1. Patients The Key to Real World Data? Alan G. Wade

2. Real World Data Sources

3. Reflects the average patient in a real-world setting Demographics –Sex –Age –Social status –Education Diagnosis Co-morbidities Co-medications Medical system Social impact Work impact Family impact Impact on Quality of Life What is real world data?

4. Pre market entry disease, burden, unmet need, treatment pathway mapping Licensingwhen impact only known by patient or difficult to assess Labelling extensionValidated PRO’s Market AccessHTA; effectiveness Post licensesafety, benefit:risk (registry),risk/management plan Guideline development ??? Uses for “real world” data?

5. Source Randomised Controlled Trials PMS Studies Physician driven Patient registries Prescribing data Database – physician recorded Focus groups Patient organisations Patients Traditional data sources

6. Hierarchies of evidence 1.Systematic reviews of randomised controlled trials (RCTs). 2.RCTs. 3.Controlled observational studies - cohort and case control studies. 4.Uncontrolled observational studies - case reports. 5.Expert opinion ?KoL

7. Randomised Controlled Trials “the gold standard” for demonstrating (or refuting) the benefits of a particular intervention. Important limitations

8. Limitations of RCT’s Patients –Age - Effectiveness in younger or older patients –Sex –Severity - effectiveness in mild or severe –Risk factors - effectiveness in patients with risk factors for the condition (eg, smokers) –Co morbidities - Influence of other conditions –Ethnicity - effectiveness in other ethnic groups –Socioeconomic status - effectiveness in disadvantaged patients Treatment –Dose - high dose used in RCTs? –Timing of administration Influence on adherence (compliance) to treatment regimens –Duration of therapy - effectiveness during long-term use –Co medication - adverse interactions –Comparative effectiveness - in comparison with other products used for the same indication Setting –Quality of care –Prescription and monitoring by less specialist (expert) healthcare providers –Care pathway

9. Effectiveness and efficiency Does it work in Does it contribute to a clinical trials?real life?more efficient use of resources?  COST-EFFECTIVENESS EfficacyEffectivenessEfficiency

10. To assess performance of drug in real world setting –Large numbers –Off-label prescribing –Comorbidities –Concomitant medications –Speed of reporting Do we achieve this with formal PMS? Post Marketing Surveillance

11. Hierarchies of evidence 1.Systematic reviews of randomised controlled trials (RCTs). 2.RCTs. 3.Controlled observational studies - cohort and case control studies. 4.Uncontrolled observational studies - case reports. 5.Expert opinion ?KoL 6. Patient reports ?

12. Small numbers Representative? Skill of co-ordinator/observers Focus groups

13. Who in the world most influences the pharmaceutical industry? 1.Barack Obama 2. Michael Rawlins

14. Harveian Oration Hierarchies of evidence should be replaced by accepting— indeed embracing—a diversity of approaches. The Lancet Vol 372 December 20/27, 2008

15. NICE Patient and public involvement The views of patients, carers and the public matter to NICE. We want to involve them, as well as doctors, nurses, other healthcare professionals and managers in our work. http://www.nice.org.ukhttp://www.nice.org.uk – accessed 22 06 09

16. EMA The assessment of the benefit-risk balance should be based on the available tests and trials, which are designed to determine the efficacy and safety of the product under normal conditions of use (Directive 2001/83), and which are generally performed under ideal conditions. It is important to be explicit about the perspectives of different stakeholders that are taken into account in the assessment of the benefit-risk balance, in particular the perspectives of patients and treating physicians. Considerations about how the treatment is expected to perform under real conditions of use are relevant in the context of pharmacovigilance activities, for example, to take into account any available information on misuse and abuse of medicinal products which may have an impact on the evaluation of their benefits and risks (Directive 2001/83).

17. Patient groups - the patient? EPF is the umbrella organisation of pan-European patient organisations active in the field of European public health and health advocacy. The European Patients’ Forum (EPF) currently represents 57 patient organisations and an estimated 150 million patients across the 27 Member States throughout Europe.

