Monthly Archives: September 2009

Risk, statistics and ethics: the AIDS Vaccine

This idea of risk that we have been discussing on TBU for a while now has come up again. The results of a new HIV/AIDS vaccine study were released this week. The Thai trial has shown some promise. The incidence of HIV was 30% lower in the group vaccinated with RV 144 than the control group.

First: the basic bioethics question. Was it OK to give a lot of people a placebo which might let them think they were protected from HIV when they were not at all protected? (Answer: Yes) First-off, they were not told that they were getting an effective drug. They were told they were getting either a placebo or a probably ineffective, experimental vaccine. So the subjects knew beforehand that this shouldn’t be considered a real vaccine.

Second question: why not just give the vaccine to everyone in the study (16,000 people) and compare the effectiveness to the general population? The problem is that you would have a change in HIV incidence that was due to lots of factors. Behavior, knowledge, unknown risk factors (maybe people at higher risk had a greater desire to be in the study than the general population) all could affect the measured efficacy. How would you know which produced your result?

If the vaccine were 100% effective, then there would be no need for a placebo controlled trial. But nothing is 100% effective and – besides – how would you know before you tried?

Now, here’s the more difficult bioethics question: if you have a 30% effective vaccine, who should get it?

This is more tricky. You don’t want to encourage risky behavior (the ‘conservatives’ are always concerned about this). So there is a question to be answered by a careful psychology study: do people modify their behavior after receiving a drug that may or may not prevent a transmissible disease? It seems like they might, but scientists don’t make decisions on “might” if they can avoid it. We make decisions based on what is demonstrably consistent with experiment.

But then it becomes a quantitative statistics problem (more statistics!). It’s only worth vaccinating people if their behavior changes don’t outweigh the efficacy. And then it’s only worth vaccinating people who are at risk… but what if the higher risk people are more prone to behavior modifications? Is is possible to isolate a medium-risk category?

And in all of this, there are massive political problems, not the least of which are form the anti-vaccination people, which I will talk about next week. The vaccine is a real achievement, in any case. Lots of people thought it wouldn’t work. And it reminds us how complicated it gets when trying to do the right thing with imperfect tools.


The data will not lie

Consider empirical skepticism: a high standard for physical evidence before committing to a belief. One might be tempted to think that this means “I’ll believe it when I see it.” Strangely, this is not the case. Example: A few short centuries ago, doctors “saw” imbalanced humors and bad vapors, and they “saw” people cured when those conditions were relieved. The “evidence,”confirmed their incorrect theories because it was limited and not properly examined. Skepticism was the idea that maybe the deductive reasoning from the theoretical premises of the day (four Aristotelian elements, humors, etc.) might be flawed because the theories were affecting the perceptions of the outcome.

Skepticism said: “Don’t trust your eyes. Trust the data.”

Modern surgical technique was developed by Joseph Lister who reportedly said “it’s as important to wash your hands before surgery as after.”

Think of how radical that is! It is tantamount to saying “don’t trust what you can see. I know you can’t see the thing on your hands that will kill your patient. I don’t even know what it is. Some Frenchman named Pasteur thinks maybe he’s on to something about that. Look, just trust my blind data that tells me that more people survive surgery if I wash my hands.”

We fancy now that it’s so obvious that there are these invisible things called “bacteria,” that anyone with any sense would figure that out from a few simple observations and “common sense.” Quite the contrary. As a doctor or a researcher, it is critical to remember that your conception of the world changes your perception of the world. The data is the only thing that will tell the truth, and it will only tell you the truth insofar as you ask the right question with your experiment.


Statistics, drugs, and hard ethical questions

The New York Times has an article this morning on the FDA and drug approval process and some interesting controversy surrounding experimental cancer treatments. (Did you know you can get the NYT on the Kindle? Cool stuff)The FDA’s lead cancer guy is under attack from both sides of the debate. Some people say that he’s letting unsafe, unproven drugs get through and others say he’s holding back life saving treatments with unnecessary bureaucracy. Strangely, both camps are talking about the same drugs. It’s a pretty good article. It gets to the heart of the matter: Gleevec has obvious, amazing benefits. It goes through FDA review really quickly. Other drugs are subtle. And in that subtlety is the controversy.

Arthur Benjamin did a TED talk where he suggested that high schools forgo calculus in favor of statistics. I tend to agree – calculus is really important for scientists, but they can get it in their freshman year at University. To make sense of this and many other important ethical issues, everyone needs some statistics background. How many people need to suffer as a control group without treatment in order to assess whether a drug is subtly helping?This is a pretty hard statistical question. “Just look in your heart and your conscience will be your guide” just doesn’t cut it for these kinds of questions.

