Today the Wall Street Journal ran an editorial urging the FDA to approve Avastin, a drug used to help treat colorectal cancer, for breast cancer. It’s an angry—and ultimately, wrong-headed—piece.
In December, an FDA advisory committee voted against allowing Avastin for breast cancer treatment; the FDA is expected to make a final decision this weekend that either affirms or rejects the committee’s recommendations. The Journal supports a rejection the committee (and approving the drug) because “in clinical trials, Avastin demonstrated the longest reported ‘progression-free survival’ for patients with advanced breast cancer.” In other words, patients “live longer before their disease spreads or worsens” when they take the drug. So, says the WSJ, the FDA has a moral obligation to approve Avastin, because it “translates into an improvement in quality of life by delaying the onset of symptoms.”
But in reality the situation isn’t nearly this simple—and for all its good intentions, the Wall Street Journal trips over its own logic.
Clinical trials show that Avastin plus paclitaxel (the scientific name for the brand drug Taxol) helped to keep cancer from growing for five months longer than in patients on paclitaxel alone—this much is true. But there’s more: as an American Cancer Society summary of the original December decision notes, “overall survival was not significantly better [for those who took Avastin] and women who received Avastin had more serious side effects compared to those who got paclitaxel alone.”
The Journal is quick to note that “not significantly better” refers to the fact that women on Avastin “lived slightly longer, a median of 26.5 months compared with 24.8 with Taxol alone.” That means that, even though cancer was slowed for five months, the average lifespan of an Avastin-taker was ultimately only lived two-months longer than it was for those who didn’t take the drug. The newspaper is angry that the FDA trivializes this time be deeming it a statistically insignificant extension. But there are other things to consider besides time—like side-effects.
The side-effects observed in the Avastin trial include “high blood
pressure, blood clots, heart problems, holes forming in the colon
(bowel perforation) and high levels of protein in the urine, which is a
sign of kidney damage.” The drug’s website lists other possible side-effects:
“severe bleeding,” congestive heart failure (which the website notes is
most likely for patients undergoing breast cancer treatment), reduced
white blood cell count (meaning a greater risk of infection), and
diarrhea. Not all of these are associated with breast cancer treatment,
but the basic point is clear: Avastin is not a risk-free drug. This
raises an obvious question: even if you had an extra two months to live, but
spent that time with a hole punched through your colon and a bum heart,
how would you feel?
Ironically, the Journal claims that concern over the quality of
patients’ life is exactly why the FDA should approve Avastin. The FDA’s
opinion that the drug’s two-month life extension doesn’t warrant
approval is said to be short-sighted; a clear indication that “approval
criteria should be broadened beyond crude mortality rates.”
But focusing only on progression-free survival, i.e. how long a patient
can go without a disease getting worse, is no better. As The Moss Report,
an online cancer newsletter, notes, progression-free survival means
that “a drug may change the shape of the patients’ survival curve, but
not alter the ultimate outcome. Treated patients may die on average at
the same time as those who were not treated; sometimes they may even
die sooner.”
In this case, we know that, any additional time comes with significant side-effects. In other words,
the FDA’s stance is not just a question of time, but of quality.
Indeed, progression-free survival has the potential to be more
devastating than standard deterioration. Imagine if, after two months
of cancer stabilization, your loved one died at the same time as
another patient who had been in worse shape for longer—that would be
quite a blow.
The Moss Report points out that “patients who believe their disease is
being controlled can feel an even greater sense of loss and
disappointment when the disease again progresses than do those without
any illusions about being cured of the disease.” Often abruptly dashed
hope is more painful than a longer process, because the latter gives us
time to prepare and come to grips with loss. If the Journal really
wanted to think holistically about survival and benefits, it would be
arguing against FDA approval of Avastin—not for it.
Yet the paper says that the FDA’s reluctance is symptomatic of an
obstructionist “bureaucratic culture” bulwarked by “political pressure
from Congress, where Members know they can always get headlines by
calling for a crackdown on Big Pharma or exploiting public safety
anxieties.” This isn’t fair. If we really want to make sure we maximize
the benefits of medical science, we need to think hard about the
incentives of drug companies—not just those of public officials.
