using pros to measure secondary endpoints

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