FDA to let women try new breast drugs earlier

CHICAGO Sun Jun 3, 2012 12:00pm EDT

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CHICAGO (Reuters) - Regulators are moving the goal posts in testing new drugs for breast cancer in the hopes of giving more women with aggressive, early-stage cancers the chance to try breakthrough drugs while they have the best shot at a cure.

A new guidance document issued this week by the U.S. Food and Drug Administration will allow drug companies to test their medications for a few months on women with highly aggressive breast cancers before they have surgery, instead of waiting until the drug has been proven first in gravely ill patients.

"We're looking at introducing drugs into a very early stage of breast cancer, where a patient has a primary tumor and the chemotherapy is given before surgery," Dr. Richard Pazdur, director of the FDA's cancer drug office, said in an interview at the American Society of Clinical Oncology meeting in Chicago.

"The aim of this therapy would be to cure the woman of breast cancer," Pazdur said. "It's moving a very promising drug into a early stage of the disease with a curative intent."

If a drug succeeds in eradicating the cancer to the point where there is no sign of it in the breast or lymph nodes - something called pathologic complete response - companies could win accelerated approval.

That represents a significant change from the current approach, in which promising drugs only are tested in earlier stage cancers after they have first proven to be safe and effective in advanced, metastatic cancer.

"If you are a patient with early stage breast cancer and you hear about a great new drug for metastatic breast cancer, it's probably not going to be available to you under the current model for a decade," said Dr. Tatiana Prowell, a cancer specialist at Johns Hopkins in Baltimore and a medical officer for the FDA.

Prowell and Pazdur wrote about the guidelines in the current New England Journal of Medicine.


The change is part of a push at the FDA to spur innovation and get more effective drugs to the patients who need them.

"We really do want to be very forward-leading," FDA Commissioner Dr. Margaret Hamburg said in a briefing with Reuters on Thursday.

"We understand the importance of taking an advance in science as quickly as we can to the patients who need them, always being mindful of our responsibility of looking at the issues of safety and efficacy."

FDA is taking a risk with the new strategy, which will expose women with much earlier-stage disease to potential safety issues of new medications.

Traditionally, by the time new drugs are tried on women with earlier-stage disease they have been tested in thousands of women with much more advanced disease, for whom the risk of trying the drug is balanced with its potential for prolonging their lives.

To help mitigate these risks, the new guidance document will apply to women with an especially deadly form of breast cancer called triple-negative breast cancers.

Most breast tumors are called estrogen-receptor positive, because they are fueled by the hormone estrogen. About 20 percent are HER2-positive, because a protein called HER2 is involved. A third type is driven by the hormone progesterone.

These types of cancer have good treatments.

Then there are basal-like or triple-negative tumors, so named because they lack estrogen, progesterone or HER2 receptors needed for most breast cancer drugs to work.

Triple-negative breast cancers tend to grow and spread more quickly than most other types of breast cancer, and they occur more often in younger women and in African-American women.


"This is not for every patient. It should be for patients that are most likely to benefit and also those that are at highest risk of having a recurrence of the disease," Pazdur said.

Trials would be structured so that women are treated with either chemotherapy or chemotherapy plus an experimental drug for a few months prior to surgery.

If no sign of the cancer is found during surgery, the woman has achieved a complete pathological response. Researchers would then compare response rates in the two groups, and if the drug has helped cure significantly more cancers, it would be given a provisional type of approval called accelerated approval.

Drug companies would continue to follow women for several years to see if their cancers come back, and if women continue to be disease-free, companies could get full approval for the treatment. FDA is accepting comments about its draft plan through the end of July.

Reaction so far has been positive.

"We clearly need new approaches to getting stuff to the early-disease setting," said Dr. George Sledge, co-director of breast cancer program at the Indiana University Simon Cancer Center and immediate past president of ASCO.


He said the new approach is not a perfect solution to the problem, but it's a good first step.

"It recognizes that we want to try to move drugs up front into an early disease setting as soon as possible - not wait until the patient is beat up and out of chances and out of hope before we throw a drug at the patient and hope it does something."

Leerink Swann analyst Howard Liang said the new approach could potentially speed access to several breast cancer drugs in development, including treatments by Roche, GlaxoSmithKline , Celgene Corp, Onyx Pharmaceuticals, Bayer, Boehringer Ingelheim, Eli Lilly and Co, Eisai Co Ltd and Puma Biotechnology Inc.

