John Abramson MD has an excellent book out called Overdosed America in which he criticizes pharma, the FDA and the medical journals for, at the least, bending the truth. To get a flavor of it, read the piece he wrote for TCHB last month. To get a bigger flavor of it those of you with no lives can watch his talk on C-SPAN on Sunday at 5pm–presumably the rest of you have Tivo!

Meanwhile, the final part on the Drew/King story has been bumped till Monday. Sorry to those of you waiting for it!

On December 8th medical students across the nation are going to protest overly intrusive marketing from drug reps. I can’t help wondering that, given the relative geekiness and terrible work hours of medical students/residents and the typical physical characteristics of detail babes reps, isn’t this a somewhat excessive piece of self-sacrifice?  Where else are they going to meet hot chicks/hunky guys?

Regular contributor, and one of several token free-marketer contributors to this deeply socialist blog, Atlas, does not like what he sees from the apparently failing effort of Illinois governor Rod Blagojevich to enroll anyone in the campaign to buy drugs from Canada.

Today on our local NPR outlet, Rahm Emmanuel (D-IL) was asked why the Illinois reimportation juggernaut had only signed up 1,200 Illini. His answer–well, we don’t have the money to advertise it. Hello? Where does he think big pharma gets the ad budgets that the great state so lusts for? From charging more than the cost of chemicals in Ireland and the UK, that’s where! Guess "great" ideas don’t sell themselves, eh? Well, guess what? Neither do great medicines! None of this stops our intrepid Governor from exporting his import fiasco like a dangerous contagion to other demagogues in charge of unfortunate states–Kansas is the latest victim. One wonders how much all this interstate politicking costs the taxpayer.

Later on the same program, Dr. Quentin Young (a former Cook County health commissioner and academic who is no friend of pharma) acknowledged that although AIDS is a pandemic worldwide, it is reduced to a chronic condition domestically. By what? Pharmaceuticals!

Meanwhile, while our Governor traipses across the fruited plain running for VP on a Clinton 08 ticket or whatever it is that he is trying to accomplish, Illinois Medicaid (which funds real FDA approved drugs for the needy, including many AIDS sufferers) is criminally underfunded due to the Governor’s foolish pledge (reminiscent of Bush the Elder) to never raise taxes regardless of how much his pharma bashing campaign accompanied by a bloated and corrupt security phalanx drains from the treasury. What’s more, having gambled and lost on the Presidential election, IL now faces the spectre of Federal retribution for its flouting of law and FDA regulation prohibiting reimportation in the form of denial of a Medicaid tax and spend maneuver that it was counting on to plug a multimillion dollar hole in the budget. What comes around, goes around.

Those of us who retain some semblance of sanity and economic literacy here in the Land of Lincoln can hardly wait to lose this loser of a Governor. Wish us well.

I did have to respond to Atlas because the hint of sanity, or at least of not running up a huge deficit just to avoid a tax increase, was implicit in his rant. And that gets us close to the ultimate heresy among Republicans of calling for a tax increase (even if George HW Bush’s tax increase did set us up for the party that was the 1990s). Atlas responded:

I can’t speak for the Republicans (I’m an independent you know). But if you’re going to write a check you’re going to have to cash it. Politicians of every stripe these days seem to be incognizant of this. Even Democrats won’t raise taxes in some cases, and Republicans seem to think deficits don’t matter. To some extent they may have a point (leveraging and all that), but at some point common sense dictates they do matter, and I think we’re getting there.

I think low taxes are good in that they stimulate the economy, and rates prevalent in the US and UK in the 60s (70%-90% at the highest marginal brackets) are counterproductive, except in that they inspired the Beatles to record "Taxman". But many people, I among them, would not object to paying more taxes if the money was really used for practical solutions to pressing problems.

The trouble is much of the money is wasted on corruption and folly. Having grown up in Chicago, I can assure you that many if not most of our tax dollars are wasted if not outright stolen by featherbedders and mobsters. So social reform must be accompanied by political reform, or many will trust in the private sector as the least worst vehicle for good works.

