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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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May 27, 2011

The Ethics of Avastin

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Posted by Derek

When we last spoke about the Avastin-and-breast-cancer story here, the FDA had rescinded its provisional approval for that indication, and a number of people were shouting that here it was, health care rationing based on price, right in front of us. As I said at the time, I think that those worries were misplaced: the reason Avastin was approved for metastatic breast cancer was that it seemed to work (a little). But when the numbers were firmed up with more studies, it turned out that it didn't. The whole point of a provisional approval is that it can be rolled back if things don't work out they way that they looked at first.

Now Genentech is coming back to the FDA next month asking for approval again. Here's an op-ed in the New York Times that I think does a good job of laying out the case against the whole idea:

Genentech presented progression-free survival as a surrogate for better quality of life, but the quality-of-life data were incomplete, sketchy and, in some cases, non-existent. The best that one Genentech spokesman could say was that “health-related quality of life was not worsened when Avastin was added.” Patients didn’t live longer, and they didn’t live better.

It was this lack of demonstrated clinical benefit, combined with the potentially severe side effects of the drug, that led the F.D.A. last year to reject the use of Avastin with Taxol or with the other chemotherapies for breast cancer.

In its appeal Genentech is changing its interpretation of its own data to pursue the case. Last year Genentech argued that the decrease in progression-free survival in its supplementary studies was not due to the pairing of Avastin with drugs other than Taxol. This year, however, in its brief supporting the appeal, Genentech argues that the degree of benefit may indeed vary with “the particular chemotherapy used with Avastin.” In other words, different chemotherapies suddenly do yield different results, with Taxol being superior. The same data now generate the opposite conclusion.

Another problem, as the piece says, is that the whole cancer drug approval process has a tendency to slip into ancedotal form: tearful patients testify that the drug saved their lives. But the plural of anecdote is still not data, and never will be. In oncology, there's really not much way of being sure about any individual patient's response. There are so many different types of cancer, and they occur in so many different kinds of people. The only way to say anything useful is in a well-designed clinical trial setting.

Now, that doesn't mean that you just have to round up thousands of people with all kinds of cancer and let things rip. It's perfectly acceptable - in fact, very useful - to screen the patients that go into the trials so that you're sure that they, as far as can be told, all have the same sort of disease. But you have to do that up front to really trust the conclusions. Data-mining, running things in reverse, is tricky, and if you're going to do it, it should be used to tell you how to run your next trial, not to argue for approval. Only when you've run these kinds of experiments can you say with any certainly that a cancer therapy is useful.

But that's a hard sell, compared to someone who is convinced that they're alive because of cancer drug X (or is convinced that a loved one would be alive, if they'd only been able to get it). If you're trying to persuade a crowd (or a mob), that would be the way to go: Aristotle's appeal to pathos. But keep in mind that Aristotle (and the rest of the Greeks) looked down on that technique, and they were right. Logos, used properly, is what we're after here, mixed in with the ethos of a disinterested observer who's trying to find the truth.

And this gets to the moral dilemma at the heart of the modern drug industry: are we trying to find drugs that work? Or are we trying to sell drugs, whether they work or not? Roche/Genentech has every right to make its case and to petition the FDA for whatever decision they want. But they (and every other drug company out there) owe the rest of us, and the rest of the world, something while they're doing it: to present all the solid data they have, and to let the numbers speak for themselves. But if the numbers can't persuade, then a company should go back and get some more before trying again.

Comments (23) + TrackBacks (0) | Category: Cancer | Clinical Trials | Why Everyone Loves Us


COMMENTS

1. luysii on May 27, 2011 10:04 AM writes...

Derek's conclusions are so true and obvious that it's a shame they must be reiterated again and again (but they must).

Consider this -- in the 60s the median survival for a child with acute lymphocytic leukemia was 18 months. Presently we worry about reproductive success and long term cognitive effects in the ADULT survivors (which is most of those getting ALL as kids). Why? Because year after year, new regimens of chemotherapy and radiation were compared with what the best regimen was at the time, and the less effective abandoned. Progress was slow and incremental.

Had we relied on testimony rather than data, we wouldn't be where we are today.

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2. AlchemistOrganique on May 27, 2011 10:07 AM writes...

