Headache/ Migraine eCOA Therapeutic Area Guide - eCOA Clinical Science & Consulting - ERT
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eCOA Therapeutic Area Guide
Headache/
Migraine
eCOA Clinical Science
& Consulting
May 2021eCOA THERAPEUTIC AREA GUIDE | HEADACHE/MIGRAINE
CONTENTS
Introduction ..................................................................................................................................................... 3
Common Assessments ................................................................................................................................... 4
Regulatory Guidance ....................................................................................................................................... 6
US Food and Drug Administration (FDA) .................................................................................................. 6
European Medicines Agency (EMA) .......................................................................................................... 7
International Council for Harmonisation (ICH) ......................................................................................... 7
Literature Best Practices ............................................................................................................................... 8
Advanced Training ......................................................................................................................................... 11
Advanced Subject/Caregiver Training ..................................................................................................... 11
Advanced Site Training ............................................................................................................................ 11
ERT Services in Headache/Migraine ........................................................................................................... 11
Acronyms ........................................................................................................................................................ 12
2 | © ERT 2021 eCOA Clinical Science & ConsultingeCOA THERAPEUTIC AREA GUIDE | HEADACHE/MIGRAINE
INTRODUCTION
Starting a clinical trial can be an overwhelming process, as best practices and
regulatory guidance are constantly shifting.
To help you get your study up and running successfully, ERT’s eCOA Clinical Science &
Consulting Team have developed this guide as a useful resource for clinical trials in this
therapeutic area. If you’d like to discuss your protocol in more detail or get additional
insight from our experts, contact the eCOA Clinical Science & Consulting Team.
3 | © ERT 2021 eCOA Clinical Science & ConsultingeCOA THERAPEUTIC AREA GUIDE | HEADACHE/MIGRAINE
COMMON ASSESSMENTS
Copyright
Clinical Outcome Assessment COA Standardized
Endpoint (links
(COA)* Type /homegrown
embedded)
Preventive Treatment
Daily Headache Diary: PRO Primary/ Homegrown N/A
Secondary
• Headache duration
• Headache pain severity (e.g. 4-point likert: none,
mild, moderate, severe)
• Pain features (e.g. pulsating/pounding/throbbing vs.
tightening/pressure, unilateral or bilateral)
• Symptoms (e.g. aura, nausea, photophobia,
phonophobia)
• Other pain medication (e.g. rescue medication)
Acute Treatment
Headache Diary (episodic): PRO Primary/ Homegrown N/A
Secondary
• Report start of headache
• Pain intensity (e.g. 4-point likert: none, mild,
moderate, severe)
• Other pain medication
• Pain features (e.g. pulsating/pounding/throbbing vs.
tightening/pressure, unilateral or bilateral)
• Symptoms (e.g. aura, nausea, photophobia,
phonophobia)
• Most bothersome symptom
• Functional disability
• Take study medication
Post-Dose Migraine Diary: PRO Primary/ Homegrown N/A
Secondary
• Completed at specific time points e.g. 0.5, 1, 1.5, 2,
3, 4, 6, 12, 24, and 48 hours
• Pain intensity (e.g. 4-point likert: none, mild,
moderate, severe)
• Symptoms (e.g. nausea, photophobia, phonophobia)
• Functional disability
• Rescue medication
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Preventive & Acute Treatment
Secondary/
Migraine Disability Assessment (MIDAS) PRO Standardized License required
Exploratory
Pediatric Migraine Disability Assessment Questionnaire Secondary/ License may be
PRO Standardized
(PedMIDAS) Exploratory required
Migraine-Specific Quality of Life Questionnaire Secondary/
PRO Standardized License required
(MSQ) v2.1 Exploratory
Secondary/
Migraine Specific Quality of Life Questionnaire (MSQoL) PRO Standardized License required
Exploratory
Secondary/
Headache Impact Test-6 (HIT-6) PRO Standardized License required
Exploratory
Secondary/
Migraine Physical Function Impact Diary (MPFID) PRO Standardized License required
Exploratory
Work Productivity and Activity Impairment Secondary/
PRO Standardized Free access
Questionnaire: Migraine (WPAI:Migraine) Exploratory
Secondary/
EQ-5D-5L PRO Standardized License required
exploratory
Patient Global Impression of Severity, Change, Secondary/
PRO Homegrown N/A
Improvement (PGI-S, PGI-C, PGI-I) Exploratory
Primary/
Electronic Columbia Suicide Severity Rating Scale
PRO Secondary/ Standardized ERT
(eC-SSRS)
Safety
Primary/
Columbia Suicide Severity Rating Scale (C-SSRS) ClinRO Secondary/ Standardized License required
Safety
Secondary/
Beck Depression Inventory – Second Edition (BDI-II) PRO Standardized License required
Safety
**Assessments listed here represent most commonly seen in headache/migraine studies. The list is not all inclusive and some studies may also include
additional assessments.