So there really is some dissension on the free-market right from the Rove-Bush-Cheney "deficits don’t matter" orthodoxy. Perhaps Atlas and I will be burnt at the same stake?

I said a while back that I wouldn’t do just tell you to go read other stuff, but there’s a deluge that you just must pay attention to–all out in the last 24 hours.

1) Kaiser Family Foundation is out with a confirming study that those seniors at the bottom with high drug spending will be better off from the drug-benefit in the MMA, but that many more in the middle will not be.

2) Arnie Milstein shows why he believes that the "shark" of rising health care costs will be contained by the efficiencies brought to the system by the "engineers".

3) The continued aftershocks of the Vioxx hearings continue very very loudly. JAMA is out with a whole raft of articles mostly suggesting that major FDA reform is needed, and that drug company studies have routinely withheld data from the public and by inference JAMA and its fellow journals. While a lawyer for Bayer fires back very aggressively, Astra-Zeneca CEO McKillop seems to be breaking with PhRMA orthodoxy and admitting that there’s a real problem–possibly in an attempt to save Crestor before it falls victim to the Vioxx syndrome.

Given that my work putting together the FierceHealthcare newsletter (go sign up!) was, shall we say, made somewhat challenging by this plethora of activity, I suggest that you go take in some of these articles, and I’ll be back with more comment later in the day/week.

Thank God we get to take the end of the week off!

Meanwhile one of my true fans has nominated THCB for the worst medical blog over at Echojournal!

Last week the NY Times had an NY article about drug pricing that suggested a new approach for keeping innovation while controlling prices. In particular it suggested changes to the way the patent system works, and how the Federal government might change some of the ways it spends the $30bn the NIH spends on basic research and the $40bn it spends via various programs as a purchaser on drugs:

The government could compensate drug companies for their inventions as an incentive for them to keep innovating. How to determine how much an innovation is worth? One possibility would be for the government to selectively buy patents at a premium over the price a private bidder was willing to offer, and then put them into the public domain, Professor Kremer said. Aidan Hollis, an assistant professor of economics at the University of Calgary in Alberta, devised a different approach: the government would set up a fund to compensate drug companies based on how much their new drugs improve the quality of life and how often they were used. These alternatives would carry several benefits, economists say. In addition to making drugs available at lower prices, they would make it much less profitable for pharmaceutical companies to spend millions of dollars to develop drugs, like Nexium and Clarinex, that are protected by patents but offer little improvement over similar drugs already on the market.

The goal is not to spend less to develop new drugs, Professor Hollis said, but to get more therapeutic bang for the buck – by channeling investment to where it matters most – as well as to increase access to the resulting drugs. "This can be done within the same budget as we devote to pharmaceuticals now," he said.

The Industry Veteran is intruiged by this ray of innovative thought in the nation’s paper of record. He writes  for THCB that:

There are some cute ideas here, but in what is rare for a piece of mass media journalism, the author did a good job of pointing out the flaws in each one of the patent-altering proposals. My own ideas on this matter are somewhat similar to one of the proposals. Let the government fund and conduct all new drug research from pre-clinical up through Phase I clinical trials. At that point they would auction off the compounds, each carrying patent exclusivity to run from the auction date and extending a specified number of years. Since the Big Pharma companies are, essentially, late development managers and marketers, my scheme would just rationalize the process. The auctions would attract high bids because the compounds would carry patent exclusivity and not, therefore, become immediate generics. Of course, I don’t know how much this process would reduce drug costs. I suspect it wouldn’t be much at all. The main virtue of my plan is that it would allow clinical needs and scientific evaluation to drive research instead of profit potential. Then too, it might knock down the fiction that Big Pharma propagates about their high R&D costs for introducing every product. People familiar with the situation already know that their claim is BS, but I suppose the current fiction diverts the general public.

Isn’t it just like economists to advise fixing the basement when the roof is leaking? You want to reduce drug prices? Use price controls the way Europeans do. Afraid that will stifle innovation? Use tax policy to end the 50% tax credit and the expense deductions for me-too’s and for cock-raising, wrinkle-smoothing, lifestyle products. That way you give drug companies a simple message: innovate or die.