The basic logic of the pharmaceutical industry is as follows: (1) a
manufacturer creates a drug and runs trials, showing that it confers
some benefit, either large or small. (2) The drug is approved by the
FDA for a given use, and eventually for a wider array of conditions so
that (3) use of the drug can proliferate across patient
populations—thus allowing market share to grow. This leads to (4)
increased profit, which leads to (5) nice, shiny Porsches.
These steps—or at least, one through four—make up the fundamental business
model of prescription drug companies. All the cost is concentrated in
steps one and two—research, development, and haggling with the FDA to
get to market. To maximize profit, drug companies want to cut these
costs as much as possible.
Now, if the FDA concedes that progression-free survival is enough to
warrant approval, it essentially sets the bar very low for these early
stages. The message is that manufacturers should go for the low-hanging
fruit and focus on maximizing the number of ways to apply existing
medications—rather than developing truly innovative new ones. The
standard of proof is lower—so why not try and push through existing
products, rather than incurring the costs of ground-up development?
No business in its right mind would say “no” to this opportunity.
Already, drug companies spend more on promotion than on R & D
because the effort is less and the financial reward is at least as
promising—if not more so—than that attached to development. If the FDA
were to “modernize” the way the Journal wants—in other words, watering
down its standards to approve any drug with any semblance of a
benefit—a similar cycle of profit-driven mediocrity would establish
itself.
In the end, the Wall Street Journal expresses good intentions. It
argues that we should take a more complex view of survival, success,
and quality, and that institutional steps should be taken to promote
truly beneficial drugs. But if the editors really wanted all of this to
happen, they’d be arguing that the FDA should stick to its guns on
Avastin.
The problem with averages is that they are averages. What would be more instructive would be to know the proportion of people who are outside the usual range of outcomes, in other words, the shape of the distribution curve.
For example, if there were an equal amount of people who had no benefit and those who had four months longer life then the average would be two. In that case the drug would actually be more beneficial than the averages indicate. Those who got no benefit just “wasted” some health care money, while the others did better.
Similarly for side effects. Is there any correlation between side effects and efficacy? Do those who benefit the most have fewer or more side effects?
The number of people having side effects and their severity can’t be determined from averages either.
Once again the problem is that current screening techniques don’t reveal which people will be most helped and with the fewest side effects. This is a problem with many of the drugs being used these days. We now have probabilistic medicine, a far cry from the introduction of antibiotics, when nearly everyone had a dramatic improvement.
I don’t have a solution, but the drug companies should at least release more detailed information and let others make judgments for themselves.
Two problems here:
1) Progression-free survival is not the same as “symptom-free” survival. Progression is assessed through regular scans and x-rays and is unrelated to symptoms – in most cases progression is detected before it becomes symptomatic.
2) The two month difference in survival is not “significant” not because two months of life isn’t valuable but because there is a good chance that the difference may be due to statistical noise rather than the drug. In the same way, if patients on Avastin lived two months less than placebo patients, it wouldn’t necessarily mean the drug shortened their lives.
As the previous commenter noted, even if the drug really does prolong survival, it is incorrect to think in terms of the drug giving two extra months to everyone in the trial – it’s an average. Because the trial has to come to an end in a reasonable period of time, you can’t say the patients who did not have a recurrence were “cured”, although many of them may have been. It’s closer to the truth to say that some (perhaps, small) proportion of the patients who were treated were either cured or had a lengthy prolongation of survival while many others received no benefit and some (probably a smaller number) had their lives shortened.
The extra two-month life extension is for the group in the study, not the “individual” patients treated in the real world. One person may live two months, another two-hundred days, and even some only two additional days. What may work in some patients, may not work in other patients.
The caveat about Avastin in colon cancer deals with gastrointestinal perforations. If Avastin is given within at least 28 days following major surgery (or before), it results in an abscess formation. This is due to the impaired wound healing induced by Avastin.
By Avastin working like it’s supposed to work, not only does it cut off blood supply to the tumor, it also cuts off blood supply to the colon entirely causing the tissue to die. Avastin can cause you to loose your colon.
Most bowel perforations with Avastin have been in cases where there is tumor going right through the wall of the colon. Avastin causes the tumor to melt away, leaving a hole. With Avastin, the tumor dissolves, but scar tissue won’t form because it can’t make a blood supply.