18. EU drugs agency working with patient groups bankrolled by big pharma 23.04.10 @ 19:17 Patient organisations

19. But equally, we have a right and responsibility to look at the interests of other patients who use the healthcare system. What I am critical of, however, is patient organisations that are acting on behalf of pharma companies. I am not alone in complaining about them. The Lancet Vol 372 December 20/27, 2008 Harveian Oration

20. “Big Data”

21. No single agreed definition but The bottom line: whatever the disagreements over the definition, everybody agrees on one thing: big data is a big deal, and will lead to huge new opportunities in the coming years. Big Data - definition http://timoelliott.com/blog/2013/07/7-definitions-of-big-data-you- should-know-about.htmlhttp://timoelliott.com/blog/2013/07/7-definitions-of-big-data-you- should-know-about.html Accessed 27 01 14

22. Big Data – Pharma??? 22 Registries Claims Databases (US) e - Medical Records Also Pharmacy databases Specific hospital databases Specific disease or procedure databases

23. What do you want from a registry? Large numbers Patient level data Immediacy of data Longitudinal data Representative population Presence of YOUR required data Linkage of data fields of interest Confirmation of diagnosis Standardised measurement Validated PRO’s

24. Existing registries Strengths Large numbers Immediate access Longitudinal data Prescribing data Weaknesses Inherent biases Representative population Diagnostic drift Patient level data Surrogate outcomes Completeness of data Family social and work history To effectively use any registry it is important to understand how it has been developed and its strengths and weaknesses

25. Some treatment effects only known to patient Pts provide unique perspective on treatment Provide information on QoL, work, social and family Formal assessment may be more reliable than informal interview Patient Reported Outcomes Why & How? 25

26. What the Patient Knows What the Patient Shares What the physician understands What the Physician records Big Data Addressing registry weaknesses Ask the patient – but how?

27. Real World Data Sources

28. Conclusion Collect data directly from patients Patient Reported Outcomes PRO’s

29. “any aspect of patients health status that comes directly from patient” - FDA “insight into way patients perceive their health & impact treatments or adjustments to lifestyle have on their quality of life” –DH Patient Reported Outcomes - Definition 29

30. FDA Guideline report Dec 09

31. Pt recording versus doctor Pt understanding of question/form Validity of question (in that format, pt popn) Reliability of question Ability of question to detect change For licensing – need set as per RCT Patient Reported Outcomes – concerns 31

32. Definition of “Real Data from Real Patients” Collecting data from patients receiving “routine care” BUT Not affecting their prescribers/ healthcare professionals behaviour

33. Methodology 33 PROBE Patient Reported Outcome Based Evaluation

34. Process set-up Define question - protocol Define patient group of interest Determine location of group e.g. Specialist unit, community setting, geography Review options for accessing patient group –Orphan indications Design questionnaires and reports –development and testing Structure customised database

35. Bespoke – ask required questions Innovative Prospective Hosted on Patients Direct site Interactive Global Coverage Structured patient registries 35

36. Is on-line collection satisfactory? Will patients cooperate How do you recruit? –Methodology –Achieving a representative population Problems

37. www.InternetWorldStats.comwww.InternetWorldStats.com 2009

39. Age? Education? Social class? Carer reporting? –Alz Dis –children On-line reporting

40. Age and Social Media

41. Conclusion Generally require alternative data collection routes Nurse manned telephone

42. Outlet for their feelings and views – might be a threat to their relationship if they report problems to their healthcare professional – we’re neutral Altruistic - Assist in developing new and better treatments Obtain better information and knowledge through participation Feel valued through regular contact/ interaction Desire to make sure the patients voice is heard Why do people participate? 42...the benefits and attraction to each individual will differ but we believe the main reasons are :

43. 7. REPORT CONCLUSIONS. The above report has shown the public’s enthusiasm towards a system that would let consumers report adverse drug reactions through the Internet. The findings of the survey carried out by us revealed to us this enthusiasm. The report has further shown that health professionals have a positive opinion towards such a system, which works in favour of the overall mission of Patients Direct. Not only has the report articulated the publicity campaign that Patients Direct can carry out to raise its awareness, but also examples of different medicine inserts has been provided with reasoning behind them that could be used by the company to make itself different from its competition. Patients Directs corporate identity is important to begin the process of publicity. IT has been noted that establishing a user friendly website that is easily navigable is fundamental to setting the pace for a strong brand and image that will appeal to Patient’s Direct customers. Will patients cooperate? 43 EDGE Survey - Market Research, 2008