5 | © ERT 2021 eCOA Clinical Science & ConsultingeCOA THERAPEUTIC AREA GUIDE | HEADACHE/MIGRAINE
REGULATORY GUIDANCE
US Food and Drug Administration (FDA)
Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims
S U M M A R Y:
This guidance is from December 2009 but represents the current stance of the FDA. However, the FDA
is in the process of updating this with the 4 guidance documents detailed below.
FDA Patient-Focused Drug Development Guidance Series for Enhancing the Incorporation of the
Patient’s Voice in Medical Product Development and Regulatory Decision Making
• Guidance 1: Collecting Comprehensive and Representative Input (Final Guidance, June 2018)
• Guidance 2: Methods to Identify What Is Important to Patients Guidance for Industry, Food and Drug
Administration Staff, and Other Stakeholders (Draft Guidance, October 2019)
• Guidance 3: Methods to Identify What is Important to Patients and Select, Develop or Modify Fit-for-
Purpose Clinical Outcome Assessments (Discussion Document Available)
• Guidance 4: Incorporating Clinical Outcome Assessments into Endpoints for Regulatory Decision
Making (Discussion Document Available)
Migraine: Developing Drugs for Acute Treatment Guidance for Industry (February 2018)
S U M M A R Y:
This FDA guidance for industry provides recommendations for developing drugs for the acute treatment
of migraine, where patients take the drug as soon as they experience a migraine of moderate to severe
intensity. This guidance does not cover preventive treatment of migraines. Patients should have a diagnosis
of migraine with or without aura according to the International Headache Society (IHS) criteria. Baseline
information about the headache should be collected (i.e., headache intensity, presence or absence of
associated symptoms, unilaterality or bilaterality of the headache, aggravation by exercise, throbbing or
nonthrobbing) to verify that it is an acute migraine. Rescue medication should not be used until at least 2
hours post dose. Primary endpoint cannot be pain alone, but can have four co-primary endpoints: pain,
nausea, photophobia and phonophobia, or the preferred approach is pain and most-bothersome symptom.
Patients are asked to identify their most bothersome symptom either before the migraine attack (e.g.
baseline visit), or at the time of the attack but before treatment. Using this approach, the two co-primary
endpoints are: (1) no headache pain (pain free) at 2 hours post-dose, (2) demonstrated effect on most
bothersome symptom at 2 hours post-dose. Headache pain should be measured using a 4-point likert
(i.e. 0=none, 1=mild, 2=moderate, 3=severe). Secondary endpoints could include: achieving “no headache
pain” at various time points, requiring additional medication post-dose, achieving “sustained pain-free” with
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no headache pain from 2- 24 hours or 2- 48 hours with no use of rescue medication, and incidence of pain
relapse. Treatment observation should be at least 48 hours with the following recommended time points:
e.g., 0, 0.5, 1, 1.5, 2, 3, 4, 6, 12, 24, and 48 hours. Studies in pediatric populations are needed due to the high
prevalence of migraine in this population. Studies should be conducted with the following age subgroups:
ages 6 to 11, and ages 12 to 17 years old (either separate or combined studies).
