Black Wednesday at the FDA

[Paul B]

Black Wednesday at the FDA
By MARK THORNTON
May 14, 2007

May 9, 2007, should be cited in the annals of cancer
immunotherapy as Black Wednesday. Within an eight-hour period
that day, the FDA succeeded in killing not one but two safe,
promising therapies designed and developed to act by stimulating
a patient's immune system against cancer. The FDA's hubris will
affect the lives and possibly the life spans of cancer patients
from nearly every demographic, from elderly men with prostate
cancer to young children with the rarest of bone cancers.

The dream of stimulating a person's immune system to fight his
cancer is older than the modern era of cancer chemotherapy. Over
a hundred years ago, Dr. William Coley at Memorial Hospital in
New York City experimented with bacterial agents that appeared to
have properties in stimulating immune responses against sarcoma,
a cancer of the muscles and bones. Advances ebbed during the era
of chemotherapy in the mid-20th century, but over the last 25
years cancer immunotherapy has received much research focus and
periodic support from the biotechnology industry.

Progress and investment, however, have been unsteady as tumor
shrinkages following treatment never quite translated into
"hard," clinically relevant outcomes such as prolongation of the
survival of the patient. Still, this type of approach remains the
Holy Grail of cancer treatment. One day current treatment
approaches such as surgery, radiation and chemotherapy, which
often kill most but not all of a cancer, could be made obsolete
by a potent immune response that eradicates the cancer cells and
provides subsequent protection against return and relapse.

Thus it was remarkable that in the last several months two
different biotech companies, with products utilizing two
completely different cancer immune approaches, came before the
FDA's Advisory Committee Meeting for judgment. The first product,
Provenge, made by the Dendreon company, is a cellular therapy
that tackles prostate cancer. The results of the Provenge
clinical trial in men with prostate cancer who had failed all
other therapies appeared before the committee that advises on
cell-based cancer products for the FDA Center for Biologics. This
committee was comprised of immunology and oncology experts. The
second product, Junovan, made by the IDM company, was tested in
children with osteosarcoma, a rare bone cancer that affects just
900 children per year. The results of the Junovan clinical trial
appeared before a different committee -- one that judges protein
cancer agents and was comprised solely of oncologists with no
immunology experts.

Both the Provenge and Junovan clinical trials provided evidence
that patients lived longer compared to control groups. But
according to the FDA, these "survival advantages" that
statisticians talk about had "issues." When the issues were
discussed in the Provenge public meeting the majority of the
committee (in a 13-4 vote) thought the issues, while relevant and
important, were superseded by the solid immunology science behind
the product.

However, those voting in the minority, very powerful members of
the oncology community, launched an unprecedented PR campaign
accusing those in the majority of incompetence and naiveté in
matters relating to cancer products. The arrogance of this
campaign overlooked the notion that survival data from
immune-based products may be qualitatively different from, and
may need to be judged by different criteria than, survival data
from chemotherapy drugs.

But such intriguing academic discussions never had a chance to
take root. Instead -- just a few weeks after the favorable ruling
on Provenge -- the Junovan product came before the FDA's Advisory
Committee for approval. Incredibly, the improvement in the
survival rate of children with bone cancer who received Junovan
was summarily dismissed as irrelevant by the committee. Why? The
statistical data showing the odds of efficacy were 94% surety
instead of the usual goal of 95% surety. This 1% difference was
all the committee needed to justify a 12-2 "No" vote.

The Junovan meeting was chaired by the very physician who
launched the PR campaign against Provenge. Unlike the meeting on
Provenge, however, all discussion time on Junovan was spent
kneeling before the altar of statistics -- not a single comment
was made about the immunology science supporting the efficacy of
Junovan. Remarkably, as the Junovan vote was taking place, the
FDA folded under the pressure and announced that it would not
abide by the favorable vote on Provenge. Instead, the FDA called
for more testing that -- if the product is not killed outright by
its maker Dendreon -- will take at least three years to complete.

In the span of eight hours, the dawn of a new era in cancer
immunotherapy was driven back into the night. It will be years
before we know the full impact of these decisions and how many
cancer patients, young and old, have had their lives cut short as
a result. For now, however, one thing is clear: While our
lawmakers obsess over FDA "safety reforms," no one is holding
this government agency accountable for its complicity in stalling
therapies for life-threatening diseases.

Dr. Thornton, a former medical officer in the FDA Office of
Oncology Products, volunteers as president of the Sarcoma
Foundation of America.

[Zoom]

I don't quite have a handle on this . . .
I'm not sure what the political/economic/power rationale is here.
Could you guys who follow this kind of thing help me out in
understanding? Do these committees & chairmen have "other" interests
besides our possible cures that cloud their decisions? Is everyone
scared off because of the recent Vioxx situation? Are these guys
appointed? By whom? If it's litigious paranoia, why not have the
patient simply sign a form saying they wouldn't sue? I had thought
Provenge was a glimmer of light at the end of a tunnel . . .

