Methodology of drug trials in migraine: History and suggestions for the future.

There is a multitude of scientific papers and guideline papers on the methodology of drug trials in migraine. Here, we try to condense this into a single paper and to make proposals for future consideration. Literature known by the authors and from reference lists of relevant publications was used for the history. Relevant literature for our proposals was searched on PubMed. The main headings in published guidelines, namely, Patient selection, Trial design, Evaluation of results and Statistics, have remained unchanged over the years. Most of the methodology has remained unchanged but the changes that have taken place are important. Chronic migraine has been studied separately from episodic migraine, children and adolescents distinguished from adults, and migraine without aura from migraine with aura. In trial design, the group comparison design has taken priority over the cross-over design, but the latter is suggested for investigator driven, comparative, dose finding and aura trials because of its superior power. There is a confusing number of possible primary end points: number of migraine attacks, number of migraine days, number of headache days and number of 50% responders in prophylactic trials, whereas two-hour pain free is agreed in acute trials. However, also 24- and 48-hour pain free have been suggested and headache relief is sometimes still used against recommendations. Most bothersome symptom has been requested as a co-primary end point by Food and Drug Administration (FDA). Our future suggestions are meant to provide food for thought for future committee work. We suggest that most bothersome symptom needs to be discussed with FDA as a co-primary end point in acute trials. It could also be discussed whether episodic- and chronic migraine need separate study. Migraine with- and without aura should be studied separately. Furthermore, two-hour pain free should be maintained as the primary end point but the use of stricter outcome parameters should be explored. In prophylactic trials, migraine days are recommended over migraine attacks and over 50% responders. For investigator-initiated trials, comparative trials and proof of concept trials by small companies, the cross-over design with its superior power is still recommended. Finally, the need to lump various guidelines into one major document should be considered. The methodology of drug trials in migraine has been worked out in detail. It is important that these guidelines be followed in all clinical trials. We highlight several issues that merit attention in the future.