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.

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.

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.

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?

“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.”

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?