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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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October 14, 2011

Avastin: False Hope for Metastatic Breast Cancer

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Posted by Derek

There should be a decision soon on the controversial Avastin-for-metastatic-breast-cancer indication. I've written about that several times here, and my position is unchanged: the preliminary clinical data made it worth a provisional approval, but the follow-up data didn't back it up. This happens. The provisional approval should, I think, be withdrawn, because based on the best evidence we have (which is a lot more than we had when the approval was granted), Avastin is not effective for metastatic breast cancer, and carries notable risks all its own.

Now, via NPR's Scott Hensley, I see that one of the members of the FDA's committee on this issue has published a letter in the New England Journal of Medicine explaining his vote. Says Mikkael Sekeres of the Cleveland Clinic:

"The responsibility of ODAC is to carefully consider the scientific data presented as part of an FDA application for a cancer drug and weigh the benefits that the drug may provide to patients with cancer against the risks posed by the drug's side effects. We try to be dispassionate, but we always think about the person we face in clinic sitting a foot or two away from us in our cramped examination rooms, waiting to hear what treatment we can offer to get rid of her cancer. What kind of conversation would I have with such a patient if I were trying to convince her to take a treatment like this?

“Well, I can offer you a drug that will not make you live longer, won't make you feel better, and may have life-threatening side effects, but it will keep your cancer from worsening by an average of 1 to 2 months.”

Hope? Or false hope?"

Survival is the first thing you have to consider with a cancer therapy. And right next to it comes quality of life, because extending someone's life for a brief period at the cost of horrible side effects is no bargain, either. Should women with metastatic breast cancer take Avastin? It does not, as far as anyone can tell, extend their lives. And it does not improve their quality of life - if anything, it makes it worse. Avastin can be a good drug against other forms of cancer, but it's not for this one. I very much hope the FDA follows the recommendation of the advisory panel.

Comments (22) + TrackBacks (0) | Category: Cancer | Regulatory Affairs


COMMENTS

1. deceased on October 14, 2011 8:02 AM writes...

Sure, the quality of life of the patient may decrease, but the quality of life of people selling avastin will increase ;)

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2. Steven Walker on October 14, 2011 8:24 AM writes...

Dr. Sekeres does not treat breast cancer patients. In fact, none of the physicians on the panel that voted against retaining approval of Avastin for metastatic breast cancer at the hearing were breast cancer oncologists. Dr. Sekeres has never had and likely never will have a conversation with a breast cancer patient about any treatment option, which makes the journal's decision to print it a bit surprising. Many oncologists who do treat breast cancer patients and routinely have those conversations want the approval retained. The European Medicines Agency, looking at the precisely the same data, retained its approval, and the National Comprehensive Cancer Network (NCCN), an alliance of 21 of the world's leading cancer centers, also supports its continued use - an important determination because CMS relies on their recommendations for coverage decisions. In fact, CMS, based on its own review and deliberations, has announced that it will continue to cover Avastin for the treatment of metastatic breast cancer. Derek, you and Dr. Sekeres are not in the mainstream of expert or patient opinion on this. Most in the cancer patient community (as confirmed by comments to the hearing docket) want Avastin to remain approved and covered for metastatic breast cancer.

The panel hearing opinion you refer to was rife with irregularities. Dr. Sekeres and his colleagues were all appointed to ODAC by Dr. Richard Pazdur (a fact confirmed by agency advisory committee staff), head of the FDA's oncology offcie and the official who decided to try to pull the approval. FDA has never provided an acceptable explanation for why the subset of ODAC members selected for the hearing included no breast cancer specialists, instead consisting only of four panel members whose positions on the approval were already known to be negative from prior votes, and one new ODAC member selected by Dr. Pazdur after the hearing was scheduled and his control over any aspect of the proceedings was supposed to have been eliminated through separation of functions. Even the "patient" representative selected for the hearing had twice voted against the approval, in clear contradiction of the position of the real patient community (i.e., women who actually have metatstic breast cancer). The hearing was on its face a sham and a set up to validate the poorly supported position against the drug taken by Dr. Pazdur and his deputy Dr. Patrica Keegan. I think the ice is exceedingly thin under your and Dr. Sekeres positions, and it would be a serious misapplication of FDA authority should Dr. Hamburg follow the advice of the hearing panel. The real votes are in, and the oncology world overwhelmingly thinks that based on the available information, Avastin is a useful drug for the treatment of metastatic breast cancer and should remanin approved, covered and available. The opinion of Dr. Sekeres, an oncologist who has never treated a breast cancer patient and likely never will, should not carry any weight at all with Commissioner Hamburg. In fact, Dr. Sekeres hubris is on full display.

