Avastin: Breast Cancer Drug or NOT? Testimony to ODAC

Thanks in part to Roberta's excellent testimony, ODAC has made what may turn out to be an historic recommendation to the Food and Drug Adminsitration to revoke Avastin's approval for breast cancer,and the FDA will most likely do so. . But some interest groups are protesting, saying that this is a "sneaky" attempt to "ration health care." Avastin costs $88,000 a year wholesale. Insurers may well decide not to pay for it for breast cancer. Patients may try to get the drug off label but they will have to face the question, Is it Worth It? In clinical trials, serious side effects like hypertension, bleeding or hemorrhaging and febrile neutropenia and even death clearly outweighed the few weeks gain in progression-free survival shown in the best cases. (No overall survival benefit was shown.) So guess what:, of course health care is and must be rationed. We as advocates have to think hard about where we want health care dollars spent, because the health care dollar bucket has a bottom.. Avastin offers a really good opportunity to start this thinking process.

— Gail Garfield Schwartz

i've read both Roberta Gelb's and Andrew Pollack's article and although this is not an issue for me, I believe that if I were faced with metastatic breast cancer I would want a drug that not only could extend my life but would also offer quality of life positives.
While I welcome fast track approval based on limited study for advanced cases of any cancer, I believe that if future studies do not support the original findings then approval should be withdrawn for that particular cancer group.
It is of little value to cancer patients if subsequent studies of a drug, such as Avastin, do not prove efficacious and keeping it on an approved list only delays the kind of research that could supply better results for that group.

— Sandy Berger

While ODAC is ostensibly independent, it is in practice a creature of the FDA and the FDA's political masters in Congress. The agency appoints the rotating ODAC members, which is like a prosecutor choosing his jury. The agency's oncology leaders—led by cancer drugs chief Richard Pazdur—routinely stack the panel with people who share their dislike for industry and accelerated approval. In recent years the FDA has also tightened conflict-of-interest rules, which means that ODAC's "experts" often have no specific expertise treating the diseases that the drugs they are adjudicating are meant to treat. .There was only one breast cancer oncologist on the ODAC panel.

EXCERPT FROM THE ESTEEMED PANEL:
Since PFS (progression free survival) is the endpoint being studied,” said Dr. Wyndham Wilson, the ODAC chair, “what we are here to judge is whether or not there is a clinically meaningful—from a patient’s point of view—[difference in] quality of life between the patients who received Avastin and those who didn’t.”

The committee found any such difference impossible to ascertain, since the trials had not collected patient-reported quality-of-life data that could show an improvement in symptoms or psychological state in tandem with PFS. The AVADO trial collected a set of quality-of-life data, but only to show that the addition of bevacizumab (Avastin) did not decrease patients’ quality of life. Sponsors of future trials evaluating PFS should take this issue to heart, stated Dr. Pazdur. “Sponsors really need to pay very close attention to [measuring quality of life], build it carefully into their protocols, and approach it with the same degree of caution and resources…as one would with a primary endpoint,” he said. But every month a survivor lives, some new treatment may be discovered.