What is distubring, are oncologists’ comments that this is common with Avastin, but is never mentioned until it is too late.
The same thing applies to bowl perforations with Avastin in advanced ovarian cancer. Advanced ovarian cancer commonly involves bowel walls. The problem is a direct result of the drug’s ability to kill tumor cells that have replaced healthy bowel tissue, leading to a dead area that then perforates.
With conventional chemotherapy, as the tumor melts away, new connective tissue forms a patch. But Avastin can inhibit the growth of capillaries into newly forming tissue, as well as in tumor tissue. If one does not have any known bowel involvement, one would probably be okay.
Avastin has shown activity in many solid tumor types such as breast, lung and ovarian cancer. However, as with most “targeted” therapy drugs, Avastin does not necessarily benefit every patient. Until now, there were not tests that existed to show reliably who would benefit from anti-angiogenic agents.
There is a “functional” bio-marker developed for microvascular viability to identify potential responders to Avastin (as well as Nexavar and Sutent), and other anti-angiogenic drugs. It was discovered that endothelial cells are present in tumor microclusters and it appears that drug effect upon these cells can be assessed in this assay.
Many of these new “targeted” therapies often get a pass on toxicities because they are just so darn cool (Herceptin and CHF in the adjuvant setting is another example). The problem is that few drugs work the way oncologists think and few of them take the time to think through what it is they are using them for.
Let’s not forget that the pharmaceutical industry is under no legal obligation to publish all of it’s studies, sometimes more importantly is not what the available data says, but the unavailable data. Literally they could have had five trials before this that showed no benefit or actual harm!!
Colon perforations and most of the other side effects occur only in a small number of patients, and the point that some patients experienced less than average PFS is obviously off set by the fact that an equal number experience a longer PFS – someties much longer. that is the nature of aversges and it applies to the results for every single approved cancer drug. These are limitations of all cancer drugs, and lamost all of them cause serious and even potentially fatal side effects. FDA has approved a number of cancer drgs based on PFS alone for breast cancer and other diseases, and the benefit of getting medical advances to pateints quickly has been overwhelmingly positive. Avastin is a drug that has been given to many thousands of patients with colon and lung cancer, and many thousands more off label with breast andoter cancers. The WSJ got it right, and a lot of oncologists and others knowledgeable about the drug and the approval process agree that Avastin should be approved.
Steve, overwhelmingly positive? you mean like Vioxx? antidepressants in teenagers? the antiarythmics in early MI? it would be interesting to see if we have killed and maimed more than we have helped but I think “overwhelmingly positive” is a rather big stretch.
As a physcian cancer survivor with a wife with breast cancer I certainly understand the emotional side of this debate. I feel that it should be up to the patient and the oncologist to decide to use a particular agent and to consider the side effects. The FDA should approve new medications that may improve a patients clinical course. My wife recieved Avastin along with taxol. She did suffer a major side effect (a perforation of the nasal septum). However I think that both of us were willing to take that chance for possible clinical improvement. When one is dealing with stage 4 cancer one must balance possible side effects with possible gain. However one can only do this is there are drugs to try.
The FDA today, rejected the recommendation of its advisory panel, which last December voted 5-4 against the drug, because the benefit in slowing tumor growth wasn’t believed to be worth the added risk of serious side effects, including high blood pressure and death. This mirrors the statin debacle. Drug companies didn’t have to prove that lowering cholesterol did anything positive for patients, just that it lowered cholesterol.
The Breast Cancer Action executive director says the FDA has lowered the bar on the approval of breast cancer therapies. Well, the validation standard private insurance companies are accepting from molecular profiling tests is accuracy and not efficacy. That bar has been instantly lowered. No longer will it be essential to prove that the use of a test improves clinical outcomes, all they have to do for these molecular profiling tests is prove that the test has a useful degree of accuracy.
So we’re back to square one again. Instead of showing a drug can increase survival, all they have to do is show that it can shrink a tumor. Didn’t we just come from that neanderthal moment?
From above:
“I feel that it should be up to the patient and the oncologist to decide to use a particular agent and to consider the side effects.”
This is a common theme, but is a misunderstanding of how regulations are supposed to work. No one can be an expert on everything. People may not have the expertise to make good judgments, or may not have access to sufficient data.