Steven Walker, Abigail Alliance

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3. MDACC Student on October 14, 2011 9:51 AM writes...

@2 Steven Walker
I agree that breast cancer specialists should have been involved...and it is interesting what you said about the NCCN...but it Derek's point of view [and Mikkael Sekeres, MD] is still valid. The outcome is what the panel is looking at. I'm not sure what it involves but you don't need expert of experts to check survival statistics and quality of life data.
You wrote a very long post arguing for specialists to make the decision but you didn't really mention WHY it should stay approved. Is there some indication in a subpopulation of patients we are not familiar with? I'm respectfully asking because I myself am not a breast cancer expert.

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4. Jonny on October 14, 2011 10:25 AM writes...

Steve, I think FDA are looking Avastin in MBC through a pretty objective lens.

I don't doubt that some breast cancer oncologists would prefer to keep Avastin in their arsenal; however, FDA's remit is to adjudicate based on rigorous clinical trial data, not on anecdotal stories of patient benefit (which are anecdotal for a reason, as there's no way of saying for sure on an individual basis whether Avastin benefited a specific patient).

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5. pete on October 14, 2011 11:35 AM writes...

@2 Steven Walker
It'd be one thing if we could separate the economic component from this decision, but we can't. Approval means insurers will remain on the hook for covering use of Bevacizumab/Avastin in metastatic BC.

Should we insure bevacizumab for mBC given current evidence?
- expensive drug
- demonstrable PFS increase in some large studies, but more modest than originally suggested
- no demonstrable effect on OS
- no identification of "super-responder" subpopulations, as far as I know
- some instances of scary, antiVEGF-dependent side effects
- not-infrequent devel. of tumor resistance to antiVEGF agents with chronic use

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6. FormerGenentecher on October 14, 2011 12:04 PM writes...

@Steven Walker

Missing from all yor rhetoric is a focus on the trial data or from my perspective as a scientist/regulatory professional the "facts". I don't care who Richard Pazdur chose for the hearing or all the other arguements you bring to the table.

Data is data and @pete has already summarized this nicely in his bullet points. You do not have to be an oncologist to understand that there is little to no benefit in the patient population as studied. In fact there may even be a higher level of risk to the patient.

Genetech has the right to retest this in a sub-population study since I am sure there is a group of women that benefit from the drug. That is clear based on the patients who have shown good results while on Avastin. However based on the trials run to date, we cannot at this time define what that population is.


A breast cancer patient can if they so choose find a doctor to treat them with Avastin so it is still "available". This isn't about patient access or who will pay (well it is in a sense) but the "real" issue is a scientific one............

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7. johnnyboy on October 14, 2011 12:26 PM writes...

As someone who hasn't been following this issue very closely, I found the article below a very good summary of the situation.

http://www.nejm.org/doi/full/10.1056/NEJMp1106984?viewType=Print&viewClass=Print&

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8. David Young MD on October 14, 2011 12:44 PM writes...

As best as I can tell, medical oncology specialists have lacked some objectivity towards anti-angiogenesis drugs. The idea of anti-angiogenesis was introducted by Dr. Folkman many years ago, with evidence that "tumors rely on blood vessels to grow" and "drugs that inhibit the growth of tumor blood vessels do not lose their potency." We all though that we had a cure of cancer on our hands. Well, history has taught us that tumor do indeed become resisant to Avastin. Yes, Avastin seems to truly help improve survival and remissions in colon cancer, but even here the tumors do in fact become resistant after a while. And it may be possible that they grow faster after the resistance develops. Avastin doesn't help in pancreatic cancer so it is certainly reasonable to suspect that it might not help in other cancers such as breast cancer. We shouldn't be ashamed to admit that Avastin is a dissapointment in several cancers, including breast cancer. There may be other investigational drugs out there that deserve our attention much more than Avastin. And keep in mind,... Avastin is terribly expensive. some 4 to 8 thousand dollars a month.

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9. CMCguy on October 14, 2011 1:37 PM writes...

