Interestingly, our local paper ran a column ("Let them have Avastin") the same day by a local woman currently taking Avastin (and chemo and surgery) for colon cancer which had spread to other organs. She relates her success with the drug for her colon cancer to breast cancer patients need for access to the drug. A very powerful and persuasive story

The PFS that you cite was i believe from the first study that was not replicated in additional studies.

Whats missing from the criticisms of the FDAs decison is that there of course was a detailed review of the trials by the ODAC group where the manufacture's reps and FDA oncologists presented their findings and reviews of the trials. Along with Q&A. Instead, the criticisms focus on the death panel inclined FDA for an assumed focus on the drug's costs. No where in the meeting is the drug's cost discussed, other than by Dr. Grem's comment that the cost of the drug should not be discussed. In that she is correct. But her comment alone has become the critics 'hidden' reason why the ODAC group decided as they did, in spite of the 12 oncologists who explained their vote, based not on costs but on their medical opinion which included both a lack of effectiveness and the drugs sideaffects.

The comment you cite by Grem is very popular. Its in the editorial that you cite. The quote usually is described as...

Jean Grem let the cat out of the bag when she explained her anti-Avastin vote by observing, “We aren’t supposed to talk about cost, but that’s another issue."

Unfortunately, its a cherry picked comment. Grem's full comment was...

DR. GREM: Jean Grem. I voted no because I don’t think a median progression-free survival of .9 months is clinically meaningful. And the toxicities can be substantial. We haven’t -- we aren’t supposed to talk about cost, but that’s another issue.

If the WSJ wanted to accurately report her "explanation for her anti-Avastin vote", they would have also reported that in the same meeting she also stated...

DR. GREM: Jean Grem. I voted no because the confirmatory trials did not confirm the original findings.

DR. GREM: (Answering the question “Should the indication for the treatment of metastatic breast cancer be removed from the Avastin label?”) Jean Grem. I voted yes. Obviously, we’re all disappointed with the results of these follow-up studies.

Grem also wondered if the initial greenlight for the drug by the FDA, contrary to the intitial ODAC vote, was a mistake.

DR. GREM: So previously ODAC voted against approval. And in that case FDA does not have to follow the recommendations of the ODAC. So I don’t want to feel guilty for, you know, basically, I think maybe FDA made a mistake. And they did it with good intentions. But, you know --

DR. GREM: Jean Grem. I voted no for the reasons stated by others. [referring to the 6 other doctors' reasons for voting no which included the comments]

"- no overall survivor data to support it or symptom-improvement data to support it"
"- concerns about toxicity and not necessarily demonstrated safety in terms of survival"
"- The risk-benefit ratio isn’t sufficient to give it a favorable vote"
"- It does not support significant improvement in time to progression"
"- I think the, again, the bulk of the evidence leads me to vote no on this)"

Besides the critics never mentioning these other observations made by Grem in the same ODAC meeting, the critics never reference the other doctors reasoning for their rescind vote.

DR. FREEDMAN: Ralph Freedman. I voted yes basically, based on the decisions that we’ve made with AVADO and RIBBON 1 and the substantial defects that occurred in the original trial, which I think could have contributed to physician equipoise.

DR. LOGAN: Brent Logan. I voted yes. Here we have two well-controlled and well-conducted studies that overcame a number of the potential issues that occurred in the initial trial. We have a similar patient populations in these studies. There’s no reason to think the combination with paclitaxel behaves any differently than the other regimens, at least at this point. So I felt like they reduced magnitude of benefit that we saw in these well-conducted studies indicated that the indications should be removed.

DR. D’AGOSTINO: Ralph D’Agostino. I voted yes also. I think that we have a process laid down the accelerated approval. I think we had questions, we did have substantial questions with the previous study. The sponsor did perform excellent studies. We can say there’s either two or three studies that we were presented with and they did not achieve the clinical significance that we would have hoped for. They did emphasize the risk-benefit problem, the safety problems. I think a vote to remove the indication was quite consistent. Again, I did vote yes.

DR. BUZDAR: I voted yes because even though these were very good studies, but they failed to confirm the finding of initial study on which the accelerated approval was given.

DR. RICHARDSON: It’s regrettable that we couldn’t advance this field and in the end, as has been said many times, survival trumps everything, and we haven’t shown a survival benefit here.

