The Futile Cycle

In the latest entry into the whole Avandia (a.k.a. rosiglitazone) deal, yet another meta-analysis published in the Annals of Internal Medicine shows no statistically significant increase in cardiovascular risk from Avandia, further giving weight to the quote from Ernest Rutherford, “if your experiment needs statistics, you ought to have done a better experiment.” Or weight to any number of other quotes, including Mark Twain’s, “there are three kinds of lies: lies, damned lies, and statistics.”

So, in conclusion, drugs have side effects, sometimes which are risky. (oooh.) Maybe Avandia has some, too, but no one knows. All Steve Nissen’s study shows is that we should conduct a clinical trial specifically to address this issue before making any more definitive conclusions.

A great post by Rangel MD on why medicine will always, no matter what, have inequality of care, at least unless you ban private healthcare, and paying doctors extra cash to treat you better.

On the BBC, Israeli scientists try to circumvent chemotherapeutic sterility for girls with cancer. Essentially, the problem is that little girls with cancer can generally be cured with chemotherapy, but the aggressive regimes can sometimes leave the girls sterile. Thus, what the scientists did was isolate (surgically) unmatured oocytes and chemically induce them to mature, turning into eggs, which can be frozen to be used for in vitro fertilization (IVF) later in the girl’s life. An interesting idea, essentially “time-shifting” the eggs.

Anyway, they have a strange quote from an activist, Josephine Quintavalle, who demonstrates that she doesn’t know biology very well:

Josephine Quintavalle, of Comment on Reproductive Ethics expressed concern that if the eggs were donated to a woman of childbearing age, a resulting child could have a biological mother who was only a few years older. She said: “Are we going to end up with a child who has a mother who is just six years older? What happens if the child dies? Could the eggs be donated to someone else?

In case Ms. Quintavalle doesn’t realize, the current model of egg maturation in humans is that eggs essentially remain dormant, and usually only one matures at a time during each menstrual cycle (if more than one matures, it can lead to fraternal twins, triplets, etc.). Which means that a woman’s eggs in her ovaries haven’t aged very much compared to the woman herself, anyway.

To put it another way, let’s say someone donates eggs, and they sit for 100 years until someone else uses them for IVF. Assuming the science can actually do that, is it wrong that the “biological mother” (i.e. the egg donor) might be some 120 years older than the child? It’s not really any different (from an ethical point of view) from having the egg donor be a 5-year-old. Eggs are eggs, as long as they’ve matured properly. Now, there are plenty of objections one can make on the biological viability of the eggs, or the ethics of creating life by a procedure that may or may not lead to unexpected health consequences. This objection seems pretty groundless.

Strange that an activist on “reproductive ethics” would demonstrate so little knowledge of human biology. Really, what Ms. Quintavalle is exhibiting is nothing more than being squeemish:

I feel uncomfortable about this development.

That’s really the only thing she’s correct about.

Genentech’s CEO, Dr. Arthur Levinson, gives an interview in the Wall Street Journal on drug pricing and development. It’s a great article, and it can answer a lot of questions that people might have for the seemingly outrageous prices of biological drugs such as Avastin, Herceptin, and Lucentis, all of which are made by Genentech. There’s nothing here that people in the biotech industry wouldn’t already know, but it’s a wonderful look inside for the general public. Levinson also has a great point about generic biologics:

Makers of pharmaceutical pills can show chemical equivalence easily. But if you are producing a biological, it is not made by chemical synthesis. It is made by a Chinese hamster’s ovary cell or an E. coli bacterium — a very complex route. We do not yet have analytical techniques to tell you that a copy is clinically identical to the innovator’s drug. Our recommendation to the FDA would be to simply require a clinical trial to make sure that the drug is behaving in the clinic as expected.

I sometimes jokingly refer to the study of metabolic pathways as “old school” biochemistry, from the era of Hans Krebs, Melvin Calvin, and Konrad Bloch. More often than not, when you hear “biochemistry” uttered by a molecular or cellular biologist these days, they’re referring to measurements of how much proteins stick to each other, not studies of the biosynthesis of a sugar or other molecule. Really, it’s kind of a divide between biologists and chemists. When organic chemists talk about biochemistry, they still pretty much have old school biochemistry in mind, whereas biologists don’t seem to think of that too often.

Still, “old school” biochemistry is still kicking, and its study still generates great life-saving cures, like the Statins, which inhibit HMG-CoA reductase. Metabolic diseases are still some of the highest causes of death in the world, so the study of all these pathways by med students is still of great use. As an aside, Harvard, of all places, doesn’t really seem to have a biochemistry course (the closest is the “Chemistry 27″ course on topics in bio-organic chemistry). Guess they figure the students can always look it up and learn it later if they need it.

