The Provenge Anniversary: A Plea From A Patient
17 CommentsBy Ed Silverman // April 2nd, 2008 // 9:24 am
The ongoing controversy over the Provenge prostate cancer vaccine is now one year old, and some of the prostate cancer patients and investors in Dendreon, which is developing the vaccine, are commemorating the saga by taking out full-page newspapers ads. The missives, which are sponsored by Care To Live, a non-profit that has filed a lawsuit hoping to compel the FDA to approve Provenge, are aimed squarely at FDA officials, though, because they are running in The Rockville Gazette, the local newspaper in Rockville, Maryland, where FDA offices are located.
In what promises to be a series, this ad is in the form of a letter written by Ted Girgus, a 60-year-old with end-stage prostate cancer who begs the FDA not treat him “like a statistic.” He both chastises the agency for demanding more Provenge trials and pleas with agency officials to change their minds. To what extent he composed this entirely by himself isn’t clear, but the message - like earlier YouTube videos by others - personalizes the issue for FDA employees to see in ways the non-profit’s lawsuit can’t accomplish.
The controversy erupted last spring, when the FDA ignored the recommendation of its own advisory panel and decided not to approve the Dendreon product. This turnabout came after two panel members took the unusual step of privately writing FDA officials to hold off. The move created a ruckus - the two panelists say they received threats; the episode fueled debate about the use and approval of experimental meds, and the Care To Live lawsuit alleged the two panel members held undisclosed financial conflicts of interest and a Byzantine power play inside the agency.
The anniversary, by the way, was also marked the other day when some Dendreon investors sent white roses to FDA commish Andy von Eschenbach, prompting the agency to send two agents from its Office of Criminal Investigation to quiz a local florist. An FDA spokeswoman later explained such procedures are routine when unannounced gifts arrive for Andy and that the flowers were donated.
Kerry
IS THERE A GOOD MAN IN THE FDA?
By Kerry M. Donahue, Esq.
CareToLive is an advocacy group that has been taking on the FDA, in the media, in Congress and in the Courts, because they believe that a safe and effective treatment for late stage prostate cancer patients called Provenge, was denied FDA approval merely to appease certain individuals in the FDA who had their own agenda, without regard to the actual science.
CareToLive presented the FDA with a way to correct this mistake without the need for Congress or the Courts to intervene. There is a device set up that was designed to give the FDA the chance to address its own mistakes. It’s called a “Citizens Petition”. This vehicle allows citizens to ask the FDA to review a wrongful action that the citizens believe requires reconsideration.
A Citizens Petition is the only way for a citizen to be formally heard by the agency.
CareToLive filed a Petition on July 27, 2007 and received a non-responsive reply in January 2008. That reply frim the FDA’s Center For Biologics Evaluation and Research (CBER) division head Jesse Goodman did not comply with The Code of Federal Regulations.
The reply in pertinent part stated:
“In your citizen petition you request the Commissioner of Food and Drugs to reconsider FDA’s failure to grant a biologics license application for Provenge…..We are still considering your request and supporting information stated in your citizen petition….We will respond to your petition as soon as we have reached a decision on your request”.
The Code indicates that within 6 months the FDA Commissioner must respond by approving the petition, denying the petition, or by providing a tentative response, indicating why the agency has been unable to reach a decision on the petition. The tentative response may also indicate the likely ultimate agency response, and may specify when a final response may be furnished.
At a minimum the FDA must indicate the reason “why”, when they choose to provide a tentative response. Since they did not comply, they are currently in violation of 21 CFR (e)(2)(iii). The citizens are also left asking the question: did Mr. Goodman just do as the FDA legal team instructed so as to avoid making a “final decision” and thus avoid Judicial or Congressional review, or is he really trying to do the right thing by revaluating whether Provenge received the proper due process of law it was entitled to. Every day that passes, another 80 patients die of Prostate Cancer, making the answer seem more and more apparent as each day passes.
