In 1991 the Clinical Trials Subcommittee of the
International Headache Society (IHS) published its
first edition of the Guidelines on controlled trials of
drugs in migraine (1). The Guidelines’ overarching
goal was to improve ‘the quality of controlled clinical
trials in migraine’, which could be achieved by using
scientifically robust methods of clinical research. The
report highlighted the complex nature of migraine clinical
trial methodologies and offered a road map to clinical
investigators who were interested in the field. The
Migraine Guidelines were adopted widely (2–7),
although – for a variety of reasons, including regulatory
restrictions – not universally (8–11), and this was
the impetus for the development of similar guidelines for tension-type headache (12,13) and for cluster headache
(14).
The second edition of the guidelines was published in
2000 (15) and, based on the second edition, the
European Medicines Agency published in 2007
‘Guidelines on Clinical Investigation of Medicinal
Products for the Treatment of Migraine’ (16).
Have investigators then followed the recommendations
in these guidelines for randomized controlled
trials (RCTs)? Unlike the case of RCTs for migraine
prevention where the recommended primary efficacy
measure of migraine attack frequency was used in
72% of 52 RCTs (17), adherence to the recommendations
in the guidelines for acute migraine treatment has
not been overwhelming. Indeed, the recommended
measure of freedom from pain after 2 h was the primary
efficacy measure in 31% of 145 acute RCTs between
2002 and 2008 (17). Instead, headache relief after 2 h
(a decrease from moderate or severe to none or mild)
was used in 39% of such trials. Notwithstanding, the
proportion of RCTs using pain freedom as the primary
efficacy measure has continued to increase over time
(17), and is even used in recent large clinical trials
(18–21).
Following the publication of the IHS Clinical Trials
Guidelines, several clinical drug development programmes
emerged, notably for acute migraine (e.g. 5-
HT1B/D agonists, triptans) and for prevention (e.g.
topiramate). The majority of these RCTs were performed
mainly for registration purposes (16). This
exponential increase in migraine clinical research, the
accumulating experience of clinical researchers and the
pharmaceutical industry alike, and the trend towards
large multi-centre and multi-national studies, call for
a timely revisit and a refresh of the original guidelines
and their second edition.
The third edition of Migraine Clinical Trials
Guidelines is a consensus summary that was developed
by experts in the field, and its purpose is to recommend
a contemporary, standardized, and evidence-based
approach to the conduct and reporting of migraine
RCTs.
Broader discussions of clinical trials methodologies
can be found elsewhere (22–30). Also, ethical considerations
in migraine clinical research have been published
separately (31). Finally, it should be noted that the
revised Guidelines represent Research Practice
Parameters and are the highest level in the hierarchy
of Evidence-Based Recommendations in the absence of
published Standards of Research Practice. Therefore,
the IHS endorses the adherence to the Guidelines
unless there is scientific justification for deviations
from the recommendations.
The Third Edition of The Migraine Clinical Trials
Guidelines is organized similarly to the previous two
editions. Notably, RCTs for acute attacks of migraine
are addressed in the first section of these guidelines and
are followed by discussions and recommendations
relating to RCTs for migraine prevention, including
short-term prophylaxis or ‘mini-prophylaxis’ for predictable
migraine attacks, such as those associated
with menses (32). Sub-sections include: patient selection,
trial design, evaluation of results and statistics.
A toolbox for each type of trial (acute and prevention)
is provided at the end.
R
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