European Medicines Agency (EMA)
Guideline on Clinical Investigation of Medicinal Products for the Treatment of Migraine (July 2007)
S U M M A R Y:
The EMA adopted this guideline for medicinal products for the treatment of migraine in 2007.
However, this guideline is currently under revision, as noted in this concept paper, to include chronic
migraine. The revised guideline is not yet available, but the concept paper notes the current guideline
still applies, although a slight adaptation may be discussed. Unlike the FDA guidance, this guideline
includes both acute treatment and prophylactic (preventive) treatment. For acute treatment, the
recommended primary endpoint is pain-free at 2 hours post-dose. Secondary endpoints could include:
pain-free at 2 hours with no use of rescue medication and no relapse within 48 hours, incidence of
relapse, efficacy on other symptoms (nausea, vomiting, photophobia, and phonophobia), intensity of
headache at various timepoints, headache relief, use of rescue medication, functional disability at 2
hours. For migraine prophylaxis, the recommended primary endpoint is frequency of attacks within
a pre-specified time period, e.g. mean frequency of migraine attacks per month. The number
of attacks should be recorded irrespective of their duration. Secondary endpoints could include:
responder rate, migraine days per month, intensity of headache, speed of effect, drug consumption for
acute treatment. For acute treatment studies, rescue medication use from 2 hours onward should be
part of the protocol. For prophylactic treatment studies, acute therapy should be allowed.
International Council for Harmonisation (ICH)
The ICH has a library of efficacy guidelines addressing the design, conduct, safety, and reporting of clinical
trials. Generally, the FDA, EMA, and other member organizations will adopt and follow ICH recommendations.
E9: Statistical Considerations for Clinical Trials
S U M M A R Y:
This guidance has information about the principles of statistical methodology applied to clinical trials.
E9(R1) EWG Addendum: Statistical Principles for Clinical Trails
S U M M A R Y:
Adopted in November 2019, this addendum to guidance E9 outlines the use of estimands in clinical
trials, including requirements for when estimands must be used.
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LITERATURE BEST PRACTICES
International Headache Society (IHS)
The IHS is a professional organization that publishes Guidelines, including the International Classification of
Headache Disorders (ICHD) and Clinical Trials Guidelines. The ICHD defines and classifies all known headache
disorders and is used to determine eligibility in clinical trials:
• International Classification of Headache Disorders (ICHD) (3rd Edition)
Clinical Trial Guidelines:
• Cluster Headache
- Guidelines for Controlled Trials of Drugs in Cluster Headache (1995)
• Migraine
- Guidelines for controlled trials of preventive treatment of migraine attacks in episodic
migraine in adults (2020)
- Guidelines of the International Headache Society for controlled trials of acute treatment of
migraine attacks in adults: Fourth edition (2019)
- Guidelines of the International Headache Society for controlled trials of preventive treatment
of chronic migraine in adults (2018)
- Guidelines of the International Headache Society for controlled trials of preventive treatment
of migraine in children and adolescents, 1st edition (2019)
- Guidelines for Controlled Trials of Drugs in Migraine, 3rd ed. A guide for investigators (2012)
• Tension-type Headache
- Guideline for Controlled Trials of Drugs in Tension-type Headache: Second Edition (2009)
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Table 1: International Classification of Headache Disorders (ICHD-3) Summary of Key Requirements
Tension-type
Episodic Migraine Chronic Migraine Cluster Headache
Headache
Frequency At least 5 attacks Headache on ≥15 d/mo Infrequent episodic: Every other day to 8
for >3 mo 10+, 3 mo periods lasting
7 d-1 y (untreated),
Chronic: ≥15 d/mo on
separated by pain-free
average for >3 mo
remission periods of
≥3 mo
Chronic: No remission
period, or remission
1 of
or lacrimation;
photophobia or
b) nasal
phonophobia
congestion and/or
(Chronic: or mild
rhinorrhoea;
nausea)
c) eyelid oedema;
d) forehead and
facial sweating;
e) miosis and/or
ptosis
2. restlessness or
agitation
Aura* Can be with or without Can be with or without No Aura No Aura
Aura Aura
*Additional requirements for Aura can be found in the ICHD-3 Guide.