FDA is basing much of its plan on a clinical trial known as I-SPY 2, a Phase II breast cancer trial being conducted by the Biomarkers Consortium, a public-private partnership run through the Foundation for the National Institutes of Health.

The trial, being run by Dr. Laura Esserman at the University of California at San Francisco and Dr. Donald Berry of MD Anderson Cancer Center in Houston, relies on specific genetic signatures or biomarkers in tumors to select those who might benefit from testing with this new approach.

The trial uses an approach called adaptive design, in which researchers continuously monitor which patients are responding to drugs and try to give drugs to those most likely to respond.

"If a therapy is doing well in a particular subset of patients, it gets a higher probability of being assigned to a patient in that subset," Berry said.

The design allows the team to test new treatments with far fewer participants and in half the normal time, cutting back on the costs of developing treatments.

Hamburg said she is meeting with the board at the ASCO cancer meeting this week to discuss this and other approaches to innovative clinical trial design.

"We feel more powerfully than ever before that how the studies are structured from the get-go really matters for our ability to do our job in an effective and efficient manner," she said.

"We really do want to be part of the scientific discussions early on to help shape how research is done."

Breast cancer is the second-leading cause of cancer death in women, exceeded only by lung cancer, according to the American Cancer Society.

(Editing by Eric Walsh)

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Comments (4)
Secruss wrote:
In other words, the FDA is realizing their regulations quash innovation and cutting edge technology that can be used to help people.

Jun 03, 2012 12:46pm EDT  --  Report as abuse
StevenWalker wrote:
Dr. Sledge is correct in stating that the guidance from FDA for early stage testing of breast cancer drugs “isn’t perfect.” It is an exceedingly small step forward in regulatory thinking that remains mired in obsolete approaches developed in 1962 at the FDA. The archaic thinking at FDA is firmly rooted in the ideologies of the agency’s cancer drug office leadership, headed by Dr. Pazdur. He is unswervingly focused on establishing that a treatment has a statistically significant effect on a measurement referred to as overall survival. To measure it, he insists that drug companies randomize women to two groups, some who get the new, highly promising treatment, and usually an equal number who don’t, often under blinded conditions (meaning neither the women or their doctors know what they are getting). He then wants them to forgo any further treatment until they die. The difference in the average life spans of the two groups, only measurable after several years after a sufficient number of women die to allow calculation of statistical significance, is where the overall survival measurement comes from. It is the difference in months measured as the average number of extra months the women who got the promising treatment live, compared to the average number of months lived for the women who didn’t. Dr. Pazdur is not giving up his overall survival endpoint. He is saying only that, under enormous pressure from patients, the clinical research community and Congress, he is going to grant accelerated (conditional) approval to some drugs if it shows an astounding positive effect on eradicating breast cancer tumors up front, but if it doesn’t result in a statistically significant improvement in overall survival several years later, he will withdraw the approval. This sounds reasonable until one considers that it has become impossible to statistically measure an overall survival advantage in breast cancer patients when one is looking for that advantage to come from the first therapy women receive after diagnosis. Women with breast cancer are not going to just wait around for their cancer to come back and kill them, as Dr. Pazdur would prefer, so he can measure the pure difference in effect between two treatment groups. They are going to seek and receive multiple treatments after the first one, as needed and medically appropriate, in consultation with their qualified physicians, because their goal is a cure, or at least extension of their lives for as long as they can get. Those subsequent treatments do what Dr. Pazdur would prefer to prevent, confounding the overall survival measurement because those later treatments help a lot of women live longer regardless of which treatment they got in Dr. Pazdur’s early stage trial, lessening the difference between those who got that initial promising treatment and those who didn’t, eroding his statistical significance measurement – not because the new treatment didn’t work, but because all the women ended up living longer because of the many treatment options now available for breast cancer patients, used skillfully by their doctors. Dr. Pazdur is a linear thinker who believes that the only way to test a new drug now and forever, is a randomized controlled trial designed to provide a simplistic comparison of a single outcome, like time to death. The field has moved far beyond him and his senior colleagues in the FDA’s cancer drug office. It is time for more dramatic change than proposed by Dr. Pazdur, a committed, ideological physician-statistician. It is time for a physician-scientist to head the FDA’s cancer drug office.

Jun 03, 2012 2:42pm EDT  --  Report as abuse
jeff81201 wrote:
BigPharma hides and minimizes side-effects when obtaining approval for drugs. Trust neither them nor the FDA.

Jun 03, 2012 3:13pm EDT  --  Report as abuse
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