Respectful Insolence

Last week, The New York Times started a rather unusual series in its medical section entitled, The Evidence Gap, described thusly:

Articles in this series will explore medical treatments used despite scant proof they work and will consider steps toward medicine based on evidence.

When I first saw the series, I was prepared for a crapfest. My experience has generally been that when reporters start examining the evidence for and against a treatment they usually do a pretty lousy job. This is most obvious when it comes to “complementary and alternative medicine” (CAM), where we are routinely treated to utterly credulous articles touting the latest poorly designed study demonstrating that this or that fairy dust cures cancer and the common cold (I exaggerate, but not by much) or “exposes” on the latest misdeeds by big pharma, in which risks are either exaggerated or not put into perspective. Oddly enough (or not so oddly enough) seldom does the misinformation go in the other direction, with excessive credulity towards pharma-produced evidence and excessive skepticism for evidence relating to the efficacy and safety of CAM modalities, but that’s a topic for another day. I don’t so much mind the tighter skepticism regarding the claims of big pharma, given its history; I only wish that similar skepticism applied to the claims of big CAM. In any case, the point is that generally medical reporting tends to be very poor at doing a fair, objective analysis of the state of the actual evidence regarding a treatment modality, so much so that I sit up and take notice when I find an exception.

Depending on how the the rest of the articles in the series play out, this New York Times series may very well be one of those exceptions. As a maven of science- and evidence-based medicine, I approve–thus far, anyway. The first two entries are on cardiovascular testing and cancer chemotherapy. I’ll spend the most time on the latter, but I can’t resist a brief treatment of the former before I get to the latter.

The first installment in the series was Weighing the Costs of a CT Scan’s Look Inside the Heart, which provided a mostly balanced look at the latest bandwagon fad among cardiologists, CT angiography. Unfortunately, the article gave Dr. Harvey Hecht of the Lenox Hill Heart and Vascular Institute of New York license to say some spectacularly stupid things, like:

“It’s incumbent on the community to dispense with the need for evidence-based medicine,” he said. “Thousands of people are dying unnecessarily.”

Bullshit. More like there are hundreds of ideologue doctors with a financial incentive that distorts their objectivity convinced that their shiny, expensive new machines are the latest and greatest–doctors like Dr. Hecht, who has, as far as I can tell, not produced one whit of evidence that using his device to guide therapy saves even a single life.

Fortunately, the NYT actually did a pretty good job of pointing out the price and lack of evidence supporting the widespread use of these scans for screening. When used indiscriminately, they also could risk leading to more unnecessary angioplasties and coronary artery stenting in much the same way that ever more sensitive tests for cancer can lead to overtreatment. Unfortunately, Dr. Hecht appears no better than woo-bosters Dr. David Katz, who wants a “more fluid concept of evidence” supporting CAM or Dr. Andrew Weil, who wants to emphasize “uncontrolled clinical observations” (i.e., anecdotes) in evaluating evidence. The only thing different is what kind of modality he’s trying to change the rules to support.

Cardiologist blogger Dr. Wes, as well as medical bloggers Matthew Holt, Dr. Ray Poses, and Dr. Guy Clifton have already ripped Dr. Hecht a much-deserved new one for his idiocy. I also happen to know that Dr. Harriet Hall over at Science-based Medicine is planning an installment for tomorrow. The issue is well-covered, even by medical students, and I’ve also touched on many of the same issues before the last time this sort of technology was overhyped. From my perspective, the only shortcoming of the NYT article is that it didn’t adequately discuss the question of what the best science-based recommendations are for when a CT-angiogram is appropriate.

More interesting and relevant to me is the second article in the series, Costly Cancer Drug Offers Hope, but Also a Dilemma. It’s right up my alley in that (1) it’s about cancer and (2) it’s about my area of research interest, angiogenesis inhibitors. Specifically, it’s about one angiogenesis inhibitor in particular, namely Avastin.

