Pain eCOA Therapeutic Area Guide - eCOA Clinical Science & Consulting - ERT
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eCOA Therapeutic Area Guide
Pain
eCOA Clinical Science
& Consulting
MAY 2021eCOA THERAPEUTIC AREA GUIDE | PAIN
CONTENTS
Introduction ...................................................................................................................................................... 3
Common Assessments .................................................................................................................................... 4
Regulatory Guidance ........................................................................................................................................ 5
US Food and Drug Administration (FDA) ................................................................................................... 5
European Medicines Agency (EMA) ........................................................................................................... 5
International Council for Harmonisation (ICH) .......................................................................................... 5
Literature Best Practices and Professional Organizations ........................................................................... 6
National Institutes of Health: NIH Pain Consortium and Interagency Pain Research Coordinating
Committee .................................................................................................................................................. 6
European Medicines Agency, Committee for Medicinal Products for Human Use (EMA/CHMP) ............ 6
IMMPACT: Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials ....................... 7
Advanced Training ............................................................................................................................................ 9
Subject/Caregiver Training ........................................................................................................................ 9
Site Training ............................................................................................................................................... 9
ERT Services in Pain ...................................................................................................................................... 10
Acronyms ........................................................................................................................................................ 11
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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 | PAIN
COMMON ASSESSMENTS
Copyright
Clinical Outcome Assessment COA Standardized
Endpoint (links
(COA)* Type /homegrown
embedded)
Unidimensional Scales: Pain Level
Numeric Rating Scale (NRS) or Numeric Pain Rating Primary/
PRO Standardized Public domain
Scale (NPRS) Secondary
Primary/
Visual Analog Scale (VAS) PRO Standardized Public domain
Secondary
Secondary/ Standardized/
Verbal (Categorical) Rating Scale (VRS) PRO Public domain
Exploratory Homegrown
Secondary/
Faces Pain Scale-Revised (FPS-R) PRO Standardized License required
Exploratory
Pain Improvement
Secondary/
Patient Global Impression of Change (PGIC) PRO Standardized Public domain
Exploratory
Multidimensional Scales
Patient Reported Outcome Measurement Information Primary/
PRO Standardized License required
System (PROMIS) Secondary
Primary/
The Health Assessment Questionnaire (HAQ) PRO Standardized License required
Secondary
The Short-Form McGill Pain Questionnaire (SF-MPQ Primary/
PRO Standardized License required
(also see SF-MPQ-2)) Secondary
Primary/
Brief Pain Inventory Short-Form (BPI-SF) PRO Standardized License required
Secondary
Public domain
West Haven-Yale Multidimensional Pain Inventory Primary/ translations may
PRO Standardized require permission
(WHYMPI) Secondary
Prof. Robert Kerns
Primary/
Treatment Outcomes of Pain Survey (TOPS) PRO Standardized License required
Secondary
Primary/
Chronic Pain Grade Scale (CPGS) PRO Standardized Public domain
Secondary
C-SSRS (Columbia Suicide Severity Rating Scale) ClinRO Safety Standardized License required
eC-SSRS (self-report version) PRO Safety Standardized ERT exclusive
* Assessments listed here represent most commonly seen in pain studies. The list is not all inclusive and some studies may also include additional
homegrown diaries. In addition, there are pain scales available for disease specific therapeutic areas; e.g. osteoarthritis, neuropathic pain, back pain,
headache/migraine, and cancer.
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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 as of January 2021.
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)
IMPORTANT NOTE: The FDA Guidance for Industry Analgesic Indications: Developing Drug and Biologic
products (Draft 2014) was withdrawn by the FDA in 2019.
European Medicines Agency (EMA)
Guideline on the clinical development of medicines for the treatment of pain released for public
consultation (May 2013)
S U M M A R Y:
The EMA document provides guidance for the investigation of treatments in nociceptive pain
and central and peripheral neuropathic pain. It covers study design, drug/placebo comparators,
assessment of treatment efficacy (COA) and dealing with special populations, such as children and
elderly.
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.
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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.
