On Avastin: FDA Chooses Science over Politics

December 17, 2010

In the end, science, not politics, prevailed.

The Food and Drug Administration announced Thursday that it plans to withdraw its conditional approval of Genentech’s Avastin for treatment of metastatic breast cancer. The agency had been under intense pressure to grant permanent approval by the company, by some patient advocacy groups and conservatives on Capitol Hill who accused the agency of wanting to “ration” Avastin.

An outside advisory panel that carefully weighed the evidence last July concluded by a 12-1 vote that the drug’s risks, which include serious side effects like internal bleeding, hypertension and vascular perforations, did not outweigh its benefits. Still, Genentech, a unit of Roche, immediately announced yesterday that it would demand another hearing to present new data that might convince the FDA to rethink its decision.

Avastin’s fate has bitterly divided the politically active breast cancer advocacy community. Susan B. Komen for the Cure, the best-known group through its ubiquitous pink-ribbon campaigns, called on insurance companies to continue paying for Avastin while the company conducts new clinical trials that may prove that some women benefit.

But other leading groups like the National Breast Cancer Coalition applauded the decision “for responding to the scientific evidence in the face of significant political and public pressure. Women deserve access to treatments that evidence proves effective.”

Breast Cancer Action, a San Francisco-based advocacy group that often is at odds with the drug industry, highlighted the absence of any benefits from the drug. “The FDA (should) not approve drugs unless they can be shown to 1) improve overall survival, and/or 2) improve quality of life, and/or 3) cost less than therapies already available. Unfortunately, Avastin fails on all counts,” its statement said.

The FDA clearly fears a backlash from Capitol Hill, where numerous incoming Congressmen ran on platforms attacking government control of health care. Janet Woodcock, the director of the Center for Drug Evaluation and Research at FDA, encouraged the company to conduct new clinical trials that might identify a subset of patients who would benefit from the drug.

But, she said, “none of the four trials (submitted to the agency) showed a survival benefit. It didn’t prolong the life of women with metastatic breast cancer, but it added many serious side effects. That’s sort of the bottom line.”

The original trial that led to the drug’s conditional approval in 2008 had lengthened the length of time before tumors began growing again by five months. At the time, FDA reviewers said that represented a clinical benefit all by itself.

The agency and the company were fairly confident that subsequent trials would confirm that women on the drug would live longer, too. European regulators even gave the drug their full blessing based on that limited evidence.

But when the final results of three larger trials were unveiled late last year, the-time-to-tumor progression had shrunk to a few months or less. More importantly, patients on Avastin did not live any longer than patients who received only chemotherapy.

“I understand these results are disappointing to patients,” said Richard Pazdur, director of the oncologic drugs division at FDA. “But these results are disappointing to the FDA as well. . . Given the number of serious and life threatening side effects, the FDA does not believe there is a favorable risk to benefit profile.”

The drug, which is designed to inhibit the development of blood vessels that feed solid tumors, will remain on the market because it is still approved for lung, kidney, and brain cancers. That means physicians can still prescribe it “off label” for metastatic breast cancer.

So the next front in the Avastin battle will now shift to insurers, including Medicare. Their decision makers will be confronted with the same political pressures – and the same scientific evidence.

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8 Responses to On Avastin: FDA Chooses Science over Politics

  1. anon on December 17, 2010 at 1:52 pm

    Your projective reversal is soooo cute. I mean, who could see that this is obviously a political decision based on your pathetic need to simply reverse the words?

  2. Gregory D. Pawelski on December 17, 2010 at 3:20 pm

    Dr. Robert Nagourney is medical and laboratory director at Rational Therapeutics, Inc., in Long Beach, California, and an instructor of Pharmacology at the University of California, Irvine School of Medicine. He is board-certified in Internal Medicine, Medical Oncology and Hematology. His take on this Avastin controversy is interesting.

    There are no perfect drugs. There are simply drugs that work for certain patients. VEGF down-regulation is an attractive and highly appropriate therapy for a subset of cancer patients with many different diagnoses whose tumors use the VEGF pathway to their advantage. Avastin combined with carboplatin and taxol has improved the survival of lung cancer patients. Avastin plus folfox has improved survival for colon cancer patients. Avastin plus chemotherapy improves the survival of some breast cancer patients. The problem is that it doesn’t improve the survival of all breast cancer patients.