Societies have learned (the hard way) that the best way to protect the largest amount of people from harm is to delegate the evaluation of risks and benefits to experts. That’s why we have food inspectors rather than each shopper testing every steak they buy for bacterial contamination. It’s why the FDA and similar regulatory agencies were established. Each was the result of some horrific disaster in earlier times.
What’s happened in recent years is that the regulatory agencies have stopped doing their jobs as they have become captives of the industries they are supposed to regulate.
The way to fix this is not to suggest that each person become their own health expert, but to work to restore the roles of the agencies.
How does a doctor evaluate the value of a treatment? All he has to go on are the same studies that the FDA uses. So one person should make a determination instead of a panel? That’s not a good basis for making decisions.
Robert,Marc, Gregory, Dr. Matt, Steve, Kenneth–
Thank you for your comments.
This is a very interesting thread.
Robert: You wrote: “The problem with averages is that they are averages. What would be more instructive would be to know the proportion of people who are outside the usual range of outcomes, in other words, the shape of the distribution curve.”
I agree entirely. When I was in Texas I met a very interesting doctor who has written a paper on “the tyranny of the randomized controlled trial” pointing out that it doesn’t take into account just how unique our bodies are. (He hasn’t been able to get the paper published)
While these trials can be very good at showing what is likely to be effective (or not effective) for most people, they don’t address the outliers–the small group who might benefit greatly.
That said, I’m not sure that I see an extra 4 months as a great benefit. (Much would depend on quality of life)
But I definitely agree that we need more detailed information. And I’d rather that someone other than the drug companies was overseeing the trials and releaseing the information.
Robert, you also wrote: “What’s happened in recent years is that the regulatory agencies have stopped doing their jobs as they have become captives of the industries they are supposed to regulate.
“The way to fix this is not to suggest that each person become their own health expert, but to work to restore the roles of the agencies.”
I couldn’t agree more.
Marc–
You wrote:
“The two month difference in survival is not ‘significant’ not because two months of life isn’t valuable but because there is a good chance that the difference may be due to statistical noise rather than the drug. In the same way, if patients on Avastin lived two months less than placebo patients, it wouldn’t necessarily mean the drug shortened their lives.”
Exactly–that’s one reason why I’m not enthusiastic about having Medicare spend large amounts for drugs that supposedly give the average patient an extra few months. AS you say, this conclusion may be based on statistical noise–noise that drug companies use to get their products through the FDA.
I would be much more interested in knowing that the drug consistently gave a small group of people 2 or 3 years of high quality life–and then spending money on research to figure out who those people are, what they have in common, how they can be identified.
Gregory–You wrote “Many of these new “targeted” therapies often get a pass on toxicities because they are just so darn cool . .”
Yes–and thank you for pointing out the serious risks of this drug.
Dr. Matt- You wrote:
“Let’s not forget that the pharmaceutical industry is under no legal obligation to publish all of it’s studies, sometimes more importantly is not what the available data says, but the unavailable data. Literally they could have had five trials before this that showed no benefit or actual harm!!”
This is a very important point. You and Robert are both saying that we need ALL of the information that drug companies have about their trials. And I think that the only way that will happen is if someone else is overseeing the trials (even if they are done by the drug companies.)
Steve and Dr. Matt –as others on this thread have suggested, the drug may well have great benefits for some patients.
But I agree with Dr. Matt– from what we’ve seen of the research, “overwhelmingly positive” is quite a stretch.
Kenneth- I can only imagine what you and your wife went through. . Both of you having cancer–and the fact that you are a doctor which must have increased the pressure on you to find a solution in both cases.
I agree that new drugs need to be available, but I don’t think the FDA should be putting them on the market for everyone.
Instead, I think these drugs shoudl be available for people willing to sign up for randomized controlled trials–and for people able to pay out-of-pocket for these drugs.
Let me be clear: I’m completely opposed to two tiers of medcine (one for the rich, another for the rest of us) but insofar as there are many
very wealthy people in this country who can afford to pay out of pocket, they can contribute to research by
adding their records to the database as we try to figure out which drugs work.
Robert,Marc, Gregory, Dr. Matt, Steve, Kenneth–
Thank you for your comments.
This is a very interesting thread.