Avastin is the trade name for bevicuzimab, which is a humanized monoclonal antibody against a protein called vascular endothelial growth factor (VEGF). A “humanized” antibody is an antibody raised in mouse cells the nonspecific or invariable part of which (in other words, the part that doesn’t recognize and bind to the target antigen) have been replaced with its human counterpart in order to reduce the likelihood of an immune reaction against a foreign protein. VEGF is a protein that is secreted by both normal cells and cancer cells in order to stimulate the ingrowth of new blood vessels, a process known as angiogenesis. In the case of normal cells, VEGF is only secreted in response to injury or a physiologic need for more nutrients and oxygen. Tumors, on the other hand, hijack this normal physiological function to their own nefarious ends, often by cranking out huge quantities of VEGF or other angiogenesis-stimulating proteins to feed their ravenous glucose and oxygen requirements. Targeting tumor angiogenesis as a means of “starving” tumors has been an area of my research interest for over ten years now, and it is the area of research pioneered by one of my scientific and surgical heroes, the late Dr. Judah Folkman, who demonstrated the feasibility and effectiveness of antiangiogenesis as a therapeutic strategy against cancer.

Antiangiogenic therapy is attractive because, in theory at least, it could target almost any solid tumor. In addition, in the mouse and, as we now know, in humans it is a therapy that generally produces low toxicity, at least compared to chemotherapy. Hypertension, edema, poor wound healing, and, paradoxically, bleeding appear to be the most common side effects. Another less common but very serious side effect is gastrointestinal perforation, thought to be due to compromise of the blood supply to an area in the GI tract. Still, all in all, the drug has a favorable side effect profile compared to many cytotoxic chemotherapy regimens, and it’s been shown to be effective in prolonging life for certain metastatic tumors, particularly when combined with chemotherapy, a phenomenon I’ve described before.

The problem, as the NYT article points out, however, is that Avastin is very, very expensive. It can cost as much as $100,000 a year, depending on the specific tumor, which influences the dose regimen necessary. It’s here, as the article describes, where a question that we as Americans find far more uncomfortable than perhaps many other nations with nationalized health care systems do, rears its ugly head: How much are an additional few months of life worth?

Antiangiogenic therapy was all the rage 10 years ago in the research realm. Dr. Folkman’s dramatic results in mice using angiostatin and endostatin fueled hype in the mainstream media that a “cure” for cancer was at hand or that, at least, Dr. Folkman’s dream of turning cancer into a chronic, manageable disease like diabetes was finally being realized. Avastin was the first of the new generation of antiangiogenic drugs to make it into widespread clinical testing, thanks to the efforts and R&D money of Genentech. Unfortunately, its results when used alone against various cancers were disappointing to nonexistent. Fortunately, against metastatic colorectal cancer, combining Avastin with standard chemotherapy prolonged median survival from 15.6 months to 20.3 months. While chemophobes (as I like to call those who can’t ever admit that chemotherapy does any good) would scoff, I’d point out that that represents a 30% increase in survival, generally with good quality of life.

However, as the article points out, newer chemotherapy regimens seem to be more effective on their own and less synergistic when combined with Avastin:

In February 2004, 15 years after Dr. Ferrara’s initial discovery, the Food and Drug Administration approved Avastin for patients with advanced colon cancer. A blockbuster was born.

But now there is a question mark over that evidence. That first exciting result compared Avastin with a type of chemotherapy that has since been widely replaced by a more effective regimen.

In a later, larger study comparing Avastin with current chemotherapy, Avastin slowed the growth of tumors but did not extend life by an amount considered statistically significant.

Although GI cancers are not my specialty, I do know enough to say that the therapy of metastatic colorectal cancer and the evidence supporting it is in a state of flux, and this may indeed be the “true” case rather than a fluke in a study. Still, the evidence for the efficacy of Avastin is probably the strongest for colorectal cancer, both in terms of magnitude of the benefit in terms of the increase in life expectancy and quality of evidence. On less compelling evidence, Avastin was also approved for lung cancer, as well.

Perhaps the approval for Avastin that caused the most controversy was one that occurred earlier this year. I really should have written about it at the time, but for some reason I never did. Here’s what how the article describes the approval:

The third approval for Avastin, for advanced breast cancer, came in February of this year. The clinical trial found it significantly slowed the progression of cancer but did not significantly extend life. The F.D.A. went against its own panel of outside experts, who had voted 5 to 4 against approval.

The agency’s action has not sat well. Senator Charles E. Grassley, Republican of Iowa, asked the Government Accountability Office to look into the F.D.A.’s approval of Avastin and some other drugs that “appear to have little to no effect in protecting lives and increasing health.”

