More on IRBs and restraint on science

Stories over the last couple of days lead us to interrupt our series on natural selection with this brief post on research and ethical conundrums. It's a continuation of a couple of posts from last week (here and here) about IRBs (ethical review committees), bioethics and the idea of societal restraints on what scientists do or are permitted to be funded to do.

Nobody likes restraint, but science is supported by the public and science also has important public implications.  Nothing human is perfect or without potential down sides, including risks.  If society expects to benefit from new knowledge, it will have to pay for things that go nowhere and will also have to assume some risk.  The problem is how to assess work that shouldn't really be done, or paid for, and how to assess risk.

Our posts last week were about the indomitable scientist whose controversial work on engineering viruses--gain-of-function experiments--to make them dangerous went on despite disagreement about the public health consequences of the work.  Is it more important to protect public health by exploring the viruses in greater detail and thus enable the manufacture of better vaccines, or to do absolutely everything possible to prevent the public health disaster that could ensue if the viruses were to escape the lab?  That is, not make the organisms in the first place. 

Again, scientists are basically no more or less honorable than others in our society, and our society isn't exactly famous for its collective unity.  To the contrary, in a selfish society like ours, and when scientists have an idea and there may be money to be made (commercially or in grant funds), or potentially great public benefit, they are going to do what they can think up to get around rules that might stymie the objects of their desires.  That may include shading on honesty or not being as clear or forthcoming, or obfuscating.  Whatever works.  We're great at that--as can be seen in research papers (often, buried in the massive 'Supplemental' material!).  If you think that's not how things work, what planet do you live on?

But by coincidence, just since our posts about IRBs, infectious disease and science ethics, several significant and relevant events have come to light.  Six vials of smallpox virus were found buried in a lab freezer at the NIH in Washington, having been there since the 1954 (as reported by infectious disease writer Maryn McKenna in one of her fine series on this issue) when research into vaccines against the disease was underway, and before smallpox was eradicated; the last case on Earth was seen in 1978.  The vials were sent to the Centers for Disease Control in Atlanta (CDC), where it was discovered that 2 of them contained viable virus; McKenna reports that the samples will be destroyed after they've been thoroughly analyzed.

Officially, only 2 labs in the world still have smallpox samples; the CDC and a lab in Siberia.  The rationale for maintaining these stockpiles is that this would quickly enable whatever research would be necessary if the disease were to reappear -- presumably through biological warfare or terrorism rather than accidental release, but this does now put the latter possibility on the table.

But then in a widely reported story, the CDC found a 'lapsed culture' in infectious disease laboratories, the lax control potentially exposing workers to anthrax and shipping dangerous flu viruses.  The labs have been closed at least temporarily and external review requested.  No one hurt--this time.

Researchers do need to send potential dangerous samples to collaborators, and to work on them in their own labs (where, of course, employees do the actual work, not investigators).  The problem is that if or when an accident does occur, it could be of massively awful proportions.  The problem isn't new -- indeed, McKenna links to a 2007 piece in the USA Today reporting a long list of accidents in US labs handling "deadly germs".  Where is the line, and how do we draw it, to balance between the self- or selfish interest of scientists, the proper concern of government for public health measures, the potential for personal or corporate gain, the potentially major benefit to society, and the risks due to culpable avoidance of ethical standards (such as getting around the IRBs) or ordinary human fallibility?

Life involves risks as well as gains.  But unfortunately, risky research requires regulatory decisions about these issues by insiders, those with the knowledge but also conflict of interest, because it involves regulating themselves.  This is an area in which the public doesn't seem to have adequate means to be the guardians of our own interests.  No obvious solution comes to mind.

Universal statins: scam....or just honest good luck for Pharma...or what?

The American Heart Association and American College of Cardiology issued new guidelines on Tuesday for reducing risk of heart disease and stroke (the first of five explanations of these new recommendations is offered here).  If you've got a 7.5% risk of heart disease or higher, as measured by their risk calculator (downloadable here), they recommend you go on statins.  This means, according to the panel, that 70 million Americans should now be considering taking these drugs.  This is perhaps 70% more than the number who now take them, and would put at least one third of all adults in the US on this drug.  For life. 

These recommendations have caused quite a ruckus, but perhaps for the wrong reasons. Before Tuesday, people were put on these drugs to lower their LDL cholesterol levels beyond a given threshold, but, confusingly to many, that threshold which we had supposed was a well-established rock-solid risk factor, has now been eliminated!  Before Tuesday, the indication for going on statins was high LDL, but the indications have now been broadened to include other risk factors such as diabetes and obesity.  So, people now taking statins wonder if they should continue, and others wonder if they need to start.  Some doctors commenting on these changes hasten to add that the most important protection against heart disease is a healthy lifestyle -- don't smoke, exercise, lose weight -- but if these can't be accomplished, statins are recommended (see Dr Harlan Krumholz on "The Newshour" on PBS, e.g.).

Wikipedia

But the new recommendation seems strange. First, a word about statins, drugs designed to control circulating lipids (fats), which confer heart-disease risks. They inhibit an enzyme called 'HMG-CoA reductase' which is expressed in liver cells as they produce cholesterol from raw ingredients and secret it into the blood stream.  Lower enzyme activity, lower circulating lipids.  But in fact, there is evidence that for some reason statins target inflammation in irritated arteries and veins, which may be what reduces risk of heart disease rather than any effect on cholesterol, so there is mystery even in the supposed reason for their supposed effectiveness.


Now, according to John Abramson and Rita Redberg in an editorial in the Thursday New York Times, statins aren't actually effective at preventing heart disease.