Robert: You wrote: “The problem with averages is that they are averages. What would be more instructive would be to know the proportion of people who are outside the usual range of outcomes, in other words, the shape of the distribution curve.”
I agree entirely. When I was in Texas I met a very interesting doctor who has written a paper on “the tyranny of the randomized controlled trial” pointing out that it doesn’t take into account just how unique our bodies are. (He hasn’t been able to get the paper published)
While these trials can be very good at showing what is likely to be effective (or not effective) for most people, they don’t address the outliers–the small group who might benefit greatly.
That said, I’m not sure that I see an extra 4 months as a great benefit. (Much would depend on quality of life)
But I definitely agree that we need more detailed information. And I’d rather that someone other than the drug companies was overseeing the trials and releaseing the information.
Robert, you also wrote: “What’s happened in recent years is that the regulatory agencies have stopped doing their jobs as they have become captives of the industries they are supposed to regulate.
“The way to fix this is not to suggest that each person become their own health expert, but to work to restore the roles of the agencies.”
I couldn’t agree more.
Marc–
You wrote:
“The two month difference in survival is not ‘significant’ not because two months of life isn’t valuable but because there is a good chance that the difference may be due to statistical noise rather than the drug. In the same way, if patients on Avastin lived two months less than placebo patients, it wouldn’t necessarily mean the drug shortened their lives.”
Exactly–that’s one reason why I’m not enthusiastic about having Medicare spend large amounts for drugs that supposedly give the average patient an extra few months. AS you say, this conclusion may be based on statistical noise–noise that drug companies use to get their products through the FDA.
I would be much more interested in knowing that the drug consistently gave a small group of people 2 or 3 years of high quality life–and then spending money on research to figure out who those people are, what they have in common, how they can be identified.
Gregory–You wrote “Many of these new “targeted” therapies often get a pass on toxicities because they are just so darn cool . .”
Yes–and thank you for pointing out the serious risks of this drug.
Dr. Matt- You wrote:
“Let’s not forget that the pharmaceutical industry is under no legal obligation to publish all of it’s studies, sometimes more importantly is not what the available data says, but the unavailable data. Literally they could have had five trials before this that showed no benefit or actual harm!!”
This is a very important point. You and Robert are both saying that we need ALL of the information that drug companies have about their trials. And I think that the only way that will happen is if someone else is overseeing the trials (even if they are done by the drug companies.)
Steve and Dr. Matt –as others on this thread have suggested, the drug may well have great benefits for some patients.
But I agree with Dr. Matt– from what we’ve seen of the research, “overwhelmingly positive” is quite a stretch.
Kenneth- I can only imagine what you and your wife went through. . Both of you having cancer–and the fact that you are a doctor which must have increased the pressure on you to find a solution in both cases.
I agree that new drugs need to be available, but I don’t think the FDA should be putting them on the market for everyone.
Instead, I think these drugs shoudl be available for people willing to sign up for randomized controlled trials–and for people able to pay out-of-pocket for these drugs.
Let me be clear: I’m completely opposed to two tiers of medcine (one for the rich, another for the rest of us) but insofar as there are many
very wealthy people in this country who can afford to pay out of pocket, they can contribute to research by
adding their records to the database as we try to figure out which drugs work.
I think there is a lot of politics that goes on with these diseases.
Breast cancer treatments are kind of a third rail, they garner a lot of public opinion and there are many vocal groups who would support the approval of this drug on the hope that someone (who is not just a statistical average) would benefit greatly.
It’s my personal feeling that I’d rather see the resources be spent on finding a CURE.
No matter how reliable a drug appears to be, there’s simply little hard evidence it would make a long-term difference in a person’s prolonged survival. Drugs are tested to show they are safe and effective before being approved by the FDA. But a clinical study is not the real world, and just because a drug leads to a statistically significant improvement doesn’t guarantee that the desired effect will follow.
There are molecular and cellular tests available to weed out those cancer patients that chemotherapy wouldn’t have any benefit, what chemotherapy works the best for those that chemotherapy would benefit, and further monitor treatment success or disease progression.
Cancer and the Presidential Candidates
An article that is causing a buzz after it was picked up by Google – “Cancer and the Presidential Candidates: Clinton, Obama, and McCain compared.”
http://www.cancermonthly.com/iNP/view.asp?ID=208
Ginger–
You wrote: ” Ithink there is a lot of politics that goes on with these diseases.
