‘N=1 trials can provide evidence for medicine in rare diseases’

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Drug studies in which one patient receives both a placebo and the drug several times are suitable for demonstrating the effect of a drug in rare diseases. Bas Stunnenberg argues this in his thesis N-of-1 trials for personalized treatment.

A rare disease affects a maximum of one in two thousand people. That does not mean that almost no one has a rare disease. Because there are about six thousand different rare diseases, about 8 percent of the population has a rare disease. ‘In the Netherlands, that is equivalent to all residents of the province of Utrecht’, says Stunnenberg, who conducted his PhD research within the departments of Neurology and Health Evidence at Radboud university medical center.

Lack of evidence

If a disease is relatively rare, it is difficult to find enough patients for randomized research with a control group (RCT). This type of research is used, among other things, to demonstrate the effect of medicines in a patient group. ‘A lack of RCT evidence can mean that a medicine is not (any longer) reimbursed for a certain disease or condition.’ This was also the case with non-dystrophic myotonia (NDM), a muscle disease that Stunnenberg focused on during his PhD research.

What further complicates group-level research is that this disease can manifest itself differently in different people – even if two family members have exactly the same DNA error in the voltage-dependent sodium channel of the muscle, Stunnenberg shows in his thesis. ‘By lumping together patients in whom a disease manifests itself differently, the results may partially cancel each other out, and an average says little about individual results.’

Group analysis

Stunnenberg advocates N=1 trials in rare diseases, in which one patient receives a placebo or drug for several consecutive periods. ‘During the examination, the patient writes down how the symptoms are going on a daily basis. This gives you a good idea of ​​whether a medicine is helping to tackle a patient’s symptoms.’

According to Stunnenberg, combining data from several N=1 trials can provide evidence that is equivalent in terms of reliability to that of RCTs. ‘With great effort and international cooperation, other researchers managed to set up an RCT for the drug mexiletine in patients with NDM, in which 57 patients participated. We found the same level of evidence in a group analysis of eleven N=1 trials: a similar mean and comparable margins of error.’

Stunnenberg analyzed a total of thirty N=1 trials for this study. ‘That provided more accurate evidence compared to the RCT, while these trials are also more efficient, cheaper and more personal.’ Mexiletine proved to be effective in 27 of the thirty NDM patients.

Rural center

Stunnenberg uses Bayesian statistics to analyze the data from the N=1 trials. ‘This allows you to predict how likely it is that one specific patient will respond to a drug.’ Stunnenberg was assisted by experienced statisticians in performing these statistical analyses. ‘I would like a national center for N=1 trials to support doctors and researchers in this kind of research in order to remove a barrier.’

According to Stunnenberg, this way of doing research is interesting for many rare diseases. ‘Maybe half as much,’ he estimates cautiously. ‘Diseases are only eligible if the disease and/or symptoms are relatively stable over time, otherwise you cannot make a reliable comparison between the periods that a patient receives a placebo or medicine.’

Undermining health care system

Stunnenberg’s study, which showed that mexiletine is effective in counteracting muscle stiffness in patients with NDM, had an unwanted side effect. Shortly after they published that the drug was effective, a drug manufacturer registered mexiletine as an orphan drug and obtained a ten-year patent. Subsequently, according to Stunnenberg, the manufacturer tried to increase the price of the drug twentyfold from 4,000 to 80,000 euros per patient per year. ‘The Healthcare Institute ruled that this high price undermines the solidarity of our healthcare system, and argued in favor of not reimbursing this form of the drug.’

The drug is now made by four compounding pharmacies in the Netherlands, each of which is allowed to supply a maximum of 150 patients. ‘As a result, there is enough of the drug available. This variant is reimbursed from the basic insurance.’

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