Howard Scher, in a 2007 symposium titled, "Improving Upon Current Standards: The Integration of Novel Therapies in the Treatment of Androgen-Independent Prostate Cancer," sponsored by Novacea, that Howard suggested that when doctors consider whether to prescribe certain treatments, “It may be time we focus less on statistical significance alone, and more on patient benefit.” – MedPage Today, February 26, 2007

Ironically, this is exactly what the 13 members of the CTGT panel did by voting yes to whether Provenge provided substantial evidence of efficacy.

How sad that Dr. Scher had it exactly right in February of 2007 when he uttered this line but got it so wrong when he launched his now infamous campaign in The Cancer Letter –which in effect told the 13 members of the CTGT that more time has to be spent on statistical significance and less time on patient benefit.

So Mr Been There, let’s be clear:

Biostatisticians would call the Provenge alpha p=.052 “nominally statistically significant.” Laypeople would call it “close enough.”
Hypothesis-generating? Don't think so.

So it looks like 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


"Cancer vaccines such as Provenge aim at stimulating the immune system. As that process usually takes at least 8-10 weeks to fully activate, such drugs would not have much of a chance to have impact on TTP."

So Provenge was measured using standards applied to chemotherapy trials and misses that endpoint by only .002! and the FDA insults all of us by calling that alpha miss a miss...and then throws out all the survival data as Hypothesis-generating?...

It would be comic tragedy--throwing the baby out with the bathwater if so many lives were not at stake. As it was, the FDA's CRL was an insult not only to good science but also to human life.

America should not quietly accept this outrage.

[PoopDoggy]

Hi, Been There -

Howie? Maha? Is that you? Maybe a little too much time on your hands? I think it's genuinely nice that Dick has given you access to his office computer, especially now that there's a lot more room on his hard drive. I'd ordinarily say, "Don't be a stranger," but clearly I don't need to, given your high level of activity today. Take care now, and say Hi to Andy for me!

[BSR_David]

"Been There" doesn't have the facts straight. Let's look through them...

> Provenge failed to prove effectiveness several years ago, but did
> show an apparent activity in a subset of patients. Dendreon then
> did a second phase III trial in the subset as requested by the FDA.

The IMPACT trial (9902b) was originally designed by Dendreon to look at Gleason < 8 patients. This was not at the request of the FDA. IMPACT was subsequently amended to look at patients of any Gleason score. 9901 showed a survival advantage and was nominally statistically significant on the primary endpoint of survival. When adjusted for imbalances favoring the control arm, 9902a was also statistically significant for survival. Pooled data from the two trials, which were designed to be pooled, showed a statistically significant survival advantage on an adjusted and unadjusted basis. In each case, the survival advantage was also highly clinically significant.

> Recently Provenge failed to show efficacy in that subset, but
> apparently did show efficacy in a subset of the subset.

I have no idea what you are talking about here. There have been no substantially new data on Provenge since 2005. All data ppints mentioned above were intent-to-treat analyses and not subset analyses.

> The FDA should now require a third phase III trial to prove that
> Provenge actually works in the subset of the subset.

The "third" IMPACT trial was started years ago and enrolls all HRPC/AIPC men with minor pain. This is not a subset nor a subset of a subset.

> I would suggest that Dendreon find a biomarker for the subset of
> the subset of patients, because if they can not identify the subset
> of the subset of the patients that walk into a doctors office, then
> their patients will not be able to be identified and I suspect the
> responsive patient numbers will be under ~10% of the total patient > population and Provenge will not be approved.

Again, there is no need for a subset biomarker since the survival data were positive across all men regardless of Gleason score in a standard intent-to-treat analysis of the entire randomized population.

In the first two trials, Dendreon screened patients for PAP expression since Provenge is targeted to the PAP antigen. This was dropped in IMPACT and it remains to be seen if it will have any effect. Since only 5% of men were screen failures in 9901/9902a due to PAP expression, it is mathematically unlikely the lack of screening will make a difference.

> The patients may be unhappy, but there is a background of cancer
> patients who will actually survive without chemotherapy or
> immunotherapy, again a group who can not, as yet, be identified,
> prospectively.

Actually, they can be identified prospectively. It's called a nomogram and was published by Halabi et al a number of years ago. There have been several other concepts put forth to identify HRPC patients of high, medium, and low risk. Provenge would be best used on the latter two categories as a monotherapy. In high-risk patients, Provenge has been shown to confer a survival advantage, but that advantage might be magnified when used in conjunction with chemotherapy for younger men and/or those can stand the considerable side effects of Taxotere. A prospective combination trial needs to be run on combination therapy.

While comparisions between the 9901 and TAX-327 trials are difficult, it appears Provenge provides superior survival benefit to Taxotere at comparable projected costs and lower side effects across all patient subsets.