Thanks for any input.
Z

On Mon, 14 May 2007 12:11:06 GMT, Paul B
<[email protected]> wrote:

>Black Wednesday at the FDA
>By MARK THORNTON
>May 14, 2007
>
>May 9, 2007, should be cited in the annals of cancer
>immunotherapy as Black Wednesday. Within an eight-hour period
>that day, the FDA succeeded in killing not one but two safe,
>promising therapies designed and developed to act by stimulating
>a patient's immune system against cancer. The FDA's hubris will
>affect the lives and possibly the life spans of cancer patients
>from nearly every demographic, from elderly men with prostate
>cancer to young children with the rarest of bone cancers.
>
>The dream of stimulating a person's immune system to fight his
>cancer is older than the modern era of cancer chemotherapy. Over
>a hundred years ago, Dr. William Coley at Memorial Hospital in
>New York City experimented with bacterial agents that appeared to
>have properties in stimulating immune responses against sarcoma,
>a cancer of the muscles and bones. Advances ebbed during the era
>of chemotherapy in the mid-20th century, but over the last 25
>years cancer immunotherapy has received much research focus and
>periodic support from the biotechnology industry.
>
>Progress and investment, however, have been unsteady as tumor
>shrinkages following treatment never quite translated into
>"hard," clinically relevant outcomes such as prolongation of the
>survival of the patient. Still, this type of approach remains the
>Holy Grail of cancer treatment. One day current treatment
>approaches such as surgery, radiation and chemotherapy, which
>often kill most but not all of a cancer, could be made obsolete
>by a potent immune response that eradicates the cancer cells and
>provides subsequent protection against return and relapse.
>
>Thus it was remarkable that in the last several months two
>different biotech companies, with products utilizing two
>completely different cancer immune approaches, came before the
>FDA's Advisory Committee Meeting for judgment. The first product,
>Provenge, made by the Dendreon company, is a cellular therapy
>that tackles prostate cancer. The results of the Provenge
>clinical trial in men with prostate cancer who had failed all
>other therapies appeared before the committee that advises on
>cell-based cancer products for the FDA Center for Biologics. This
>committee was comprised of immunology and oncology experts. The
>second product, Junovan, made by the IDM company, was tested in
>children with osteosarcoma, a rare bone cancer that affects just
>900 children per year. The results of the Junovan clinical trial
>appeared before a different committee -- one that judges protein
>cancer agents and was comprised solely of oncologists with no
>immunology experts.
>
>Both the Provenge and Junovan clinical trials provided evidence
>that patients lived longer compared to control groups. But
>according to the FDA, these "survival advantages" that
>statisticians talk about had "issues." When the issues were
>discussed in the Provenge public meeting the majority of the
>committee (in a 13-4 vote) thought the issues, while relevant and
>important, were superseded by the solid immunology science behind
>the product.
>
>However, those voting in the minority, very powerful members of
>the oncology community, launched an unprecedented PR campaign
>accusing those in the majority of incompetence and naiveté in
>matters relating to cancer products. The arrogance of this
>campaign overlooked the notion that survival data from
>immune-based products may be qualitatively different from, and
>may need to be judged by different criteria than, survival data
>from chemotherapy drugs.
>
>But such intriguing academic discussions never had a chance to
>take root. Instead -- just a few weeks after the favorable ruling
>on Provenge -- the Junovan product came before the FDA's Advisory
>Committee for approval. Incredibly, the improvement in the
>survival rate of children with bone cancer who received Junovan
>was summarily dismissed as irrelevant by the committee. Why? The
>statistical data showing the odds of efficacy were 94% surety
>instead of the usual goal of 95% surety. This 1% difference was
>all the committee needed to justify a 12-2 "No" vote.
>
>The Junovan meeting was chaired by the very physician who
>launched the PR campaign against Provenge. Unlike the meeting on
>Provenge, however, all discussion time on Junovan was spent
>kneeling before the altar of statistics -- not a single comment
>was made about the immunology science supporting the efficacy of
>Junovan. Remarkably, as the Junovan vote was taking place, the
>FDA folded under the pressure and announced that it would not
>abide by the favorable vote on Provenge. Instead, the FDA called
>for more testing that -- if the product is not killed outright by
>its maker Dendreon -- will take at least three years to complete.
>
>In the span of eight hours, the dawn of a new era in cancer
>immunotherapy was driven back into the night. It will be years
>before we know the full impact of these decisions and how many
>cancer patients, young and old, have had their lives cut short as
>a result. For now, however, one thing is clear: While our
>lawmakers obsess over FDA "safety reforms," no one is holding
>this government agency accountable for its complicity in stalling
>therapies for life-threatening diseases.
>
>Dr. Thornton, a former medical officer in the FDA Office of
>Oncology Products, volunteers as president of the Sarcoma
>Foundation of America.