For instance: Aspirin seems to help prevent heart attacks. Out of 22,000 people, 56 per year had heart attacks with aspirin as compared with 96 not on aspirin. That implies that taking aspirin is a good idea, but without thousands of data points, it would be impossible to tell. If you only had 220 people, you get absolutely no conclusion. Look at it this way: if you take aspirin every day and don’t have a heart attack this year, you may be one of the 40 people who aspirin saved, or one of the 21,904 who wouldn’t have had a heart attack anyway! All you know for sure is that you’re not one of the 56 people who had heart attacks.

What we know is not what we think we know or what our gut instinct or common sense might tell us. At 546:1 odds against low-dose aspirin having any effect, it seems stupid to take it except that it’s so cheap it’s almost free, virtually no side effects, and heart attacks are serious as… um… well, they are really serious. If aspirin cost $10 per dose and caused erectile dysfunction, I doubt it would be worth taking. But what if it cost $1 per dose and sometimes (1:10,000) caused permanent deafness? Should your grandmother take it? Let your heart be your guide.


nootropics, smart drugs, supplements and natural focus for medical students

It seems that medical students are using nootropics, or smart drugs (AKA brain enhancers, energy enhancers, focus, liquid nap, etc.). These things are supplements, prescription medications, and non-prescription gray-market pharmaceuticals which some literature suggests may make a person more able to perform academically. They make you “smarter,” but probably only some of them and probably only a little, and probably not really “smarter,” but rather more focused or attentive. And, of course, they all are supposed to be a lot better than good, old fashioned, cheap caffeine.

Some of the more common ones I’ve heard about are Adderall and Ritalin, both of which are (technically speaking) stimulants. I’ve heard anecdotes from people who have stayed up all night studying on amphetamines (highly illegal and not in the least recommended). The newer designer drugs like Provigil are becoming popular as well.

They all work a little differently. The stimulants tend to produce symptoms like OCD (obsessive compulsive disorder). In fact, even pseudoephedrine (Sudafed, cold medicine) can cause OCD-like impulses as a side effect. Psuedoephedrine is related to ephedrine, which can be harvested from the Ephedra plant which is now illegal as a dietary supplement (because it’s basically speed). Don’t be fooled, “natural” speed will cause as many problems as synthetic speed. I suspect that all those kids who can’t pay attention in class could be better served than inducing a low-level OCD compusion for studying, but that’s neither here nor there.

Provigil is a more targeted stimulant that shuts down the sleep/tiredness centers of the brain. No jitters, no OCD, and no urge to sleep at all. If you need to stay up, this is probably safer than high doses of caffeine. Why do you need a prescription? Eh, who knows, probably because doctors like to charge you a couple hundred for the privilege. Oh, and the pills cost about a buck a pop.

If you need to bone up on a subject quickly, you may be able to get your physician to prescribe any of the above (even speed, interestingly, though no reputable doctor would give that out as study aids). I’ve never acquired any of the above, but if I wanted Provigil I would complain of persistent tiredness that was interfering with my daily life and mention that I read about Provigil in Reader’s Digest.

OK, what about “natural” alternatives? Well, there are lots. I take cod liver oil since I don’t eat much fish and the omega fatty acids are supposedly good for me and (who knows) it might help my brain. It comes in totally benign little liqui-caps and it’s cheap. There are lots of others. They probably don’t work better than a placebo. But then, a placebo might be exactly what you need! So give them a try. Choline, Ginko, Dimethylaminoethanol (also known as DMAE) are all sold in health food stores and might be just the placebo you’re looking for.

There are also a bunch of unregulated compounds that the FDA has not forbidden or approved (as far as I know). They can be imported from outside the U.S. if you want to risk being the person that the government decides to make an example of. Adafinil Adrafinil is one that can be acquired that way, as well as Piracetam. Honestly, I would recommend against going that route, but hey, if you want to try unregulated pharmaceuticals from France, google up a batch and let me know how it goes!

In the next few hours if you got here looking for something right now, caffeine is probably the best bet. There are cheap pills and even caffinated mints available at your local pharmacy over the counter if you just can’t stand coffee.


Know your placebo: fight depression with blank pills

The placebo effect is far more interesting than it might seem at first glance. It’s not just lying to oneself. A fake painkiller actually does kill pain, not just convince the subject to say that they feel less pain. So, when the placebo effect gets stronger and overwhelms real pharmaceuticals with good biochemical research to back them, what is a scientist to do?


Wired magazine explore the issue. If you’re a medical student, or a scientist you must consider the effect of your control on your interpretation. It’s a common benchmark for drugs to assess efficacy (does it work?) by comparing to a placebo. That’s reasonable. But it’s probably worth also including a null, no intervention control to see how well the placebo works, too, if possible.