Cancerfighter’s Weblog

Alternative cancer therapies and ideas

How a drug company tries to expand its market for a drug

Posted by Jonathan Chamberlain on May 1, 2008


The following report (from the Ralph Moss newsletter) gives us an idea as to how some chemotherapy
drugs which may be of no benefit to patients get approval from the
FDA and go to market – being prescribed by doctors and ingested by
patients. This drug, Avastin, sells for $4,400 per month and last
year it generated $2.3 billion in the US alone. You can understand
why the company that makes it want to expand its market.

From the Ralph Moss newsletter:

A REPORT ON THE CHEMOTHERAPY DRUG, AVASTIN
Two months ago, the Oncology Drugs Advisory Committee (ODAC) ruled 5-
4 that the Food and Drug Administration (FDA) should not approve the
drug Avastin (bevacizumab) as a treatment for advanced breast cancer.
(Currently, Avastin is only approved for use in patients with
colorectal cancer.) The committee’s reason for recommending against
approval for use in breast cancer was that –

***Avastin had not been proven to convey significant patient
advantage in terms of either improved overall survival or quality of
life.***

Since December, executives of the California-based biotech firm
Genentech (which manufactures Avastin), and its major stockholder,
Roche, have been working and lobbying hard to overcome this FDA
hurdle. This week they finally revealed their strategy and, unless
there is an upsurge of objections from medical consumers, they may
well get approval of the drug by FDA‘s February 23rd decision-making
deadline.

On Tuesday, February 12, Genentech issued a statement on the so-
called AVADO study, which is being conducted by ROCHE.[REMEMBER THAT
ROCHE IS GENENTECH’S BIGGEST STOCK HOLDER] The study was designed to
compare outcomes in 736 patients with advanced breast cancer, all of
whom received the standard chemotherapy drug docetaxel (Taxotere®),
but half of whom also received Avastin.

Genentech believes that the results of the AVADO study provide
confirmation of Avastin’s efficacy and safety in this patient
population,” the company said in its statement.

On what basis did Genentech make this confident assertion? What were
the actual results of the study? Apparently nobody except a handful
of company insiders and a few individuals at FDA know, since all the
company was prepared to release publicly was a very general statement
claiming that Avastin had “met its primary endpoint of prolonging
progression- free survival (PFS) in patients who had not received
prior chemotherapy for their locally recurrent or metastatic HER2-
negative breast cancer. No new safety signals related to Avastin were
observed. These data will be submitted for presentation at an
upcoming medical meeting.”

…progression- free survival (PFS) and overall survival are not the
same thing. Progression- free survival refers to the length of time a
patient survives after treatment with no sign that the disease is
advancing. By contrast, overall survival (OS) refers to the
percentage of people in a study or treatment group who are alive for
a given period of time after diagnosis or treatment.

The difference between these two measures is not trivial. PFS is by
no means always synonymous with increased survival. Neither is
progression free survival easy to measure objectively. As both FDA
staff and ODAC members pointed out at the December meeting, it is
difficult to gauge precisely when a cancer starts to progress, or
worsen. Although achieving a period of stabilization or remission
sounds like a worthwhile objective, if the patient does not live any
longer as a result of this interlude its benefit is, to say the
least, questionable.

In other words, a drug may change the shape of the patients’ survival
curve, but not alter the ultimate outcome. Treated patients may die
on average at the same time as those who were not treated; sometimes
they may even die sooner. So what has one actually accomplished with
the intervention? Advocates of chemotherapy are apt to say that at
least chemotherapy may improve patients’ quality of life by
increasing the period of time in which they are in remission.
Remission is, they say, a psychological benefit. But that assumption
is debatable, since patients who believe their disease is being
controlled can feel an even greater sense of loss and disappointment
when the disease again progresses than do those without any illusions
about being cured of the disease. Disease-free survival in any case
does not seem like sufficient reason to approve a new indication for
a drug.

