Medicines mainly effective for the ideal test subject

Medicines mainly effective for the ideal test subject

What if international criteria are so strict that 80 per cent of all patients are excluded right from the start?

03-02-2022 · Science

Medicines that are prescribed in the case of psychoses are only tested on patients with mild symptoms, a recent UM study showed. And not so surprisingly, they seem to work best for them. It does raise the question to what extent test subjects are representative of all patients?

They are known as the golden standard in medicine, the randomized controlled trials, or RCTs. For this, you split the patients into two groups, of which one group receives a new treatment or medicine and the other doesn’t. Then you calculate whether one group did better than the other. This looks like a watertight procedure, one would say, until you zoom in on the test subjects. What kind of patients are they? Do they actually form a good reflection of the patient population as a whole? 

Last week, a study into antipsychotics led by Maastricht University, showed that this is not always the case. Antipsychotics are pills for patients who suffer from psychoses - a total of 150 thousand people in the Netherlands. 

Patients must meet all kinds of criteria for participation in these medical studies. That is not so strange, but what if these international criteria are so strict that 80 per cent of all patients are excluded right from the start? Anyone who is or has been an addict, for example, is not welcome, just like all those who are taking antidepressants, those who have physical complaints, those who have suicidal tendencies, et cetera. 

Researcher and psychiatrist Jurjen Luykx, who works for the universities of Maastricht and Utrecht, applied this criterion to 40 thousand psychotic patients from medical records in Sweden and Finland. Then is appears that only 20 per cent of the patients are suitable for participation in such RCTs. Only the patients with minor symptoms. 

New medicines work best for them, Luykx analysis showed. The rest gained from it too, but also reported side effects more often. 

Lung cancer

The exclusion of large groups of patients is an important and well-known problem, says André Knottnerus, emeritus professor of Medicine at the UM and former chairman of the Health Council. Not only in psychiatry, but in medicine as a whole.  

A study conducted in Utrecht last year showed that the test subjects who participated in the research into a new treatment of lung cancer lived a quarter longer than patients who received the same treatment in practice. The selected test subjects here also turned out to be fitter and less sick.

Knottnerus: "The stricter the selection through exclusion criteria, the less diverse and often less seriously ill the group of test subjects. Doctors therefore notice that the tested treatment or medicine doesn’t work as well sometimes for their own patients in the surgery."

Haemorrhaging

Patients are excluded for two reasons, says Knottnerus. "In the first place, researchers fear that vulnerable patients won’t come through the experiment without suffering damage to their health. If you are testing an anticoagulant, you don’t want test subjects with additional diseases that increase the risk of haemorrhaging. At the same time, the medicine is also relevant for this group. This cautiousness may thus result in the group of test subjects being healthier than the average patient.”

"In addition, researchers expect to be able to show the effects of a new treatment more easily when the group of test subjects is homogeneous, if the seriousness of the disease, the symptoms, and personal characteristics (such as age) are similar.

There is something to be said for that, says Knottnerus. "But I would say: first do a pilot with a small, homogenous group and if that is effective, broaden the research with one or more representatives and more diverse group of test subjects. In that case, the findings will also apply to a larger target group."

N=1

It is well-known everywhere that at some stage, many treatments were only tested on men, as a result of which they had less effect on women. But the elderly are also often excluded, says Jos Schols, professor of Geriatric Medicine. "Researchers exclude them, because they often have several disorders, with problems in various areas. One is socially vulnerable, the other has psychiatric complaints, the one takes five medicines, the other fifteen."

That is why researchers prefer to test treatments on adults under the age of 65 and then work on the basis that the treatment will also have some effect on the elderly, says Schols. "That is the way it also goes with antipsychotics and antidepressants. It is only in practice, years later, that it becomes clear how the elderly respond to them. The advice given to geriatric specialists is often: start off with a somewhat lower dose."

RCTs are great and powerful studies, but according to Schols, different designs are necessary for the elderly. "Lately, we have been looking at real-life trials, in a less strictly controlled setting than the classic RCTs. The effect is then less powerful, there is more noise, but this can partly be corrected by statisticians." 

These are referred to as pragmatic trials, says Knottnerus, and as far as he is concerned, they are a solution. "In such studies, researchers try to include as many different patients as possible, unless the medical risk is too great."

There is a growing body of opinion in favour of testing treatments on individuals, says Schols. “These are called multiple N=1 studies. In this case, you follow a single patient, whether they receive treatment or not.”

Pictographs

Not only the elderly, but also patients with mental disabilities often don’t participate in large-scale international studies, says professor Geraline Leusink. She is a member of the Board of Governors of Maastricht UMC and professor of Primary Health Care for people with a mental disability. 

"It has never been researched, but there are clear indications for this. People with an IQ between 50 and 85 find it difficult to even fill in a form about their health. Reading, writing and arithmetic are not easy for them. Researchers should go to more trouble to reach these people. This can be achieved through a more accessible use of language, short films and pictographs.”

It is especially important to include this group, because many of them score lower for health, says Leusink. “They die, on average, ten to fifteen years earlier. Also, because they often have less favourable socioeconomic backgrounds. It is a vulnerable group with multiple simultaneous medical problems.”

Photo: Pixabay

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