Dr. Lee Newcomer, an oncologist and executive at the insurer United HealthCare, said patients were not well served, and neither were insurers, nor the public, which ultimately foots the bill. If a drug just stops tumor progression, without the woman’s living longer or feeling better, without her noticing anything different, Dr. Newcomer said, “you’re treating an X-ray.”

I must admit that I was even skeptical of this approval. Basically, what is being discussed here is whether a drug affects overall survival (OS), which is mortality from all causes in a cancer patient, versus whether it affects progression-free survival (PFS), which is the period of time before a given tumor progresses. Surprisingly, at least to non-oncologists and lay people, OS and PFS are often unrelated. If, for example, a drug slows tumor growth sufficiently to demonstrate a significant affect on PFS, it doesn’t necessarily mean that OS will be better too. Sometimes it will, sometimes it won’t. Moreover, it’s long been a debate over whether PFS is a valid endpoint for approving a drug. Traditionally, the thinking has been that if a drug does not improve OS, then it probably shouldn’t be approved as a first line agent given up front to new cancer patients who have not been treated yet, although it can be approved as a second-line or third-line agent, to be tried after first line agents fail.

However, thinking has been evolving over the last few years towards accepting a somewhat looser standard of valuing PFS. Dr. Kathy Albain of Loyola University Medical Center and the Cardinal Bernardin Cancer Center, a passionate defender of using using PFS as an endpoint, makes the argument this way:

“Assuming that there is a real treatment benefit for whatever agent you are testing, I believe that PFS should be accepted as a proper surrogate,” Albain maintained. She pointed out that in metastatic breast cancer in particular, it may never be possible to prove surrogacy for overall survival, given the thousands of patients that would be needed.

Says Dr. David Miles, lead investigator on the AVADO study on Avastin and breast cancer:

“As a practicing physician,” AVADO lead investigator David Miles said he views PFS as a reflection of the period of time where the disease is controlled and the patient remains relatively well. There is an expectation that the patient is “doing better than if their disease is not controlled,” he told the press briefing.

“We have studies where PFS does reflect overall survival and studies where it doesn’t,” Miles observed. “I think when you have a patient whose disease is well-controlled, there is benefit to that, there is utility to that. Particularly when studies are not powered for overall survival.” None of the Avastin breast cancer studies have been designed for a full survival analysis.

Indeed, Dr. Albain polled oncologists about whether they accept PFS as a valid endpoint, and this is what she found:

Albain took it upon herself to conduct a survey, sending out a questionnaire to a sample of 47 experts. She was overwhelmed by the volume and vehemence of the replies. The clear consensus was that PFS should be considered a meaningful approval endpoint. Getting to “the crux of the matter,” Albain’s group suggested PFS should be used in Phase III trials, but maybe it should be prospectively determined how large a benefit is desired. For full approval perhaps two trials should be required, or perhaps there should be a mandatory cross-over design.

In a world where cost is no option, I’d agree. However, resources are not endless, and one has to ask how much a few months of PFS without a concomitant increase in OS are worth. I don’t know the answer to that one, as this is a very difficult debate that we in the U.S. have thus far been able to avoid. Our colleagues in nations with nationalized health care systems cannot avoid it, though. For example, in Canada, it’s been estimated that the addition of Avastin to breast cancer and lung cancer treatment would add $299 million a year to Canada’s health care costs. In a country like Canada, the only choices are to cut money out of other programs to pay for this or to raise taxes. In the U.S., our insurance premiums just go up.

These issues are difficult, and the NYT article gives a fairly balanced overview up until this point. However, when it comes to discussing off-label use of Avastin, the bioethical and financial issues become harder still:

Doctors are free to prescribe Avastin, or any other drug on the market, for unapproved uses, at their discretion. As much as 75 percent of cancer drug use is of this “off label” variety, according to an estimate by the National Comprehensive Cancer Network, a group of big cancer centers. And some doctors say that with patients dying, they simply cannot wait for airtight evidence.

“Of course we want everything to be evidence-based,” said Dr. Yashar Hirshaut, an oncologist in Manhattan. “I also like the American flag and apple pie.”

But, he explained, “You say, ‘This person is dying right here and I need something that will help, and there’s a logical construct that I can see how it will help.’ “

I must point out that in this case “off-label” use does not usually mean non-evidence-based. What it usually means is that the evidence supporting the treatment choice is weaker or that the clinical trials haven’t been done yet to show if a therapy works or not. Even the most die-hard advocate of EBM understands that if you have a patient in front of you dying right now, you’re willing to try something for which the evidence may not be particularly strong. That’s why I’m not making sarcastic comments about Dr. Hirshaut the way I did about Dr. Hecht; the two situations are apples and oranges.