One thing I really like about medicines targeting metabolic pathways is that sometimes (and this is just sometimes), there’s something just refreshingly intuitive about the approach to those diseases. Too much cholesterol? You can keep it from being made (e.g. via statins) or you can get rid of the excess (via bile acid sequestrants, like cholestyramine). The latter method is quite interesting; though statins get all the press, bile acid sequestrants apparently also work quite well (but they’re not as easy to take as popping a statin pill). These are essentially resins that a patient swallows, which then absorb bile in the intestine. Thing is, bile is made from cholesterol, so if you remove a lot of bile, the body tries to make more from the cholesterol, thus draining the amount of cholesterol in the system. Pretty harmless.

Another really interesting application of “old school” biochemistry in medicine cropped up in the science news recently, with a 25-year study that was published in the NEJM today. See, the urea cycle processes the nitrogen in the body, breaking down proteins and removing the nitrogen parts as urea, which goes into urine. Some people, however, are born with defects in the urea cycle, which can lead to having too much nitrogen in the blood in the form of ammonia. Ever smelled ammonia? Yeah, don’t want too much of that in the blood. People fall into comas because of it.

So, what to do? How about supercharging another pathway in the body that gets rid of nitrogen atoms? One way is to hike up the synthesis of hippuric acid, which is the form in which the body gets rid of benzoic acid. Hippuric acid is just benzoic acid with a glycine molecule attached; glycine is an amino acid with one nitrogen atom in it. So, just add a bunch of benzoic acid (or sodium benzoate, which is equiavalent), and when the body tries to get rid of that, glycine will hitch a ride! It works quite well, according to the study. The other way to help is to form phenylacetylglutamine, which is phenylacetic acid stuck to a glutamine molecule (which is another amino acid). Glutamine has 2 nitrogen atoms per molecule. Even better! So just hike up the phenylacetic acid in the body, and in the race to get rid of that excess, the body will get rid of a bunch of glutamine with it. Put the two ways together, and you get a great way to reduce the ammonia levels in the blood. Pretty neat, I say!

One of the most popular mathematical modeling topics in immunology is that the slow crumbling (over the course of almost a decade) of the immune system in an HIV infected patient, specifically the decline of “helper T cells” (technically known as the CD4+ lymphocytes). There are many hypotheses about how and why this happens, but each model has difficulty explaining all aspects of the disease.

Recently, in PLoS Medicine, a cool mathematical model rules out one of the hypotheses, the “runaway” theory. In that model, helper T cells, which recognize infections and activate other cells in the immune system, keep getting destroyed because each T cell gets infected, which produces more HIV, and which activates more T cells, which get infected, and so on, like a grain of sand snowballing into a giant avalanche. The mathematical model captures the essence of the immunological processes, and although (Camelot!) it is only a model, the whole point was to show that, at least based on our current understanding of the immune system, the “runaway” hypothesis would predict T cells numbers to fall very quickly (in a few months), rather than taking many years to fall.

Strangely, they do not mention Martin Nowak’s pioneering work in HIV population dynamics, which is well summarized in a review article from Bioessays (D. Wodarz, M. A. Nowak (2002), Bioessays 24, p. 1178-87). I took a great mathematical evolutionary dynamics course from him last semester, and he walked us through the logic for his phenomenological model. Essentially, he hypothesizes that any specific form of HIV is hunted down by the immune system relatively quickly and destroyed, which can be seen by the sharp drop in a patient’s viral levels shortly after infection. The human body generates very specific T and B immune cells to hunt down that version of HIV. The problem is that HIV mutates so rapidly that new forms of HIV are constantly being evolved within the patient, and over time, as the immune system tries to generate more and more different versions of T and B cells to go after each of the different cell types, the immune system just stops being able to keep up with the evolutionary rate of the HIV virus. Eventually, the HIV just mutates fast enough that all the different versions, together, overwhelm the immune system and cause AIDS. Using some experimental estimates, Nowak actually simulated his model on a computer, and found that it reproduces the time course of the disease, the slow drop in helper T cell levels, and so on.

I find it interesting that even after all these years, people are still “discovering” this mechanism for HIV, who seem to be unfamiliar with Nowak’s work. These physicists from 2006, for example, seem to just reproduce Nowak’s work, and don’t cite him at all. Note that Nowak came up with his model in the mid-1990s, so it’s been almost ten years, and still his model gets missed!

I never really understood this, but for whatever reason, some people really think of vitamins as kind of a be-all-end-all cure for all sorts of health issues – and many times, this is how they are marketed. I think it might have started with Linus Pauling and his bogus Vitamin C obsession, but the strange idea that large doses of vitamins will prevent all sorts of cancers and metabolic diseases seems to have caught on very strongly in a variety of weird parts of the country, especially the New Age, alternative medicine crowd. I think that might have something to do with the perceived high price of drugs, the popular hysteria about “artificial chemicals” and their effects on the body, and a distinct anti-corporation distrust of the pharmaceuticals industry and mainstream medicine.