Provenge is the immunotherapy for late stage Prostate Cancer patients that was voted by 17 experts handpicked by the FDA, to be safe (17-0), and substantially proven to be effective (13-4), but which was then denied approval by the FDA, in part due to extensive lobbying by two of those experts who had substantial conflicts of interest. One of those experts was employed by a direct competitor to Provenge. A recent CareToLive Freedom of Information Act (FOIA) response proved this conflicted expert was even directly lobbying the Commissioner himself.
CareToLive, along with other advocacy groups, Abigail Alliance, Cancer Cure Coalition, Prostate Health Education Network and Arighttolife, seek quicker access to potentially life-saving medicines for late stage diseases such as Androgen Independent Prostate Cancer (AIPC). Every treatment that the Abigail Alliance previously sought early access to was eventually approved by the FDA.
It will take a good man to have the courage and the strength to act in the face of the political forces within the FDA. That man can and should be CBER head Jesse Goodman. He has the authority to begin saving lives with the stroke of his pen. As the head of CBER, the fate of 90,000 AIPC patients is currently in his hands. What we do not know is whether his response to the CareToLive petition was genuine, or whether it was a tactical response made merely to avoid review. We will know soon if the patient’s good man has been won over by the darker forces within the FDA. Patients can only hope that the time lapse to date is not an indication that their hope cannot live up to his name.
The FDA has never granted any petition presented by an advocacy group on behalf of patients seeking access, and thus the process is apparently always a futile one. The FDA has corrupted this “process” and apparently uses it only to delay and avoid oversight. One man can change this, because the process gives him the absolute power to act in response to a Citizen Petition and to act NOW.
Hopefully, Mr. Goodman can have the courage to act as the man the FDA needs, leading them into a new era; one where the voices of patients are heard and one where the needs of patients come first!
The Provenge Anniversary: A Plea From A Patient · Prostate Cancer
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Hard Ball
It might take two or three “good men”, Mr. Donahue, of which you are surely one of them.
May you and Mr. Goodman find the way.
Kyoto27
Today, we are learning once again that the Provenge Story was never about ‘good science.’ It is about reflecting on the guilt of Congress and all Americans for having allowed the FDA to conduct “real meetings” in secret and AC panel meetings in public.
We got what we deserved. 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…”
No, the time has come now for this insanity to stop:
What is needed is complete access by the public to FDA records –who calls for the “real meetings”; who attends the “real” meetings; transcripts of all arguments, notes and votes of those who attended.
Instead, the FDA expects 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?
Who in Hell benefits in this country from giving the FDA absolute sovereignty over matters of Life & Death without due process? Not good science; and not patients. The absolute corruption and arrogance it has engendered is symbolized in the FDA’s goons harassing a florist for having delivered roses to the FDA’s commissioner and in bullying peaceful protestors who are acting like all Americans should act—with outrage.
America’s Fourth Estate, and our legislators need to be equally outraged:
Taking the “due” out of “due process” was not just a ‘deliberate wrongdoing’ –it shreds the entire fabric of this Republic.
The FDA needs to chill out, wake up and smell the roses.
Moonshooter
27 - 0 for Safety
13 - 4 for efficacy
What’s not to like about that? The good man from CaretoLive, the Goodman from the FDA, the good man Teddy who expressed himself so well, they would make a good combo.
Let’s give prostate cancer patients more time, more time to smell the roses. Just do it!
—–
We never know how high we are
Till we are called to rise;
And then, if we are true to plan,
Our statures touch the skies.
Emily Dickinson
Tony F
My prayers are for Ted & family and the hundreds of thousands of other prostate cancer patients as well as for the 83 men and their families who die each day from this horrible disease. Hopefully, those with the authority and responsibility will soon see their way to, at the minimum, a conditional approval which will allow public access to this treatment yet allows the FDA to yank it’s approval at any time–as is true with any drug/treatment they regulate.
And I extend my kudos to all those who continue to work so diligently and selflessly for acquiring a viable treatment for this disease and for those in the media like you, Ed, and Mike Huckman for keeping the public informed by just telling the facts without injecting “spin” on the story.
Blessing to the cancer patients everywhere and their families!
Teddyboy
Ed,
I just want to let you and your readers know, that the letter mentioned above was written by me and me alone.
