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October 20, 2004

PHARMA: The New Yorker, Industry Veteran and Atlas on pharma pricing and where the industry goes next.

There's a pretty long article by Malcolm Gladwell in the New Yorker called High Prices in which he essentially places much of the blame for big pharma's current state on the other actors in the system being too dumb to stop them. To quote his conclusions.

For sellers to behave responsibly, buyers must first behave intelligently. And if we want to create a system where millions of working and elderly Americans don't have to struggle to pay for prescription drugs that's also up to us. We could find it in our hearts to provide all Americans with adequate health insurance. It is only by the most spectacular feat of cynicism that our political system's moral negligence has become the fault of the pharmaceutical industry.

There is a second book out this fall on the prescription-drug crisis, called "Overdosed America", by John Abramson, who teaches at Harvard Medical School. At one point, Abramson discusses a study that he found in a medical journal concluding that the statin Pravachol lowered the risk of stroke in patients with coronary heart disease by nineteen per cent. That sounds like a significant finding, but, as Abramson shows, it isn't. In the six years of the study, 4.5 per cent of those taking a placebo had a stroke versus 3.7 per cent of those on Pravachol. In the real world, that means that for every thousand people you put on Pravachol you prevent one stroke--which, given how much the drug costs, comes to at least $1.2 million per stroke prevented. On top of that, the study's participants had an average age of sixty-two and most of them were men. Stroke victims, however, are more likely to be female, and, on average, much older--and the patients older than seventy in the study who were taking Pravachol had more strokes than those who were on a placebo.

Here is a classic case of the kind of thing that bedevils the American health system--dubious findings that, without careful evaluation, have the potential to drive up costs. But whose fault is it? It's hard to blame Pravachol's manufacturer, Bristol-Myers Squibb. The studys principal objective was to look at Pravachol's effectiveness in fighting heart attacks; the company was simply using that patient population to make a secondary observation about strokes. In any case, Bristol-Myers didn't write up the results. A group of cardiologists from New Zealand and Australia did, and they hardly tried to hide Pravachol's shortcomings in women and older people. All those data are presented in a large chart on the study's third page. What's wrong is the context in which the study's findings are presented. The abstract at the beginning ought to have been rewritten. The conclusion needs a much clearer explanation of how the findings add to our understanding of stroke prevention. There is no accompanying commentary that points out the extreme cost-ineffectiveness of Pravachol as a stroke medication--and all those are faults of the medical journal's editorial staff. In the end, the fight to keep drug spending under control is principally a matter of information, of proper communication among everyone who prescribes and pays for and ultimately uses drugs about what works and what doesn't, and what makes economic sense and what doesn't--and medical journals play a critical role in this process. As Abramson writes:

When I finished analyzing the article and understood that the title didn't tell the whole story, that the findings were not statistically significant, and that Pravachol appeared to cause more strokes in the population at greater risk, it felt like a violation of the trust that doctors (including me) place in the research published in respected medical journals.

The journal in which the Pravachol article appeared, incidentally, was The New England Journal of Medicine. And its editor at the time the paper was accepted for publication? Dr. Marcia Angell. Physician, heal thyself.

Now Gladwell may have caught Angell out here, albeit at a remote distance, and I haven't always been too kind to her on the pages of THCB. But there is a battle going on for the soul of big pharma with one side urging the best pharmaceutical be used at the best time, creating the real information behind that, and accepting that a generic may be more cost-effective than a brand. On the other side is the decision to beef up the sales force, fudge the details of the science at the marketing margins, and financially smother physicians and politicians. The disinterested observer would not incorrect in noticing that whenever big pharma has had the choice to go down the former road, they've almost always taken the latter. The Industry Veteran, it may not surprise you to know, has limited time for Caldwell's analysis:

It's ostensibly a review of Marcia Angell's book but it's actually a New Yorkerized version of the PhRMA boilerplate. His major argument rests on his assertion that volume of drug usage (due to an aging population and greater awareness) is the principal driver of increasing pharmaceutical cost, not unit pricing. The reason this Gladwell fellow is a shill is that he completely ignores the malevolent DTC advertising by the drug companies and their role as the principal provider of continuing therapeutic education for physicians. It is Big Pharma's propaganda that drives patients and physicians toward the ever more costly, branded me-too's and away from the vastly cheaper generics.

Gladwell then takes a flying leap into the arms of the Bush ideologues when he defends the me-too's, claiming that their proliferation drives down prices. Perhaps that obtains in an ideal world or in some Friedmanite wet dream, but in reality the oligopolistic behavior of product competitors in a therapeutic drug category almost never restrains prices.