(As an aside, I myself have noticed that Asians seem to be very partial to the “supplement craze”; maybe it has a lot to do with their centuries-long fascination of bogus health remedies and bodily “balance”, as with the Daoists? But Europe does have some past with that kind of thought, such as the balance of the bodily humors idea of Galen. So why does Daoism still have such a great hold on Asian popular thinking, while the humors theory lies in the wasteland of discarded thought? Is it because of the Enlightenment that took hold in the West?)

Anyway, vitamins probably aren’t really a cure for anything except, well, vitamin deficiency, and finally more and more studies are coming out debunking the “New Age-y” obsession with vitamins and multivitamins. It doesn’t seem that there’s much science at all to support any of the vast claims that supplement manufacturers claim.

First, the direct-to-consumer side of things. A recent NEJM article raises a good point about the legal feasibility of congress banning direct-to-consumer ads; there’s the first amendment, after all, and there’s a history of the Supreme Court overturning federal bans on the advertising of a variety of substances in the interest of public health, including alcohol, tobacco, and so on.

I, for one, don’t believe that direct-to-consumer ads have any educational value whatsoever, but the preservation of the freedom to advertise in a public forum is very important. We want to make sure that there is enough freedom for things like political advertising, but we also want to make sure that advertising that lowers the overall societal welfare, such as direct-to-consumer ads, get regulated, or even banned. After all, the first amendment is primarily oriented towards politically motivated speech.

Another article, from a few weeks back, was “Following the Script”, from the April issue of PLoS Medicine. It reveals a window into the world of pharmaceutical drug representatives (Drug Reps), who market pharmaceuticals to doctors. Of course, drug marketing is very similar to other business-to-business marketing, in that there is endless networking, false smiles, gifts, hand-shaking, memorization of personal details, tailoring of the message to the target, and so on. Still, the article does show how these are applied specifically to doctors. I really enjoyed reading the table showing how the marketing is tailored to the doctor’s personality. Particularly interesting is the way they approach the “Aloof and skeptical” doctor:

I visit the office with journal articles that specifically counter the doctor’s perceptions of the shortcoming of my drug. Armed with the articles and having hopefully scheduled a 20 minute appointment (so the doc can’t escape), I play dumb and have the doc explain to me the significance of my article.

The intent of the marketing is not education, no matter what the drug companies might claim. Marketing is always about sales. After all, (as the article says) “If detailing were an educational service, it would be provided to all physicians, not just those who affect market share.” Still, one cannot deny that there is currently no good substitute for drug education by drug companies. Even though studies show that doctors still accept gifts from drug companies, drug reps do accomplish getting the name of obscure drugs out, and they do distribute scientific literature. Doctors are busy people; they don’t have time to trawl through the literature all day, as it takes time away from patients. A short blurb from a drug rep can be better than nothing.

In addition, the whole situation marketing situation is a giant prisoner’s dilemma; if a drug company decides to be “noble” and not market to doctors, it will lose sales pretty quickly to the drug companies that don’t have such idealism. There’s really no good incentive for drug companies to stop marketing. If one has to criticize anyone, perhaps one should criticize the doctors for being so easily swayed; but doctors are human, after all, and marketers are very, very good.

Perhaps the group the public should really criticize is the AMA, which for all its statements of ethical guidelines for gifts to physicians, still sells a demographic database to drug companies for more than $40 million a year that allows drug reps to figure out the prescription habits of each individual doctor.

In the Pipeline has a nice post about why it’s kind of hypocritical that Brazil break Merck’s patent on an HIV drug. Seems all sorts of disputes are occurring these days as drug development becomes a more international issue, and as poorer nations become wealthier, but balk at the responsibility that such wealth comes with. Novartis has been having similar problems with the Gleevec issue, still.

There is a really great post and discussion on Marginal Revolution on a book, Money Driven Medicine (by Maggie Mahar) about the source of the spiraling costs in American health care that don’t seem to improve patient health at all. The best part is the comments, I think. There are some good commenters, and then the author comes to respond to some of their questions.

I really like this part of a comment from Yancey Ward:

Our problem is that we treat medical advances differently than we treat other technological advances…

In the early 80’s, the first personal computers cost over $10,000 a piece. Such computers were only purchased by people with the means to do so, and no one really questioned this inequality- for almost all new goods and services, it is only the upper income cohort that can afford to purchase them. This was true for personal computers in 1981 as it was true for automobiles in the early 20th century….In addition, one will surely find examples of luxury goods and services that never really spread down through the lower income cohorts because they were ultimately found to have no benefit or use-in other words, they were found to have no larger potential market.