“Breast cancer treatments are kind of a third rail, they garner a lot of public opinion and there are many vocal groups who would support the approval of this drug on the hope that someone (who is not just a statistical average) would benefit greatly. ”
I agree. Breast cancer has been politicized and has become such an emotionally
charged issue while other
diseases (including management of chronic diseases) are neglected.
The article Greg linked to in his comment above raises this question:
“The NCI has spent over forty billion dollars in [cancer] research in just the last ten years alone. Drugs companies also spend tens of billions of dollars on cancer research. Yet with all this money, there have been no significant breakthroughs in the treatment of advanced or metastatic solid cancers since the “war on cancer” was launched on January 22, 1971, during President Nixon’s State of the Union Address. The median survival rates for solid advanced or metastatic cancers are measured in weeks or months and are largely unchanged. Thirty seven years later, people continue to run for the cure, march, bike, and shave their heads to raise more money. How much money is needed? We have already spent well over one hundred billion dollars since the “war” was launched. Should we spend another hundred billion? Or do we need to spend a trillion? What is the price tag to cure cancer?”
The article goes on to point out that “The FDA does not allow all potential cancer treatments to reach the market, only those that they approve after a drug company invests an estimated $500 million to take the treatment through clinical trials. Drug companies, however, will only invest this much money in treatments they can patent. A patent allows the pharmaceutical company to control the product, set the price, and make a profit. The problem, of course, is that patentable cancer drugs are by definition synthetic; they are made in a lab. This shuts out virtually every naturally occurring compound that already exists in nature and explains why no mushroom, vitamin, herb, or other naturally occurring whole entity has ever been FDA approved for the treatment cancer. This also explains why “terminal” cancer patients have so few viable options with conventional medicine.”
Finally, the authors argue that “the FDA admits that many conventional drugs ‘routinely used’ to treat cancer patients can have serious or life-threatening effects. In fact, many chemotherapy drugs are listed as known or suspected human carcinogens with the National Toxicology Program, whose participating agencies include the FDA, NIH, and the Centers for Disease Control (CDC).
“The FDA’s position, therefore, is that a cancer patient may be poisoned with a known carcinogen (i.e. chemotherapy), but it would be too dangerous for the patient to take a natural agent that is only theoretically carcinogenic.”
I don’t know anything about the potential efficacy of natural agents in treating cancer–
Greg–can you or anyone comment?
Julia Schopick, a patient advocate and web-based public relations consultant, has some good information about natural medicine at her web site http://www.HonestMedicine.com. She did an extensive interview with Dr. Ronald Hoffman, one of the foremost integrative medicine physicians.
http://www.honestmedicine.com/2007/08/dr-ronald-hoffm.html
Ann Fonfa, of the AnnieAppleseed Project, provides information, education, advocacy and awareness for people with cancer who are interested in complementary or alternative medicine (CAM) and natural therapies from a patient’s perspective.
http://www.annieappleseedproject.org/
Sandra Gooman, Ph.D., author of four books, including “Nutrition And Cancer: State Of The Art,” and editor of Positive Health, http://www.positivehealth.com a professional magazine devoted to complementary medicine, has researched the efficacy of natural therapy treatments.
http://www.drsgoodman.com/nutrition_cancer.php
Cancer Monthly is a centralized source of the survival rates and side effects of hundreds of the latest cancer treatments, as well as reports on alternative and integrative approaches to treatment.
http://www.cancermonthly.com
Cancer and the Presidential Candidates
(url update)
http://www.cancermonthly.com/iNP/view_printer.asp?ID=208
The True Costs And Benefits Of Avastin
What may limit the effectiveness of Avastin is that there are multiple ways by which tumors can evolve that are independent of VEGF and independent of angiogenesis. Tumors can acquire a blood supply by three different mechanisms: angiogenesis; co-option of existing blood vessels; and vasculogenic mimicry. All must be inhibited to consistently starve tumors of oxygen.
Instead of growing new blood vessels, tumor cells can just grow along existing blood vessels. This process, called co-option, cannot be stopped with drugs that inhibit new blood vessel formation. Some types of cancers form channels that carry blood, but are not actual blood vessels. Drugs that target new blood vessel formation also cannot stop this process, called vasculogeneic mimicry. The realization is that starving tumors by shutting off their blood flow requires that all three mechanisms be addressed.