Next, Gladwell gets all dreamy eyed and rhapsodic over PBMs and how their role in the Bush Medicare scheme, starting in 2006, can restrain prices by pushing people to generics and less costly brands. Were it only so. In his eagerness to exculpate Big Pharma, he completely ignores the fact that they try to subvert the very algorithms and step formulary approaches he suggests through mutli-therapy bundling, volume incentives and rebates that require the exclusion of competitors.

Gladwell then finishes with a minor anecdote, claiming that the sleight-of-hand conclusions that appeared in a journal article on Pravachol were not the fault of Bristol-Myers Squibb. Instead he blames the investigators and the journal's editor: Marcia Angell. Someone's got to take this guy out back and beat the crap out of him.

In general I agree with The Veteran although probably not about the crap beaten out of him part. There's almost no evidence to show that multiple "me-too" drugs in a class lower the overall costs. Lipitor is much costlier than Crestor, and bang for the buck wise, much much much costlier than Mevacor which is now generic. So which one is the most prescribed drug? I don't have to tell you. PBMs have been co-opted by pharmas and made far too much of their money by playing favorites among brand-managers, with their rebates from manufacturers exceeding their income from medical management. Finally, while the NEJM article might have been in dispute, that's not how doctors really get their news. I'm sure that the BMS detail babes gave a fair and balanced discussion of what was in effect quasi off-label use for Pravachol in the few minutes they got in front of a doctor, but let's face it, that session rather than academic probing of journal articles is where doctors get their information, and what drives the prescribing decisions.

But, and I'm sorry to harken back to this, I think that there is both a middle ground here, and the inevitability that pharma must change in and of itself, whether the health care purcasing market demands it or not. Atlas, who is on the other end of the political spectrum from The Veteran comes to much the same conclusion in this article in which he bashes Angell and all those socialists, but more importantly notes that the party can't go on forever.

Marcia Angell and her Harvard/Martha's Vineyard/New England Journal of Medicine fellow travelers live in a worker's paradise that is in permanent denial of the evident failures of socialism and communism. For years, they have been pushing for a national healthcare system to no avail, because, thankfully, most Americans are not fooled by their well meaning naivete into believing that there is a free lunch. We all wish we could get something for nothing but we can't so we work. This sort of commonsense eludes the overeducated hothouse flowers who promulgate such wishful thinking on the unsuspecting electorate.

All that having been said, is there room for improvement in the pharmaceutical business? You bet. And it will come soon. The next decade will be then Gotterdamerung for the deities of big pharma. It will not kill them (hopefully) so it will make them stronger. Bye bye DTC. Bye bye salesforce. Bye bye CME. Bye bye sampling. Hello efficient, effective marketing like real businesses do--direct marketing, business to business advertising,and al the good old fashioned stuff that has been replaced by six figure deliverymen bearing so much free product that the typical group practice sample cabinet is better stocked than most Wal Mart pharmacies.

The recent Rx marketing orgy isn't sustainable and nobody knows that better than its perpetrators. Somebody has to blow the whistle and fill the penalty box, and it will be surely be Kerry if he's wearing the striped shirt. But even a Bush II administration will be giving big pharma a buzz cut, although they may use a scissors instead of a razor.

So it's a fair bet that many of the bad excesses will be driven out by a combination of regulation and market forces. I agree here too, which yet again puts me in the wishy-washy political middle ground! And at that point the system (hopefully prodded by some sensible bodies acting something like the UK's NICE) will begin to determine what drugs really work at what cost overall, and those with the desire to play the "full cost of care" argument within the pharmas will take over from those who've been running the "marketing orgy".

October 20, 2004 in Pharma | Permalink


The needed change in the "war on cancer" will not be on the types of drugs being developed, but on the understanding of the drugs we have. There are already over 100 different therapeutic drug regimens out there, and 400 are in the pipeline. Any one or combination of them can help cancer patients. The system is overloaded with drugs and under loaded with wisdom and expertise for using them.

There are many cancer drug regimens, all of which have approximately the same probability of working. The tumors of different patients have different responses to chemotherapy. Tumors grow and spread in different ways and their response to treatment depends on these unique characteristics. The amount of chemotherapy that each patient can tolerate varies considerably from patient to patient. It requires individualized treatment based on testing the individual properties of each patient's cancer.

