Using PROs to measure secondary endpoints


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Using PROs to measure secondary endpoints

  1. 1. The Diabetes Health Profile: Using PRO Measures to Support Endpoints PRO/COA Summit Philadelphia 6th May 2014 Dr Keith Meadows
  2. 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. 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. 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. 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. 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. 7. To maintain blood glucose levels within the normal range (HbA1c <7.0%) The management of diabetes
  8. 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. 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. 10. “If the endpoint is not meaningful, then the result will not really have an impact.” Niko Andre - Roche
  11. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 23. The Diabetes Health Profile The conceptual model diabetes
  24. 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. 25. Conceptual Framework for the DHP-1 and DHP-18
  26. 26. The Diabetes Health Profile (DHP-18)
  27. 27. The Diabetes Health Profile (DHP-18)
  28. 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. 29. Previous and Current Users of the DHP Type 1 & Type 2 Respondents Have completed the DHP-1 / DHP-18 More than
  30. 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. 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. 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
  33. 33. 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
  34. 34. • 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
  35. 35. Thank you Q & A