Aw Derek, who can put a price on life? As a society that has become addicted to fantasies, can't we be allowed to buy miracle drugs that offer the smallest iota of hope for longer life?

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3. johnnyboy on May 27, 2011 10:22 AM writes...

As you put very well in your post, the Ethos is the crucial part, and the one that is sorely lacking at the upper echelons of pharma management. Unfortunately, executives are unlikely to be hired or evaluated based on their ethos (ie. their even-handedness, their level of care about the truth, and about doing the right thing). This is the difficult and paradoxical part of having drug development be handled through the capitalist system, in that a company's management has to answer primarily to shareholders - not to patients, ethical standards or to a higher truth. CEOs and pharma PR firms can speechify ad nauseam about how much they care about curing diseases, but the cruel truth is that the one overarching concern of any pharma management team is the bottom line (profits, stock price, whatever); the bottom line is the one final determinant of whether they are seen as doing their job properly. This is why scandals based on ethical or illegal marketing practices come up again and again, and have irredeemably tainted our industry. Unfortunately, I can think of no other model than the capitalist which could handle the massive degree of investment and risk necessary to develop drugs nowadays, so such ethical issues are unlikely to disappear.

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4. Kay on May 27, 2011 10:37 AM writes...

I completely agree about looking at data rather than anecdotes. However, I worry a bit that the current clinical trial model doesn't distinguish very well between a drug that has average-to-low effectiveness for everyone, and a drug that doesn't work for most people but works very well in a subset of patients that have some factor we can't identify that makes them more susceptible to this particular drug. That's especially true when you're looking at the news reports and summaries and not at the raw data. Unfortunately, we don't know that much about how different people respond to treatments and what variables might cause some people to respond differently.

I think the clinicians are more aware of this (and if this was the case for Avastin, Genentech would be making that argument). However, when I read news articles about "comparative effectiveness studies", it seems like too many people see medicine as one size fits all - if a study shows Drug X is best, then every person should take Drug X. There's no recognition that different people respond differently.

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5. simpl on May 27, 2011 10:40 AM writes...

This is Hobsons choice, and there are further alternatives. Can't we sell drugs which work, but we don't know why? Or drugs that might work, but only in some cases? Or determine drug prices according to their proven efficacy? I find it equally disturbing that effective natural products are being squeezed from the European market for lack of studies - and that Chinese medicine will lose many a medical achievement in the rush for scientific proof if they join in.
In truth, cancer cures are still few and far between, as you point out. Progress has long been made by rich ill persons consulting imaginative, lucky or well-informed doctors - Goethe's being treated for syphilis with mercury salts springs to mind. One thing that has shifted is that people are expecting insurance to cover these medical experiments, while doctors are exhorted not to consider the costs. This rant is not to belittle the call for data, but to question that the decisions are purely scientific.

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6. soydegales on May 27, 2011 10:45 AM writes...

great post. but "this must work!", right? however, it would appear actual clinical data are in the way of prevailing ideology that has been heavily sold. so, the spin/conclusion is these data need to be re-interpreted. if DNA/Roche believe they see a benefit with appropriately selected combinations/stratification that's great news, but they should go back and do the definitive studies - preferably looking at overall survival this time. equipoise anyone?

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7. Rick on May 27, 2011 10:54 AM writes...

To extend Derek's narrative, if "logos" = science and "the ethos of a disinterested observer who's trying to find the truth" = scientists, then this is the expected outcome of eliminating scientists from the CEOs office of every major pharma and replacing them with marketing people, who appeal to the pathos. It seems as though we have been blessed with many similar stories lately. Watch the developing story of the failure of reformulated niacin (a.k.a. Abbott's Niaspan) for a rerun of this sad situation. "Don't let a few facts spoil a good story" seems to be the order of the day.

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8. barry on May 27, 2011 11:07 AM writes...

I'd go further. Any drug that get's through the FDA on a surrogate endpoint (in the case of cancers, anything short of a change in mortality) should get a provisional approval only. The drug company would then have to show that the drug does extend life in "Phase IV". That's a burden that would only fall on compounds that already had a revenue stream.

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9. AvastunDefender on May 27, 2011 2:10 PM writes...

