By ANDREW POLLACK
ruling in an emotional issue that pitted the hopes of some desperate patients against the statistics of clinical trials.
The commissioner, Dr. Margaret A. Hamburg, said that the drug was not helping breast cancer patients to live longer or control their tumors, but did expose them to potentially serious side effects such as severe high blood pressure and hemorrhaging.
“This was a difficult decision,” Dr. Hamburg, said in a statement. The F.D.A. “recognizes how hard it is for patients and their families to cope with metastatic breast cancer and how great a need there is for more effective treatments. But patients must have confidence that the drugs they take are both safe and effective for their intended use.
“After reviewing the available studies,” she continued, “it is clear that women who take Avastin for metastatic breast cancer risk potentially life-threatening side effects without proof that the use of Avastin will provide a benefit, in terms of delay in tumor growth, that would justify those risks. Nor is there evidence that use of Avastin will help them live longer or improve their quality of life.”
Avastin will remain on the market as a treatment for other types of cancers, so doctors can use it off-label for breast cancer. But some insurers might no longer pay for the drug, which would put it out of reach of many women because it costs about $88,000 a year.
Medicare, however, has said it would continue to pay for the drug’s use in breast cancer.
The decision is a setback for the drug’s manufacturer, Genentech, which fought long and hard to keep the approval.
Analysts had previously estimated that loss of the breast approval could reduce sales at Roche, the Swiss company that bought Genentech in 2009, by about $1 billion. It appears that much of this decline has already occurred and Avastin appears to have lost its status as the world’s best-selling cancer drug to Roche’s own Rituxan, a medicine for lymphoma.
Genentech said in a statement that it was “disappointed with this outcome.” It said it would continue with plans to conduct another clinical trial in an effort to regain approval. It also said it would continue to provide help through its patient-support programs to breast cancer patients who might not be able to afford the drug.
Dr. Hamburg’s decision, outlined in a 69-page memorandum, agrees with the unanimous recommendation to revoke the approval made by an F.D.A. advisory committee in June, after an emotion-packed two-day hearing. The fact that it took Dr. Hamburg nearly five months to make a final decision attests to the sensitivity and complexity of the issue.
Some women who say the drug has been keeping them alive have pleaded desperately for the approval to be retained. So the revocation risked subjecting the Obama administration to criticism of being cruel. In addition, some Republicans had cited the possible action as an example of rationing under health care reform. (The F.D.A. has insisted that cost issues were not considered.)
Yet pressure came from the other direction as well. The administration had pledged to make scientific decisions on the basis of science. That made it difficult for Dr. Hamburg to go against the conclusions of the F.D.A.’s own staff and the strong recommendations of the outside experts on its advisory committee.
There was also pressure to uphold the integrity of the accelerated program that was used to approve Avastin for breast cancer. That program, started in response to pressure of AIDS activists in the early 1990s, allows the F.D.A. to provisionally approve drugs with less than the usual evidence of effectiveness, subject to further confirmation.
The agency has been criticized for failing to make sure the follow-up studies are done, or to remove approvals if those studies did not confirm the expected benefit.
The case of Avastin, in which subsequent studies did not show the same level of effect as the initial study, is one of only a few in which an approval had been revoked and the first one in which the manufacturer had protested and requested a hearing.
Even before the decision Friday, a handful of insurers had already stopped paying for Avastin as a treatment for advanced breast cancer, according to Genentech. Most have said that they would wait until after the F.D.A. commissioner made a final decision before evaluating their policies.
But Medicare, which covers many women with breast cancer, has already said it would continue to cover the cost no matter what the F.D.A. decided. Medicare is obligated to pay for off-label use of cancer drugs that are listed in references known as compendia, such as the one published by the National Comprehensive Cancer Network, an organization of major cancer hospitals.
In July, shortly after the F.D.A. advisory committee voted to revoke the approval, a committee of breast cancer specialists assembled by the cancer network reaffirmed that Avastin should remain listed as “an appropriate therapeutic option for metastatic breast cancer.”
UnitedHealthcare, the big insurer, has also said its payment decisions would be guided by the cancer network’s compendium, so it, too, should continue to pay for Avastin.
Still, the F.D.A.’s move to revoke the approval has already sharply cut the use of Avastin as a treatment for breast cancer, according to Genentech. Some doctors have said the new data show the drug simply is not as useful as they once thought.
Roche has reported that global sales of Avastin in the first nine months of 2011 declined 8 percent, to 3.942 billion Swiss francs, or about $4.3 billion. In the United States sales fell more sharply, down 15 percent to 1.774 billion Swiss francs, or $1.93 billion.
The issue of whether Avastin should be approved for breast cancer has been contentious for years.
An initial clinical trial showed that Avastin, when combined with the drug paclitaxel, which is also known by the brand name Taxol, delayed the progression of disease by about five and a half months, compared to use of paclitaxel alone. However, the women who received Avastin in the study did not live significantly longer and they suffered more side effects.
Based on that data, the F.D.A.’s cancer drug advisory committee voted 5 to 4 against approval in December 2007. But two months later, the agency granted provisional approval.
In subsequent studies, in which Avastin was combined with different chemotherapy drugs, tumor growth was delayed by only one to three months. And Avastin did not prolong lives at all, nor did it improve quality of life.
In July 2010, the F.D.A.’s cancer drug advisory committee recommended 12 to 1 that the approval be revoked. The F.D.A. itself moved to do that in December of that year.
Genentech then requested the hearing that was held in June. It was held in front of a smaller group from the same advisory committee that had voted against the drug in December. None of the six members on the panel was a breast cancer specialist.
Genentech argued that the subsequent trials did not undermine the first trial’s finding that Avastin worked well with paclitaxel, and that perhaps the background chemotherapy mattered. It urged that the approval be maintained while it conducted another study of Avastin in combination with paclitaxel.
Many breast cancer specialists say that Avastin does appear to work very well for some patients, but that the effect gets drowned in a clinical trial that looks at overall results. Some doctors and patient advocates argued the drug should remain available for that reason.
But there is as yet no way to determine in advance who those patients are. So the advisory committee relied on the overall statistics from the clinical trials.
Europe has retained the approval for Avastin, and Japan just approved it in September for breast cancer.