My read on this is that Avastin does help a limited number of breast cancer patients although currently don't know going in how a particular patient will respond. So #6 FG is correct is a scientific issue and major questions at least twofold IMO: Science needs to identify which patients will best respond and secondly based on overall experience what can be learned to do better next time in this disease and for other drugs.

Pazdur and the panel appear to want black & white answers, disguised as objectiveness, which rarely ever are so clear cut in clinical trials, particular in cancer treatment. While it is easy to decide "withdraw approval" based on lack of sufficient evidence for entire group there are practical aspects of such that likely would severely limit as a treatment options being used and thereby patients who could be helped now won't have opportunity to find out (until something better can be found). I would favor a more subjective approach that does include anecdotal observation but unfortunately that is where the side effects/costing makes more complicated.

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10. MTK on October 14, 2011 1:50 PM writes...

The issue here is not whether the FDA will approve or not for MBC. It's all about reimbursement. Any MD can prescribe it and any patient can take it, since it is already approved and marketed. If they can afford it.

Did not Medicare say earlier this year that they'll reimburse Avastin use for breast cancer regardless of what the FDA decides? Meanwhile, Blue Shield of California announced that they would not cover Avastin for breast cancer treatment should the FDA remove approval. I'm sure others will follow suit.

I guess what I'm saying is that the controversy here is really about who is going to pay for it.

Permalink to Comment

11. FornerGenentecher on October 14, 2011 1:55 PM writes...

@ MTK

maybe so but really the FDA does hold the cards since the last time I checked they "approve" drugs for marketing and unless this is the case most if not all insurance companies will gladly drop reimbursement of an expensive drug that doesn't do much. The NCCN, insurance companties etc do not approve drugs and they can say what they want.....

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12. Imaging Guy on October 15, 2011 9:20 AM writes...

“ .... it will keep your cancer from worsening by an average of 1 to 2 months.”

This last part of the sentence does not agree with the preceding part. When he says "“ .... it will keep your cancer from worsening by an average of 1 to 2 months.”, I think he means the size of the tumor as seen on the scan will not become bigger by an avearge of 1 to 2 months. I think there is a saying " Do not treat the scan, treat the patient". It seems to me that this drug does not do any good at all.

Permalink to Comment

13. Steven Walker on October 15, 2011 9:32 AM writes...

Great discussion. In fact, a close look at the data does not clearly support a conclusion that Avastin does not provide a survival benefit for MBC patients. The confirmatory trials the FDA is now rejecting were not powered to detect a survival benefit - a fact the FDA was aware of at the time of their acceptance of the trials as Phase IV confirmatory trials. Confirming progression free survival was the primary endpoint, which was met in all three confirmatory trials. All three trials, each using Avastin with a different chemotherapy drug, showed positive progression free survival. The magnitude of PFS for each of the trials was different, which would be expected using three different drug combinations. It became quite clear during the hearing process that FDA changed the rules after Genentech completed the trials, with the endpoint FDA would accept for conversion of accelerated approval to regular approval being changed from PFS overall survival (OS). But again, the confirmatory trials approved by the FDA several years earlier were not powered to detect a statistically significant survival benefit. Further compliacting this is the fact that the indication is for first line treatment of MBC, so women participating in the underpowered trials eventually progressed regardless of which arm of the trial they were in (chemo with or without avastin), were taken off study, and then went on to receive additional serial therapies, some even including Avastin, eventually succumbing to their disease months or years later, thus producing a "survival" data point. These subsequent therapies, each providing, or not providing, a survival benefit very unevenly to each of the women, confounded the ability to see a survival advantage conferred by the first therapy the women received upon diagnosis of MBC in one of the confirmatory trials. Thisis basic stats guys. Too many uncontrolled variables. When Avastin was granted accelerated approval some of the discussion regarding the use of PFS as the primary endpoint revolved around the recognition of the difficulty of seeing an overall survival advantage for a first line treatment in the MBC setting, because there are so many approved and off-label options available for women to try after first line, and they do, because they want to continue living. It may actually now be impossible to see anything but a very large OS advantage for a first line MBC indication because of this post-trial confounding effect. There is more to support retaining the approval with some of them being technical and others purely regulatory, but it would take pages to explain it all. I listed the authorities who have considered all of the factors more appropriately and scientifically than the FDA because they, in fact, have done that and arrived at a conclusion opposite from Dr. Pazdur and his staff. That is an extremely important point. The EMA and NCCN don't use 8-balls to make there decisions, they look at all the information (not just the stats for OS) and arrive at an informed and responsible decision. Pazdur, on the other hand, has long and forcefully held that only the stats metric matters, even if designing a trial to produce a meaningful one may be impossible. There is also a backstory behind this action by Dr. Pazdur and his staff, having to do with a long-standing and ill-considered Phase IV enforcement program he began in 2003 to impose an inflexible requirement for meeting statistical metrics that weren't very meaningful in terms of evaluating risk/benefit in populations with unmet needs. His enforcement program effectively eliminated accelerated approval as it was intended to be used by Congress. The Avastin action was consistent with that program, and it was perhaps his "bridge too far." The pressure now mounting from outside the agency to reinstate accelerated approval (which was working quite well before the enforcement program began) is now enormous, and there are some signs that the commissioner is now responding to that pressure.