Five drugs are in risk of being the next Vioxx, the Senate panel looking at Vioxx was told this morning. The remark was made by the US FDA reviewer who is not allowed on the Bextra review panel as he’s already made his call about that one (thumbs down). Crestor, which has been multo discussed on TCHB over the last 18 months is on his list (as is Bextra), and Astra Zeneca’s stock fell nearly 10% as a consequence.

The Viagra "wild thing" ad was adjudged by the FDA to be too hot for prime time (or something) and has now been pulled. Over at Pharma-Mkting list serv John Mack notes:

The FDA pulled the ads because they crossed the line for "reminder ads" – a line that will now be a precedent for judging other reminder ads. But just where is that line? Why don’t the Levitra and Cialis ads also cross that line? If, as mentioned in the WSJ, a woman wearing a man’s loose dress shirt is advertising short-hand for a woman who recently has had sex, why didn’t FDA pull the Levritra ads? Eye of the beholder…

…which gives me the chance to show this great Boondocks cartoon about the first Levitra ads, with the guy throwing the football through the tire (get it? get it??)

60 Minutes had a second (or third) to market piece on Vioxx on Sunday night. It’s about time CBS had a fish in a barrel to shoot, given their complete horlicks they made of the "Bush desertion to rehab in Alabama" story. But they shot this fish, although I don’t think there’s anything new here. Other, of course, that middle America doesn’t read the WSJ or the NY Times, but they do watch 60 Minutes and now perhaps Dodgeball will no longer be a standard procedure in sales teams across America. As one wag on the PharmaMarketing list serv mentioned, how much more does it take for people in corporate America to realize that anything written down in an email may come back to bite you? As the Industry Veteran summarized the Vioxx story:

We should point out the bitter irony that the damning Vioxx memos we’ve been seeing come from Merck, the outfit long regarded as the industry’s most science-driven company and the one with the highest ethical standards. I think for four or five years in a row, they were ranked by Tom Peters or some other flack as the "Best Company to Work For." (Of course that was such a sham because they bought that designation for themselves.) Well what do you know; a memo from their head of R&D, Edward Scolnick, shows they found out in 2000 that Vioxx had a real problem but they spent the next four years trying every which way not to acknowledge it. Then they tried to intimidate researchers who wanted to study Vioxx’s cardiovascular effects, for example, telling the department chairman of an eager Stanford researcher that the latter’s career would "flame out" if he persisted. They also withdrew over $300,000 in funding from the program of a Spanish researcher who was similarly interested in Vioxx’s dangers. To really put the cherry on the whipped cream, Merck started training its sales reps to play "dodgeball" with any physicians who asked about Vioxx’s harmful cardiovascular effects. And these are the guardians of our healthcare for whom we should raise the percentage of GDP spent on healthcare to 18%?

It certainly doesn’t exactly inspire confidence, or give much justification for Bob Ingram of GSK’s latest set of demands for the rest of us to provide the pharma industry.

Will Celebrex and the other Cox-2s follow the Vioxx path? Indications from Canada based on 14 reported deaths suggest that they might. Meanwhile Pfizer is initiating an ambitious and potentially risky clinical trial to try to prove that Celebrex is good for your heart (or at least not as bad for it as Vioxx!) Given that the risks of Vioxx were known for several years by Merck and some others, is the FDA paying enough attention to the safety of the nation’s drugs? I don’t know and I’m sympathetic to the argument Sydney made in Medpundit a while back about the good of the many taking Vioxx versus the incremental risk for the few. However, John Abramson, the author of Overdosed America: The Broken Promise of American Medicine is pretty sure. He writes this for THCB:

Research on Vioxx done for my book, Overdosed America, was included in Monday’s Wall Street Journal article. The lack of public discussion about the two most important lessons to be learned from the Vioxx recall guarantees that this debacle will be repeated again, and again, and again.