LITERATURE BEST PRACTICES AND PROFESSIONAL ORGANIZATIONS
National Institutes of Health: NIH Pain Consortium and Interagency
Pain Research Coordinating Committee
The Federal Pain Research Strategy indicates, “Objectively measuring pain and predicting which patients
are at risk for developing persistent or recurrent pain and responsiveness to treatment are of utmost
importance.” Measurement of pain without consideration for other, non-pain domains that are impacted
by pain may not result in a clinically meaningful outcome. It is important to consider how pain impacts
sleep, mood or emotional functioning, cognitive function, activities of daily living and overall quality of
life in addition to the standard dimensions of pain measurement such as peak or average intensity and
duration, for examples.
Assessments such as the Beck Depression Inventory (BDI), Profile of Mood States (POMS), Short-Form
Medical Outcomes Scale (SF-36) Health Survey and the Pain and Sleep Questionnaire (PSQ-3) may be
appropriate measures to consider in a clinical trial.
European Medicines Agency, Committee for Medicinal Products for
Human Use (EMA/CHMP)
Guidance from the EMA/CHMP has recommended that when choosing primary and secondary endpoints,
factors that should be considered include:
1. Intended indications
2. Study design and study population
3. Pain characteristics (e.g. intensity, duration, sensitivity to movement)
4. Associated pathology
5. Concomitant medication
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The most frequently used and validated scales for nociceptive and neuropathic pain are VAS and Numeric
Rating Scales (NRS). Likert scales or VRS: pain descriptor scales may be easier for some participants
to use. When assessing complex pain models such as cancer, multidimensional assessment tools that
are validated for nociceptive pain (e.g. McGill Pain Questionnaire (MPQ) and Short-Form McGill Pain
Questionnaire (SF-MPQ)) or neuropathic pain (e.g. Neuropathic Pain Scale (NPS) or Neuropathic Pain
Symptom Inventory (NPSI)) may be appropriate. The EMA also suggests that it is important to include
tools to assess the impact of pain on activities of daily living and quality of life.
The timing of pain assessments may depend on the model of pain or condition being studied, for example
post-surgical pain or chronic/constant pain.
Specific tools have been developed for use assessing pain in children that have been validated based on
clinical situation, age, developmental status, language and culture. Self-report in children is preferred if
possible. However, observer-rated assessments may be more appropriate for very young children.
IMMPACT: Initiative on Methods, Measurement, and Pain Assessment
in Clinical Trials
Identifying important outcome domains for chronic pain clinical trials: An IMMPACT survey of people
with pain (Turk et al. Pain, 2008; 137:276-285)
S U M M A R Y:
This survey reports on the domains of functioning that people with chronic pain consider important.
The results confirm that in addition to the ability to assess pharmacological or other treatment
interventions for their efficacy in reducing the physical aspects of pain, comprehensive PRO measures
are needed to address the various impacts of chronic pain on everyday life. People suffering from
chronic pain experience a toll on their emotional, physical, economic and social interactions. Assessing
improvement in these domains should be considered when determining treatment efficacy.
Core outcome measures for chronic pain clinical trials: IMMPACT recommendations (Dworkin et al.
Pain, 2005; 113:9-19)
S U M M A R Y:
The IMMPACT & IMMPACT-II meetings were held to develop consensus reviews and recommendations
for improving clinical trials of treatments for pain.
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The IMMPACT meeting resulted in a recommendation for consideration of six core outcome domains when
designing clinical trials in chronic pain. The IMMPACT-II meeting identified core outcome measures as
suggestions for consideration to address the outcome domains.
1. Pain
a. 11-point (0-10) NRS of pain intensity
b. Use of rescue analgesics
c. Categorical rating of pain intensity (none, mild, moderate, severe) in circumstances in which
numerical rating scales may be problematic
2. Physical functioning (either measure)
a. Multidimensional Pain Inventory Interference Scale
b. Brief Pain Inventory, interference items
3. Emotional functioning (at least one of these measures)
a. Beck Depression Inventory
b. Profile of Mood States
4. Participant ratings of improvement and satisfaction with treatment
a. PGIC
5. Symptoms and adverse events
a. Passive capture of spontaneously reported adverse events and symptoms and use of open-ended
prompts
6. Participant disposition
a. Detailed information regarding participant recruitment and progress through the trial, including
information specified in the Consolidated Standards of Reporting Trials (CONSORT) guidelines.
Optimal recall periods for patient-reported outcomes: challenges and potential solutions (Stull et al.