On the question of subsets, there is some pretty compelling evidence (that Pazdur dismisses as anecdotal because he refuses to look at subsets) that there is a population of MBC patients that respond very well to Avastin therapy (the super-responders) and Genentech and others actually have been working hard to try to find biomarkers to identify them in advance. Genentech has proposed a follow up trial program (effectively a second Phase IV program) this time powered to try to meet the FDA's new OS endpoint, but also to evaluate whether they can predict responses using a candidate biomarker. We are about to find out, it seems, whether FDA is going to be reasonable about its own numerous mistakes and regulatory inconsistency in this case by allowing Genentech to do the studies the agency now says it wants - which are different studies than the ones FDA approved several years ago that met their pre-specified endpoints, but that the FDA then decided to reject.

On the side effects issue - look at the data reagrding the side effects and you will see nothing new, nor will you see an indication that Avastin is out of line with most of the other drugs we have for treating MBC. They all have serious side-effects, including treatment-caused mortality, and the size of the subsets of patients that experience the serious ones are similar across the various MBC therapies.

Finally, metastatic breast cancer is a terminal form of the disease. The 5 year survival rate is awful. Some of the other MBC drugs FDA is not proposing to pull from the market have also never been proven to confer a survival advantage, all are toxic, and most are not targetable to patients likley to respond. The way to remove drugs like Avastin from the MBC space is not to rescind approval for a drug that is having an effect, and probably a large effect for certain individuals, because of a shfiting and uncertain FDA stance on endpoints, but rather to improve its use (which the company has agreed to try to do), and to find new treatments that are so much better that these first and second generation biologics we are now using simply fade away. The direction we need to be moving is forward, not backward, and that is our primary problem with Dr. Pazdur and his team. They are a regressive bunch in a time when we need to be leaning aggressively forward.

On the cost, new science is expensive - and it is made more expensive by regulatory actions like this one. The debate about whether we are going to pay for new cancer drugs has been far too narrow to this point, and based on short-term thinking. We need a less angry and more informed conversation. If we make our efforts to conquer disease nothing but a discussion about what we can "afford," then the effort will begin to evaporate. In fact, that is already happening. These new drugs cost to too much, but it also costs way too much and takes far too long to develop and gain approval for a new, safe and effective cancer drug. The FDA's stance on Avastin is a manifestation of their position as one of the major barriers to acceleratin progress against cancer. Let's have that discussion, but I warn you, to have it in an informed way, you are looking at spending a lot of time (probably thousands of hours) understanding how it now actually works (or actually mostly doesn't work), and if you do that, you will come away with a lot less confidence that FDA is doing a good job.

This is way too much work for a Saturday. I am now going for a long bike ride.

Permalink to Comment

14. Observer on October 15, 2011 7:08 PM writes...

Steven, it is simply incorrect that the FDA "shifted the goalposts" to OS. The goalposts stayed at demonstration of clinically meaningful prolongation of PFS -- even the best of the three groups presented across AVADO and RIBBON-1 had a PFS prolongation of 2.9 months, with no quality of life improvement. The other groups were even weaker, at 0.8 and 1.2 months. These are far shorter than was seen in E2100 (where there were a number of methodological concerns). Set against the known risks, this was not considered clinically meaningful, and therefore did not support maintaining the (accelerated) approval.

Roche Genentech is free to do the studies you outline, to identify high responders, regardless of the labeling. Your rhetoric about personalities and processes obscures the real issues here of a drug with minimal if any efficacy in this group, and real risks.