Please see the ICHD-3 Guide for full requirements. (min=minute, d=day, mo=month, y=year)
9 | © ERT 2021 eCOA Clinical Science & ConsultingeCOA THERAPEUTIC AREA GUIDE | HEADACHE/MIGRAINE
Headache/ Migraine and eCOA
An electronic diary on a palm device for headache monitoring: a preliminary experience
(Allena M. et al. J Headache Pain. 2012 Oct; 13(7): 537–541)
S U M M A R Y:
Medication Overuse Headache inpatients (n = 85) given electronic handheld daily headache diary and
traditional paper diary, to be completed over 7-10 days. Patients evaluated each version on a 10-pt
numerical rating scale (0, not at all; 10, very). 98% of patients completed 100% of electronic diaries.
Age, education, and baseline headache disabilities did not affect diary completion. 97% of subjects
rated instructions adequate and clear. Electronic diary rated easier to understand (p < 0.01) and easier
to use (p < 0.0002) vs. paper. 99% (84/85) of patients preferred the electronic diary over paper diary
(p < 0.01).
A Qualitative Study to Assess the Content Validity of the 24-Hour Migraine Quality of Life Questionnaire
in Patients with Migraine
(Speck RM et al. Headache. 2020 Oct; 60(9): 1982–1994)
S U M M A R Y:
Concept elicitation, cognitive debriefing, and usability study was performed to determine the content
validity of the 24-Hour Migraine Quality of Life Questionnaire electronic patient-reported outcome
(24-Hr MQoLQ ePRO) and to assess the usability of an electronic handheld device. “Overall
impressions of the ePRO device were overwhelmingly favorable, and the ePRO device was preferred
to paper and pencil by all participants.” 91% of participants commented that the ePRO device was
easy to use. 100% of participants preferred the ePRO version over the paper version stating it was:
“faster, easier, less likely to make an error, and conforms with today’s technology.”
eCOA Alarms and Phonophobia
Ictal and interictal phonophobia in migraine—a quantitative controlled study
(Ashkenazi A et al. Cephalalgia. 2009 Oct; 29(10): 1042–1048)
S U M M A R Y:
Sound aversion thresholds (SATs) during a migraine (ictal) and between migraines (interictal) were
determined as the minimum sound intensity perceived as unpleasant or painful in subjects with
episodic migraines (n=60) and healthy controls (n=52). The SAT for control subjects averages 105
db and the SAT for migraine patients between attacks (interictal) is 91 db. The SAT of 91 db between
attacks for migraineurs further decreases to an average of 76 db during a migraine (ictally). These
values are useful as a comparison to e-diary alarms. (See ERT Science Brief: Suitability of eCOA
Handheld Alarms for Use with Migraine Patients that Suffer from Phonophobia).
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ADVANCED TRAINING
Advanced Subject/Caregiver Training
In headache/migraine studies, the primary outcome is usually a patient-reported outcome (PRO), typically
headache/migraine pain or frequency, and can include symptoms such as nausea, photophobia and
phonophobia. Inconsistent and inaccurate data can arise when patients do not have an understanding of the
diary terminology on which they are reporting. In addition, headache/migraine studies can also be conducted in
pediatric and adolescent patient populations, and require caregiver assistance. Pain is subjective and it is vital
that caregivers should report as an interviewer, and only record the patient’s response without amendment
or interpretation. As such, the FDA PRO Guidance (2009) and the European Medicines Agency’s (EMA, 2010)
Reflection Paper specify that training and instructions should be given to patients and caregivers to improve
data quality and compliance.
Training should provide subjects or caregivers with explanations on the purpose of the assessments, their role
in the trial, instructions on how to complete instruments and symptom diaries accurately, and definitions of key
terminology (e.g. nausea, photophobia, phonophobia, aura). Importantly, subjects should be trained on how to
rate their symptoms and how to differentiate between the different categories on the scale in a standardized
manner that would improve intra-rater reliability. Migraine studies often have high placebo response, and
therefore placebo response training should be included. In addition, since most headache/migraine studies
require collection of analgesic mediation (e.g. for rescue medication), training is also recommended on how to
accurately report analgesic medications using the medication module.