Derek, in three trials, Avastin showed clinical benefit in terms of extended PFS. That was the supposed to be the basis of Avastin's full approval, no more and no less. However, once the results were in, the FDA changed the rules of the game. After the two follow up trails did not show the same magnitude of benefit as the original trial, the FDA only then stated that the criterion for approval was that the magnitude of the PFS in the follow up trials was supposed to match the first trial.
At no time was quality of life an end-point of the trials and Genentech did not propose this. Of course, it makes sense that for most patients, the longer a patient can be free of cancer progression, the better the quality of their life. For Dr. Tucker to use one supposed statement by one Genentech official that was not part of the official FDA proceedings is meaningless at best and gratuitous at worst.
As for the side effects of the drug, there were no reported new side effects discovered in the follow up trials after the initial trial. Yet the FDA granted the accelerated approval for Avastin based on the same data it later decried as unsafe.
You also failed to state that using the same data as the FDA, the European Medicines Agency, the FDA’s European counterpart, approved Avastin for use with Taxol on the very day that the FDA went negative on Avastin. The EMA recommended extending this approval for use with Xeloda on April 15, 2011.
The use of Avastin is still recommended in some circumstances for metastatic breast cancer by the National Comprehensive Cancer Network, a coalition of 21 leading U.S. cancer institutions that issues guidelines for treating cancer that are followed in over 100 countries. These practicing oncologists, unlike the theoreticians that tend to compromise the panels that make FDA decisions, work daily on cancer patients in such institutions as Memorial Sloan Kettering, Dana- Farber, MD Anderson, Johns Hopkins, Stanford, etc.
What you and the FDA are missing in the entire Avastin saga is that the patients and their oncologists, who report remarkable success with Avastin, probably represent some sub-population of patients for whom this drug is a lifesaver. Just because the drug does not work for all (no drugs do), how dare anyone take a drug away from a patient who is fighting for her life against an incurable disease, showing success almost certainly attributable to Avastin, wishes to stay on the drug, and is doing so with the full advice and consent of her oncologist? There is a reason that there are tearful patients out there and unless we protect them from a disastrous decision by the FDA, we will be willingly sending these women to a premature death.
Genentech has offered to run additional trials to confirm its original trial data and to try to identify biomarkers for Avastin. The FDA should allow this and while these trials are being conducted, should not deprive women doing well on the drug from continued usage.
At $100,000 per annum, this drug is unaffordable to all but the wealthiest Americans without insurance coverage. If the FDA pulls it approval how can we rely on Medicare and private insurance companies to keep their existing coverage in place.
The only ethical solution is to preserve life if there is any doubt and there is plenty in this case. The burden should not be on patients to have to beg to keep that which they and their physicians have chosen.

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10. petros on May 27, 2011 2:15 PM writes...

Bring back the snake oil salesman?

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11. Hap on May 27, 2011 5:48 PM writes...

Money spent on something that doesn't work (which is apparently what the stats say) is money that can't be spent on things that do work, or might work, or money that can't be spent to save other people from things that you can do something about. Approving something that doesn't do what it's supposed to because otherwise insurance won't pay for it is hosing both patients and insurers for the maker's benefit. Not a win.

The determination that improvement is "almost certainly attributable to the drug" (as opposed to another component of treatment, or placebo), is a statistical one (which doesn't allow you to tell what happened in a particular case). The problem is that the data to justify that assertion aren't there.

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12. Still Scared of Dinosaurs on May 27, 2011 11:17 PM writes...

>> Of course, it makes sense that for most patients, the longer a patient can be free of cancer progression, the better the quality of their life.

That's why we have QoL measures. If the treatment improves QoL then the relationship to PFS is interesting but tangential. If the tx does not improve QoL then PFS is meaningless. Listen to the good folks at FDA.

Safety and Efficacy is one thing. If it's not both then it's not either. If the benefit/risk where benefit is defined in terms of PFS is not compelling then FDA is right.

And this has nothing to do with the classis but misguided anti-post hoc bias. There's a gigantic difference between wrong and almost always wrong.

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13. cancer_man on May 28, 2011 1:38 AM writes...

"But the plural of anecdote is still not data, and never will be."

Huh? Sure it is. Maybe not clean, organized data, but data it is.