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15. Steven Walker on October 16, 2011 8:59 AM writes...

To Observer: You are correct that the PFS durations for the three trials were less than the 5 plus months from the original trial supporting accelerated approval, but the agreed standard for conversion to regular approval between FDA and Genentech when FDA accepted the trials was confirmation of a PFS benefit and no adverse effect on Overall Survival. I have read everything submitted for the hearing, and I was there suporting the dozens of women who came at their own expense and on their own volition to speak for themselves in favor of retaing approval. The trials met those endpoints. FDA's position is based solely on their judgement that the PFS from the three confirmatory trials was not "good enough." The women and their physicians disagree. The hearing record clearly shows that FDA did change the goalposts, shifting to an OS endpoint for trials not powered to show an OS advantage. Whatever you believe regarding the exact prior communications between Genentech and FDA, Dr. Pazdur and his staff would not have accepted trials underpowered for OS as the primary endpoint if in fact OS was the primary endpoint in their minds. Maybe they now feel that not insisting on OS was mistake, but where does that leave MBC patients? Assuming FDA has decided it made a mistake, then we are left at worst with some uncertainty regarding a drug that is clearly active, confers a PFS advantage confirmed four times in well-run clinical trials, and appears to benefit a subset of women sunstantially. Your solution seems to be that FDA should take that drug out of the clinic while we wait for data to resolve the uncertainty? Avastin still clearly meets the standards for Accelerated Approval, and Genentech (and by the way many patient groups including ours) have asked that Accelerated Approval be retained while the confirmatory trials FDA now wants are run. It is a reasonable and responsible position, and one Drs. Pazdur and Keegan vehemently disagree with despite the rest of the expert oncology world and regulatory bodies decisions that Avastin is a useful drug for MBC and should remain available.

As explained in my earlier posts, the data also show that the risks posed by Avastin in combination with chemo fall within the profile of risks for most of the drugs we have for MBC.

Finally, the ideologies of the persons involved (not their personalities) and the policies of the leadership of the FDA's oncology drug office are extremely important to the effective functioning of FDA's regulation of cancer drugs. It is a fact that Dr. Pazdur has imposed aggressive enforcement of post-accelerated approval Phase IV randomized controlled trial completion over the last 8 years, actually very clearly stating numerous times that because they are so difficult to complete (mainly for ethical reasons), he is disinclined to grant accelerated approval to any highly promising new cancer drug until the same trial is started, fully enrolled and run to at least an interim analysis point as a pre-approval Phase III trial, before he will even consider granting Accelerated Approval - a clear contravention of the intent of Congress. Even more troubling was the fact that Accelerated Approval was working very well before he decided to eliminate it by raising the standard for Accelerated Approval to effectively, the standard for full approval, and delaying delivery of new cancer drugs to terminal patients by about 1.5 to 2 years (or in some cases - like Provenge - much longer). Lost in all of this is the fact that terminal cancer patients can't just wait around for a new drug (or an older one FDA decides to remove). Instead they die waiting. Dr. Pazdur's selection of his ODAC members (which by the way is a pretty clear violation of a core tenet of the Federal Advisory Committee Act - he shouldn't be the one selecting them) allows him to select members that agree with his narrow view of risk/benefit analysis - meaning that they reject any and all information regarding cancer drugs except for an arcane statistical metric called a p-value. This problem would be well illustrated by the names of nominees he has rejected over the years - some of whom are physicians responsible for developing cures for some forms of the disease, and who have ben quite vocal about their disagreement with Pazdur's policies and decisions. We know this because we have nominated some of them. Dr. Pazdur has used his ODAC as an enforcement club and turned them into adversarial affairs where he is the prosecutor and judge, and the jury (meaning the ODAC) has been hand-picked by him and almost always follows his lead closely (which is what happened at the hearing). Sounds crazy, I know, but it is the truth. You state that Genentech is free to do the studies, but will MBC patients have the option of obtaining the drug (especually triple-negative patients for whom the treatment situation is pretty grim right now), while we wait for the results, which will take several years to arrive? The data for Avastin in MBC is mostly positive (four trials now showing a positive PFS), and Genentech has asked for retention of Accelerated Approval in only one combination (the one showing - now twice - the greatest PFS) while it conducts the trials the FDA now says it wants. MBC patients want the drug to remain available and covered. Breast cancer docs want it, CMS continues to say they will cover it, and it will be available elsewhere in the world. In three or four years when the results are in, we will know a lot more and it is much more likely than not that Avastin will still be proven a useful drug for MBC, perhaps with better information on how to focus its use. Pulling it now because we don't yet know everything we would like to know would be an extremely poor choice. There is broad and growing agreement among patient advocacy groups, regulated industry and many physicians that FDA's handling of cancer drugs over the last decade has been something of a disaster. A few supporters of Dr. Pazdur's policies remain, but they are quite isolated. I suggest you read the hearing record and posts to the docket, then read the information available regarding EMA's decision (they have a great website), and also look at NCCN's decision. It is not just me making the arguments you see in this string. Far from it. FDA admits its science is stagnant, and Commissioner Hamburg is talking incessantly about the agency's problems and her efforts to fix them. The real-world manifestations of those problems are on full display with Dr. Pazdur's handling of Avastin for MBC.

