BARCELONA, Spain — Head-to-head drug comparisons are more suitable for making crucial decisions about medication availability in Europe than the current gold standard randomized, double-blind, placebo-controlled trials, according to experts speaking at a plenary session at the 17th European Headache Congress in Barcelona. "Unfortunately, these head-to-head comparisons are not available for the majority of new drugs," said Hans-Christoph Diener, professor of neurology at the University of Duisberg-Essen, Germany.
In Europe, individual member states are responsible for deciding when drug costs are covered by national insurance schemes. Once a new drug is authorized for marketing within the EU, national health technology assessment bodies evaluate if it has an additional therapeutic value compared to existing treatments. Whether a drug is reimbursable will depend on these assessments and how much the drug costs. Placebo-controlled trials are insufficient for this purpose, explained Diener. Instead, he argued, head-to-head drug trials in Europe have been more useful, both for clinicians and for health technology assessment bodies.
For example, in Germany, a head-to-head trial compared the efficacy and safety of intravenous aspirin with that of subcutaneous sumatriptan and of a placebo for the acute treatment of migraine. The findings showed that aspirin was as effective as the significantly more expensive sumatriptan. This led the assessment bodies in most European countries to agree to reimburse intravenous aspirin, Diener explained.
Another trial Diener was involved in compared the efficacy of topiramate in migraine prophylaxis to an active propranolol control and to placebo. This showed that propranolol was as effective as the more expensive topiramate but had fewer side effects. So now in Germany, topiramate is prescribed for people who do not respond to propranolol, in which case there is no restriction on its reimbursement.
A third trial in Germany compared the efficacy of a new monoclonal antibody, erenumab, to the traditional migraine prevention medication topiramate. It showed that the more expensive erenumab not only had higher tolerability but also was more effective. So now, based on this trial's results, erenumab can be prescribed and reimbursed in Germany in the case of patients who fail one class of the cheaper oral preventive drugs.
Measuring the Right Outcome
Michel Ferrari, a professor of neurology at Leiden University in the Netherlands, further argued that placebo-controlled trials are typically designed to measure the statistical significance of specified outcomes that are often neither clinically relevant nor important to patients.
Trials typically use a pain-free response 2 hours after dosing as the primary outcome, but this does not consider migraine features such as relapse.
"Patients want uninterrupted, normal functioning for longer periods of time," said Ferrari. "That's the logical endpoint, but sustained pain-free rates are considered too low for marketing."
Patients also report that they want relief from other migraine symptoms without experiencing side effects from their medication, which can leave them unable to function normally despite being free of pain.
In light of this, Ferrari and his colleagues recently proposed time lost due to an attack as a new outcome measure for measuring the efficacy of migraine treatments, and others have suggested that complete freedom from migraine and its associate symptoms should be the ultimate aim of treatment.
"What you need is the comparison with existing treatments and placebo using a clinically relevant outcome measure," said Ferrari. "The major challenge is that when you compare two active drugs, the difference will be smaller, so you need larger study populations in order to detect as statistically significant difference, but this is more expensive."
Moheb Costandi is a freelance writer based in London.
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