Statins are effective for people with known heart disease. But for people who have less than a 20 percent risk of getting heart disease in the next 10 years, statins not only fail to reduce the risk of death, but also fail even to reduce the risk of serious illness — as shown in a recent BMJ article co-written by one of us. That article shows that, based on the same data the new guidelines rely on, 140 people in this risk group would need to be treated with statins in order to prevent a single heart attack or stroke, without any overall reduction in death or serious illness.

If the recommendation is not based on evidence that everyone can agree is reliable then, where is it coming from? Partly, we think, it's a reflection of our belief that we're immortal, partly a general belief in the benefits of drug intervention.... and partly it's a reflection of the fact that some of the recommendation-makers have a vested interest in statins.

The first reason, our belief in immortality, is cultural, and of course very natural.  Few of us, even apparently those with strong religious belief in life hereafter, want to test out that belief.  Heart disease is the number 1 killer in the US and most of us don't want to die of it.

The second reason is more problematic. The most reliable way to lower heart disease risk is through diet, exercise and not smoking.  Indeed, lean, fit, non-smoking individuals whose only risk factor is high LDL are generally at low risk of heart disease.  Until this week, the purpose of statins was to lower LDL cholesterol, but that doesn't reliably lower risk of heart disease. So, are statins a good replacement for life-style?  The answer is No.

But what about the vested interest issues?  As Abramson and Redberg say:

The process by which these latest guidelines were developed gives rise to further skepticism. The group that wrote the recommendations was not sufficiently free of conflicts of interest; several of the experts on the panel have recent or current financial ties to drug makers. In addition, both the American Heart Association and the American College of Cardiology, while nonprofit entities, are heavily supported by drug companies. 

This kind of conflict of interest means that one must be highly suspicious.  One might argue that industry reps are the most knowledgeable about the benefits of their product.  If you want to know how to cure a toothache, ask a dentist, after all.  But how are we to judge the motive behind the recommendations?  Corporate-sponsored research is notoriously biased toward findings favoring their sponsor.  This doesn't mean the bias is intentional, but the evidence suggests that often it is.  At least, the corporate-sponsored research the corporate sponsors tell us about is that which favors their product, since they aren't in fact required to report all their results, and often don't.  (This is why Ben Goldacre, physician, writer and epidemiologist, started the AllTrials campaign to require that all clinical trials be registered, and all results be reported, positive and negative.)  So, when the science isn't convincing, and vested interests are involved in decision-making, it's not unreasonable to be suspicious.

Contingency and context
In addition, the related roles of context and contingency are fundamental and important to understand here.  Risk of heart disease is based on the context--genomic and environmental exposures affect the levels of statins and their consequences.  The risk in an individual is contingent on his/her situation at present, and that can change.  This seems so hard for the established system to understand!

Statins have side effects.  Risk of statin-related disease is estimated in the context of current culture.  If that culture changes, then the risks will change and by all that we know, they'll change dramatically.  If the major contexts change--better diets and so on, things we know a lot about--then the overall risk of heart disease will change.  Models can only do so well at estimating the interaction among the various factors (as the above quote suggests).  If people live healthier lives and if physicians actually pay attention to risk calculations, many may be able to go off their statins, or not start on them, as a result.

But how many will actually risk going off?  Will they keep taking, or their physicians not dare to recommend stopping, for various subjective, inertial, or even emotional reasons?  Will drug companies recommend cessation if, say, body weight goes below some value?  Will they fully advertise the fact that if other factors are favorable, to stop buying their product?  What does history--including their history--suggest to you?

And 10 years from now, how accurate will the predictions have been on which lifelong medications are now being recommended?  Will results be contingent, for example, on the current recommendations themselves?   For example, if you're on statins, will you be more likely to take that second helping of fries, feeling protected by the drug?  The Times Op-Ed puts it this way:

Perhaps more dangerous, statins provide false reassurances that may discourage patients from taking the steps that actually reduce cardiovascular disease. According to the World Health Organization, 80 percent of cardiovascular disease is caused by smoking, lack of exercise, an unhealthy diet, and other lifestyle factors. Statins give the illusion of protection to many people, who would be much better served, for example, by simply walking an extra 10 minutes per day.

These are not secret or new issues by any means, but they tend to be overlooked or minimized by a system that tries to be 'objective' based on current data.  The Op-Ed is written by respectable authors, but they are also known skeptics of the over-medicating problem, with its built-in conflicts of interest as we noted above.  So is their skepticism itself a disqualifying issue--does it mean they bias their views in a similar way to having Pharma-supported people on the panel that made the new recommendations?

Clearly, the issues are complex as so many issues related to late-onset disease are.  After all, you don't get a heart attack even at a young age like 40, unless you live to be 40.

Like second-hand smoke?  The real beneficiaries
Smokers get all sorts of diseases, because of the direct effects of the ugly weed.  But those who live in the same house also get diseases, indirectly, courtesy of their smoking cohabitant.  We have just the opposite story here.  The vendors of statins will get filthy rich as a direct result of their recommendations, whether or not they actually prevent heart disease.  And if they do, some other people--maybe the same people--will get even richer as an indirect result of the same recommendations!

If we don't die of heart disease or its associated diseases, we may live longer but that means more of us will get the slower, nastier, very expensive lingering ailments of old age.  The surgeons, retirement homes, cancer and dementia drug-makers will rake it in big-time!

We've written a few times about the subtle, surreptitious problem of competing causes, and this is another manifestation of the problem.  It's largely unavoidable that if you survive the quick-hitting earlier causes of death, you'll last and linger in service to the slower causes.  They're even more expensive.

We would not credit (nor blame) the statin-promoters for the diabolical scheming that would be involved in salivating over the indirect benefits of statin use.  That takes more perception and a longer view than most people, even scientists, usually have.  It is clear that most drug companies, not to mention the scientific research community itself, as we often write, are in for the quick kill, so to speak.