Curr Med Res Opin, 2009; 25(4): 929-942)
S U M M A R Y:
This review focuses on the optimal recall periods for assessing patient-reported outcomes. This article
calls attention to important information to consider when determining the appropriate PRO to use in a
study and identifies factors that impact recall. Pain recall is explored in detail.
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ADVANCED TRAINING
The goals of training participants and site personnel are to improve consistency. PROs are valuable, yet
highly subjective measures collected directly from the patients about their symptoms and health related
quality of life, without the input of clinicians or caregivers. Inconsistent and inaccurate data can arise
when patients do not have an understanding of the instrument or diary terminology on which they are
reporting. Clinician-reported measures are impacted by inconsistencies in administration techniques
and understanding of administration instructions. Training improves inter-rater reliability and reduces
variability due to these inconsistencies, leading to improved ability to detect treatment signal relative to
noise or error variance.
Subject/Caregiver Training
Pain is subjective. Thus, self-report is considered the gold standard for measurement of pain. To this
end, patient reported outcomes (PROs) are often the primary outcome measure in clinical trials on pain.
The FDA recommends that data quality for PROs is improved through standardized training on the PRO
instruments. This is especially important when the PRO will be used to support labeling claims.
One important consideration when assessing pain is susceptibility to bias and placebo response. Training is a
valuable solution that facilitates participants accurate reporting of their experience when completing PROs.
Site Training
While PROs are the most common assessment in pain, many disease-specific therapeutic areas include
clinician rated outcome measures (ClinROs) or performance outcomes (PerfOs). Effective site training is
vital to achieving high clinical trial data quality and minimizing errors.
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ERT SERVICES IN PAIN
Below is a summary of the potential ERT services that can be used to support studies in pain.
Service Line
eCOA Clinical Outcomes are a required endpoint and are of increasing importance when evaluating
treatment effects and adverse events. Regulatory guidance and best practice strongly
recommend the use of electronic data collection to improve compliance and data accuracy.
eCOA ensures that data comply with the FDA’s data integrity guidance known as ALCOA:
attributable, legible, contemporaneous, original, and accurate.
For example, in pain studies, PROs are often reported in a daily diary. Electronic diaries
(eDiaries) require participants to enter a PIN, ensuring the data entered are attributable.
eDiaries are programed with alerts to let participants know when it is time to complete their
PROs and data are time/date stamped providing confirmation of when they are completed.
Imaging Medical imaging can be a useful tool for diagnosing or identifying changes in disease specific
conditions. For example, in osteoarthritis, X-ray, magnetic resonance imaging (MRI) and
computed tomography (CT) are used to assess examine and identify changes in bone and soft
tissue in osteoarthritis.
Respiratory Respiratory function is an important aspect of acute pain-related physiological impairment.
It is also important to monitor respiratory function in clinical trials on pain particularly with
regard to opioid medications and other drugs that might have respiratory depressing effects.
Cardiac Acute pain can be dangerous for cardiac function, particularly in patients with pre-existing
Safety cardiovascular problems. In addition, analgesics may be harmful to the cardiovascular
system. Electrocardiograms are recommended as an objective safety measure when
assessing novel treatments in clinical trials on pain.
Wearables Activity monitoring to assess physical functioning and activity in people experiencing pain is a
and Digital relatively new and exciting method for obtaining objective measures of pain impact.
Biomarkers
Trial Trial oversight is a key tool for monitoring participant recruitment and compliance, ensuring
Oversight clinical trials remain on target towards achieving the desired sample size with enough
complete data to result in meaningful statistical analyses.
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Acronyms
BPI-SF Brief Pain Inventory Short-Form
ClinRO Clinician Reported Outcome
COA Clinical Outcome Assessment
CPGS Chronic Pain Grade Scale
eCOA Electronic Clinical Outcome Assessment
EMA European Medicines Agency
FDA Food and Drug Administration (USA)
FPS-R Faces Pain Scale – Revised
HAQ The Health Assessment Questionnaire
NRS/NPRS Numeric Rating Scale/Numeric Pain Rating Scale
PGIC Patient Global Impression of Change
PRO Patient Reported Outcome
PROMIS Patient Reported Outcome Measurement Information System
SF-MPQ The Short-Form McGill Pain Questionnaire
TOPS Treatment Outcomes of Pain Survey
VAS Visual Analog Scale
VRS Verbal (Categorical) Rating Scale
WHYMPI West Haven-Yale Multidimensional Pain Inventory
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