Steven Walker, Abigail Alliance

Permalink to Comment

16. Anonymous on October 17, 2011 5:45 PM writes...

Didn't Roche just publicize an old therapy for breast cancer that was "taken off the shelf" to fill the Avastin void (see below)????? Looks to me like the greed has been digging to find new entities to replace the failure. Could be a ploy to move the stock up!!

http://www.bloomberg.com/news/2011-09-24/roche-study-shows-shelved-drug-s-magic-against-breast-cancer.html

64,000 dollar question...why was it shelved. Looks like toxicity to me.

Permalink to Comment

17. Steven Walker on October 18, 2011 5:33 AM writes...

T-DM1 did not just get dusted off. It has been in human clinical testing for a quite a while, many experts think it is already proven to be better than herceptin alone, and FDA (meaning Dr. Pazdur) refused last year to agree to an Accelerated Approval pathway, which imposed at least a 2 year delay (nd probably longer) on its availability to women with Her-2 positive breast cancer. That action by FDA was part of the same ill-considered campaign by Pazdur to eliminate Accelerated Approval. I am often perplexed by the tendency among some to automatically think that everything happening in the cancer space is about nothing but greed. Our system is far from perfect on all sides of the process, but virtually all the drugs we have that actually do effectively treat cancer arrive as the result of major efforts by drug companies, regardless of whether they were originally conceived by the drug companies or others. Women with breast cancer need drugs like T-DM1 - which does not contain Taxotere and is much less toxic. The new results are from a trial that compared treatment with T-DM1 to treatment with a combination of Herceptin and Taxotere. T-DM1 - which is much less toxic, proved to be far more effective.

Why doesn't anyone on this blog ever seem to consider the undeniable fact that sometimes (actually fairly often) the FDA is screwing up by delaying or sometimes even denying, availability of new (and old) drugs that work to patients who need them. It happens a lot more than you might think. Do some real research on what has been happening with T-DM1 and you might find yourself wondering why this drug isn't already approved by the FDA.

Incidentally, the "shelved" drug referred to in the article isn't shelved at all. Taxotere is still very much approved, still used and still quite toxic. It is exactly the kind of drug researchers and Roche are trying to improve on, and Genentech/Roche developed a combination of Herceptin and DM1 to try to do that. T-DM1 is a good drugm, a fact now known for several years from well-run clinical trials. FDA has been sitting on it, requirirng more data and refusing to fast track it - which by the way drives up the development costs by hundreds of millions of dollars - which in turn drives up the cost of the drug after approval. Please check your facts. You are simply wrong on this one. Genentech/Roche are not the problem here. The FDA (yes, Dr. Pazdur again) is the problem.

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18. ex-Pfizerite on October 18, 2011 2:03 PM writes...

Steven, most commentators on this board are people who work in the pharma industry and although we may seem cynical it is because we have seen to many positive phase II clinical trials that were not replicable in a powered phase III clinical trial. After a while in the industry you only believe a fully powered clinical trial and then you believe that trial only after it has been confirmed with another fully powered clinical trial. I believe that anecdotal reports are only indicative of something to study more closely via cell based assay or an animal model before even beginning to think about a clinical trial.

I also think that most of the people who read and comment on this board, while they may have had projects that they feel were delayed by the FDA or felt that the FDA had moved the goal posts, would also agree that the FDA does a very difficult job in an exemplary manner and making personal attacks on a FDA official is uncalled for.