[Paul B]

On Mon, 14 May 2007 09:30:18 -0500, Zoom wrote:

> I don't quite have a handle on this . . .
> I'm not sure what the political/economic/power rationale is here.
> Could you guys who follow this kind of thing help me out in
> understanding? Do these committees & chairmen have "other" interests
> besides our possible cures that cloud their decisions? Is everyone
> scared off because of the recent Vioxx situation? Are these guys
> appointed? By whom? If it's litigious paranoia, why not have the
> patient simply sign a form saying they wouldn't sue? I had thought
> Provenge was a glimmer of light at the end of a tunnel . . .
>
> Thanks for any input.
> Z


The short answer is "yes". There are conflicts of interest, and
one advisor has been caught blatantly lying about it.

There is statistical legalism. When the provenge trials were
conceived no one understood that training the body to fight
cancer would take longer that shock treatments like chemo. So the
trials' primary endpoint, time to progression, in retrospect was
not a good choice. Legalists now do not want to allow survival as
a valid endpoint, even though TTP is acknowledged to be merely a
surrogate for survival.

Yes, there is regulatory paranoia because of Type I errors - the
VIOXX's, etc. But far more frequent are type Ii's - not letting
safe drugs on the market for various unjustifiable reasons. But
til now the people hurt by those decisions have not had the
political voice that people hurt by Type I's have had.

Dr. von Eschenbach of the FDA has been going around for months
talking up his vision for opening up the agency to allow worthy
drugs through. Apparently he couldn't control some entrenched
senior staffers who stand in the way of progress.

Economics? There is a lot of vested interest in the status quo
cancer industry. Research grants, careers. The immoral hedge
funds, which corrupt the market, have targeted Dendreon for
destruction. Over a billion shares traded in some twenty days -
an impossible feat except that the shares were counterfeit,
driving the price down.

30,000 men die of PC each year. They have delayed provenge
perhaps 3 years, maybe more, maybe permanently. The math isn't
difficult. The decision is unconscionable.

p.

[Justin Case]

"Paul B" <[email protected]> wrote in message
news:[email protected]..
: Black Wednesday at the FDA
: By MARK THORNTON
: May 14, 2007
:
: May 9, 2007, should be cited in the annals of cancer
: immunotherapy as Black Wednesday.

<Remainder snipped>

I think I read this article word-for-word in today's Wall Street Journal.
Attribution would be appropriate.

Ken Bland

[Richbro]

I thought all the FDA asked for was more data .................... I'm
confused.

Rich

[kh]

On May 14, 7:11 pm, Richbro <richbro...@msn.com> wrote:
> I thought all the FDA asked for was more data .................... I'm
> confused.
>
> Rich

Some of the data can be produced quickly. Some might take additional
"trials". This takes time. 2008 and 2010 are mentioned in some news
reports.

Other reports suggest that Dendreon might go out of business and not
be able to produce Provenge. The reasoning is that it takes many
millions of dollars per month to run a 21st Century biotech R&D
company. The "burn rate" for Dendreon is such that they may run out
of cash before the FDA allows them to bring Provenge to market.

Yes, they could sell the company, partner with a big biotech, raise
additional operating capital by diluting the stock. None of these are
as good as an FDA go-ahead.

What can you do? Lobby though the Prostate Cancer support
organizations. Write to your Senator and congressman.

This affects everyone here. Remember this quote:

"Two patients exhibited a transient 25-50% decrease in prostate-
specific antigen (PSA). For a third patient, PSA dropped from 221 ng/
ml at baseline to undetectable levels by week 24 and has remained so
for more than 4 years. In addition, this patient's metastatic
retroperitoneal and pelvic adenopathy has resolved."

This was out of a small trial of 19. All 19 had metastatic, hormone
resistant cancer!

Of the 19, Provenge pulled two back from the brink and apparently
"cured" a third.

Sure, it's not a guarantee and they need to do more work on the
treatment but it sure looks better than the alternative.

What else can you do? You might buy some Dendreon stock (symbol
DNDN) to show support. It's a little over six bucks a share today.

-kh still looking for a silver bullet.

[[email protected]]

FDA perhaps is thinking how to solve this kind of problems. "Unlike
the meeting on
Provenge, however, all discussion time on Junovan was spent
kneeling before the altar of statistics -- not a single comment
was made about the immunology science supporting the efficacy of
Junovan. "
Why not rediccuss the alter of statistics?
Why not consult immunological experts?