Under this approach, scientists study how an individual's cancerous cells respond to drugs. Doctors have learned that even when the disease is the same type, different patients' tumors respond differently to chemotherapeutic drugs. More and more physicians and patients are turning to "individualized therapies" to treat cancers, not just "targeted therapies." Without individualized testing, it's difficult to determine which drugs are best for patients who don't respond to standard therapies.

Herceptin is only for the estimated 20% of breast cancer women at risk for recurrence. However, Gene Expression Assays are panels of markers that can predict the likelihood of cancer recurrence in various populations. By testing the gene expression markers of a patient, oncologists can identify those patients unlikely to benefit from chemotherapy from those that would, saving the other 80% of cancer patients the added expense, suffering and even death from having to take chemotherapy.

What a cancer patient would like ideally, is to know whether they would benefit from adjuvant chemotherapy. If so, which active drugs have the highest probability of working, which Chemotherapy Sensitivity and Resistance Assays can test for drug activity against a tumor, and what drugs are relatively non-toxic in a given patient , which Pharmacogenomic Testing can identify.

Whether a patient would benefit from adjuvant therapy depends on two things: (1) whether the tumor is "destined" to come back in the first place and (2) whether the tumor is sensitive to drugs which might be used to keep it from coming back.

The gene expression markers (assays) actually can be calibrated to provide information both about the possibility of recurrence and also chemosensitivity. The problem is dissecting one from the other. Studies to date have just looked at whether people had a recurrence.

You can identify gene expression patterns (via assays) which correlate with this. But it can be hard and even impossible to tell what exactly you are measuring: is it intrinsic aggressiveness of the tumor? sensitivity to adriamycin? sensitivity to cyclophosphamide? sensitivity to taxol? sensitivity to tamoxifen? You find a gene expression panel which correlates with something, but picking apart the pieces is hard.

You can begin to do this if you combine gene expression studies with cell culture studies. Use the cell culture as the gold standard to define the difference between sensitivity and resistance. Then see which pattern correlates with which for individual tumors and individual drugs. It can theoretically be done (and certainly will be done, over time), but it's not easy.

And then you come to the 1,000 pound gorilla of a question: What effect will the different individual drugs have in combination in different, individual tumors? This is where cell culture assays will always be able to provide uniquely valuable information. But it's not one versus the other. The best thing is to combine these different tests in ways which make the most sense. One month's worth of herceptin + avastin costs $8000. That's without any docetaxel and blood cell growth factors and anti-emetics. If nothing else, we can't afford too much trial and error treatment.

Posted by: Gregory D. Pawelski | Nov 14, 2005 10:35:58 AM

Fair and Impartial ASCO Tech Assessments? Give me a break!!!

A so-called ASCO expert panel did a tech assessment in 2004 on cell culture assay tests (chemotherapy sensitivity and resistance assays) which included only three investigators who had ever worked in the field of cell culture assay technology: Dan Von Hoff, Anne Hamburger, and a German named Hanauske who worked with Von Hoff in San Antonio and then returned to Germany to continue using Von Hoff's methods (which were Hamburger and Salmon's methods). All three were old line "Human Tumor Stem Cell" (clonogenic) assay workers, who, along with Salmon, convinced the oncologic community that clonogenic assays were the only valid approach to chemosensitivity testing (no one had ever heard of apoptosis back then). The clonogenic assay failed and it dragged down the whole field of inquiry along with it. So basically, the panel consisted of various oncologists who knew nothing about the technology and data, along with three proponents of a long-ago discredited approach which had nothing to do with the technologies (assays with cell death endpoints), and with no one at all who understands anything at all about the newer technologies and published data pertaining to them.

In the tech assessments, the authors invented a brand new criterion for validating a laboratory test. The existing standard had always been the "accuracy" of the test. This is true for every single test used in cancer medicine, from estrogen receptors to bacterial culture and sensitivity testing to panels of immunohistochemical stains to diagnose and classify tumor to Her2/neu and CA-125 to MRI scans, CT scans, PET scans and on and on. Yet they never even attempted to review the voluminous literature which defined the "accuracy" of cell death assays, and instead restricted their analysis to a consideration of papers which tried to address the issue of whether the use of the assays actually improved patient outcomes. They lumped together the old and long abandoned technologies (clonogenic assay, subrenal capsule assay, etc.) with the cell death assays. And yet, even in their own review, there were five studies with cell death assays and patient outcomes that were improved in four of the five studies and one negative study wasn't even relevant, because the authors did their tests on subcultured cells (as opposed to "fresh" tumor cultures) and tested the cells in monolayers (as opposed to three dimensional cell clusters). They ignored all studies having to do with "accuracy," the criteria used in tech assessments of all previous laboratory and radiographic tests, and only included studies dealing with "efficacy," a standard never met by any laboratory or radiographic test.