> So, at the moment, Provenge does not seem to be any better than
> no treatment or at least the standard treatment, which is not very
> good either.

This is simply not accurate. The data clearly contradict. You can also examine the positive advisory committee vote on the two questions of safety and efficacy. Finally, a careful analysis of the committee transcript shows a majority (9-8 or 10-7, depending on how you score) of panel members also thought the drug should be approved.

> The author owns no cancer vaccine stocks, but does agree that
> committee members with the stock ownership indicated should not
> be on the committee for this compound.

Part of the problem here is the concept of conflict of interest is limited to stock ownership. It took a decade to get the current large Taxotere adjuvant trials started. It was clear from Hussein and Schers' letters they were worried that the approval of Provenge would hurt enrollment of these trials, which they personally and financially benefit from either directly or through their institutions' participation in these trials.

> However, I also think the last advisory committee was incompetent
> to judge Provenge

The committee members included some ofthe country's leading immunology and immunotherapy experts. Special expertise in cardiac effects of immunology was added to address adequately questions of CNS safety. Only someone who is hung up on the chemo-centric practice of oncology would say the panel was incompetent.

I could also argue there should have been no oncologists on the panel at all, since the treatment of asymptomatic HRPC is almost exclusively the province of urologists. So if the lack of more urologists is leading you to make the statement above I agree.

Oncolgists are economically threatened by this drug. Its easy and essentially side-effect free administration and survival benefit means urologists will hang on to patients (and their revenues) longer.

Oncologists are only now comprehending the idea of a cancer drug that has patient benefit without shrinking tumors. I suggest you look up the 2006 NCI/FDA symposium on immunotherapy and brush up on the science before assuming oncologists are the only people qualified to judge cancer drugs.

> I am happy the FDA stuck to their
> principles.

This is a joke. In the last 18 months, the FDA turned down multiple oncology drugs that hit a primary surrogate endpoint but failed to show statistically-signific... survival benefits under the rationale that surrogate success without survival benefit is not success at all.

Contradicting this reasoning, they turned down Provenge because it was only nominally statistically significant on a primary endpoint TTP (an endpoint ODAC said in 2005 was not suitable for making an approval decision on in PCa) ignoring its highly and robustly statistical significance on survival.

Contradicting themselves again, they approved Avastin for breast cancer against the recommendation of their ODAC panel. Avastin was positive on the surrogate of PFS, but negative on survival.

I have no idea what "principles" you are referring to, but there aren't any in the oncology division by any objective analysis of their decisions in the Pazdur era.


None of this is proof the IMPACT trial will be successful. If it was, we wouldn't have to run the trial. It does prove, or at least cast serious doubt, on the idea you are familiar enough with the facts of this situation to comment authoritatively.

[frogmister]

Been There...here's the data you requested. Note the historical data supports the last group's survival numbers, which are small samples. For those not familiar with the trials, patients had the option to "crossover" to recieve chemo upon progression.

Provenge PIII 36 month survival data:

Provenge Arm 9901: 28/82 = 34.1%
Provenge Arm 9902A: 21/65 = 32.3%
Provenge Arm Pooled: 49/147 = 33.3%

Placebo Arm 9901: 5/45 = 11.1%
Placebo Arm 9902A: 7/33 = 21.2%
Placebo Arm Pooled: 12/78 = 15.4%

Placebo Arm Crossovers 9901: 4/34 = 11.8%
Placebo Arm Crossovers 9902A: 6/24 = 25% or 6/25 = 24%
Placebo Arm Crossovers Pooled: 10/58 = 17.2% or 10/59 = 16.9%

Placebo Arm Non-Crossovers 9901: 1/11 = 9.1%
Placebo Arm Non-Crossovers 9902A: 1/8 = 12.5% or 1/9 = 11.1%
Placebo Arm Non-Crossovers Pooled: 2/19 = 10.5% or 2/20 = 10%

[MrSerious]

Hey Been There, it looks like your flawed reasoning was well addressed by some good scientific minds here. Now I would like to point you to this document:

www.caretolive.com/CTL...

This legal document shows the shenanigans the FDA allowed Pazdur and Scher to carry out. For Dr. Von Eschenbach to come out with his fireside chat when he is well aware of these shenanigans is another slap in the face of us hardworking taxpayers and the hurting late stage prostate cancer patients and their families. Von E, Pazdur and Scher need to be bounced out of their positions of government service and held accountable for this incredible injustice to their fellow countrymen.

[Gates]

Glad to see Been There taken to task. I wonder how "short" he is or how "short" his hedge fund employer might be. lololol

The real question that keeps going through my mind is how you get to be a Been There or a hedge fund ruler or a Van E or a Scher and can knowingly make it your goal to prosper at the expense of thousands of lives. Very Hitler like if you ask me!!!