    When the FDA rules on the clinical utility of a drug, they use a broad-brush approach that looks at the global outcomes of all patients, determining whether these glacial trends reflect a true climate change. The problem is that while Bethesda, Maryland may not be noticing significant changes in ocean levels, people who live on the Maldives are having a very different experience. As these scientists ponder the significance of Avastin, some breast cancer patients are missing out on a treatment that could quite possibly save their lives.

    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. Our solution to this problem has been 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. Our results to date in patients with non-small cell lung cancer, colorectal cancer and even rare tumors (like medullary carcinoma of the thyroid) suggest this to be a highly productive direction for future development.

  3. Kate Murphy on December 18, 2010 at 3:01 pm

    It isn’t exactly accurate — or honest to patients — to use the words “life-saving drug.”

    Even in the best of situations, even for some subset of women, Avastin is only palliative. It may prolong life, but it doesn’t cure.

    And it does so at the risk of some “life-threatening” complications.

    If we knew which women would really benefit with improved survival without serious risk, the drug could be confidently prescribed for them. Since we don’t it isn’t fair or right to place all women with advanced cancer in a crapshoot where the odds are against them.

    This isn’t about money or rationing but providing the best evidence-based care we can.

  4. Steven Walker on December 20, 2010 at 5:01 am

    A couple of points. The FDA’s decision regarding avastin for first line treatment of metastatic breast cancer is based on a cobbled together string of “logic” that actually does not support the decision. The EMA actually considered the data from the four trials that FDA looked at, and made a rational decision on what the data actually says – that avastin does provide significant benefit when added to one of the several accompanying chemotherapy regimens tested in the trial. The EMA (European Medicines Agency) decided to continue approval based on what is actually best for woemn with breast cancer. The FDA decided to pull it based on a highly judgmental and biased decision that is not supported by the data. Behind the “science” claimed by Janet Woodcock, your readers should know that determining whether a first-line treatment in metastatic breast cancer extends survival when most of the women who participated in the trial went on to receive one or more different treatments (some also getting avastin as part of those treatments) utterly confounds the ability to determine with statistics whether the first line treatment is, or is not, conferring a survival benefit. Understanding why this is true requires some knowledge of how FDA calculates survival benefit and the severe limitations of the statistical methods they use. They know any attempt to draw a conclusion regarding overall survival in this case using their simplistic statistical methods is shaky, which lends even more credence to thir decision being less than scientifically supported. As for cancer therapies being life-saving or merely palliative, if a drug adds five months of disease control, and an improvement in quality life because it prevents disease symptoms (that’s right – cancer has very serious, life-limiting effects)for the person receiving that treatment it is life saving. It’s one of those “you have to have been there things.” Perspective is very, very important and many of the people who seem to have storng opinins about FDA decisions never have been there. On needing better biomarkers, everyone knows that, but as we transition from population-based medicine, which the FDA is almost completely failing to do, it is hardly the right thing for cancer patients to start yanking good drugs off the market because we don’t yet have good biomarkers we can use to select the right patients for every one of the approved drugs we have. FDA is mainly just making speeches on how it needs shift from population-based to personalized medicine and doing next to nothing in terms of changing the way it actually regulates drug development, mainly because they have no idea how they are going to handle it, and have barely started moving. Their review offices are staffed and lead by people whose skills are built entirely around the simplistic, 50 year old, statistical models that produced most of the drugs we now have for cancer, most of which help only a fraction of the patients who receive them. Where very targeted, scientific targeted drugs like, for example a new drug for metastatic melanoma that helps 80 percent of the patients who have a certain biomarker, with that result shown and confirmed in mulitple well run clinical trials, the FDA is still insisting on a randomized trial agains an old, barely effective toxic drug prior to approval, and is refusing to apply new more scientific methods to its approval process. This decision by FDA on avastin is more evdience of the desperate incompetence and stagnation of the agency than it is evidence of the FDA looking out for women with metastatic breast cancer. It is an error that will result in suffering and premature deaths for a lot of women. As for the National Breast Cancer Coalition (NBCC) being a pat8ent advocacy group – well some advocacy groups are advocates for patients (e.g., Komen), and some are advocates for FDA, certain special interests and scientific stagnation. NBCC is one of the latter, and is definitely not in the mainstream when it comes to ongoing discussions regarding the need for better regulatory science at the FDA.

