FDA officially yanks Avastin for breast cancer

[Joan M]

FDA Commissioner announces Avastin decision

Drug not shown to be safe and effective in breast cancer patients
SILVER SPRING, Md., Nov. 18, 2011 /PRNewswire-USNewswire/ --FDA Commissioner Margaret A. Hamburg, M.D., said today she is revoking the agency's approval of the breast cancer indication for Avastin (bevacizumab) after concluding that the drug has not been shown to be safe and effective for that use.
(Logo: http://photos.prnewswire.com/prnh/20090824/FDALOGO )
Avastin will still remain on the market as an approved treatment for certain types of colon, lung, kidney and brain cancer (glioblastoma multiforme).
"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," Dr. Hamburg said. "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."
Avastin's risks include severe high blood pressure; bleeding and hemorrhaging; heart attack or heart failure; and the development of perforations in different parts of the body such as the nose, stomach, and intestines.
Today's decision, outlined in Dr Hamburg's 69-page opinion, involves Avastin used in combination with the cancer drug paclitaxel for those patients who have not been treated with chemotherapy for their form of metastatic breast cancer known as HER2 negative. This indication must now be removed from Avastin's product labeling.
Dr. Hamburg's decision is based on an extensive record, which includes thousands of pages submitted to a public docket, data from several clinical trials and the record from a two-day hearing held in June, 2011.
Avastin was approved for metastatic breast cancer in February 2008 under the FDA's accelerated approval program, which allows a drug to be approved based on data that are not sufficiently complete to permit full approval. The accelerated approval program provides earlier patient access to promising new drugs to treat serious or life-threatening conditions while confirmatory clinical trials are conducted. If the clinical trials do not justify the continued approval of the drug or a specific drug indication, the agency may revoke its approval. In this case, the accelerated approval was based on promising results from one study that suggested that the drug could provide a meaningful increase in the amount of time from when treatment is started until the tumor grows or the death of the patient.
After the accelerated approval of Avastin for breast cancer, the drug's sponsor, Genentech, completed two additional clinical trials and submitted the data from those studies to the FDA. These data showed only a small effect on tumor growth without evidence that patients lived any longer or had a better quality of life compared to taking standard chemotherapy alone – not enough to outweigh the risk of taking the drug.
FDA's Center for Drug Evaluation and Research, which is responsible for the approval of this drug, ultimately concluded that the results of these additional studies did not justify continued approval and notified Genentech it was proposing to withdraw approval of the indication.
Genentech did not agree with the Center's evaluation of the data and, following the procedures set out in FDA regulations, requested a hearing on the Center's withdrawal proposal, with a decision to be made by the Commissioner. That two-day hearing, which took place June 28-29, 2011, included recommendations from the FDA's Oncologic Drugs Advisory Committee (ODAC), voting 6-0 in favor of withdrawing approval of Avastin's breast cancer indication. After the hearing, the public docket remained open until Aug. 4, 2011. (In an earlier meeting of the ODAC, that committee had voted 12-1 in favor of the removal of the breast cancer indication from the Avastin label).
"FDA is committed to working with sponsors to bring promising cancer drugs to market as quickly as possible using tools like accelerated approval," Dr. Hamburg said. "I encourage Genentech to consider additional studies to identify if there are select subgroups of women suffering from breast cancer who might benefit from this drug."
For more information:
Avastin Decision
http://www.fda.gov/NewsEvents/Newsroom/UCM279485
FY2011 Innovative Drug Approvals
http://www.fda.gov/AboutFDA/ReportsM.../ucm276385.htm
Media Inquiries: Karen Riley, 301-796-4674,
Consumer Inquiries: 888-INFO-FDA
SOURCE U.S. Food and Drug Administration

Web Site: http://www.fda.gov/

[gdpawel]

One breast cancer patient’s life saving therapy is another’s pulmonary embolism without clinical benefit. Until such time as cancer patients are selected for therapies predicated upon their own unique biology, we will confront one Avastin after another.

The solution to this problem is to investigate the VEGF targeting agents in each individual patient’s tissue culture, alone and in combination with other drugs, to gauge the likelihood that vascular targeting will favorably influence each patient’s outcome.

The Avastin saga is but one example of what will occur repeatedly. The one-size-fits-all paradigm is crumbling as individual patients with unique biological features confront the results of the blunt instrument of randomized clinical trials.

According to Merriall Goozner (who occasionaly writes for the Journal of the National Cancer Institute), two clinical trials showed no improvement in mortality among women with metastatic breast cancer. Those trials didn’t even replicate the delay in progression of disease that had been shown in the original trial that led to accelerated approval in 2007. Now comes the firestorm from patient advocacy groups, who will use anecdotal stories to claim the drug works for some women.

Here’s the truth of those matters: Anecdotes are not science. Those who insist their use of the drug is the reason why they are remaining alive longer than average will still have access to the drug since most insurance companies and Medicare will continue to follow the National Comprehensive Cancer Network guidelines.

NCCN’s guideline writing committee, a third of whom have financial ties to Roche/Genentech, has said it will not withdraw Avastin’s use in metastatic patients. A few years ago, CMS passed a rule that said it would reimburse any use of a cancer drug, even if the FDA had not approved it for that use, if it was included in the NCCN guidelines and accompanying formulary.

