using pros to measure secondary endpoints
TRANSCRIPT
The Diabetes Health Profile: Using PRO Measures to Support
EndpointsPRO/COA Summit
Philadelphia 6th May 2014
Dr Keith Meadows
Dr. Keith Meadows PhDPhD – 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.
• 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
• 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
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
• 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?
To maintain blood glucose levels within the normal range (HbA1c <7.0%)
The management of diabetes
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
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
“If the endpoint is not meaningful, then the result will not really have an impact.”
Niko Andre - Roche
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
• 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
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
• 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
“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
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
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
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
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
Item 1Item 2Item 3Item 4Item 5
Item 6Item 7Item 8Item 9
Generic and Condition-specific: Making the Choice
Item 6Item 7Item 8
Item 9Item 10
Item 6Item 7Item 8Item 9
Item 10Item 11Item 12
Domain Ascore
Domain Bscore
Domain Cscore
• 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
Simplified Endpoint Model for Reducing Hypoglycaemia
Desired claims:
1. Reduction in symptoms
2. Improvement in HRQoL
Reduction in hypoglycaemia
Improved HRQoL
MeasureSymptom checklist• Sweating• Fatigue• Trembling• Dizziness
• Lowered anxiety• Improved mood• Increased social
activity
MeasurePRO Measure
EndpointModel
Clinical Endpoints
PRO Endpoints
PRO Conceptual
Framework(s)
Interrelationship between PRO Conceptual Framework, Endpoint Model and Label/Value Claim
ConceptualModel
Label/value claim
The Diabetes Health ProfileThe conceptual model
diabetes
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.
Conceptual Framework for the DHP-1 and DHP-18
The Diabetes Health Profile (DHP-18)
The Diabetes Health Profile (DHP-18)
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
Previous and Current Users of the DHP
10,000Type 1 & Type 2
RespondentsHave completed the
DHP-1 / DHP-18
More than
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
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
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
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
• 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
Thank you
Q & A