The VIGOR study that Merck completed in March 2000, comparing the safety and efficacy of Vioxx to naproxen (Aleve), showed clearly that even among those without a previous history of cardiovascular problems, Vioxx doubled the risk of heart attacks, strokes, and blood clots. Vioxx actually increased the number of serious cardiovascular problems more than it decreased the number of serious gastrointestinal problems. The FDA’s cardiology reviewer wrote in February of 2001 that the increased risk of cardiovascular complications with Vioxx "could lead one to conclude that naproxen…would be the preferred drug."

And the most important finding of the study: The people who took Vioxx developed 21% more serious complications (the kind that cause hospitalization or death).

The problem is that neither of these two findings was included in the November 2000 issue of the New England Journal of Medicine. So doctors were left believing that, even though Vioxx is no more effective at relieving arthritis symptoms and cost many times more than naproxen, Vioxx was the better drug for their patients.

The more general issue (and the primary theme of my book) is that most of even the best information available to doctors and patients is produced and disseminated by commercial interests with the goal of improving their bottom lines, not the health of the American people. Seventy to 80 percent of our clinical studies are now funded by the drug and medical device companies. Among the highest quality research, the odds are still 5 times greater that commercially sponsored studies will favor the sponsor’s drug than will non-commercially funded studies.

If the health care market is to serve the interests of society, the quality of the information that provides the basis for health care decisions must be impartially overseen. The situation that we now have with drug companies funding and controlling most of our clinical research is like a professional football team generously providing the referees for its games.

Many people say that the last thing we need is another federal regulatory body. But not even libertarians suggest that the government should back out of its role in the enforcement of business contracts. In our "information age," accurate medical knowledge is as fundamental to the quality (and cost) of our health care as is the enforcement of contracts to the function of markets.

The fundamental "lesion" in American health care is the normalcy of commercial bias in our medical knowledge–which now grows toward corporate profits the way that plants grow toward sunlight. Until this problem is addressed unsafe and unnecessarily expensive drug like Vioxx will continue to achieve "blockbuster" status, and Americans will continue to pay more than twice as much for health care yet have the worst health of 22 industrialized nations.

As I mentioned the other day, I have another article on oncology in the queue which got pressed for space as the election heated up. Larry Weisenthal, MD, is a board certified medical oncologist with a 25 year history of full time work in the field of cell culture drug resistance testing (otherwise known as “chemosensitivity testing”). More about Larry may be found by looking at his CV. He writes:

The issues and data relating to chemosensitivity testing defy concise summary and can be reviewed on my website. For the moment, I just want to make a brief response to the comments of Harvey Fry (on THCB a couple of months back). Harvey had written about chemosensitivity testing:

I fought for chemo-sensitivity testing of cancers over 20 years ago, and finally lost because of the problems with the tests. First, it’s often hard to get a representative sample of tumor cells by biopsy. Then it’s hard to get them to grow. Then you’re not sure whether the cells that grew out are the tumor cells, or normal matrix, like fibroblasts. Then there’s the delay in starting treatment while waiting for the cells to grow out. Then there’s the question of whether cells in metastases have the same response as those in the primary. But the killer was that the clinical response was not that well predicted by the cell survival tests in the lab. And of course, there was the expense.

Unless there has been some major advance in the intervening years, I can understand the reluctance of some oncologists to go back to it. Alternatives to growing the cells and seeing what kills them may now exist, but they are only surrogates for the real end-point of interest.

Firstly, Dr Fry obviously has no understanding whatsoever of the current technologies, which are based on cell death and not cell growth. To put things into historical perspective, interest in “culture and sensitivity testing” for cancer received a tremendous boost with the publication of a preliminary paper describing a cell growth assay in the New England Journal of Medicine in 1978. When the NEJM talks, people listen. Within a year, hundreds of laboratories were working with this particular cell growth assay, and it did, indeed, pose the problems cited above by Dr. Fry. These problems were exposed in a devastating, negative editorial, published in the NEJM in 1983. The NEJM giveth; the NEJM taketh away. All the laboratories shut down; research in the field virtually ceased, and the take home message in the minds of most clinicians was that the assays had been discredited. Dr. Fry’s comments reflect this thinking.