[Soccermom]

Thanks for the clarification re those who are currently in treatment and have are doing well on Avastin.. No one should be "unplugged" at stage 4 if the therapy is believed to be prolonging their life.
Marcia

[gdpawel]

Some industry-insiders have suggested the Compassionate Use Program could work for Roche, with Avastin. Now that the FDA has rejected Avastin for breast cancer, breast cancer now becomes a non-approved indication and therefore any investigator wishing to do a compassionate use trial would have to do so under a Treatment IND.

In 1987, the FDA enacted regulations that provided increased access to experimental drugs for patients with life-threatening or seriously-debilitating diseases when no alternative treatment exists. These guideline, commonly called Treatment IND (Investigational New Drug), provide for rapid review of new therapies even when clinical trial results proving efficacy have not been established.

Typically Treatment IND applications are made for drugs that are in Phase III trials; however in rare cases the FDA approves a Treatment IND for a drug that has not yet progressed beyond Phase II. In order to stay compliant with the protocol, the drug developer must continue to collect safety and efficacy data on test subjects in order to better establish a drug's therapeutic benefit to patients.

Additionally, it must continue to make a good faith effort to win final approval from the FDA; if the drug developer stops working on the product, the Treatment IND can be rescinded and patients may lose access to the drug.

The company would have to write the protocol with prettly strict inclusion/exclusion criteria and thus Roche has to ask the question as to whether it's worth it since they can't sell it for this purpose.

[Rich66]

Ok..so which is it? Largely continued use because of NCCN guidelines or widespread yanking due to FDA disapproval with unlikely availability via IND?

[gdpawel]

$1B vs ......

[Rich66]

Eh??
.......................

[gdpawel]

Roche stands to lose around $1 billion in sales from its total $6 billion revenue from the drug.

[gdpawel]

According to Tia Ghose at TheScientist, after the FDA revoked its approval of Avastin for the treatment of metastatic breast cancer, the drug maker says it will initiate new trials.

In the wake of the US Food and Drug Administration’s decision to revoke approval of Avastin for the treatment of metastatic breast cancer, drug maker Genentech says it will conduct a new clinical trial to determine which patients are likely to benefit from the drug.

The decision came after an advisory panel unanimously voted to revoke approval in June. The panel found that the drug only slightly decreased tumor size and didn’t increase lifespan compared to patients on standard chemotherapy.

But many patients and doctors suspect the drug is helping at least some women. ”There absolutely may be subsets of carefully chosen breast cancer patients who benefit from Avastin,” Elisa Port, co-director of the Dubin Breast Center at Mt. Sinai Hospital in New York, told Reuters. But currently there is no way to identify those patients.

After the announcement, Genentech said it would an initiate a new Phase III trial to determine if there are certain chemical or genetic markers that could help doctors determine which, if any, patients might get a survival boost from Avastin.

The decision could cost Genentech and its parent company Roche up to $1 billion in sales a year, The New York Times reported. While doctors can still prescribe the drug off-label for use in metastatic breast cancer, the FDA decision could lead insurance companies to drop coverage for the drug, which costs nearly $100,000 a year, ABC News reported.

[Laurel]

At the end of the day, subsets must be identified so treatment can be tailored to the individual. Unfortunately, the baby gets thrown out with the bathwater if a drug only benefits a few, unless of course, as Genentech must now attempt to do, the drug company can identify the subset the drug benefits. Of course, we as members of the Her2 pos subset well know defining who will benefit can be lifesaving.

[Ellie F]

Totally agree. It seems we have this difficulty with virtually every drug.
At present the fight goes on to get T-DM1 approved both in the States and then in Europe but the problem remains that it's unclear which sub-group of patients will benefit from this also. Sometimes it feels like a pick and mix of trying different regimes in the hope of hitting on the right combo! My onc frequently reminds me that all tumours are individual as are all immune responses. Granted small early tumours usually do better but not always and the reverse is also true that some women with large tumours survive seemingly against the odds.
We also have an efficient targeted drug in herceptin but we are still a long way away from understanding why and how resistence occurs.
Sorry for the rant but sometimes it feels we have a long way to go.
Ellie

[gdpawel]

This is starting to sound very much like the situation with Herceptin years ago. Herceptin drew fire from the FDA and other groups, including ASCO, because of its expense and the fact that it helped only 11-20% of patients who received it.

There were tons of data showing that pathologists were "over-calling" the cases of HER2-positive via IHC and manual microscopy. There were tons of data showing that use of automated image analysis virtually eliminated "over-calls" and very reliably normalized IHC scoring among pathologists of all levels of experience.

Even Dennis Slamon (one of the inventors of Herceptin) had told Genentech, they had a drug that is even better than they knew. It only has to be administered to the right patients. The disinterest on the part of Genentech was palpable.

In the end, the FDA did force them to work with someone to develop a reliable pharmacodiagnostic test. Genentech put their muscle behind FISH.

However, in the end, they couldn't completely supplant low-tech IHC and both received FDA approval. Herceptin is now approved for patients who are positive via FISH or IHC, even though patients considered Her2-negative using both tests benefited from Herceptin.

In other words, the problem was never solved. It's an inconvenient truth which everyone involved conveniently chooses to ignore. Sheesh!

[gdpawel]

Patients can either wait for Genentech to get its act together or they can act "individually" for themselves by having an assay done on their own cancer cells.

http://cancerfocus.org/biomarker_for_avastin/46708