10th October 2026
The ethical issues preventing black and white clinical studies
Medical research is very difficult. Always has been, always will. One of the main reasons is that designing a study to prove a hypothesis, beyond any doubt, could well be completely unethical. You would be stopped.
To use a historical example. You believe that smoking causes lung cancer? Well, find a few thousand non-smokers, start half of them smoking, and tell the other half not to smoke. Wait a few years and then see what happens?
Bong!
Clearly you are not allowed to ask people to do something you suspect to be harmful. Because of this ethical dimension, there has never been randomised, controlled study (RCT) done on smoking
Nor did anyone try the reverse. By which I mean, find a group of people who are already smoking. Then convince half of them to stop while the other half carry on. Wait a few years, then see what happens.
Why was this not allowed? Well, apart from the fact that smoking is addictive, and stopping is tough, so you are very unlikely to get half of them to stop, if you believe smoking is damaging, you cannot let people smoke away for the sake of your study. You should be trying to dissuade them, not let them continue.
Because of such ethical considerations, Hill and Doll used an ‘observational’ study design. Which means they didn’t ‘intervene’ in any way. Instead, they watched doctors who smoked vs. doctors who didn’t. Then found out who got lung cancer. As it turned out, the difference was massive. Smokers were twenty-five times more likely to suffer the condition.
Observational studies are often criticised for their potential bias(es), and confounding factors. Sticking to the smoking theme here, smokers may differ from non-smokers in many other ways. They could take less exercise, or drink more, or do other unhealthy things. Therefore, any difference you find between the groups could be due to these other confounding factors. And there may be others, you never even thought of at the time.
This ‘confounding factor ‘problem is always a major hurdle in medical research, especially in observational studies. Because of this, Bradford Hill stated anything less than a doubling, or halving in risk, can be safely ignored in any observational study. Too much noise, not enough signal.
However, once you reach a certain point, you overwhelm all possible confounding factors. With smoking, Hill and Doll found a difference of twenty-five. Which means they were looking at something as close to absolute proof as you are ever going to get. Some epidemiologists set the observational ‘proof limit’ at six. I am not entirely sure why this figure was chosen.
The confounding problem also explains why Hill and Doll studied doctors. They reasoned doctors lived pretty similar lives to each other – other than their smoking habits. They then did a lot of research on the matter, by surveying doctors about their personal habits. As it turned out, they really didn’t need to.
Smoking is not alone – there is also LDL/Cholesterol
Smoking is a relatively extreme example when it comes to the level of harm caused. But there are very similar ethical problems in many other areas. Looking at LDL/cholesterol for instance. The best study you could possibly do, leaving ethics to one side, would be to find a way to increase LDL, and see if this leads to an increase in cardiovascular disease.
Obviously, you would never be allowed to do this. What researchers were allowed to do, in the past, was lower LDL to see if this reduced the risk of cardiovascular disease (using statins mainly).
However, the ethical target does not stand still. For example, it is no longer ethical to do a cholesterol lowering study today without giving statins to everyone, in both groups. Once a drug has been shown to be beneficial, you cannot withhold it.
Ergo, the study cannot be:
New drug vs placebo
Instead, the model has to be
New drug and statin vs. placebo and statin
This can also be referred to as ‘new regime vs. standard regime.’
Confounding still stalks the land of randomised controlled trials (RCTS)
Moving onto the ‘gold standard’ of randomised controlled trails (RCTs). Even here, you can still run straight into confounding problems. For example, does a drug that lowers LDL levels have additional effects that could explain any benefit? Effects that you had no idea about at the time.
This is a long-standing argument I have about statins. They lower LDL … fact. They also reduce the risk of CVD, although I believe this relatively small benefit to have been massively overhyped. But statins do not just lower LDL. They have many other additional ’off target’ actions. In medical jargon these are known as pleiotropic actions.
One of the most important of these pleiotropic actions is that statins help to maintain the health of endothelial cells (the cells lining all blood vessels). This is important because endothelial dysfunction is now recognised to be a key trigger for cardiovascular disease.
Statins help to promote endothelial cell health by activating a process called Nitric Oxide signalling. Without getting hyper-technical, here is the key conclusion from a paper on that issue:
‘Statins are widely used to treat hyperlipidaemia and provide pleiotropic effects on the vascular system by regulating eNOS*-NO signalling. Existing evidence suggests that statins activate eNOS-NO signalling to improve endothelial dysfunction and provide a potential therapeutic target in preventing cardiovascular event.’ 1
*Endothelial nitric oxide synthase (the enzyme that creates Nitric Oxide)
There is a very big confounding factor in all statin trials. One that was not known to exist when the trials were done. Does this mean that the benefits of statins are due to increasing nitric oxide levels, not lowering LDL levels. How can you now know?
