Diabetes Mellitus eCOA Therapeutic Area Guide - eCOA Clinical Science & Consulting - ERT
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eCOA Therapeutic Area Guide
Diabetes
Mellitus
eCOA Clinical Science & Consulting
May 2021eCOA THERAPEUTIC AREA GUIDE | DIABETES MELLITUS
CONTENTS
Introduction ..................................................................................................................................................... 3
Common Assessments ................................................................................................................................... 4
Regulatory Guidance ....................................................................................................................................... 5
US Food and Drug Administration (FDA) .................................................................................................. 5
European Medicines Agency (EMA) .......................................................................................................... 6
International Council for Harmonisation (ICH) ......................................................................................... 6
Literature Best Practices ............................................................................................................................... 7
Advanced Training ......................................................................................................................................... 11
Advanced Subject/Caregiver Training ..................................................................................................... 11
ERT Services in Diabetes .............................................................................................................................. 11
Acronyms ........................................................................................................................................................ 12
2 | © ERT 2021 eCOA Clinical Science & ConsultingeCOA THERAPEUTIC AREA GUIDE | DIABETES MELLITUS
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 | DIABETES MELLITUS
COMMON ASSESSMENTS
Copyright
Clinical Outcome Assessment COA Standardized
Endpoint (links
(COA)* Type /homegrown
embedded)
Diary:
• Automatic scoring for complex ClinROs (PASI, EASI,
SCORAD)
• Built in logic for complex ClinROs (PASI, EASI, PRO Secondary Homegrown N/A
SCORAD) to make evaluation more efficient and
consistent between raters
• Alarms to remind participants to complete itch
diaries
Diabetes Treatment Satisfaction Questionnaire, status
PRO Secondary Standardized License required
and change versions (DTSQs and DTSQc)
SF-36 PRO Secondary Standardized License required
Secondary/
EQ-5D (3L or 5L) PRO Standardized License required
exploratory
PRO
Pediatric Quality of Life Inventory- Diabetes Module Secondary/
or Standardized License required
(PedsQL Diabetes Module) Exploratory
ObsRO
Treatment Related Impact Measure for Diabetes Secondary/
PRO Standardized License required
(TRIM-D) Exploratory
Treatment Related Impact Measure for Diabetes Device Secondary/
PRO Standardized License required
(TRIM-D Device) Exploratory
PRO
Hypoglycemia Fear Survey or Adult Low Blood Sugar Secondary/
or Standardized License required
Survey (HFS) Exploratory
ObsRO
Diabetes Quality Of Life Clinical Trial Questionnaire Secondary/
PRO Standardized License required
(DQLCTQ-R) Exploratory
**Assessments listed here represent most commonly seen in diabetes studies. The list is not all inclusive and some studies may also include additional
assessments.
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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.
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)
Type 2 Diabetes Mellitus: Evaluating the Safety of New Drugs for Improving Glycemic Control Guidance
for Industry (draft)
S U M M A R Y:
The FDA released this draft guidance in March 2020, which is to replace two withdrawn guidances:
“Diabetes Mellitus – Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2
Diabetes” (December 2008) and “Diabetes Mellitus: Developing Drugs and Therapeutic Biologics for
Treatment and Prevention” (February 2008)”. The current draft guidance provides recommendations
on the size of safety databases and patient characteristics in diabetes mellitus trials, only. It does not
include recommendations on assessing efficacy.