Look at resveratrol. With anecdotes streaming nicely into an admittedly messy data set, we can be 98% certain (+/- 4%) that people have increased stamina when taking 500mg a day.

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14. Steven Walker on May 29, 2011 9:02 AM writes...

Derek, this post on the Avastin subject is a real disppointment. The NYT op ed contained virtualy none of the facts that have caused the FDA's pending action to be considered controversial. For example, no mention of the EMA and NCCN, looking at the same data, deciding that Avastin is a useful drug in MBC and should remain approved. They arrived at that conclusion based on some very sound reasoning based on the data. FDA's decision is not based on sound science or medicine. In fact, their explanations fail to stand up to even a cursory examination of their basis. This decision is about an 8 year effort at FDA, and specifically in the Office of Oncology Drug Products (OODP), to eliminate Accelerated Approval (created in FDAMA as part of the Fast Track program in 1997) as a viable regulatory pathway for developing and gaining approval for new cancer drugs. The reality is that all the efficacy data for Avastin in MBC is either positive (PFS) or trending toward increased overall survival (OS). Since none of the three trials at issue were powered to establish OS, a fact FDA knew when the two most recently completed trials were accepted as confirmatory trials, it is not at all surprising that the question of wheter OS is increased remains unresolved. Then there is the severe confounding problem caused by multiple subsequent therapies recieved by the owmen afetr leaving the trials - a problem the FDA has lightly dismissed as somehow unimportant, rendering their position on OS at best irresponsible and I would argue scientifically incompetent. Data regarding whether Avastin increases the risk of treatment related death is also statistically inconclusive, with some data suggesting it does by a small amount, and other data suggesting it doesn't. That means if it does increase treatment related death, it doesn't increase it very much. It's not like the other drugs available for MBC are risk free. They aren't. If you think the NYT op ed was an accurate discussion of this issue, you either haven't researched what is really happening, or you don't understand what is happening. Your assertive statement that Avastin doesn't work is misleading and based on an exceedingly simplistic interpretation of the facts. Those facts are readily available. The FDA and Roche/Genentech have been uncharacteristically transparent about the logic behind their respective positions, and the FDA's position is so weakly supported scientifically and medically, I find it somewhat astounding that you didn't pick up on that and point out that the FDA is standing on some very thin ice. And just what is your opinion of the positions taken by the EMA and NCCN? Given that this drug will remain approved in most of the rest of the modern medical world, but won't remain approved in the US, wouldn't that cause most rationale and responsible observers to ask and try to answer the question: Why did the world's other two top decision-making bodies regarding the medical usefulness of cancer drugs come to the opposite conclusion than did the FDA regarding Avastin for first-line MBC? The agency is really grasping at this point to try to justify their position, now saying that this is about the regulatory meaning of Accelerated Approval. Finally, they are admitting that this is much more about the elimination of Accelerated Approval, and not really about the risk/benefit profile of Avastin. If they use their near absolute power to ram it down everyone's throats, which seems quite likely, I think the repercussions for FDA will be quite significant. They will almost certainly be sued by multiple parties, and Congress is already looking at this and other actions by the agency's cancer drug office, and beginning to wonder just what is going on over there. They really are off track scientifically and judgmentally, and no where in FDA is that more true than in the Office of Oncology Drug Products. Are you one of the few remaining FDA pundits that hasn't yet recognized that we have a big problem in OODP?

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15. Cellbio on May 29, 2011 9:29 AM writes...

SInce he didn't declare, but his name is a link, I looked at Mr Walker's affiliation. He is part of a group that advocates for drug approval. Not a bad thing. However, the website includes a tab for the "myths" that detractors forward in their unjust criticism of his group. A really really big red flag.

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16. Still Scared of Dinosaurs on May 29, 2011 1:57 PM writes...

A big possible reason Avastin could be approved ex-US is that everywhere else an "approval" is only half the hurdle. Without agreement to pay for the drug they it's not equivalent to approval here. Not sure if it's relevant to Avastin but I've always had higher respect for FDA's review than EMEA in part because I've felt EMEA mixes in a few negotiating ploys into their requests.

And I have no great love for PFS. It is not adequate for approval in most cases I've worked on. Basically, if the delayed progression is not associated with symptom reduction (or actual increase in survival) it's not the basis for a stong case.

