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Thread: The issue surrounding Avastin

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    Distinguished Community Member gpawelski's Avatar
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    Default The issue surrounding Avastin

    FDA Withdraws Avastin's Breast Cancer Indication. 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.

    http://www.fda.gov/NewsEvents/Newsroom/UCM279485

    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.
    Gregory D. Pawelski

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    Default FDA Yanks Breast Cancer Indication For Avastin

    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.
    Gregory D. Pawelski

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    Distinguished Community Member gpawelski's Avatar
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    Default Compassionate Use for Avastin?

    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.
    Gregory D. Pawelski

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    Default Genentech Plans New Avastin Trial

    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.
    Gregory D. Pawelski

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    Default Biomarker for Avastin

    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
    Gregory D. Pawelski

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    Default Re: The issue surrounding Avastin

    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!

    The way that you get responses to Avastin is by (temporarily) destroying the vasculature, not by normalizing blood vessels in tumors (or "pruning" the vasculature). The problem is that the vessels grow back (quickly). The most vulnerable vessels (to Avastin) are the most newly formed, which are at the vanguard of the advancing tumor.

    It is possible to correctly administer Avastin by measuring the vasculature of a tumor with an anti-angiogenesis microvascular viability assay called AngioRx. The test works by measuring drug effects upon endothelial cells which make up blood vessels. Its use could prolong lives, save money, and spare patients exposure to the harmful side-effects of ineffective chemotherapy treatments.
    Gregory D. Pawelski

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