Another breast cancer expert approached by Medscape Medical News, Gabriel Hortobagyi, MD, FACP, professor of breast medical oncology at the University of Texas M.D. Anderson Cancer Center, who was present at the ODAC meeting, said: "This is an interesting development."
"Bevacizumab is clearly active in breast cancer, and there is more experience with this agent in metastatic breast cancer than with many, if not most, other agents evaluated for the metastatic breast cancer indication," he said. In 3 separate randomized trials, adding bevacizumab to various commonly used chemotherapy regimens resulted in significantly improved overall response rate and time to progression. These beneficial effects were consistently found in all 3 trials and in all subgroups examined, he pointed out.
"Anecdotally, bevacizumab combinations can produce dramatic responses in individual patients, and it is my clinical impression that responses of such quality are seldom seen with the same chemotherapy programs without bevacizumab. As a frequent user of this agent, I have also found that it is very well tolerated by the great majority of patients; in very few do I need to modify dose or schedule, and in even fewer do I need to discontinue treatment because of toxicities."
However, a "puzzling observation" in all 3 studies is the total absence of a survival benefit - "the survival curves of the control and bevacizumab arms were entirely super imposable," Dr. Hortobagyi said. It is difficult to demonstrate a significant survival benefit in first-line therapy of metastatic breast cancer, because such benefit is often diluted by multiple subsequent treatments and crossover designs, he explained, but "we often see some separation of the curves, even if the difference doesn't reach statistical significance."
"In the trials in question, and as you would expect simply by chance, some parts of the bevacizumab curves were slightly above and others slightly below the control-arm curves. While none of these differences (whether positive or negative) were statistically significant, the FDA reviewer elected to present them in an incredibly biased manner, where positive (but nonsignificant) survival differences were labeled 'no difference,' and negative (also nonsignificant) differences were labeled as favoring the placebo arm," Dr. Hortobagyi explained.
"This either denotes ignorance of common statistical methods or an underlying agenda to place the agent in an unfavorable perspective. There were other surprising statements made by the FDA reviewer attributing certain toxicities to bevacizumab, when in fact those toxicities are well recognized as being associated with the underlying chemotherapy. For instance, bowel perforations are a well-recognized complication of taxanes, especially docetaxel; angina and myocardial infarction are reported complications of capecitabine; and congestive heart failure is a well-known complication of anthracyclines (doxorubicin and epirubicin)," he continued.
"The FDA reviewer continuously referred to these complications as bevacizumab-related, creating an artificially high bevacizumab-related mortality rate in the minds of ODAC members," Dr. Hortobagyi said.
He summarized the outcome of the meeting as follows: "ODAC members found the benefit of bevacizumab insufficient in view of the toxicities listed by both the sponsor and the FDA reviewer, and based on that belief, they felt that the 2 new trials failed to confirm the encouraging results of E2100, and that there was insufficient efficacy to expand or even maintain the metastatic breast cancer indication of bevacizumab."
However, he added that "during the discussion, I got the strong impression that several ODAC members had a poor understanding of clinical trials and statistics (based on some of the questions that were somewhat bizarre!), and that very few had any experience using bevacizumab in the clinic. Otherwise, they would have known that the frequent toxicities reported on paper caused few symptoms and actually did not affect quality of life, and perhaps they would have seen the response and progression-free survival benefits in a different light."
"I thought that the discussion brought to light some issues in the process. The sponsor complied entirely with the FDA's requests when accelerated approval was granted; however, the FDA instructions were vague, and the 'magnitude of benefit' was never defined. Despite the fact that the FDA never requested prolongation of survival, much of the discussion by ODAC members was based on this lack of survival benefit. Therefore, there was a major disconnect between the FDA and ODAC," Dr. Hortobagyi explained.
"Ultimately, ODAC members acted on their understanding of the risk/benefit ratio of the drug, and recommended removal of the metastatic breast cancer indication. I think this was the wrong recommendation, although witnessing the process I can see how inadequate instruction by the FDA, unfamiliarity with the drug, and a biased presentation by the FDA reviewer led to this result," he said.
"I am concerned, in part, because this recommendation might remove an important treatment option from patients with metastatic breast cancer. I am also concerned because 'clinical benefit' remains poorly defined. This precedent will set many drugs currently under development up for failure. It would be important for the FDA to clearly define expectations from sponsors and provide clear guidance to ODAC members, so that disconnects such as those observed during this discussion stop happening," Dr. Hortobagyi told Medscape Medical News.
The Wall Street Journal ran an aggressive pro-Avastin editorial
FoxNews (along w/ other outlets) has covered not only the
issue itself, but the fact that there have been Congressional inquiries
regarding the ODAC recommendation. We have some reason to believe
that the Congressional and public interest in the issue led FDA to take
considerably longer to release a final decision than was initially
expected.
It makes a big difference that Komen (the world's largest breast cancer
organization) and some other groups have come out publicly against the
recommendation.
This miracle drug must remain available and between patient and oncologist. I love my wife dearly and I want her around for a long time. She had her Avastin treatment this morning, and went back to work. For nearly two years it has kept her CTC markers at zero and there has been no new growth. Think about your wife or daughter or mother suffering from this terrible disease and some panel or special interest group made the decision to let her live or die.

— Patrick Morgan