Ed Silverman
Pharmalot.com
After more than a year of controversy and anticipation, the FDA has decided to formally yank the breast cancer indication for Avastin after deciding the widely used medication is not safe and effective for that purpose. However, the drug - which is sold by Genentech - will remain on the market to treat cancers that affect the colon, lung, kidney and brain.
The decision marks a trying stretch for the agency as debate broke out over the wisdom of using progression free survival as a surrogate - instead of quality of life - for conferring approval, while breast cancer patients and their families lobbied hard to maintain the status quo. The episode also highlighted ongoing concerns about the FDA accelerated approval - or fast track - program that first greenlighted Avastin for treating breast cancer.
“This was a difficult decision. FDA 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,” FDA commish Margaret Hamburg says in a statement.
“After reviewing the available studies 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 either help them live longer or improve their quality of life.”
The move comes nearly a year after the FDA initially announced plans to revoke the indication, citing study results showing Avastin does not prolong overall survival in breast cancer patients or provide a sufficient benefit in slowing disease progression to outweigh such risks as severe high blood pressure; hemorrhage; swelling of the brain, and heart attack or heart failure. The agency had reviewed two additional studies that Genentech submitted in hopes of maintaining the indication.
After the agency gave its initial thumbs down, Genentech appealed, setting up an unusual two-day meeting last summer to review trial data, where the panelists voted 6-to-0 nothing to pull the breast cancer indication. The drugmaker recently offered a compromise that would have modified the Avastin usage and labeling.
The decision to revoke the breast cancer indication was seen as an important test for Hamburg, who has emphasized drug safety as a hallmark of her tenure, which began in the lingering aftermath of the corrosive Vioxx scandal. And for the past several months, Avastin has come to symbolize a willingness to brook extensive pressure to allow a drug to remain on the market amid safety issues.
“This decision sets an important precedent: accumulated science has trumped politicized argument,” says Daniel Carpenter, the Allie S. Freed professor of government at Harvard University and author of ‘Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA.’ “The agency faced enormous political pressure from the company and from organized interest groups, and yet rendered a strong decision based upon a searching reading of the available evidence.
Whether this move will put to rest some of the issues raised during the Avastin episode is unclear. In particular, critics say more data should be required before accelerated approval is employed. The FDA has also been criticized for not forcing drugmakers to provide required follow-up data more quickly. Last year, Pfizer withdrew a drug used to treat acute myeloid leukemia after a study found a lack of clinical benefit and an unexpected number of deaths, but the study began four years after approval.
“In an ironic way, this decision actually allows the FDA to expand the accelerated approval program, as there is now a strong, visible and clear precedent for withdrawing an approval when postmarket experiments for an approved drug produce disconfirming efficacy evidence and perhaps problematic new safety signals,” Carpenter says. “This is not an anti-innovation decision and could, in fact, assist pharmaceutical innovation in the years ahead…I predict its longer-term impact will be to help rebuild the agency’s reputation for science-based decisionmaking and for independence from emotionally charged lobbying.”
Some patient advocates hailed the FDA move, having argued that the FDA moved too quickly to endorse the breast cancer indication in the first place. “If we are to continue to speed up the rate at which treatments reach patients we must be able to take back approval when the evidence shows that a drug doesn’t work. Although some individual women believe that Avastin worked for them, there are many women who are not here to tell their story about how Avastin didn’t work. We all want better treatment for women with this disease. Unfortunately, Avastin is not that treatment,” Karuna Jaggar, who is executive director of Breast Cancer Action, writes us.
As for Genentech, the drugmaker now stands to lose an estimated $1 billion in sales. “We are disappointed with this outcome,” the Roche unit says in a statement. “Despite today’s action, we will start a new Phase III study of Avastin in combination with paclitaxel in previously untreated metastatic breast cancer and will evaluate a potential biomarker that may help identify which people might derive a more substantial benefit from Avastin.”
Indeed, Genentech does have an option to resubmit an application to the FDA for a breast cancer indication for Avastin if additional studies prove successful. The drugmaker also has the option of a legal challenge to the agency decision to yank the indication.
The decision is certain to have significant implications for patients, doctors and payers. A recent survey found doctors were largely split over whether they would continue to use Avastin to treat breast cancer. Nearly 45 percent would use Avastin in a first-line setting and nearly 52 percent would use the drug in combination with paclitaxel, otherwise known as Taxol, regardless of an FDA decision.
Meanwhile, the National Comprehensive Cancer Network, an organization of major cancer hospitals, reaffirmed last summer that Avastin was “an appropriate therapeutic option for metastatic breast cancer.” This decision is significant because the NCCN panel of oncologists carries great weight with other specialists and its guidelines are widely used as a reference by the Centers for Medicare & Medicaid Services and insurers for making coverage decisions.
In fact, CMS earlier this year indicated it would continue to provide coverage, even if treatment amounts to off-label use. But one big insurer recently eliminated coverage. Blue Cross of California last month decided to no longer pay for Avastin to treat breast cancer. Whether other insurers follow suit will become a closely watched sport.
For the record, the formal indication that the FDA is now revoking involves Avastin used in combination with the cancer drug paclitaxel (Taxol) for those patients who have not been treated with chemotherapy for their form of metastatic breast cancer known as HER2 negative.
Hybrid Mode