Genentech and Roche indicated that they would release the actual
AVADO data at a future scientific meeting. They did not say whether
the data would demonstrate an improvement in overall survival.
Overall survival was considered one of the “secondary endpoints” in
the AVADO study. But it is unclear if FDA has been provided with such
data. Neither they, nor the company, have made such data available to
outside scientists or to the concerned public.

Barbara Brenner, executive director of Breast Cancer Action, has
demanded the full data from the company. “We are quite disturbed that
this uninformative press release seems timed to coincide with the
imminent decision by the FDA on the currently pending sBLA
[supplemental Biologics License Application, ed.] for Avastin in the
metastatic breast cancer setting,” she wrote both Richard Pazdur, MD,
of the FDA and David Shenkein, MD, of Genentech on Feb. 12, 2008.

Brenner also demanded release of so-called Phase IV data on Avastin’s
actual performance in clinical trials with colorectal cancer
patients. (Phase IV studies are post-marketing reports on the actual
safety and effectiveness of drugs as they are used in the real
clinical setting. Such studies are often requested by FDA as a
condition of drug approval, but are rarely carried out or published
by drug companies.)

“We understand that Genentech is engaged in a thorough Phase IV trial
of Avastin in the colorectal cancer setting,” Brenner wrote. “If
Avastin is approved for breast cancer based on information other than
overall survival or improved quality of life, the FDA should require
prompt and thorough Phase IV review as a condition of approval.”

Misleading Media

Articles in the media have on the whole given the impression that
Genentech has clinched the case for Avastin’s efficacy, and that
approval would seem to be just a matter of time. The New York Times,
which often is skeptical of drug company claims, threw caution to the
wind in this instance with its headline: “In Second Trial, Avastin Is
Found Effective in Treating Breast Cancer” (New York Times, 2/13/08).
This implies that drug company claims in press releases are the same
as facts established by independent scientists in peer-reviewed
studies.

Many other news sources made the same error. Reuters, for example,
led with “Genentech‘s Avastin Meets Breast Cancer Study Goal,” and
the Wall St. Journal proclaimed: “Avastin With Chemotherapy Is
Effective in Cancer Trial.”

Huge amounts of money hang in the balance. Avastin, which costs
patients and their insurers $4,400 per month, last year generated
$2.3 billion in the US alone. Sales are projected to rise to $2.7
billion by 2009. The breast cancer market might be worth an equal or
even greater amount, since there are more new cases of breast cancer
in the US each year (181,000) than of colorectal cancer (154,000).

When ODAC recommended against extending the indication for Avastin
last December, Genentech‘s stock fell about $10 per share. This meant
an instant loss of around $10 billion for the company. It has
recovered a bit since then, and on the announcement of the AVADO
study, its shares rose 2.4 percent, to $71.60. According to J.P.
Morgan analyst Geoffrey Meacham, there is now a 50-50 chance that FDA
will approve Avastin for breast cancer. “The key question,” said
Meacham, “is whether the FDA will want better results on the drug’s
ability to improve the overall survival rate of patients. That data
will be more difficult and time-consuming to produce than data on how
long patients survive without the condition progressing” (AP,
2/13/08).

On the other hand, according to Michael Aberman, an analyst with
Credit Suisse, without survival data the new trial would not increase
the chance for Avastin’s approval this month (Pollack 2/13/08). As
Andrew Pollack wrote in the Times, “The decision is being closely
watched as a barometer of the agency’s standards toward approving new
cancer drugs or expanding uses of current medications. It is possible
the F.D.A. will delay the decision past February so it can consider
the new data.”

I once again urge readers to email FDA Commissioner Andrew von
Eschenbach, MD, and Richard Pazdur, MD, director of FDA’s office of
oncology drug products, with their opinions on this matter. Consumer
input could be crucial, especially at this critical juncture.

What I will convey to them, in my own letter, is that FDA should NOT
approve Avastin for breast cancer until and unless there is impartial
scientific proof that the drug actually extends women’s overall
survival.

[The above information is part of the Ralph Moss newsletter]

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