In 1983, other publications introduced assays based not on cell growth, but on cell death. This was a good 5 years before dissemination of understanding of the concept of apoptosis (a genetically programmed cell death pathway which exists in all cells, which is supposed to cause them to commit suicide if they become functionally deranged, but which doesn’t function properly in cancer cells, allowing them to grow abnormally without committing suicide, but which can be triggered to occur by effective anti-cancer drugs). Because clinical oncologists did not understand about apoptosis, these pioneering publications with cell death (instead of cell growth) endpoints were ignored, and neither clinical trials nor the application of cell death drug resistance assays were supported by academic and private practice clinical oncologists.

Despite the theoretical concerns expressed by Dr. Fry, the clinical utility and clinical accuracy of cell culture drug resistance testing with cell death endpoints has now been proven beyond doubt. These data may be reviewed on-line at: http://weisenthal.org/oncol_t.htm. The issues and data are also available in a 27 minute video excerpt of my testimony before an official Medicare technology assessment committee meeting in Baltimore.

Regarding the “expense” part of it. The tests cost in the neighborhood of $2,000, so it’s a legitimate consideration, but expense has to be put in context. A couple of quick examples:

1) A patient was an ovarian cancer patient with primary resistance to paclitaxel/carboplatin who then underwent tandem stem cell transplant/high dose chemotherapy regimens (at a cost of more than $250,000) without ever achieving a response. At a time when she had bulky, non-cytoreducible abdominal and pleural disease, CCDRT confirmed resistance to single agent cisplatin, carboplatin, and gemcitabine, but good activity for the gemcitabine/carboplatin combination. She subsequently received gemcitabine/carboplatin as an outpatient, achieved a durable complete response, and returned to work full time as an oncology nurse, where she remained well, for four years. The cost of ineffective therapy for this one patient alone would have paid for 125 assays.

2) One of our most “loyal” referring oncologists is financially independent and therefore he is free to manage his patients without any conflicts of interest relating to the fact that prescribing chemotherapy instead of counseling against it has financial repercussions to the oncologist and prescribing certain forms of chemotherapy over certain others likewise has financial repercussions. In the absence of information that some drugs are more likely than others to work, it is “ethical” to choose more remunerative forms of chemotherapy. The assay presents great problems for non-independently wealthy oncologists, because they take away their freedom to choose. The above oncologist recently told me of an interesting anecdote. He had a patient scheduled to come to his office on a recent Wednesday for chemotherapy. This treatment would have earned the oncologist $6,000 for a single patient, for a single afternoon’s worth of treatment. But the patient missed the appointment. The next day was the beginning of the oncologist’s vacation. So he had to arrange for the patient to be treated at the nearby, world famous, NCI-designated comprehensive cancer institute, which billed $28,000 for the treatment and which received 75% of this total (the oncologist knows this, because it had happened before).

The cost of drugs is enormous. And this is only part of it. Patients are “followed” with serial CT scans, MRIs, and even PET scans, just to ascertain if the tumor is growing or shrinking. And the hospitalizations for toxicity, etc. The point is that the cost of ineffective therapy is truly enormous, and the assays are particularly good at identifying ineffective therapy.

In summary:

There have been over 40 publications in the peer-reviewed medical literature showing correlations between cell death assay results and the results of clinical hemotherapy in more than 2,000 patients. In every single study, patients treated with drugs active in the assays had a higher response rate than the entire group of patients as a whole. In every single study, patients treated with drugs inactive in the assays had lower response rates than the entire group of patients. In every single study, patients treated with active drugs were much more likely to respond than patients treated with inactive drugs, with assay-active drugs being 7-9 fold more likely to work than assay-inactive drugs. A large number of peer-review publications also reported strong correlations between the assay results and the survival of cancer patients. These data are completely non-controversial and have
never been challenged or refuted. Thus Dr. Fry’s comment that “the killer was that the clinical response was not that well predicted by the cell survival tests in the lab” is absolutely incorrect.

The material on my website is very complicated (it is targeted to health professionals more than to laypersons). For a short overview of the most important issues, I’d recommend the Frequently Asked Questions section, which was also quoted by Wall Street Journal Health columnist Tara Parker-Pope in her weekly question and answer column appearing in the September 21, 2004 issue of the WSJ.