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17. Steve Walker on May 31, 2011 7:10 AM writes...

To Cellbio. I am Co-Founder of the well-respected and influential patient advocacy organization, Abigail Alliance for Better Access to Developmental Drugs. I was not trying in any way to hide my affiliation. We are one of the very few patient groups that aren't funded by one or more of the major financial special interests in drug development, and the most influential organization representing the very real life and death interests of people with incurable forms of cancer. I am an unpaid volunteer. If responding to people who nonsensically oppose our proposals for modernization of FDA science and a more patient-centered regulatory process on our website is a "red flag" that some how makes us nefarious in your view, then so be it. I encourage you to spend some additional time online and find the several position documents both FDA and Genentech have made public regarding their respective positions on the labeling of Avastin for MBC. You are entitled to your opinion of course, but if you haven't reviewed those documents, your opinion (and anyone elses for that matter) is woefully uninformed. After reviewing them, again take a look at Dr Tucker's NYT op ed and Derek's post lauding it. Neither suggest that the authors took the time to understand this issue. If they did, their bias is clear by their failure to mention several of the most salient facts. Fully explaining what is happening here reveals that the FDA's position on this drug is at the very best for them, a close call, and in reality quite hard to justify. Also look at the reporting on the decisions of the EMA and NCCN. The FDA really is swimming upstream on this decision, and their explanations for it really are medically and scientifically weak. A lot of people blindly support the FDA without watching closely enough to accurately understand what the FDA is doing and why it is doing it. Usually finding that out is quite difficult. The agency is generally deliberately opaque. In this case, because Genentech has chosen to make this process public, the FDA is trying to defend its decision publically, and their logic is quite flawed. Had Genentech not decided to publicize the appeals process, FDA would have claimed they could not release any information about the process in the run up to the appeals hearing - which would have been a largely correct application of the law - and we would know next to nothing about what is transpiring. You may disagree with our understanding of the facts, but the facts are out there, and anyone with an interest in this should become familiar with those facts before forming an opinion, and cite those facts when discussing that opinion, else the arguments will be unconvincing to anyone who has become familiar with those facts, and a disservice to those who haven't. Derek didn't do that in his post, nor did Dr. Tucker. Had they done so, their opinions would have been undermined by those facts. This really is a landmark decision for patients and progress against cancer, for reasons that go well beyond the labeling of this single drug, and FDA - in our very well informed opinion - is very seriously wrong.

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18. Cellbio on May 31, 2011 9:13 AM writes...

Dear Mr Walker,

I did spend a fair bit of time reading about your organization and come to the conclusion that your group, well intended, is driven by admirable passion for patient care, but passion that strongly influences your opinions and assessments of those whose opinions vary from your organization's.

The op ed piece from the NYT by a Crohn's patient is a great misservice to the good people that are trying to impact this disease. However, embedded in that piece is a reasonable position that a patient should have the right to know whether they received placebo or active agent, for purposes of continued informed medical care. Impugning the drug company and FDA do not help make that point. The author, and I assume your organization supports this position as well but don't know, also advocate that placebo treatment is unethical. A subsequent trial of the experimental agent the patient writes about was stopped because placebo rate was so high as to preclude determination of a drug effect. Crohn's trial data I have seen personally have had placebo rates up to 40% with treatment only adding single to low double digit gains. On top of this, placebo rates varied in geographic region by the same magnitude of the treatment effect. we would not being doing right by patients nor by a scientifically driven approval process to omit placebo arms from trials.

This is a tough business, one that screams for solutions, and "modernization" of discovery, development and regulatory approaches. Good luck in your efforts, but I suggest you would make more headway by listening well to your critics, not labeling them as "nonsensical".

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19. anonymous on May 31, 2011 12:10 PM writes...

@14
EMA and FDA do not necessarily look at the same data- at least not the same way. Whil EMA and FDA generally are in accord (80-90% of decisions are same IIRC), the devil is (literally) in the details. One big difference: EMA makes decisions using summary data; FDA requires individual patient data for the basis of approval. Lots of little one.

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20. Anonymous on May 31, 2011 3:05 PM writes...