It could be vastly more important to measure the net effect of all processes (systems) instead of just individual molecular targets (like VEGF). The cell is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. You need to analyze the systems’ response to drug treatments, not just one or a few targets or pathways.
There are many pathways to the altered cellular (forest) function, hence all the different “trees” which correlate in different situations. Improvement can be made by measuring what happens at the end (the effects on the forest), rather than the status of the indiviudal trees.
VEGF-targeted drugs are poorly-predicted by measuring the preferred target VEGFR. They can be well-predicted by measuring the effect of the drug on the function of live cells.
Many of these fine drugs (and Avastin is a miracle drug for the few) cry out for validated clinical biomarkers as pharmacodynamic endpoints and with the ability to measure multiple parameters in cellular screens to help set dosage and select people likely to respond. Many molecular diagnostics approved often have been mostly or totally ineffective at identifying clinical responders to various therapies.
If you find one or more implicated proteins in a patient’s tumor cells, how do you know if they are functional (is the encoded protein actually produced)? If the protein is produced, is it functional? If the protein is functional, how is it interacting with other functional proteins in the cell?
All cells exist in a state of dynamic tension in which several internal and external forces work with and against each other. Just detecting an amplified or deleted gene won’t tell you anything about protein interactions. Are you sure that you’ve identified every single protein that might influence sensitivity or resistance to a certain class of drug?
Assuming you resolve all of the preceeding issues, you’ll never be able to distinguish between susceptibility of the cell to different drugs in the same class. Nor can you tell anything about susceptibility to drug combinations. And what about external facts such as drug uptake into the cell? You’re not going to accomplish this using genetic tests.
Improving cancer patient diagnosis and treatment through a combination of cellular and gene-based testing will offer predictive insight into the nature of an individual’s particular cancer and enable oncologists to prescribe treatment more in keeping with the heterogeneity of the disease. The biologies are very different and the response to given drugs is very different.
The major obstacle in controlling cancer drug prices is the widespread inappropriate use of anti-cancer drugs. As the increasing numbers and types of anti-cancer drugs are developed, oncologists become more and more likely to misuse them in their practice. There is seldom a “standard” therapy which has been proven to be superior to any other therapy. What may work for one, may not work for another.
Literature Citation:
Eur J Clin Invest 37 (suppl. 1):60, 2007
Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 17117
“Cure: Scientific, Social, and Organizational Requirements for the Specific Cure of Cancer” A. Glazier, et al. 2005
The decision to take a drug with serious side effects should lie with the (fully informed)patient.
If they wish to attempt to live an additional few months and they are willing to accept the risk it should be their decision.
The FDA is a waste of the taxpayers money and an affront to personal freedom.
Karen–
You write “The decision to take a drug with serious side effects should lie with the (fully informed)patient.
“If they wish to attempt to live an additional few months and they are willing to accept the risk it should be their decision.”
The question is who should pay for a very expensive drug that might give the patient an additional few months?
If we all pay (through Medicare or private insurance) then that means that either: health care premiums and Medicare costs are that much higher OR Medicare or insurers must deny another patient some other expensive treatment.
The other option is to say that the patient can have the drug, but must pay for it herself.
This means that only the wealthy (who have the extra $60,000 to buy the drug) are eligible to live an extra few months.
Are you comfortable with the idea that the extra few months would be available to the wealthy, but not to the rest of us?
Also, if the patient has to pay for the very expensive drug that provides only a minimal benefit, there will be too few customers for the drug, and probably the drug company would stop
manufacturing it.
The only way that drugs like this stay on the market is if taxpayers (who pay more than half of all health care bills) continue to pay extremely high prices for drugs that provide a very small benefit.
None of this has to do with the FDA by the way.
The FDA doesn’t consider the cost of drugs when approving the to go on the market.
Bevacizumab inhibits the growth of blood vessels, which is part of the body’s normal healing and maintenance. The body grows new blood vessels in wound healing, and as collateral circulation around blocked or atherosclerotic blood vessels.
I don’t have a solution, but the drug companies should at least release more detailed information and let others make judgments for themselves.