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19. Steven Walker on October 19, 2011 8:09 AM writes...

To ex-Pfizerite: I am well aware that exposing the warts of our drug development system from the real patient perspective is uncomfortable for people who work in it. Sorry to crash your club, but you can expect patients and their advocates to be doing a lot more of that. From where we sit, the system is a disaster. In my response above, I was adding factual information to the discussion because the person who posted didn't spend the extra ten minutes it would have taken to understand what T-DM1 really is, and to also understand that what Roche is doing is not based on greed, but rather on exactly what we want the drug compaies to be doing - trying to bring better, less toxic treatments for serious diseases to market. In the case of T-DM1, a great many people, including many in the industry and some former high-ranking FDAers were very troubled (some were outraged) by FDA's decision not to fast track the drug and grant it Accelerated Approval based on early trial data. I am perhaps the nation's most focused and heeded expert on Pazdur's policy missteps over the last ten years, and his delaying action for T-DM1 was part of his aggressive policy enforcement efforts. This is not about a personal attack on Pazdur, it is about educating the public regarding a powerful official's misguided policies and the enormous negative effects those policies have had on patients (my first and primary concern) and progress against cancer (a very close second). Pazdur aggressively sought the role of oncology czar, and he has executed that role as an effectively unsupervised regulator within CDER, but in reality separate from the management structure of CDER. Because of these facts, confirmed to me by senior officials in the agency, Pazdur and his senior staff are in fact the cause of the policy problems, policies which he has clearly explained as being "his policies." They are not the policies of some amorphous "FDA." So how would you have us, the patient community, explain what we think the problem is? Use the term "unnamed FDA official/" For us, this is real life and death stuff happening in real time, to us. So how would you have us explain it? The problem is in fact Dr. Pazdur and his senior staff. Sorry if that huirts his feelings, but a dying cancer patient doesn't have time for beating around the bush.

Again, sorry to crash your party, but when people post things that are simply wrong, or take strong positions in the public debate that run counter to the best interests of real patients who will be directly, adversely effected in real time - expect us to speak up.

We think we are very important stakeholders in this process, and with all due respect, we are tired of being told by the traditional insiders that we should just shut up.

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20. Anonymous on October 19, 2011 6:26 PM writes...

@19. T-DM1 is in phase II. You know the odds of approval, I hope. Let's see the outcome of more powered trials and Phase III before we make a decision on this one. Don't criticize ex-Pfizerite...I believe this individual is very well tuned to what is going on in the Pharma industry.

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21. asdf on October 20, 2011 1:32 AM writes...

> "Making personal attacks on an FDA official is uncalled for"

Lest we forget, Richard Pazdur was never elected and effectively cannot be fired. Most people do not know his name. Most people on this blog, including yourself, have a sort of Stockholm Syndrome in which pharma's motives are suspect but the FDA's are pure.

News flash: the FDA has never requested a decreased budget. They have never requested restrictions on their statutory authority. Their officials, for the most part, have effectively lifetime tenure. They are immune from litigation should they make a mistake. Their only real mission is to avoid bad headlines for approving drugs/devices with side effects; they face no media penalty for all the cures they block.

And they hold the power of life and death over us.

Somehow it's considered cute to slam this executive or that scientist ("pfired") but the FDA bureaucrats who are the authors of so much misery get a free pass? The scope of their malfeasance extends way beyond Avastin and includes the ongoing drug shortages and the war on local farmers.

There is essentially no investigative reporting on FDA corruption. That will change soon.

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22. anonymous on October 23, 2011 9:37 PM writes...

I am a patient who has been living with aggressive metastatic breast cancer since 2005. I agree with most of your comments except I don't think the FDA should have issued preliminary approval for this drug. Genentech launched a huge marketing campaign based on a poster presentation made at ASCO that included spurious data. FDA scientists knew of the flaws in the data from the very beginning but the political and economic interests overpowered science. As patients with limited time and a life of toxicity we cannot afford false hope. Genentech has created truly life saving drugs like Herceptin but Avastin should have never achieved approval for MBC. If any oncologist truly believes this drug will help a patient they can prescribe it off-label and put their reputation behind that decision. I have witnessed a lot of my friends die of metastatic breast cancer. I know the drug development process is costly and that the issues are complex but selling us drugs that don't work and hurt us when our lives are already so hard cannot be part of the answer.

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