Dear Mr. Cellbio. Your response to my suggestion that you read the available documents regarding the Avastin decision is to attack the Abigail Alliance based on a review of some information on our website, and to attack an op ed written by Crohn's patient. I am quite sure I know moe about both of those subjects than do you, given my direct involvement. Who are you, and why does your opinion carry any weight?

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21. Steven Walker on May 31, 2011 3:07 PM writes...

Dear Mr. Cellbio. Your response to my suggestion that you read the available documents regarding the Avastin decision is to attack the Abigail Alliance based on a review of some information on our website, and to attack an op ed written by a Crohn's patient. I am quite sure I know more about both of those subjects than do you, given my direct involvement. Who are you, and why does your opinion carry any weight?

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22. Hu Yu on June 2, 2011 11:00 PM writes...

Dear Mr. Steven Walker,

I think Cellbio's criticisms are on-target, regardless of who he is. His opinion carries more weight because it is accurate, and yours less because no matter how far you puff out your chest, your title doesn't make unreasonable positions become reasonable.

"Removing unnecessary and unethical placebos from clinical trials" is a loony position. How do you back that one up? Why are they unnecessary--how do you magically glean information about a baseline without this information? The necessity for controls in experiments is almost foundational in science. Do you understand this? What is your science background like?

You say "all the efficacy data for Avastin in MBC is either positive (PFS)or trending toward increased overall survival (OS)." How is PFS positive if it is NOT accompanied by either of the two benefits it usually travels with, longer survival or a better quality of life in the time the patients have? See comment #12 by Still Scared of Dinosaurs. If the cancer does not progress, but the drug makes you as miserable as if it did progress, what have you gained?

And what is "trending toward" increased overall survival? Does that mean OS is decreased, but less and less over subsequent trials, so that you hope the effect will soon be negligible and maybe someday positive? You claim that the trials in question were not designed to study overall survival, so we don't know anything at all about overall survival without a new trial. This is not completely true; those trials may not have enrolled enough people to find Avastin's tiny-if-at-all-there benefit, but we should be able to say the benefit had to be smaller than some value X, or it would be easily measured. In addition, Genentech has had years in which to enroll new trials to shore up that data, but they chose not to do so. You are happy with that? You really want to just blindly trust that data must exist, because sick people need it? Surely Genentech would not have chosen PFS instead of OS because they knew which one would show an effect?

You are proud that the Abigail Alliance is "one of the very few patient groups that aren't funded by one or more of the major financial special interests in drug development." That's very good, but you are trumpeting the NCCN position as something the FDA should be embarrassed to go against. The NCCN is NOT one of the groups that is free of conflicts of interest. Genentech is helping to pay for their website, fer cryin' out loud. $100k per patient per year can spread a lot of grease; why are you so determined to dismantle the FDA's impartiality in favor of a group that clearly stands to gain?

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23. Steven Walker on June 7, 2011 8:46 AM writes...