The problems, however, are two-fold: First, there’s a financial incentive on the part of the drug company to encourage such off-label use, or at least not to object to it. Second, off label use makes doing the correct clinical trial difficult, and the NYT article describes one way how:

But the anecdotes and evidence from small trials that may seem to justify off-label use sometimes turn out to be misleading. That happened with pancreatic cancer. After patients and doctors decided Avastin had to be helping, cancer researchers themselves conducted a large study. So did Roche. Avastin, both studies concluded, did not prolong life for people with cancer of the pancreas.

The moral of the story above? Anecdotes can deceive “conventional” physicians as much as they can CAM practitioners. Never forget that. This is in reality not much different than the issues I discussed about whether or not patients have a right to experimental therapy. The only difference is that it’s much easier to prescribe drugs off-label than it is to prescribe experimental therapy.

One thing that bothers me about this trend is indeed the potential harm it can do to science- and evidence-based medicine. One can make an argument that perhaps PFS is a valid endpoint for approving a cancer drug (if we’re willing to pay for it), but it’s hard for me to accept arguments like this:

As word spread, Dr. Friedman at Duke and Genentech organized studies of a type generally considered less than definitive. There was no control group that took another drug or got a placebo. Everyone got Avastin. Otherwise, no one would enroll in the study, doctors argued.

Then the investigators compared the results with what they thought would have happened without Avastin. The patients lived a median of about nine months, about three months longer than the researchers estimate would have been expected.

But such comparisons have led scientists seriously astray in the past because the people being treated with a new drug often are very different from previous patients who did not take it and because overall medical care steadily improves. Nonetheless, Genentech has said it planned to apply this year to the F.D.A. for approval for Avastin to treat glioblastoma, the deadliest form of brain cancer.

Single-arm studies like this using historical controls can sometimes be used as valid evidence, but the difference between the treated patients and historical controls have to be much, much more impressive, to the point where nothing other than a major effect from the drug is a reasonable explanation for the improvement in survival. After all, selection bias alone could potentially account for a 3 month survival benefit compared to historical controls. Trying to argue for approval of a drug on the basis of such thin gruel isn’t in essence any different than Andrew Weil or David Katz, either.

With complex medical technology and expensive drugs whose benefits seem modest in relationship to their price, our health care system appears to be heading for a crisis. We in the U.S. absolutely hate to address real world questions such as whether how much these drugs cost is worth their benefit. A cancer patient will often answer a resounding yes. We’d all like to say yes to that question as well. Unfortunately, such idealism comes crashing against fiscal reality, and it’s not clear where we will draw the line and to which patients we will end up having to deny potentially life-prolonging treatments because they are just too expensive.

Comments

  1. #1 qetzal
    July 7, 2008

    Very nice post!

    I’d like to ask two follow-up questions, if I may.

    1. Are you aware of any case where a drug improves PFS but reduces OS?

    2. What’s your judgment on whether improved PFS translates to actual clinical benefit to the patient?

    The answers to these questions seem highly relevant in deciding whether PFS is a useful endpoint. If improved PFS only weakly predicts improved OS, but strongly indicates that OS won’t be worse, that seems a point in favor of PFS as an endpoint. Similarly, if PFS means the patient’s remaining quality of life is better, even if OS is unchanged, that also seems a point in favor of PFS.

    If neither of those is true, I can’t see an objective reason to continue using PFS as an endpoint. (Of course, PFS may be valuable in some cancers and worthless in others.)

    I was also struck by this:

    Albain took it upon herself to conduct a survey, sending out a questionnaire to a sample of 47 experts. She was overwhelmed by the volume and vehemence of the replies. The clear consensus was that PFS should be considered a meaningful approval endpoint.

    I’d like to think that’s based on the experts’ subjective but (hopefully) accurate judgement that PFS really does provide a net benefit to the patient. OTOH, it must be difficult for oncologists to deal with the reality that many of their patients will die of the disease. I can imagine that might lead to a strong desire to believe that their treatments are at least helping, which could create significant bias and render subjective judgments unreliable.