Or, to put it another way. What would be the best way to prove, or disprove the LDL hypothesis today? As you cannot do trials on statins anymore. There is a way. It is being done.
The best study ever?
I should probably call this, the best study possible – from an objective scientific perspective.
Returning to my original premise. If you want to find out if factor x increases the risk of disease y. You increase factor x This represents your ‘test to destruction’ experiment.
However, I just said you are not allowed to do this. Or are you? You certainly can’t ask for volunteers to have their LDL raised. Unethical would be the immediate cry.
Sometimes, though, fate intervenes in ways that you could never have predicted. As it turns out there are people whose LDL level shoots up. If, that is, they don’t eat carbohydrates. There are not that many of them, but they do exist. These people have to be thin, or lean – and there must be some genetic component here as well.
They have been labelled as lean mass hyper-responders (LMHR).
They began to turn up in higher numbers when the keto/paleo movement began to take off. This is a group who do not eat vegetables, or bread, or rice, or potatoes … at least only in very small amounts.
Instead, they eat steaks, and eggs, and cheese and bacon, and … animal fat. I have to say that I try to be keto. But it is tough Those croissants are calling, as is the gin and tonic. But vigilant Ketos do live among us. Eschewing carbohydrates in an attempt to achieve … something. Avoid dying, I suppose.
In LMHRs LDL levels shoot up. And I mean shoots up. Doubling, trebling, in some cases quadrupling, even more. Why? Let’s leave that to one side here. It gets complicated. You can read about the possible mechanism in the paper ‘Elevated LDL Cholesterol with a Carbohydrate-Restricted Diet: Evidence for a “Lean Mass Hyper-Responder” Phenotype.’ 2
So here, by chance, we have a group of people who have greatly increased their LDL levels, voluntarily. They don’t want to change their diets, and many of them do not want to take LDL lowering medications either. Does this mean they will be more likely to have heart attacks and strokes. That would be the mainstream view.
But do they? Here we have, potentially, the perfect experiment to prove, or disprove, the LDL hypothesis.
There are a couple of immediate problems that crop up. First, getting money to study this from conventional sources is almost impossible. No pharmaceutical company is going to cough up a bean – for obvious reasons.
As for other potential funders. Universities, Governmental organisations? ‘You’ want to do a study that might disprove the LDL/Cholesterol hypothesis…Next!’ No University would want their reputation tainted by such an association.
Another problem is that many lean mass hyper responders are relatively young, and also generally fit and healthy. They are unlikely to have serious health problems any time soon. Waiting for a heart attack, or stroke, could take many years. Decades even.
With regard to the first issue … money, or the lack of. This means the study had to be relatively small. As it was funded by enthusiasts, out of their own pockets. Maor pharmaceutical trials can cost hundreds of millions of dollars.
With regard to the second issue. Which is that you may have to wait a very long time to see a change in hard clinical endpoints e.g. heart attacks. You can, instead study their coronary arteries – arteries of the heart.
These are usually the worst affected by atherosclerosis (thickenings and narrowings). The most commonly used test to look for atherosclerosis is a coronary artery calcium scan (CAC scan). This is, at present, the most accurate predictor of a future cardiovascular event.
No calcium – good
Lots of calcium – bad
Calcium building up fast – very bad.
Like all such tests it is not perfect, but it is pretty good, and widely accepted by most researchers. It has been validated in many different studies.
Bringing all this together. We have a group of people eating a diet that raises their LDL levels dramatically. They don’t want to change their diet, nor take statins (or other LDL lowering medications).
At this point it becomes ethical to study what has happened to them – what is happening to them. Have they, or have they not, developed calcified more atherosclerotic plaques – compared to a well-matched group who do not have raised LDL levels.
Yes, this study is not randomised – it cannot be. It is not placebo controlled – it cannot be. It is not, directly, interventional. Although you could argue it is. In that the LMHR ‘intervened’ with their own very low carb diet. It is an interventional diet – just not one provided for them as part of a trial. Perhaps.
Given these provisos, it is pretty much as good as you are ever going to get.
Next – what happened?
1: https://www.sciencedirect.com/science/article/pii/S0753332224000738