Mr. Hu Yu,

First, trending toward survival is actually defined by FDA and the field of biostatistics. It means that there was a measured survival advantage associated with Avastin, but it did not reach statistical significance(meaning its p-value was greater than 0.05). That is what happens when there actually may be a survival advantage but the trial was not powered (meaning large enough) to discern it to a level of statistical significance (meaning to FDA - producing a p-value of 0,05 or less). They calculate this stuff when they design the trials. Second, if you read the transcripts of the various ODAC meetings and the documents going back and forth between the sponsors and the FDA, you will learn that in fact, the studies approved by FDA as confirmatory trials were not powered to measure overall survival to a level of statistical significance. The FDA knew that when they accepted the study designs at the time of Avastin's approval based on PFS as the primary endpoint (please look up "primary endpoint"), and they have actualy acknoweldged that the standard they were setting for conversion of AA approval to full approval was confirmation of a PFS advantage and no negative effect on overall survival. That is precisely what the trials showed. The trials hit their statistical marks. The FDA;s position is now based solely on a judgmental determination (an opinion) that the benefits shown are not "clinically meaningful," a judgment the NCCN, EMA and many, many oncologists who treat breast cancer patients, disagree with. Please, please read up on this. Learn how the regulatory system actually works. Understand the regulations and approval standards and the process for Accelerated Approval and Regular Approval (which is what this pending decision is about). Dig into the science and policy behind what is happening here. You may stil disagree, but the responses I am getting to my posts on this site tell me only one thing - you haven't done that. I am not at all put off when people disagree with me, but I am frequently appalled at how little most storngly opinionated people know about the drug development and approval process, or how and why the FDA makes it decisions, and perhaps even more importantly, how politicized, judgmental and intellectually-based agency decisions can be. This isn't a "good" against "evil" event. Its about making the right decision for progress and patients. You didn't know the definition of "trending toward survival," and while you clearly have some understanding of statistics, you don't seem to understand "statistical power," the relationship of statistical power to the p-values metric of 0.05 that FDA relies on to decide whether an OS benefit is a trend, or confirmed. (BTW - the selection of 0.05 is entirely arbitrary - no one can explain why that should be the determinative value - because it actually is arbitrary). Without understanding these technical ponts (and many others) involved in how FDA makes its determinations, you can't grasp how arbitrary and capricious the agency's position really is on Avastin. This string has become an exercise in tail chasing. Having an idealized view of the FDA as somehow scientifically and judgmentally superior to the rest of the oncology world - an idea that they are always right - is why the FDA is such a scientifically-stagnant mess - a fact its Commissioner openly admits every time she gives a speech. Please downlaod some of Commissioner Hamburg's speeches (actually almost any one of them) and read the admissions that the agency's science has not kept up with advances in research. It might just temper your faith in the FDA a bit. You might also take a look at the agency's own science board report on the state of FDA's science, released a few years ago. But first and foremost, read everything the FDA and Genentech have posted about the upcoming hearing. Read the two ODAC transcripts where the committee was asked for advice on Avastin in MBC. Read all this stuff objectively for facts (not the opinions of those producing them), then form your own opinion. It takes time and effort, including taking the time to figure out what terms like "trend toward survival" means, but it will better inform your own opinions. The FDA is an enormously powerful agency, and it isn't nearly as competent or infallible as many think it is. Genentech's actions in challenging this pending decision are unprecendented. Almost no other drug company has delivered more progress against cancer than this one in the last two decades. If you asked Rick Pazdur, head of the FDA's cancer drug office if that was a true statement, he would say it was. Avastin is approved and proven effective in a wide range of cancers. Its not rat poison or snake oil. Take a breath, and recognize that there realy are two sides to this story, and that the FDA does, in fact, make mistakes. The frustration with FDA's decisions in oncology among virtualy all stakeholders, including researchers, patients and the private sector has been growing for a long time. The oncology world is trying to push the cancer drug office forward, along with the FDA commissioner, but this decision on Avastin is a rush backward. For some very solid scientific and statistical reasons, OS isn't a statistically workable endpoint (please look up "endpoint") in first line MBC anymore. FDA is saying it is going to be the only endpoint they will accept. That will mean sponsors will stop trying to improve first line care because doing so will be procedurally impossible, or at least so high risk it will preclude anyone from trying. Also, do you think Accelerated Approval, the Congressionally-created approval pathway that brings new medicines to patients sooner should be eliminated? If you were following this closely, you would know that is what this action is really about. Facts, facts, facts. Then opinions.

The NCCN is not "conflict-pure," but its opinions are considered authoritative and they are followed, even by CMS (medicare and Medicaid). You didn't mention the EMA position. You might want to look at the conflict and other serious problems associated with FDA's won Oncologic Drugs Advisory Committee, which has been driectly involved in the Aavstin for MBC process from the start, and will serve as the expert panel hearing the appeal in the upcoming hearing. Did you know anything about the upcoming hearing? How it is structured? That FDA originally refused to allow patients to speak during the two daya event, then caved under enormous pressure? That the ODAC panel of about a dozen oncologists and statisticians includes only two physicians that treat breast cancer patients, and that it is the exact same panel of physicians that voted to remiove the drug 12-1 last year? They all have financial conflicts of interest identical to those of docs that serve on NCCN. Is that an impartial panel? Do you know who within FDA selects ODAC members? I know all of this and much, much more. If you want to discuss this further, e-mail our website with your contact information, and I will call you. As for the FDA's impartiality, if you think the agency is bias-free, or that it always has the best interests of people with cancer, or who will have cancer soemtime in the future - in mind, you don't know the FDA. They are regulators, not saints.

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