  2. #2 wfjag
    July 7, 2008

    Not everyone has such a favorable opinion of the NYT articles as you do. See the review at Stats.org, http://thestatsblog.wordpress.com/

    “Does the New York Times Hate American Medicine?
    Posted on June 30, 2008 by Trevor Butterworth

    While reading the New York Times’ massive investigation into whether CT Scanners are more medical scam than vital diagnostic tool, it was difficult not to give up after the following graph:

    “Some medical experts say the American devotion to the newest, most expensive technology is an important reason that the United States spends much more on health care than other industrialized nations — more than $2.2 trillion in 2007, an estimated $7,500 a person, about twice the average in other countries — without providing better care.”

    Who says this? More to the point, why is this comment even in the piece when it pushes a fact that is easily disproved? Last year, the journal Lancet Oncology published a huge comparative study of cancer survival rates in European countries and contrasted them with United States. The results:

    Colon and rectal cancer: 65.5 percent in the U.S. vs 56.2 percent in Europe.
    Breast cancer: 90.1 percent in the U.S. vs 79 percent in Europe.
    Prostate cancer: 99.3 percent in the U.S. vs 77.5 percent in Europe.

    All cancers (age adjusted), Men: 66.3 percent in the U.S. vs 47.3 percent in Europe.
    All cancers (age adjusted), women: 62.9 percent in the U.S. vs 55.8 percent for women.

    No individual country surpassed the U.S. on any of these measures – and these percentage differences add up to lives saved. If that doesn’t amount to “better care,” what does?

    The authors of the study say much of the difference reflects better “timeliness” of diagnosis in the U.S., particularly with regard to prostate cancer, resulting from more intensive screening. One of the authors, Professor Michel Coleman of the London School of Hygiene and Tropical Medicine, authors, also told the BBC that Britain’s poor showing was due to a lack of cancer specialists compared to other countries.

    Another recent study from the Annals of Oncology shows a correlation between survival rates in the U.S. and access to newer (and more expensive) cancer drugs. Britain’s Telegraph cited one of the study’s authors, Dr. Nils Wilking, a clinical oncologist at the Karolinska Institute in Stockholm:

    “Our report highlights that in many countries new drugs are not reaching patients quickly enough and that this is having an adverse impact on patient survival. Where you live can determine whether you receive the best available treatment or not.

    To some extent this is determined by economic factors, but much of the variation between countries remains unexplained. In the US we have found that the survival of cancer patients is significantly related to the introduction of new oncology drugs.”

    Now perhaps CT scanning is mostly a waste of time, with a high price tag to consumers and high dosage of radiation to boot; but it’s also the fact that a snapshot of medical technology does not reflect that major developments in health care are often evolutionary. Small benefits in technology and drugs pave the way for further small developments, and eventually, these all add up to significant changes in treatment. Initial risks can also be reduced along the way (think early x-rays), while new uses and applications can arrive through a pure inspiration.

    But the case against CT scanners shouldn’t involve deploying false claims that they are part of a massive fraud being perpetrated on the public by American medicine.”

    Thus, while you are correct that medicine as practiced in the US is expensive, it also has significantly better outcomes than elsewhere.

  3. #3 Orac
    July 7, 2008

    I may have to look at the actual Lancet article when I get a chance. A lot of the apparent differences in survival could be due to lead time and length bias if those factors weren’t very carefully controlled for in the study–especially for prostate and breast cancer.

    In brief, the evidence that cancer outcomes are so much better in the U.S. compared to Europe is anything but unequivocal, and correlation does not necessarily equal causation. Pointing out an analogy, the outcomes for stomach cancer are very different in Japan and Asia than the U.S. and the West, but it’s not because of differences in treatment, it appears to be a major difference in the biology of the disease in Asian ethnic groups.

  4. #4 Craig Willoughby
    July 7, 2008

    Orac said:
    “Pointing out an analogy, the outcomes for stomach cancer are very different in Japan and Asia than the U.S. and the West, but it’s not because of differences in treatment, it appears to be a major difference in the biology of the disease in Asian ethnic groups.”

    I think a lot of that is the difference in diet as well. Americans eat a lot more fatty foods than Asians do.

  5. #5 wfjag
    July 7, 2008

    I’ll be interested in your comments on the Lancet and Annals of Oncology published studies. Butterworth is a journalist/ statistician, and not a physician or cancer researcher. Although he does a good job in explaining the numbers, that’s different from understanding whether the numbers have a valid basis — which in cancer research, is your field.