However, when it comes to medical goods and services, especially goods and services that claim to be life-saving/prolonging, the inevitable inequality I wrote of above assaults our sense of fairness. We demand that such goods and services be available to all regardless of the cost and the efficacy. All other new goods and services first prove their worth to the small cohort that can afford the luxury of trying them out, but this is not the case with medical care- we consider it unfair that the wealthy can afford new cancer treatments of questionable worth- thus the process of real-world testing of efficacy is short-circuited. (Emphasis mine)

We seem to have the perverted thought that good health should have no price, and that all patients deserve the latest and greatest, when simply prescribing last year’s remedies (or even the old soap and water) would be significantly cheaper and create real improvement in the patient’s life, with only a tiny extra benefit from using the newest drug instead.

There’s also a good comment from “happyjuggler0″:

When Pharma comes out with a new drug treating something that was previously untreatable, it is meaningless to say that costs for that treatment have shot up, since there was no treatment for it before. Eventually, rather quickly I might add all things considered, this drug will go off patent and become dirt cheap. each year more and more drugs go off patent, and thus in reality drug costs are going down radically, not increasing.

From Maggie Mahar:

In the mid-ninties insurers were fairly successful at containing costs (if not improving care) for a few years–but the backlash was so great that they began losing customers. As a result, at the end of the nineties insurers decided to just cover whatever consumers asked for–and pass the cost along in the form of higher premiums. This explains why premiums have risen 87% in the past six years.
….
Why can’t consumers themselves push back–and demand lower prices and higher quality (as they do when shopping for other goods and services)? It’s not because they are, as Nathan puts it “you know, too lazy to actually talk to their doctor.” It’s because, first of all, they are sick….Secondly, even if they are not elderly, in pain or frigthened, the subject that they need to master is dauntingly complicated.
….
Moreover, the consumer is not in a position to push down prices because when you are dying of cancer (or congestive heart failure, etc.) you are not bargain-hunting. You become a “price-taker”–you will pay whatever price is necessary to end the pain, prolong life, be able to get up out of bed and function, etc.

Even if you are paying out of your own pocket you will do whatever is necessary to come up with the money–which is why medical bills are the leading cause of personal bankruptcy in this country.

One thing I don’t see, though, is why Maggie Mahar is lenient on insurance companies for being profit-driven, while blaming pharma companies on being profit-driven (in her comment, at least; I plan to read the book soon). She says, “After all, a for-profit corporation’s first reponsibility, by law, is to its shareholders–not to its customers,” but is far more reticent to give that excuse to drug companies: “Arguably, a for-profit manufactuer that promotes its product as widely as possible is only doing its job. (Though one would like to think “caveat emptor” shouldn’t have to apply when it comes to products that could mean the difference between life and death for the customer.)” Partly, it’s because it’s easy in this society to demonize pharmaceutical companies. It’s even possibly the fashion, right now. They do sometimes do unscrupulous things. But they don’t always, and there are plenty of people in their ranks that work hard at a very difficult task.

She also says,

For years, drug-makers and device-makers have fought tooth and nail against “head to head” comparisons that would test the effectiveness and safety of a new product against the older, less expensive product that it hopes to replace. And what’s amazing is that drug-makers and device-makers have won this battle: In order to earn FDA approval for a new product, the manufacturer only has to show that the benefits of his product outweighs the risks WHEN COMPARED TO A PLACEBO.

I really don’t see what’s wrong with comparing to placebos. The FDA is just supposed to be a gatekeeper screening for safety and efficacy. Why does everything have to be an improvement over what exists already? Knock-offs are good for consumers, too, because they increase competition and lower prices. How cheap would painkillers be if there was only one kind? Maybe cheap, maybe not, but because of competition, I can walk to a CVS and buy a 200 tablet bottle of ibuprofen (”Advil”) for $7.

Now, just because pharma makes the knock-off doesn’t mean doctors have to prescribe it. Of course, they need to know the data in order to decide what to prescribe. What is needed is an organization of researchers and doctors to do more head-to-head comparisons that would actually determine the efficacy of new drugs and determine standards of care, because doctors are really the gatekeepers of health care. I’m sure this already happens, to a certain extent, but it needs to happen more. Patients can’t negotiate the system, insurers are unwilling to, and do you really want pharma to stop producing drugs? Doctors are the ones prescribing and advising; that’s part of their job, so something should exist to help them. Now, if pharma and drug companies have been preventing head-to-head comparisons from happening at all, then fine, hound them for it. But I don’t think they are, since I’ve seen plenty of them appear in the wild.

Read the whole thread, if you have time; it’s very good, and Maggie Mahar makes some very good points, not all of which I agree with.