5 | © ERT 2021 eCOA Clinical Science & ConsultingeCOA THERAPEUTIC AREA GUIDE | DIABETES MELLITUS
European Medicines Agency (EMA)
Guideline on clinical investigation of medicinal products in 4 the treatment or prevention of diabetes
mellitus (draft)
S U M M A R Y:
The EMA released this guideline in July 2018, and it will replace the previously adopted guideline,
which is considered under revision. The guideline covers developing glucose-lowering agents
and insulin preparations for the treatment of both Type 1 and Type 2 diabetes mellitus. Glycated
hemoglobin (HbA1c) is the recommended primary endpoint as it is a well-accepted measure of
overall, long-term blood glucose control. Possible secondary endpoints include fasting plasma glucose
(FPG), post-prandial glucose (e.g. after a meal), frequency of hypoglycemia, and 7-point capillary-blood
glucose profiles (before and after each meal, at bedtime and during the night). To measure plasma
glucose, capillary glucose is acceptable such as from finger stick; however, the use of continuous
glucose monitoring (CGM) is encouraged. The guideline recommends including disease-specific
patient-reported outcomes because it may provide information on quality of life or provide context
around observed changes in continuous glucose monitoring. Relevant definitions:
Severe hypoglycemia: “An event requiring assistance of another person to actively administer
carbohydrate, glucagon, or other resuscitative actions”
Clinically important hypoglycemia: a glucose level of less than 3.0 mmol/l (54 mg/dl) with or without
symptoms
Glucose alert value: a glucose level of less than 3.9 mmol/l (70 mg/dl). Recommend to collect
hypoglycemia symptoms
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 Diabetes Federation (IDF)
International Diabetes Federation (IDF) includes over 240 national diabetes associations and publishes the
IDF Diabetes Atlas (9th edition 2019). The Diabetes Atlas includes global statistics on individual, social and
economic impact, demographics, proven and effective actions, and the worldwide toll of diabetes.
American Diabetes Association (ADA) and European Association for
the Study of Diabetes (EASD)
Diabetes Advocacy: Standards of Medical Care in Diabetes- 2021
(American Diabetes Society. Diabetes Care. 2021 Jan;44(Suppl 1):S221-S222)
S U M M A R Y:
ADA-issued recommendations that are “intended to provide clinicians, patients, researchers, policy
makers, and other interested individuals with the components of diabetes care, general treatment
goals, and tools to evaluate the quality of care.” Section 7 discusses Diabetes Technology including
self-monitoring of blood glucose and continuous glucose monitoring (CGM).
Precision medicine in diabetes: a Consensus Report from the American Diabetes Association (ADA) and
the European Association for the Study of Diabetes (EASD)
(Chung WK et al. Diabetologia volume 63, pages1671–1693(2020))
S U M M A R Y:
Consensus report from the ADA and EASD that includes expert opinions on precision therapeutics
(both prevention and treatment). Highlights the importance of patient-centered outcomes. Precision
monitoring may include biological markers (e.g. CGM), behaviors (e.g. physical activity), diet, and sleep.
Precision monitoring can be achieved using digital apps, cutaneous or subcutaneous sensors, blood
assays, etc.
Diabetes digital app technology: benefits, challenges, and recommendations. A consensus report by the
European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA)
Diabetes Technology Working Group
(Fleming GA et al. Diabetologia volume 63, pages229–241(2020))
S U M M A R Y:
Joint review by the EASD and the ADA Diabetes Technology Working Group on the current landscape
of diabetes digital app health technology (only standalone apps, not regulated medical devices such as
CGM systems or insulin pumps).
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Importance of Glycemic Monitoring and Control: Seminal Papers
The effect of intensive treatment of diabetes on the development and progression of long-term
complications in insulin-dependent diabetes mellitus
(Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993 Sep 30;329(14):977-86.)
S U M M A R Y:
The Diabetes Control and Complications Trial Research Group conducted this important study that
found that tight control of blood glucose levels reduces the risk of microvascular complications
(such as diabetic retinopathy, nephropathy, and neuropathy) in Type 1 diabetics. This study shows the
importance of monitoring blood glucose levels, such as through self-monitored blood glucose readings
(SMBG) and a patient diary.
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment
and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study
(UKPDS) Group
(UK Prospective Diabetes Study Group. Lancet. 1998 Sep 12;352(9131):837-53.)
S U M M A R Y:
Similar to the above study, this important study by the UK Prospective Diabetes Study Group found
that tight control of blood glucose levels reduces the risk of microvascular complications in Type 2
diabetics. Again, this study shows the importance of monitoring blood glucose levels, such as through
self-monitored blood glucose readings (SMBG) and a patient diary.
