The document discusses the use of patient-reported outcome (PRO) measures to evaluate diabetes treatments. It describes: 1) The importance of selecting primary and secondary endpoints to comprehensively assess treatment effects. Secondary endpoints alone cannot support labeling claims without confirmation from primary endpoints. 2) How to choose appropriate PROs by identifying relevant concepts, developing conceptual frameworks, and selecting generic or condition-specific measures. 3) An example endpoint model and case study using the Diabetes Health Profile-18 PRO measure to evaluate treatments' effects on health-related quality of life and glycemic control. The study found improvements in PRO scores correlated with meeting composite clinical endpoints.

1. The Diabetes Health Profile:
Using PRO Measures to Support
Endpoints
PRO/COA Summit
Philadelphia
6th May 2014
Dr Keith Meadows

2. Dr. Keith Meadows PhD
PhD – DHP Research
—
Keith is a Health Psychologist with over 25 years of research
experience and has held a number of senior academic and UK
NHS research positions.
Prior to setting up DHP Research & Consultancy, Keith was
Associate Director of the North East London Consortium for
Research & Development (NELCRAD). Keith's specialist areas
include, the psychological impact of living with diabetes and
patient reported outcome measurement.
Keith has published widely, avid presenter papers at major
conferences.

3. • Well-conducted randomized controlled trials are
instrumental in providing vital data on safety and efficacy
of new molecules under consideration for approval
• Acquiring such data involves huge cost and focused
scientific effort
• Selection and reporting of endpoints of a therapy is
essential to assess the effect(s) of an intervention on
overall disease control
Introduction

4. • Why it’s important to have a pre-defined
secondary endpoint
• What is the relationship between primary and
secondary endpoints
• Selecting the appropriate PRO to achieve
identified endpoints
Setting the scene

5. Diabetes is a common hormonal problem that if untreated can
lead to diabetes complications such as:
What is Diabetes?
diabetic
neuropathy
heart problems
retinopathyamputation
kidney failure
blindness

6. • Type 1 diabetes (insulin-dependent) requires insulin to treat,
is typically developed as a child or young adult, and is a
disease that destroys pancreatic cells resulting in loss of
insulin production.
• Type 2 diabetes (non-insulin dependent diabetes) is
considerably more common and typically affects people over
the age of 45, who are also overweight. Those suffering from
type 2 are unable to produce enough insulin, and sugar builds
up in the bloodstream.
What is Diabetes?

7. To maintain blood glucose levels
within the normal range (HbA1c
<7.0%)
The management of diabetes

8. 10%
ANXIETY aggression
Therapy non adherence
POOR QUALITY OF
LIFE
Disruption to social
and professional life
Eating
problems
The Psychological Impact of Living with
Diabetes

9. A PRO Measurement Strategy
Identify primary and secondary outcomes
relevant to treatment or intervention
Identify key treatment effects and outcomes
Develop endpoint model
Select appropriate Patient reported outcome
(PRO) measure

10. “If the endpoint is not meaningful, then the
result will not really have an impact.”
Niko Andre - Roche

11. The ideal clinical and statistical situation
for design of confirmatory clinical trials is
to prospectively specify a single primary
endpoint that:
• characterizes disease under study
• enables efficient evaluation of treatment
effect
The ideal endpoint

12. • Clinical relevance: must focus directly on study’s
primary objective, mechanism of action of
intervention and impact on patients’ well-being
• Reliability: must be capable of being assessed in all
subjects consistently
• Validity of comparison: must be ascertainable and
classifiable to allow comparison between treatment
groups
Desirable features of the primary endpoint

13. Primary endpoints
• Reduction in post-prandial
glucose, or high blood sugar
levels after meals
• Reduction of A1C levels at six
months
• Reduction of risk of
cardiovascular death,
myocardial infarction, and
stroke
• reductions in fasting plasma
glucose
Secondary endpoints
• Reduction in rate of overall
hypoglycaemic events
• Treatment satisfaction
• Improved health status
• Improved health-related
quality of life
• Reduced fear of
hypoglycaemic episodes
Typical endpoints in a diabetes clinical trial

14. • Secondary (components of composite) endpoints serve a
number of important roles
• These endpoints, although not considered primary, are
considered important to prescribing physicians in helping to
identify the ideal treatment for each of their patients
• Key endpoint, critical on their own (e.g., reduction in
hypoglycaemia)
• Supportive, provide more comprehensive understanding of
drug effect
• Findings based on secondary endpoints do not generally lead
to labelling claim if primary objective not met
The importance of pre-defined secondary
endpoints

15. “Successful PRO labelling claims are typically based on
primary endpoints assessing signs and symptoms. Based on
this research, studies with PROs as primary endpoints are
far more likely to facilitate positive regulatory review and
acceptance of PROs in support of labelling claims.
Although inclusion of PROs as non-primary endpoints in
clinical trials has its challenges, recent PRO labels granted
by the FDA show that they can indeed be candidates for
PRO labelling claims as long as they are supported by
evidence.”
Ari Gnanasakthy et al 2013

16. The relationship between primary and
secondary endpoints
Reduction of A1C
levels at six
months
Improved health-
related quality of
life
Reduced fear of
hypoglycaemic
episodes
Reduction in rate
of overall
hypoglycaemic
events

