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Witnessing the process I can see how inadequate instruction by the FDA, unfamiliarity with the drug, and a biased presentation by the FDA reviewer led to this [hurtful] result -- Gabriel. Hortobagyi, MD

It is not often that Avastin or any newly developed drug is a blockbuster for several cancers -- lung, kidney, breast, brain, colon -- and advanced macular degeneration. In this column, we restrict our coverage of Avastin for breast cancer because till December 17, the FDA has a chance to right a wrong and save a genuinely useful medicine. Avastin is manufactured in San Francisco by a specialist in cancer drugs, Genentech, which the Swiss drug manufacturer Roche has bought.

FDA gave accelerated approval for Avastin in 2008 “based on a study suggesting it halted progression of breast cancer for more than five months. That study paired it with the chemotherapy drug paclitaxel. The manufacturer, Roche, then applied for standard approval. In 2009 it submitted two new large clinical test results. The accelerated approval by FDA was based on the findings of a large clinical trial sponsored by the company.” The advisory board recommended accelerated approval by 5-4

In July, 2010, the Oncologic Drugs Advisory Committee (ODAC)  was presented with two new studies of nearly 2,000 breast-cancer patients. The tests showed a slowing in the progression of cancer by one to three months, less than had hoped. ODAC recommended revoking the accelerated approval by a vote of 12-1.

Basically, the decision is made by the outside independent board, ODAC, whose members the FDA names. Substantially the same ODAC had recommended the accelerated approval by 5-4. The FDA, which generally accepts the ODAC recommendation, has given itself another 90 days, to December 17, to making its determination.

Breast-cancer patients all over the world are using Avastin. Facing the prospect of losing their Avastin, some 6500 have petitioned the FDA, begging to not be deprived of Avastin.

Even if Avastin’s approval is revoked, it will still be available to doctors, but insurance companies do not like paying for drugs that FDA has not approved, and more so now when hostile ObamaCare pressure is laid heavily on them. Avastin is expensive. It costs $7,700 a month wholesale. Though cost is not supposed to be considered in reaching a decision whether to approve a drug, it is difficult for medical ideologues to ignore it.

Deaths from breast cancer, the second most important cause of death among women, have decreased dramatically but still came to 40,000 last year. The ten-year survival rate among patients treated at the University of Texas MD Anderson Cancer Center increased from 25% to 76.5% from 1944-55 to 1995-2004. Even for patients with stage IV breast cancer—the worst diagnosis, which occurs when tumor cells have already metastasized—the 10-year survival rate increased from 1944 to the present by 3% to 22%.

The first clinical test of Avastin showed the survival rate at 5.7 months. The second hearing was anticipated to extend the survival rate but did not significantly. In the opinion of ODAC, there is not enough benefit to warrant the risks: bleeding, hypertension, and a small risk of death. (Should’t FDA also consider the alternative if it fails to approve Avastin? It is not discussed in the research we have perused.)

FDA sets the criteria by which ODAC is to be guided. The benefits must outweigh the risks. The drug must show progress by stopping progression of the cancer, or giving the patient a longer average lifetime. The two additional clinical test results provided by Genentech—the drug-maker does the testing and reports the results to FDA—do not differ significantly from the earlier result which won Avastin accelerated approval.

FDA and OCDA are not supposed to consider cost in making their decision, but many believe they do. Avastin is expensive. If FDA revokes its accelerated approval, Avastin will still be available to doctors but insurance companies will not accept it.

ODAC looks at averages (the mean) but tends to forget that many patients are above the average, as well as below it. The statistical ignorance of ODAC panelists blinds them to appreciating the variances above the average. While the average of the second clinical tests may be only one to three months longer than the first, what happens to the variances above the average? That is not considered.

An observer on behalf of Genentech, Dr. Gabriel Hortobagyi was present at the second ODAC meeting. He took elaborate notes, which have been published by Medscape Medical News.

He found the meeting a sham. The FDA reviewer who made the presentation presented the data in a biased manner. Positive survival differences (though not statistically significant) he labeled “no difference,” and negative differences he labeled as favoring the placebo, Dr. Hortobagyi reported.

No survival benefit was mentioned. “This either denotes ignorance of common statistical methods or an underlying agenda” against Avastin. There were other surprising statements made by the FDA reviewer attributing certain toxicities to Avastin, when in fact those toxicities are well recognized as associated with the underlying chemotherapy.

For instance, "bowel perforations are a well-recognized complication of taxanes . . .”

“The FDA reviewer continuously referred to these complications as” related to Avastin, “creating an artificially high” Avastin-related mortality rate in the minds of ODAC members.”

Dr. Hortobagyi continued. “During the discussion, I got the strong impression that several ODAC members had a poor understanding of clinical trials and statistics [based on some of the questions that were somewhat bizarre!] and that very few had any experience using bevacizumab [Avastin] in the clinic. Otherwise, they would have known that the frequent toxicities reported on paper caused few symptoms and actually did not affect quality of life.”

FDA will make its final determination on December 17. One hopes it will take account of the near-uselessness of the second trial in this life-and-death question, and not lose what the Wall Street editorial calls lose a genuinely useful medicine.

By Natalie Sirkin


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