All I am asking is that the FDA follows the expert advice of its own advisory panel. The CBER panel voted 17-0 that Provenge was safe and 13-4 it showed “substantial efficacy”. The Board was convened at taxpayers expense and contained experts in their fields.
WHY ALLOW ME AND THOUSANDS LIKE ME TO DIE A HORRIBLE DEATH WHEN WE HAVE AT LEAST A CHANCE WITH THIS PROMISING NEW IMMUNOTHERAPY.
What in God’s name do we have to do just to have a chance to live a little longer and be with our loved ones???
I pray the FDA does the right thing.
Stay Well,
Ted Girgus
Paul
This past weekend marked the 1 year anniversary of the Provenge advisory committee meeting where an overwhelming majority of FDA experts confirmed that Provenge met the safety and efficacy criteria for marketing approval. Yet, I am unware of any action by the FDA to investigate and correct the obvious conflicts of interest that surrounded Dr. Scher’s participation or this apparent manipulation of FDA authority. Justice delayed is justice denied! This principle is the basis of the right to a speedy trial. The FDA has acted too slowly in resolving 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?
Moonshooter
Correction: 17 - 0 Safety
13 - 4 Efficacy….durn typos.
Sharon Romero
What in the hell will it take to wake up those in elected positions occuping offices of power to take action and verbalize what everyone already knows - that the FDA and its process is totally and completely corrupt. The fact the FDA overruled its own advisory comittee advocating approval for Provenge for the first time ever in it’s history should be enough to do more than just raise eyebrows. This country and those in power are a complete and utter disgrace.
CMC guy
Kyoto27 makes a claim about “good science” relative to the Provenge story and from what I have seen and heard the FDA decision here was partly driven from a (perhaps overly stringent) scientific or statistical rationale. I believe the clinical trial submitted for approval did not meet its primary endpoint (time to disease progression) and although the survival (+4.5 months) was very encouraging the analysis did not prove significance. Outcome is FDA has sought additional data to confirm the results before approval. Whether this comes from a poor design or attempt to gain approval on surrogate it is fairly common to get a request for more data (even when a study meets endpoints). The Advisory Committee apparently was willing to overlook the unsuccessful trial and see the promise treatment offered (which for this particular patient population may be justifiable pragmatically rather than with scientific certainty) but ultimately the FDA holds power/responsibility of approval as noted in role of Advisory Committee. Although rare to overrule recommendations it’s rarer to be given a pass when have not conclusively demonstrated objective. There is a clamor against drugs already not being efficacious so conceivably promotes more caution in deciding on evocable data.
Kyoto27
CMC:
At a panel discussion sponsored by the biotech company Novacea, Dr. Scher had this to say:
“It may be time we focus less on statistical significance alone, and more on patient benefit.” – MedPage Today, February 26, 2007
This is exactly what the 13 members of the CTGT panel did by voting yes to whether Provenge provided substantial evidence of efficacy.
David Miller of BioTech Stock Research, LLC wisely noted in a written response (http://caretolive.com/research) to comments that Dr. Sher published in The Cancer Letter:
“Biostatisticians are masters of a very arcane art of interpreting streams of data. Biostatisticians are most concerned with making sure a treatment benefit in a trial is not due to chance. They have set up a dizzying array of rules to prevent people from cheating and changing the rules on interpreting the data of a trial simply because they don’t like the outcome. These protections serve us well, as long as they are not taken to the extreme.
Both the first (9901) trial and the pooled data demonstrated a p-value of p=0.01. This means that there is only a 1% chance the result is due to chance. Biostatisticians and regulators have arbitrarily chosen 5% (p=0.05) as the odds of a result being due to chance
are too high for drug approval. In order to prevent people from switching things up to get results they like better, biostatisticians force trial sponsors to choose in advance which single item they will measure to prove a clinical trial is successful.
Eight years ago, the sponsors of the Provenge trial didn’t know any better and chose time to progression as that single item – 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.
Nearly all of the time, when a sponsor switches endpoints around it is a problem. They often dredge data and choose some narrow portion of patients – a subgroup – and claim victory for the trial when that subgroup shows a benefit. This is quite common, and the FDA rightfully rejects these arguments for a whole host of reasons not particularly germane to this discussion.