[Ardeis]

In China, much worse befell the head of their food and drug committee last year. The FDA hides behind it's veil of rules. Congress will eventually intervene, I predict von Eschenbach will not be renewed as Chairman and Provenge will eventually get approved; possibly in Fall 2008 or most definitely 2009. Scher and Hussain should be prosecuted but I doubt that will ever happen. Martha Stewart did fall less of a crimial infraction that these two in my opinion!

[Grateful]

Thank you, Dr. Cohen for your article. Thank you, BSR_David and others for your comments and rebuttals to "Been There." Shame on those in leadership positions at the FDA who continue to betray those they're entrusted to help.

[inhumane fda]

Resign Andy. You have lost control of your agency.

Your FDA is unable to even respond in acccordance with Federal regulation to the CareToLive Petition within 9 months despite the fact that 83 people a day die having been denied Provenge. Sorry to bother you with that..... you are so busy with more important things.

Isn't is just quite the coincidence that the 3 no votes on effectiveness were by those that had something to lose by approval of Provenge. The fourth no vote was by the FDA biostatician that said there was a 1 in 40 chance that the Provneg results on efficacy were arrvied at by chance.

Would not want the dieing patients to risk that one in 40 chance that the treatment does not work.

[singh]

FDA = funk Da A******s

[r.willett]

I believe the so called members of the FDA are a bunch of MONEY GREEDY INDIVIDUAL,that are only looking out at their PERSONEL INVESTMENTS !!! The FDA is a JOKE to foreign countries,SO get your PASSPORT & get GOOD medical treatment. FDA < FOOLS-DO-APPEAR>

[Demand_Integrity]

Evidently Dr. Scher and company missed one of their kindergarten lessons-- they put their mouths where their money is. The corruption of our regulatory agencies that enables self-serving insiders to manipulate proceedings in the promotion of their personal goals is an outrage, and the tolerance of it is as disgusting as the crimes committed. I still believe that this nation's ethical and legal foundation is made of the "right stuff," and this injustice will be dealt with when regulators with backbone are willing to blow the whistle on their corrupt colleagues.

[PortfolioManager]

I agree that Pazdur has behaved in a criminally negligent and irrational manner, with Provenge and many other therapies. Unfortunately, though, the conflict of interest question may be a bit of a red herring. Most active researchers will have multiple corporate affiliations. There will be very few without any conflicts of interest. The conflicts of interest listed above (stock ownership, consulting relationships, funding for research) are fairly visible, but there are also many other less visible conflicts of interest, allegiances, etc. Can someone who spent much of his life or her doing research on chemotherapy offer an unbiased opinion about a cancer vaccine? It will depend on the individual. But you can't evaluate cancer vaccines without involving oncologists. The only solution is to create a culture of rational debate at the FDA, and to severely discourage the making of bad, self-interested arguments.

[kyoto27]

“But you can't evaluate cancer vaccines without involving oncologists.”

Portfolio Manager,

Why? And why wouldn’t it be more proper to say you cannot involve oncologists who have no training or understanding of the science of immunology or cancer vaccines?
Let’s be honest, Dr Scher was lost at the Provenge AC and he knew it; and so was Dr Hussein. Not lost in there over the top Cancer Letter crusade , however, was an insight into their well-honed survival instincts, as noted in David Miller’s post above:

“It took a decade to get the current large Taxotere adjuvant trials started. It was clear from Hussein and Schers' letters they were worried that the approval of Provenge would hurt enrollment of these trials, which they personally and financially benefit from either directly or through their institutions' participation in these trials.”

So while they treasured their own survival, they trashed the Provenge survival data and the hopes it gave to those with no more hope. Interesting. And says a lot about both of those doctors.

[Jack Henry]

Martha Stewart went to jail, because she lied to a prosecutor investigating insider trading regarding the approval of Imclone's cancer drug. How many people will go to jail if there is an investigation regarding Dendreon's cancer drug? The FDA ruling on Provenge represents only the tip of an iceberg. It is probably one of the largest insider trading scadals of all time. When will the investigation begin?

[Texrat]

Outstanding article, and equally excellent responses for the most part.

[cchauhan]

This just prooves that the FDA obiously needs another Super FDA to police it. This was incompetence to the maximum, not forgetting all the conflicts of interests.
Simply Appaling!

[arret]

Martha Stewart's investigation was most likely retaliation from the "old Boys" she worked with when she was on eof the few female brokers on Wall Street in the 60's. Every since her co. went public, they probaly wanted to put her in her place, and used what they could to do so. Many have done much worse than she every day. Her stoic acceptance of the charges, and keeping her head high, speaks volumes about her power. She came back even stronger.

The FDA is obviously corrupt, and broken. The larger drug co's have their products approved with much less scrutiny. DNDN has little power, and probably offended others because it was "uppity", just like Martha Stewart. It will get approved once the other immune therapy treatments are established on the market.

"rules are only used as weapons"