17. Common practice
• Often based on previous
use in other studies
• Name of PRO appears to
be appropriate
• PRO (health status, QoL,
HRQoL, well-being)
concepts used
interchangeably
PRO Measurement concepts
• Health status = quality of
health e.g. functional
impairment (SF-36)
• QoL = individual’s
subjective evaluation of
psychological, physical &
social aspects of their life
• HRQoL = treatment and
illness perceived as
impacting on areas of life
considered important
Selecting the Appropriate PRO

18. Generic
• Suitable for the general
population
• Comparisons with other
conditions/disease groups
• Content may be redundant
for certain
condition/illnesses
• Not sensitive to detecting
disease-specific issues
Condition-specific
• Specific to disease group
• Sensitive to detecting
clinically significant
changes
• Content relevant to target
group
• Cannot compare with
general population
Generic and Condition-specific: Making the
Choice

19. Characteristics of
the individual
Biological &
psychological
status
Symptom status
General health
perceptions
Functional
status
Overall quality
of life (QoL)
Characteristics of
the environment
The Wilson-Cleary Conceptual model of HRQoL
Wilson IB and Cleary PD, Linking clinical variables with health-
related quality of life. JAMA 273: pp59-65. 1995

20. Item 1
Item 2
Item 3
Item 4
Item 5
Item 6
Item 7
Item 8
Item 9
Generic and Condition-specific: Making
the Choice
Item 6
Item 7
Item 8
Item
9Item
10Item 6
Item 7
Item 8
Item 9
Item 10
Item 11
Item 12
Domain A
score
Domain B
score
Domain C
score
• Also known as a content map/
measurement model
• Specifies how items fit together
in a PRO to produce a domain
score
• Developed during development
of PRO – focus groups/literature
review, patient interviews
• Validated through a process of
psychometric validation
• FDA requirements specify that
labelling of a domain has to be
meaningful with respect to all
the items in the domain
A Simplified PRO Conceptual Framework

21. Simplified Endpoint Model for Reducing
Hypoglycaemia
Desired claims:
1. Reduction in
symptoms
2. Improvement
in HRQoL
Reduction in
hypoglycaemia
Improved
HRQoL
Measure
Symptom checklist
• Sweating
• Fatigue
• Trembling
• Dizziness
• Lowered anxiety
• Improved mood
• Increased social
activity
Measure
PRO Measure

22. Endpoint
Model
Clinical
Endpoints
PRO
Endpoints
PRO
Conceptual
Framework(s)
Interrelationship between PRO Conceptual Framework,
Endpoint Model and Label/Value Claim
Conceptual
Model
Label/
value
claim

23. The Diabetes Health Profile
The conceptual model
diabetes

24. The Diabetes Health
Profile (DHP)
Representing research spanning over 20 years, the Diabetes Health Profile (DHP) is a
diabetes-specific patient reported outcome measure (PROM) developed in accordance
with FDA Guidelines and available in 29 languages.

25. Conceptual Framework for
the DHP-1 and DHP-18

26. The Diabetes Health Profile (DHP-18)

27. The Diabetes Health Profile (DHP-18)

28. Interpreting the Diabetes
Health Profile
The minimally important
difference (MID) is the
smallest score difference on
the Diabetes Health Profile
that represents the minimal
clinically significant difference.
The required MID change in
score for the DHP-18 domains
Psychological distress 7 – 11
Barriers to activity
Disinhibited eating
6.5 – 9.9
7.5 – 11.4
Investigating the minimally important difference of the Diabetes Health
Profile (DHP-18) and the EQ-5D and SF-6D in a UK diabetes mellitus
population. Mulhern B and Meadows K. Health 5: 1045-1054,2013

29. Previous and Current Users
of the DHP
Type 1 & Type 2
Respondents
Have completed the
DHP-1 / DHP-18
More than

30. PROs among patients with type 2 diabetes using
exenatide twice daily or insulin in clinical
practice.
• A prospective 24-month observational study
in six- European countries
• Exenatide (BID) (N=1114) or insulin (N=1274)
Reaney et al Quality of Life Outcomes 2013, 11. 217
Diabetes – A case study using the DHP-18

31. Composite clinical
endpoint:
• No weight gain ≤ 1kg
• Glycaeted haemoglobin
(HbA1c <7%)
• No hypoglycaemia
PRO endpoints
• HRQoL (DHP-18)
• Emotional distress
(Hospital Anxiety &
Depression Scale)
• EuroQol (EQ-5D)
Diabetes – A case study using the DHP-18

32. Key findings:
Patients meeting the composite criteria (HbA1c
<7.0%, no weight gain, no hypoglycaemia)
• Higher improvements in EQ-5D index and VAS
scores
• Numerically higher DHP-18 scores over the 24-
months
Diabetes – A case study using the DHP-18

34. What does this case study demonstrate?
• PROs not adversely affected by insulin therapy
initiation
• PRO data may aid appropriate treatment
selection for individual patients
Diabetes – A case study using the DHP-18

35. • Selection and reporting of endpoints of a therapy is
essential to assess the effect(s) of an intervention on
overall disease control
• Selecting the appropriate PRO to support endpoints must
be based on a clearly defined measurement strategy and an
understanding of the relationship between primary and
secondary endpoints
• Secondary endpoints provide more comprehensive
understanding of drug and treatment effect
• Findings based on secondary endpoints do not generally
lead to labelling claim if primary objective not met
Summary

36. Thank you
Q & A