It is important to realize that’s not what is going on here. Provenge demonstrated a survival advantage in all patients in the first trial and when all patients from both trials are combined into one analysis. All patients in the second trial saw a similar survival advantage once that trial was statistically corrected for imbalances.
Should prostate cancer patients be penalized for an eight-year old decision to make progression the primary endpoint? As Dr. Scher himself implies, sometimes you have to look beyond strict biostatistical rules and do what is right for patients. 13 panel members agreed with this point of view, and voted their belief that Provenge demonstrates substantial evidence of efficacy.”
Dr Scher had it exactly right in February 2007 when he said:
“It may be time we focus less on statistical significance alone, and more on patient benefit.”
Dr Scher is no fool; but he is also fooling no one that ‘good science’ was behind his over-the-top crusade to de-rail Provenge approval.
The good science is on the side of the Provenge supporters who rightly contend that the correlation between time to progression (91.5%-94.8%) and survival (99.0%) is so strong that the FDA should approve Provenge as soon as possible–especially considering its much milder side effect profile when compared to the treatment alternatives.
It’s time for Dr Scher to start acting like a doctor and admit what he already knows– that in the case of Provenge “it may be time we focus less on statistical significance alone, and more on patient benefit.”
Kyoto27
“CMC guy
Kyoto27 makes a claim about “good science” relative to the Provenge story and from what I have seen and heard the FDA decision here was partly driven from a (perhaps overly stringent) scientific or statistical rationale.”
I neglected CMC to add that in summary the FDA decision had nothing to do with an “overly stringent” process or rationale and a lot to do with corruption and dysfunction at the highest levels. And you obviously know that, don’t you?
CMC guy
Kyoto27 I actually agree that Provenge should have gotten approval however IMO would have been more based on 1) relative mild side effects, 2) apparent survival benefit and 3) lack of other proven effective treatments for PC. Saying that, there would have been ramifications to such an approval that go beyond this product. I do not know if it factors in but isn’t this the first drug of its type to reach this point so may be under extra pressure to get it right? From what I have read only #1 is fully supported by science while there are still open questions or current circumstances so additional data sought by FDA, a not uncommon event.
My point is a basic axiom of science is that a theory/question is posed then experiments performed to prove/disprove. In this case the clinical trial apparently did not provide information that clearly answered the specific primary endpoint: which if the time to progression increase not demonstrated then because of correlation you cite to survival such a benefit inconclusive (good science suggests more work needed). My guess is that sponsors did know what they were doing in selecting endpoint and expected to get a positive answer faster than waiting 2-3 years longer to gather mature survival data (which I think was valid approach). Its reasonable that now required to submit more data especially since missed on result and the question “changed” so have to factor in whether the study as performed can adequately answer the new question. As noted unfortunate the prostate cancer patients lose out due to delay and it takes so long to run trials that can be conclusive.
I also concur with statements regarding (FDA, therefore sponsors) being overly slavishness to statistics at expense of goal to help sick. Again this may be a narrow system that has evolved but there still must objective standards of some type even though the complexities can be great in judging true benefits.
CMC guy
Kyoto27- I know there was deplorable behind the scenes things that happen here that cloud the whole issue but what I indicated as overly stringent is exactly in line with your response post Dr Scher’s statement regarding statistics. It is not obvious if and how that operational mode played a role so I only speculate on how the FDA would handle without all the clutter and again based on science viewpoint I see shortcomings they may have used to delay approval (although admit am only viewing portions on the real data/story from blogs such as this).
Kyoto27
CMC–you ask: “Again this may be a narrow system that has evolved but there still must be objective standards of some type even though the complexities can be great in judging true benefits.”
With regard to Provenge, isn’t the real question before the FDA 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?
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.
With all due respect, Dr vonEschenbach, 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.
Kerry
I would note that an FDA employee admitted in writing that the actions of the conflicted doctors on the advisory committee effected the decision to deny approval to Provenge.
Since that is the case why have they not completed their investigation and coreected their mistake. The CareToLive Citizens Peition deserves to be responded to according to the law.
The FDA can and should fix this travesty and act quickly to get Provenge to the patients now.