When a doctor recommends chemo, consider this

[Guest guest]

The following report 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 Pazdur, MD,

of the FDA and 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.

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 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

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 von

Eschenbach, MD, and 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]