    Thank you for the excellent review of the NYT articles.

  6. #6 Orac
    July 7, 2008

    I think a lot of that is the difference in diet as well. Americans eat a lot more fatty foods than Asians do.

    There do also appear to be dietary considerations, as well as genetics and biology.

  7. #7 qetzal
    July 7, 2008

    Excerpted from the Discussion section of the Lancet Oncology article:

    Another major limitation of the EUROCARE data is the absence of information on clinical stage, which precludes comparisons of stage-matched patients.

    The authors do argue that timeliness of diagnosis is a likely factor in the difference between Europe and the US, but absent a stage-matched comparison of survival, I don’t know how you could determine whether early diagnosis actually improved outcomes, or whether the entire effect is due to lead-time bias, or some combination.

    In fact, the authors acknowledge that at least some of the difference probably is due to bias:

    With regard to the comparison between EUROCARE and US SEER data, the differences in survival were greatest in 2000-02 for the major cancer sites: colon and rectum (56·2% [95% CI 55·3-57·2] vs 65·5% [64·9-66·1]), breast (79·0% [78·1-80·0] vs 90·1% [89·6-90·5]), and prostate cancer (77·5% [76·5-78·6] vs 99·3% [98·9-99·8]), which probably represents differences in the timeliness of diagnosis. In the USA, 70% of women aged 50-70 years have reported that they have undergone a mammogram in the previous 2 years;35 SS Coughlin, RJ Uhler, JK Bobo and L Caplan, Breast cancer screening practices among women in the United States, 2000, Cancer Causes and Control 15 (2004), pp. 159-170. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (25)35 one-third of people reported that they had undergone sigmoidoscopy or colonoscopy in the previous 5 years;36 and over 80% of men aged 65 years or older reported that they had undergone prostate-specific antigen, of whom 40% had been tested in the previous year.37 That we found a 5-year relative survival for prostate cancer as high as 99·3% in the USA suggests that the increase in survival is largely an artefact from the introduction of screening of prostate-specific antigen–although, we cannot establish the effect that this artefact will have on mortality.

    The authors go on to state:

    In Europe, the 5-year relative survival for all cancers combined was 47·3% (46·8-47·8) for men and 55·8% (55·3-56·2) for women, which are much lower than the 66·3% (66·0-66·6) for men and 62·9% (62·6-63·2) for women in the USA. However, when excluding prostate cancer, the survival decreased to 38·1% (37·9-38·2) in Europe and 46·9% (46·6-47·3) in the USA, so that, in men, over half of the difference in survival between Europe and the USA can be attributed to prostate cancer. For women, the 5-year survival for all cancers combined in the USA (62·9% [62·6-63·2]) was comparable with that in some of the wealthiest European countries (from 59·7% [59·4-60·1] in Italy, up to 61·7% [61·2-62·1] in Sweden); the slightly higher survival in the USA was largely due to better survival for colorectal and breast cancer.

    (My emphasis in both quotes.)

    Taken together, that seems to say that lead-time bias contributes significantly to the overall difference in survival, at least for men.

  8. #8 noahpoah
    July 7, 2008

    The stats blog complaint (and attendant discussion here) is odd, to say the least. The Times article is discussing CT scans for cardiological purposes, not cancer detection. While there is a blanket statement about excessive cost and no improvement in care, it is backed up with at least one non-academic ‘citation’ (i.e., the mention of the Rand Corporation study).

  9. #9 Interrobang
    July 7, 2008

    In a country like Canada, the only choices are to cut money out of other programs to pay for this or to raise taxes.

    Considering that Canada has posted federal surpluses for the last dozen years, there aren’t just two options. The government, if it felt so inclined (and was actually abiding by the wishes of the electorate), could increase health spending without either cutting services elsewhere or raising taxes (not that most Canadians would mind more taxes assuming they were being used directly for healthcare, xf the Romanow Report).

  10. #10 D. C. Sessions
    July 7, 2008

    No individual country surpassed the U.S. on any of these measures – and these percentage differences add up to lives saved. If that doesn’t amount to “better care,” what does?

    Pre- and neo-natal programs, for one. At some level medical care is a zero-sum game, and that “twice as expensive” American medical system buys those 20% increases in cancer survival (leaving aside Orac’s reservations) at the cost of some truly egregious neglect for children.