    FDA blew this decision, and they will rightfully face sharp criticism and challenges from many quarters. The scientific and medical problems with this decision are numerous and should result in the dismissal of certain FDA employees who made it. The breast cancer patient community is among the most powerful, active and influential patient communities in the US. I encourage them to challenge this decision in every manner available to them.

    • J. Simha on December 20, 2010 at 1:43 pm

      Contrary to Steven Walker’s allegations and opinions, there is no organization that better represents diverse women from all walks of life better than The National Breast Cancer Coalition (NBCC). NBCC is a grass roots organization made up of hundreds of diverse grassroots member organizations and millions of women across the country affected by breast cancer. It’s Board of Directors is comprised of grass roots representatives of other organizations across the country. I, myself, represent The Young Survival Coalition as I sit on the Board of Directors of the NBCC. We know that women deserve real solutions to breast cancer. We know that it is possible to end this disease by finding drugs that make a significant impact on cancer and women’s lives and minimizing risks. We as a community are tired of incremental advances which we pay dearly for in quality of life. Women deserve the truth and better solutions to the overwhelming problem of breast cancer. The NBCC and all the grassroots advocates and organizations that are a part of the Coalition believe in demanding true progress. Our campaign, Breast Cancer Deadline 2020 is demanding that we work together to focus our resources toward the end of breast cancer. I represent a community of women who are fighting for a change. http://www.breastcancerdeadline2020.org

  5. Gregory D. Pawelski on December 20, 2010 at 7:58 am

    The problem with Avastin is the same thing that was a problem with AZT for HIV/AIDS. Early results, then rapid resistance.

    Solution is combination therapy to attack different targets. Tumor vasculature needs VEGF to survive. Avastin removes VEGF, killing blood vessels. But other proangiogenic factors can substitute: FGF, PDGF, ephrin A1, angioprotein 1, IL-8 etc.

    We need to attack these other targets, as well. If you can achieve this, then you may not need the other drugs, which really don’t get into the tumor so well. But angiogenic attack provides true selective toxicity, something which is sorely lacking with all of our other treatments.

    There are numerous drugs that can prolong life in breast cancer patients and slow the spread of cancer while improving quality of life, at so much less cost.

    In cancer medicine, it’s not a case of throwing targeted drugs like Avastin at the problem. It’s knowing “what” targeted drugs and “how” to use them in “individual” patients (not average populations). It is not clear that the purported mechanism is really what’s happening.

    The problem is that few drugs work the way oncologists think they do and it takes far more “information” to think through what it is they are using them for.

    I don’t need to know how my laptop or television works, as long as it works and I feel the same way about anti-cancer therapies. Theory doesn’t matter as much as the evidence that it does what we want it to do.

    VEGF-targeted drugs are poorly-predicted by measuring the preferred target VEFGR. However, they can be well-predicted by measuring the effect of the drug on the function of live cells.

    Some have suggested that Genentech use assays like a Microvessel Viability Assay, with functional profiling, to identify a potential targeted population of breast cancer patients that it thinks will benefit from Avastin, and then conduct a randomized clinical trail among this group.

  6. Marjorie Gallece on December 20, 2010 at 9:35 pm

    Mr. Walker needs to pay much closer attention to the details of how patient advocacy groups operate and how they educate those who directly support patient interests. Each organization has something they do well and pitting them against one another is a cheap form of distraction from the more serious issue of the slow and incremental progress that’s been achieved in trying to reduce deaths from breast cancer despite the billions of dollars spent on research.

    The National Breast Cancer Coalition is made up of numerous organizations that offer direct support services to patients. It does not pander to the interests of pharmaceutical companies but demands excellence and evidence at all levels – including government agencies.

    Avastin is horribly over priced. It carries several serious and sometimes fatal toxicities, destroying quality of life in breast cancer patients rather than prolonging life. Until this treatment is proven to benefit a specific subset of metastatic breast cancer patients, and the work is done to identify that population, it’s use should be limited. Pressure should be placed on the insurance industry to cover those patients who are showing a benefit.

  7. Jean on January 5, 2011 at 7:43 am

    My sister-in-law died of a perforated colon following just two treatments of Avastin. Reading the material on the drug up front, her brother, sister and I felt this drug would likely do more harm than good and our unscientific conclusion was confirmed by the use of this drug. I think the FDA has made the correct decision — just too late for us.

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