Reliability of blood glucose monitoring by patients with diabetes mellitus
(Mazze RI et al. The American Journal of Medicine. 1984 Aug; 77(2):211-7)
S U M M A R Y:
Early study examining the accuracy of patient-recorded blood glucose (BG) values on paper. Participants
were given a glucometer that electronically stored all BG readings by date/time. Patients also recorded
BG values on paper, unaware that actual BG values were stored in the glucometer. The study found
that BG readings were omitted 10% of the time and created 40% of the time; 26% of paper values
were not identical to electronic values; and 67% of paper values were altered to reduce the severity
of hypoglycemic and hyperglycemic events. Overall, only ~47% of the data on paper was accurate and
reliable. Similarly, see Given JE et al. 2013 for a more recent review that found just over 50% of adult
diaries are ‘accurate/reliable’.
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Diabetes and eCOA
Mechanisms for improving diabetes patient-provider communication through optimal use of e-clinical
technologies (ERT paper)
(Khurana L et al. Patient Prefer Adherence. 2019 Jun 24;13:981-992.)
S U M M A R Y:
Participants with type 2 diabetes (n=105) were surveyed about their preferences. Most participants
(81%) were interested in using electronic methods (e.g. app on a smartphone, email, or text messages)
to interact more with physicians between visits. The majority of participants were interested in using
technology to help manage their type 2 diabetes, including 62% favoring communicating with their
health-care providers via email, using smartphones to provide medication reminders (56%), clinical
visit scheduling (55%), and text messaging (49%).
Performance of an Electronic Diary System for Intensive Insulin Management in Global Diabetes
Clinical Trials (ERT Paper)
(Bastyr EJ et al. Diabetes Technol Ther. 2015 Aug;17(8):571-9)
S U M M A R Y:
Implementation of an e-diary and web portal (PHT/ERT system) in Phase 3 Clinical Trials, a
collaborative publication between PHT/ERT and Eli Lilly. Patients (n=2,938) in 31 countries used
e-diaries to transmit 2,439,087 blood glucose (BG) values. The e-diary was used to record 208,192
hypoglycemia events, 96% of which had a BG value, and 95% had treatments and outcomes recorded
in the e-diary associated with the hypoglycemic event. Patients recorded administration of 1,964,477
insulin doses. Investigators adjusted 13 basal and 92 bolus insulin prescriptions per patient-year
using the e-diary system. After 26 weeks of treatment and e-diary use in the combined study arms,
hemoglobin A1c values and fasting BG decreased in patients with Type 1 and Type 2 diabetes.
Similarly, an earlier study (Laffel LM et al. Diabetes Technol Ther. 2007; 9(3):254-64) showed that a
glucometer integrated to an electronic diary improved HbA1c more than a paper diary.
• Poster presentation of above manuscript presented at Diabetes Technology Society Conference in 2013:
“Electronic Diary Utilization in Clinical Trials Implementing Intensive Insulin Therapy”. Shows blood
glucose measurements using the glucometer-electronic diary system have a normal distribution,
similar to CGM data. Also includes overview of the insulin dosing calculator developed by PHT/ERT.
Performance of Electronic Diaries in Diabetes Clinical Trials Measured Through Overall Satisfaction of
Site Coordinators
(Jhaveri M et al. J Diabetes Sci Technol. 2007 Jul;1(4):522-30.)
S U M M A R Y:
A survey was completed by 131 site coordinators participating in 4 clinical trials using e-diaries from
3 different vendors. The survey gathered information on the site coordinators’ experience using the
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e-diary systems. The items with the highest correlation with global satisfaction were: “(1) technical
problems not easily resolved (i.e., those requiring a call to a help line, requiring a new device, or resulting
in loss of data that the patient had input), (2) the organization and ease of navigating through the e-diary
Web site, and (3) the ability of the help line service to answer questions and fully resolve any problems.”
What is the frequency of symptomatic mild hypoglycemia in type 1 diabetes in the young?: assessment
by novel mobile phone technology and computer-based interviewing
(Tasker APB et al. Pediatric Diabetes 2007: 8: 15–20)
S U M M A R Y:
Type 1 diabetes subjects (n=37) aged 7-18 years completed a paper diary for two weeks, then
randomized to either a mobile phone with daily text messages or computer with daily emails (for
two weeks) to record number of hypoglycemia events. The study found that 65% (24/37) reported
hypoglycemia on paper, 95% (18/19) reported hypoglycemia on the mobile phone, 89% (16/18) reported
hypoglycemia on computer. Using technology, frequency of hypoglycemia was >3 times than previously
recognized. Advantages of using mobile phone/computer are daily reminders, rapid response and
quick data analysis.