    If you quantify the “product” of medical care as quality-adjusted life-years, the USA isn’t looking all that “productive.”

  11. #11 sirhcton
    July 7, 2008

    A shorter version of this article appeared in my local newspaper this morning. As soon as I read the headline and followed the story, I thought of the good Orac.

    I had two trains of thought, one of which you have pretty much adressed with this entry.

    The other was more generalised. It concerned the issue of costs of medical care and life extension, and quality of life, to some degree. We are going to have to decide on the limits, no matter how much we seem to want to avoid that. I could go into great, rambling detail on my thoughts and examinations, but I am no learned writer, such as the noble Orac.

  12. #12 Clark
    July 7, 2008

    I’d be interested in your comments on DCA (dichloroacetate) which has been hyped up the wazoo since it was publicized last fall in articles like this New Scientist one. I know some have been taking DCA combined with Avastin while others are taking it mixed with high doses of caffeine. It’s so hyped that patients are more or less blackmailing their doctors to prescribe it to them. (i.e. saying they’ll get it in the active black market or across the border in Mexico and simply not tell the doctor)

    While there’s plenty of anecdotes on it having huge effects I’ve not heard of any real reliable discussions.

  13. #13 NickG
    July 7, 2008

    “Unfortunately, such idealism comes crashing against fiscal reality, and it’s not clear where we will draw the line and to which patients we will end up having to deny potentially life-prolonging treatments because they are just too expensive.”

    The problem with the expense of cancer drugs is to some extent an artificial one perpetrated by pharmaceutical companies who realize that if you have a substance that someone feels is necessary for their survival (and may very well be) the price becomes immaterial to them. Its like that whole preventing the use of Avastatin for macular degeneration bullshit that Genentech pulled. Pharma will charge exactly as much as they feel they can get out of people and will use whatever means necessary to ensure that their profits remain as big as possible. They are essentially a boil on the buttocks of humanity that make the private insurance industry and the mafia look like a bunch of choirboys.

    R&D certainly has costs, but what proportion of that R&D do we as taxpayers already pay for? The answer is often a lot. And then we turn it over to pharmaceutical companies for exploitation. There is an easy solution, but one which there is no political will to produce: the amount of profit that a pharmaceutical corporation may make off of a given drug is proportional to what they spend on development versus what is publicly funded. If a pharmaceutical company pays for 20% of the development costs of the drugs they currently sell (and no, marketing costs don’t count) then they are allowed to profit 5% above their global R&D, manufacturing, and administrative budget on the sale of those drugs (which would take into account the cost of all research even drugs that don’t go to market, manufacturing, and the cost of running a company). If they pay for 40% of the cost, they can profit 10% over than number. (We can argue about the exactly appropriate percentage and what are appropriate administrative costs, but you get the idea.) If they don’t like that deal, then feel free to do your own damn research, bring your drugs to market, and charge whatever the eff you want. However, using our tax dollars to pay for 90% of the development of a drug then holding people desperate to save their own lives hostage is complete and utter bullshit.

    No wonder Pharma sports the highest profits of any industry worldwide. I hate them. Hate. Hate. Hate. If there was a debil, they would be the work of him.

  14. #14 Tlazolteotl
    July 7, 2008

    Clark,

    Orac has indeed blogged about DCA:

    Here. and also follow the link in that post to an earlier post.

  15. #15 Clark
    July 7, 2008

    Thanks. There were some great posts on that.

  16. #16 qetzal
    July 7, 2008

    @NickG

    If tax dollars routinely covered 90% of the development of a drug, I’d agree with you. I don’t think they do – not by a long shot.

    But I admit that depends on where one draws the line. Let’s take Avastin as an example, since that’s cited in Orac’s post. Did development start with the initial generation of bevacizumab, the humanized anti-VEGF monoclonal antibody that is the active ingredient in Avastin? Or earlier, with the generation of the mouse antibody that was later humanized to create bevacizumab?

    Personally, I’d probably draw the line at the generation of the mouse monoclonal. Note that in the case of Avastin, Genetech generated the original mouse antibody, and did the subsequent humanization, and did all of the subsequent animal efficacy testing, animal safety testing, manufacturing scale-up, clinical testing, validation, etc. So in this case, at least, I’d argue that Genetech did 90-100% of the development work.