Advanced Site Training
Placebo response is a major issue in clinical trials for pain and migraine. Placebo effect can be reduced
through site training and therefore, advanced site placebo response training is recommended in headache/
migraine studies. Training should include common reporting errors that aid in placebo response and subject
and site expectations.
Advanced site training is also recommended if the study will include the medication module for analgesic/pain
medications (e.g. rescue medication). Advanced site training on subject pain medication use will instruct the
site staff on how to set up and monitor pain medication intake and ensures that pain medication information is
correctly entered into the electronic diary. This includes how to set up each subject’s custom medication list on
the device, specific steps to take when resolving a new pain medication entry that is submitted by the subject
during the study, and how to proceed when a subject reports taking a medication that is on the approved
master medication list or prohibited medication list.
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In addition, advanced site training is also recommended if the study will include the eC-SSRS/C-SSRS.
eC-SSRS workflow training is recommended to train site staff on using, interpreting and taking action in regard
to subject-reported data on suicidal ideation and behavior (SIB). C-SSRS rater training is recommended to
provide definitions of key terms and concepts, tips and best practices for administering the C-SSRS interview,
as well as training on electronic navigation.
ERT SERVICES IN HEADACHE/MIGRAINE
Below is a summary of the potential ERT services that can be used to support studies in headache/migraine.
Service Line
eCOA In headache/migraine studies, the primary outcome is usually a patient-reported outcome
(PRO), typically headache/migraine pain or frequency. In acute treatment migraine studies,
post treatment assessments at very specific and frequent time points are required. In
addition, most migraine studies require the precise collection of date and time of analgesic
rescue medications taken, as well as the precise timing of migraines and associated
symptoms, in order to calculate important endpoints such as qualifying migraine days. All
this necessitates the use of an electronic diary, with alarms and date/time stamps to ensure
good compliance, as well as meet the regulatory requirement of ALCOA (Attributable, Legible,
Contemporaneous, Original, Accurate).
Imaging In most cases, imaging for the diagnosis of headache is unnecessary. However, neuroimaging
can be used to identify imaging biomarkers for migraines and other headache disorders.
Respiratory Respiratory services are not common in headache/migraine studies.
Cardiac If the drug has the potential to have adverse vascular effects, cardiac safety studies should
Safety be performed. For example, triptans (a common class of drugs for acute migraine treatment)
can cause coronary or peripheral arterial constriction that may result in serious adverse
cardiac or peripheral vascular events.
Wearables While not common, emerging research is examining the use of wearable sensors such as
and Digital sleep sensors for early detection of migraines, since disturbed sleep has been associated
Biomarkers with migraine occurrence.
Trial Trial Oversight tools are critical to actively monitor recruitment and compliance and ensure
Oversight studies remain on target to achieve statistically meaningful results.
12 | © ERT 2021 eCOA Clinical Science & ConsultingeCOA THERAPEUTIC AREA GUIDE | HEADACHE/MIGRAINE
Acronyms
ALCOA Attributable, Legible, Contemporaneous, Original, Accurate
ClinRO Clinician-Reported Outcome
COA Clinical Outcome Assessment
C-SSRS Columbia Suicide Severity Rating Scale (interviewer-report version)
d day
db decibels
eCOA Electronic Clinical Outcome Assessment
eC-SSRS Electronic Columbia Suicide Severity Rating Scale (self-report version)
EMA European Medicines Agency
ePRO Electronic Patient-Reported Outcome
FDA US Food and Drug Administration
ICH International Council for Harmonisation
ICHD International Classification of Headache Disorders
IHS International Headache Society
min min
mo month
PRO Patient Reported Outcome
SAT Sound aversion thresholds
SIB Suicidal Ideation and Behavior
y year
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