Were they to have reviewed studies showing that the use of estrogen receptor improved treatment outcomes, they would have found no publications at all. Were they to have reviewed papers showing that the use of panels of immunohistochemical stains to subclassify tumors improved treatment outcomes, they would have found no publications at all. Were they to have reviewed studies showing that treatment outcomes were improved through the use of MRI scans or PET scans or CT scans to monitor growth and shrinkage of tumors (for the purpose of influencing the decision to continue the same chemotherapy or to change chemotherapy), as opposed to simply following patients with history, physical, simple plain radiographs, and simple lab tests, they would have found no publications at all.

A "valid" tech review would have started with the published "accuracy" of the tests, and would have included in excess of 2,000 published correlations, in all types of neoplasms from acute leukemia to breast cancer to ovarian cancer to colon cancer and so forth, every single one of which showed that patients treated with drugs "active" in the assays had significantly higher response rates than patients treated with drugs which were "inactive" in the assays. They would have noted a half dozen papers which also showed that patients treated with drugs "active" in the assays also enjoyed significantly longer survivals. They would have made note of the preliminary studies which supported the concept that the use of the assays influenced treatment decisions which resulted in superior outcomes. A "valide" technology assessment would have concluded that the weight of the available evidence supports the decisions of individual oncologists to make at least selective use of these assays in their clinical practices.

What is it that ASCO is saying? Cell culture assays should not be used outside the confines of a clinical trial setting. The same people who maintain that assay-directed therapy should not be used until proven in prospective randomized clinical trials, are the same people whose entire careers are utterly dependent upon mega-trials funded by pharmaceutical companies (that, plus fees from speeches they give for these companies), are the same people who control the clinical trials system, the grant review study sections, and the journal editorial boards. Why else would they want this technology tested under the clinical trial setting?

Opponents of cell culture assay testing can blow all the smoke screens they want, but the fact is that every single time advocates for cell culture assays have been given fair consideration by an impartial, non-ASCO adjudication, the decision has been made that this testing is a perfectly appropriate medical service, worthy of coverage on a non-investigational basis. It is only when ASCO or the insurance industry has been appointed itself as the judge/jury/prosecutor/defense rolled into one and not invited input from all "relevant" parties that the decisions have been unfavorable.

Posted by: Gregory D. Pawelski | Aug 6, 2007 9:28:44 AM

Scott Gottlieb, a doctor who is a former FDA official, in a June 24th WSJ op-ed article pointed out that Medicare has only about 20 doctors and 40 total clinicians working in its coverage office, and fewer than a dozen in the office that sets doctors' reimbursement rates.

Also, Medicare doesn't have a single oncologist on staff, yet since the year 2000, the program issued 165 restrictions and directives on the use of cancer drugs and diagnostic tools. Private insurers, on the other hand, employ thousands of doctors and nurses to do this.

I guess that would explain why there wasn’t a National Coverage Decision for the Cell Culture Assays (known officially as Oncologic In Vitro Chemorespone Assays) in 2006, but a Local Coverage Decision? That’s not enough staff to do a thorough analysis of these valuable tests.

On the other hand, private insurers employ thousands of doctors, nurses and pharmacists to do tech assessments, which would include cancer diagnostic tests. National Heritage Insurance Company and Highmark Medicare Services, contractors that administer Medicare programs, had established a positive coverage policy; a bio-marker assay that is perfectly appropriate medical service, worthy of coverage on a non-investigational basis.

When you get to the new genetic/molecular tests, even the validation standard that private insurance companies is accepting is "accuracy" and not "efficacy." The essential "proof" is that all they have to do for these tests is that the test has a useful degree of "accuracy," not that the use of the diagnostic test improves clinical outcomes.

However, the validation standard the American Society of Clinical Oncology (ASCO) wants for cell-based profiling tests is "efficacy." The cell-based profiling tests have the same entitlement to be judged by the same validation standard as genetic/molecular profiling and all other diagnostic tests. It must be noted that all types of diagnostic tests are just that, "tests" and not treatment.

That's why ASCO needs to update their tech assessment on cell-based profiling assays. And do it transparently this time!

Posted by: Gregory D. Pawelski | Jul 8, 2008 10:55:23 PM

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