    OTOH, if we count all the work on the concept of antiangiogenesis, or on the discovery of the target molecule VEGF, then the public contribution goes up considerably. Personally, I wouldn’t consider that part of the development of Avastin, but you may disagree.

    Please understand: I’m not suggesting that the example of Avastin disproves your claims about public funding of drug development. At this point, I’m merely curious what you would include in your proposal to calculate the fraction cost that pharma pays for drug development.

  17. #17 Tree
    July 7, 2008

    Hate Avastin. Hate it hate it hate it.

    On Avastin trial with Stage IIIa breast cancer, BRCA1 positive, mom dead from breast cancer, age 75 (first occurance age 38), dad dead from cancer train wreck age 79 (prostate, colorectal) combined with CHF, DVTs, AMI from 1982 (we are not healthy people). Me age 46, CR polyps already found, so drug for CR cancer must be good try, right?

    Not so much. Blood blisters in nail beds, red spots on Kleenex, dark stools, by third dose nearly bled to death when a uterine fibroid blew.

    Hate. It.

    I do not mention the squeaky Minnie Mouse voice, heart palpitations or high blood pressure. I am wondering how someone in poorer health than mine can enjoy any quality of life on that stuff.

    But lots of good trial data, it seems.

    YMMV. Have fun with those perforations.

  18. #18 NM
    July 7, 2008

    NickG

    Even if 90% of the research costs are public funding (which I also doubt- but also can’t provide evidence to support or refute) you still need somebody to produce the drug/s so people can benefit from them. Otherwise what’s the point of working out effective ways to treat people in the first place?

    BigPharma is a necessary solution that needs to be closely watched. But just imagine how screwed we’d be without them.

  19. #19 Lauren
    July 7, 2008

    The singular of data is not anecdote, BUT, Tree, my mom is alive because of Avastin. She was diagnosed with Stage III ovarian cancer 7 years ago. She’s allergic to tamoxifen, so several drugs were immediately ruled out. She’s been through ten different chemo regimens. In 2006, her healthcare provider told her to wind up her affairs, the time had come. Lucky for our family, Avastin had also come. She’s still alive, feeling better than she has in years, and we have hopes that we can buy more time with her with the Avastin. And, just to blow your mind even more, she is part of the nation’s largest HMO, which is notorious for its penny-pinching ways.

  20. #20 sailor
    July 8, 2008

    “Last year, the journal Lancet Oncology published a huge comparative study of cancer survival rates in European countries and contrasted them with United States. The results:
    Colon and rectal cancer: 65.5 percent in the U.S. vs 56.2 percent in Europe.
    Breast cancer: 90.1 percent in the U.S. vs 79 percent in Europe.
    Prostate cancer: 99.3 percent in the U.S. vs 77.5 percent in Europe.”

    When I have seen these statistics hyped before, people have pointed out that if you spend a lot on medical care you detect cancer earlier and thus get an apparent benefit, whereas you are just looking at an earlier part of the cancer cycle.

    Surely a good indication is longetivity. In this case the US does not even come in the top 10 despite spending way more on health care.

    Top Ten Countries with Highest Life Expectancy:
    Andorra (in France): 83.51
    Macau (near China): 82.19
    San Marino (in Italy): 81.71
    Singapore: 81.81
    Hong Kong: 81.59
    Japan: 81.25
    Sweden: 80.51
    Switzerland: 80.51
    Australia: 80.50
    Guernsey (in the English Channel): 80.42
    Worst Ten Countries by Life Expectancy:
    Swaziland: 32.63
    Botswana: 33.74
    Lesotho: 34.40
    Zimbabwe: 39.29
    Liberia: 39.65
    Mozambique: 39.82
    Zambia: 40.03
    Sierra Leone: 40.22
    Malawi: 41.70
    South Africa: 42.73
    Djibouti: 43.17
    Other Countries of Interest:
    Canada: 80.22
    Italy: 79.81
    France: 79.73
    Germany: 78.80
    United Kingdom: 78.54
    United States: 77.85

  21. #21 KM
    July 9, 2008

    Similar to your comment,two groups of authors suggested in issue 12 of lancet oncology that length time bias and incomplete data would explain the difference in realtive survival rates. Their comments (at least to me) are hightly convincing and the author’s reply is not good enough and the last paragraph is very strange. I would love to read your opinion of that article.

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