Patient Preference for Real-time Feedback in ePRO Assessments for Diabetes Clinical Trials (ERT poster)
(Khurana L et al. Presented at the American Diabetes Association 75th Scientific Sessions 5-9 June 2015,
Boston, MA, USA)
S U M M A R Y:
Poster presentation showing diabetes patient preferences for completing ePRO assessments. The
study found that diabetes patients “are interested in knowing estimated completion time at the outset,
tracking their progress in real time as they complete a questionnaire, seeing the data that they report
graphed as a function of time, being encouraged to complete their diary if they fall behind by positive
messaging and being thanked for their completion of a daily diary.”
Patient preferences for using technology to track and self-manage diabetes (ERT poster)
(Khurana et al. Presented at the Diabetes UK Professional Conference 2015 March 11–13; London,
England)
S U M M A R Y:
Poster presentation showing diabetes patient preferences for using technology to track and self-
manage their disease. The poster found “most patients with diabetes (68%) are already monitoring or
tracking their disease on paper (53%) and/or electronically (28%). 55% are accessing the internet on a
regular basis to learn about their disease and/or treatment, and they are most likely to research what
types of food they should eat and current treatments.”
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ADVANCED TRAINING
Advanced Subject/Caregiver Training
As with any chronic illness, appropriate training is critical to obtaining accurate results, particularly when it comes
to patient reported outcomes. Diabetes patients would benefit from training on the importance of compliance,
especially with completing the 7-9-point profile assessments, which requires taking blood glucose readings, and
completing diary entries at 7-9 different time points. If the trial includes children, adolescents or their caregivers,
training is especially recommended. Adolescents should be trained on the importance of compliance and
definitions of key terms. Caregivers should be trained on reporting as a neutral interviewer, in which case they
must only record the patient’s response without amendment or interpretation.
ERT SERVICES IN DIABETES
Below is a summary of the potential ERT services that can be used to support studies in diabetes.
Service Line
eCOA eCOA integrated with a glucometer provides reminders to collect blood glucose readings, which is
especially important when collecting 7-, 8- or 9-point profiles (an important secondary endpoint)
at specific time points. Another common secondary endpoint is symptomatic hypoglycemia. An
electronic diary integrated with a glucometer allows for the collection of symptoms and context
around hypoglycemic events, which would not be possible with CGM or BG readings alone.
Imaging Fundus photography is used to document retinal disease over time, and is helpful in screening of
diabetic patients for retinopathy. Optical coherence tomography (OCT) and OCT angiography is also
used in diabetic retinopathy.
Respiratory Patients with type 2 diabetes often have decreased lung function. Patients with diabetes are more likely
to have COPD or pulmonary fibrosis. Therefore, diabetes studies may include measuring lung function.
Cardiac Cardiac Safety is very important in diabetes trials. Adverse cardiovascular outcomes remain an
Safety important source of morbidity and mortality in patients with diabetes. The FDA recommends that
sponsors should include rigorous methods for collection of adverse cardiovascular events.
Wearables Physical activity/exercise is important in type 2 diabetes; it has been shown to improve blood
and Digital glucose control, reduce cardiovascular risk factors, and contribute to weight loss. Activity
Biomarkers monitors/wearables to assess physical activity is an emerging area in diabetes studies.
Trial Trial Oversight tools are critical to actively monitor recruitment and compliance and ensure studies
Oversight remain on target to achieve statistically meaningful results.
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Acronyms
ADA American Diabetes Association
BG Blood Glucose
CGM Continuous Glucose Monitoring
COA Clinical Outcome Assessment
COPD Chronic Obstructive Pulmonary Disease
EASD European Association for the Study of Diabetes
eCOA Electronic Clinical Outcome Assessment
EMA European Medicines Agency
FDA US Food and Drug Administration
FPG Fasting Plasma Glucose
HbA1c Hemoglobin A1c
ICH International Council for Harmonisation
IDF International Diabetes Federation
ObsRO Observer-Reported Outcome
OCT Optical Coherence Tomography
PRO Patient Reported Outcome
SIB Suicidal Ideation and Behavior
SMBG Self-monitored blood glucose
SMPG Self-measured plasma glucose
UKPDS UK Prospective Diabetes Study
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