White Paper

Considerations For Clinical Studies In Migraine Prophylaxis And Treatment

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Migraine is a neurological disorder that compromises quality of life and is disabling for a large, predominantly female population. It affects 18.2% of women and 6.5% of men annually in the United States. Although the mechanism involved is unclear, different hormone profiles have been observed for women who experience migraines. Migraine can be impacted by women’s menstrual cycles, thus many women seek treatment from OB/GYNs. However, it is treated in a variety of clinical settings. Primary care physicians, neurologists, headache specialists and OB/GYNs may all treat migraine patients.

This is an exciting time in migraine research. The understanding that the calcitonin gene-related peptide (CGRP) plays a role in the transmission of pain signals in the brain has led to the introduction of a new generation of migraine therapies targeting CGRP or CGRP receptors. The first, a monoclonal antibody, received approval in 2018. Other investigational candidates include both monoclonal antibodies and small molecules. In addition, investigational products with new delivery mechanisms intend to accelerate delivery of previously approved migraine drugs such as triptans.

"Approval of drugs for acute treatment has been based on four co-primary endpoints: pain, nausea, photophobia, and phonophobia. Patient-reported outcomes data is critical as studies rely on patients’ self-reported symptoms"

Operational and Methodological Considerations in Migraine Trials

Clinical trials of migraine drugs may involve treatment of acute migraine or prophylaxis. Inclusion/exclusion criteria must consider the severity, duration and frequency of migraines and the presence or absence of symptoms such as throbbing, nausea, sensitivity to light (photophobia) and sound (phonophobia), and aura. FDA guidance for acute treatment recommends testing multiple doses in patients with and without aura. 

Approval of drugs for acute treatment has been based on four co-primary endpoints: pain, nausea, photophobia, and phonophobia. Patient-reported outcomes data is critical as studies rely on patients’ self-reported symptoms using a four-point scale for headache and binary scale (present or absent) for other symptoms. Important considerations in migraine studies include:

  • Defining eligibility requirements based on the International Classification of Headache Disorder (ICHD-3), medical history, frequency and severity of headache pain and other symptoms, with attention to requirements for distribution of aura and other symptoms in the patient population
  • Enrollment challenges based on patient concerns about risk of randomization to placebo
  • Allowable concomitant drugs and rescue medications
  • Site selection in view of the variety of treatment settings and the predominantly female patient population
  • Management of patient diaries, including ensuring that patients complete diaries and provide data on all required symptoms
  • Patient discontinuations based on the perceived burden of study participation, especially if rescue medications are ineffective

Key Risks and Mitigations in Migraine Studies

Risk 1: A high screen-failure rate

There can be a high screen-failure rate in migraine studies because of the extensive and highly specific requirements as to medical history, frequency of migraines, severity of headache pain and distribution of aura and other symptoms.


  • Develop a robust prescreening questionnaire
  • Create paper and electronic prescreening tools to assist patients in tracking information such as number and severity of migraines prior to bringing patients in for screening
  • Use data from subjects previously enrolled in the study to increase the robustness of prescreening activities for future subjects
  • Use a centralized recruitment vendor

Risk 2: Inconsistency in completion of e-diary data on headache and other symptoms

While electronic and paper diaries each have advantages, e-diaries are increasingly preferred as they allow for the collection of  patient-reported data in closer proximity to reported events. However, use of e-diaries is not intuitive for all patients, and limitations regarding allowable time for data entry can sometimes prevent patients from entering data.


  • Work with the e-diary vendor to ensure that the study diary is simple and convenient to use
  • Provide detailed materials to support sites in training patients in e-diary use
  • Have an e-diary run-in period and exclude patients who fail to complete diaries during the run-in
  • Work with sites to develop an effective program for maintaining patient engagement in the study
  • Work with the e-diary vendor to implement an effective reminder system for diary input 
If you are developing women’s health products Make Your First Decision the Right Decision - Health Decisions

For Assistance With Your Migraine Program

As a CRO committed to improving healthcare outcomes for women, Health Decisions is determined to advance and accelerate clinical development of improved treatments for migraine. The Health Decisions clinical team has experience in central nervous system studies and understands how to address key operational issues and mitigate risks in migraine trials. Please contact us  to explore how a partnership with Health Decisions can support the efficient, timely development of your investigational migraine product.

The Leading Full-Service Women’s Health CRO from Pre-IND or -IDE to Regulatory Approval and Beyond
Health Decisions is a full-service CRO specializing in the clinical development of drugs, diagnostics, medical devices and combination drug/devices in all areas of women’s health as well development of diagnostics for all therapeutic areas. Our experience, expertise, site network, and KOL and investigator relationships enable us to address the challenges of developing women’s health products in areas including general gynecology indications, contraception, sexual health, infertility, obstetrics, menopause and osteoporosis and other indications that affect women disproportionately and profoundly, including autoimmune disorders and malefactor infertility. Health Decisions is headquartered in Durham, NC.