DR. WILSON: Wyndham Wilson. I voted yes. I think that at least from ODAC’s voting record this is a good example of the system working. I think that we got two excellent, or I should say, outstanding clinical trials done in a reasonable period of time. Unfortunately, they did not support the original effectiveness of the agent. Hence, I voted to remove the indication because I think the totality of data does not support this being effective and therefore against the risk-benefit.

MS. PORTIS: Natalie Compangi Portis. I voted yes for all the reasons that we’ve been talking about that these further studies did not give us reason to believe that this was effective, does not prolong life, and even progression-free survival, if it is a value as a surrogate, it’s very limited and there were -- still remain very serious adverse effects to patients.

Other observations made during the ODAC meeting

The shaded column lists the results of PFS, hazard ratio for PFS and difference in median PFS. For E2100 the hazard ratio was 0.8 with an increase of 5.5 month in median PFS. For AVADO, bev 7.5 and 15 milligrams, the hazard ratio was 0.7 and 0.62 with an increase of 0.8 and 0.9 month in median PFS. For RIBBON 1 trial, the hazard ratio for the taxane-anthracycline cohort was 0.64 with an increase of 1.2 months in median PFS.

There was a marginal magnitude of effect as improvement in median PFS was less than one month.

There was an 18 percent increase in overall response rate; however, there was no improvement in overall survival with the hazard ratio favoring the placebo arm.

The marginal improvement in PFS and no survival benefit comes at a cost. The addition of bevacizumab to docetaxel led to an increased incidence of serious adverse events in grade three-to-five events.

The observed improvement in median PFS is 1.2 months. There was a 13 percent increase in overall response rate. There was no improvement in overall survival.

In the bevacizumab arm there was a high incidence of cardiac events leading to death; two deaths due to myocardial infarction; two deaths due to cardiogenic shock and failure; one cardiac arrest; and one sudden death. Other events were sepsis and hepatic failure. Based on our review of the case report, forms, and narratives, five of these events are likely to be related to bevacizumab. Note that there was no death related to cardiac events in the placebo arm.

The magnitude of PFS improvement of these two trials are much smaller than compared to E2100. None of the three trials including E2100 demonstrated an improvement in overall survival. In fact, the overall survival is greater than one in both arms of AVADO and taxane-anthracycline of RIBBON 1 trial favoring the placebo arm.

To get to the "decision driven by costs" position, you have to wade into conspiratorial waters in that you have to ignore the medical opinons voiced by the ODAC.

>> Some even view this action as potentially setting back future cancer drugs.

I agree.

What work did you do in the public health arena?


>Your 'tough part' comment is spot on. But the drug would still be available and affordable to the John Galts out there. It would appear that Medicare would not be covering it (for breast cancer treatment?), which I would have thought dovetails somewhat with the GOP's historical antipathy toward the socialist Medicare system in general and the TeaParty/GOP's desire to dismantle it and replace it with a voucher system.
>
>I'm curious if you'd care to share your remarks and your John Galt cheap shot line with the 9,000 people who have signed an online petition to stop the FDA from disproving Avastin to treat metastatic breast cancer (some of whom have breast cancer and have benefited from Avastin)
>
>Here are some facts.
>
>- In trials, Avastin showed a 52% median improvement in “progression-free survival” - the time women live without their disease spreading or worsening. Avastin delayed the growth in tumors by 11 months in combination with chemo - roughly twice as long as women on chemo alone. ODAC ruled this as "not clinicially meaningful".
>
>- Some metastatic breast cancer patients (especially those with triple negative breast cancer) have gained YEARS with Avastin, some while taking Taxol in combination. Once again, ODAC views this as "not clinically meaningful".
>
>So...if Avastin is rescinded, thousands of dying women will lose a medicine that has been documented as helping them. Imagine if you had metastatic breast cancer and were responding well to this medication (which some are). May I assume you're OK with this? May I assume you're OK wth the line about "not clinically meaningful"???
>
>I am far less interested in the opinions of government medical patriarchs who live in a culture of delay, than I am in the views of physicians who prescribe the drug to thousands of women because they know it can be a useful medicine. I worked in public health for years and I am well aware of the government mindset.
>
>Most independent sources have viewed this decision as one tainted by cost. When asked if the decision was about cost, someone from the FDA replied, "we're not allowed to talk about cost". Note how the reply wasn't, "no, this doesn't have to do with cost"....but rather, "we're not allowed to talk about cost". Some even view this action as potentially setting back future cancer drugs.
>
>I've been wrong - Sarah Palin was (for once) right - these ARE death panels.