44. Individualised to project Invitation with prescription –Pharmacist –Delivery service –Insert Advertising –Newspapers/TV/www/Social media Point of delivery –Vaccines GP Databases Patient recruitment 44

45. social networking sites search engine and website optimisation public affairs articles and traditional methods of publicity e.g. Newsprint/TV Healthcare professionals –Doctors, pharmacists wholesalers, distributors Clinical trial participants patient groups Special focus can be given to groups of interest such as children if appropriate and recruitment monitored to ensure sufficient numbers in each cohort. Recruitment...tailored to attract patients of interest with a conscious effort to reduce bias and population selection issues Core recruitment methods include :

46. Recruitment Examples General – statins –Pharmacy/wholesale distributor –Advertising - Google Vaccines –Direct at vaccination Families and children –Appropriate web-sites Specialist product – home delivery –Invitation with delivery OTC – Strepsils –General advertising –Pharmacy –Package wrap

47. Inflammatory Back Pain 3 rd February 2014

48. Recruitment Recruitment Method - Facebook only First Participant Recruited – 22 nd Dec 2013 48

49. Facebook Advert Example 49

50. Facebook Advert Example 50

51. Landing Page 51

52. Respondents 52

53. Age Profile 53

54. Sex Ratio 54

55. Meets IBP Criteria 55

56. Age Profile of Respondents with IBP 56

57. Non Completers 57

58. Influenza Family Study Family Influenza Survey Households completed study946 Individuals in completer households3695 Flu-like Illness episodes in households 540 Total “Flu-like” Illness851

59. Considerations Data Protection/ Confidentiality Ethics –NRES response Industry Code of Practice Safety Reporting systems – MHRA –Automated A/E reporting –A/E cascade Medical considerations/standards –No interference with prescribing/treatment

60. Process - management Patient response handling and back up Review of data as study progresses Design of reports –A/E reporting in agreement with sponsors Statistical interpretation and reporting Publications If appropriate, patient education or further action e.g. Adherence schemes

61. Managing data – a dynamic process Real data from Real patients 61

62. RetrospectiveProspective patient Presence of YOUR required data++++ Representative population+++ Large numbers+++++ Linkage of data fields of interest?+++ Confirmation of diagnosis++ Standardised measurement++++ Validated PRO’s+++ Patient level data++++ Unfiltered patient data-+++ Response to unexpected findings++++ Immediacy of data+++++ Longitudinal data - Retro/pro..... spective+++ Sensitivity+++ Registries

63. Medical interventions are now being assessed on the basis of “real world” data Current collection methods are inadequate Novel systems for collection are required Patients are increasingly being involved in medical decision making Collecting “real world” data directly from patients may be one possible method Summary

64. www.patients direct.org Patients Direct 3 Todd Campus G20 0 XA United Kingdom

65. Output Examples Practicality Cover all 4 areas of use 65

66. Mapping Treatment Pathways Burden of Illness Drug Safety/ PV Real world “effectiveness” benefit QOL Patient Satisfaction /experience/ Adherence CVA evaluation Sleep evaluation Wellbeing Study (depression) Problem Periods survey Impact of opioid use CVA evaluation Family Flu survey Statin survey Swine vs seasonal flu vaccination Seasonal flu vaccination 2008 EQ 5D mapping 3 level to 5 level Etanercept survey Satisfaction with analgesia in OA Pulse Rate survey Etanercept survey Satisfaction with analgesia in OA Project examples 66

67. PV - Flu Vaccination 102 leaflets distributed 73 PIN numbers have been entered on the database (72%) 40 male and 33 female aged between 21 and 99 years. They were asked about pain and discomfort from the vaccination 67

68. Flu Vaccination - Day 2 70 responses were entered for Day 2 14 having side-effects. 68 In response to “What did you do about these side effects?” Reported Side Effects

69. HiVE - H1N1 Vaccination Evaluation

70. HiVE - Demographics Male – 449 Female - 663

71. HiVE - Adherence

72. HiVE – Side effects Injection site discomfort 36.4% Flu-like symptoms 23.5% Injection site pain 20.1% χ 2 -test p <0.001 H1N1 only

73. HiVE - Absenteeism

74. HiVE – Pain/Discomfort Reports CategoryOdds ratioP value SexMale female2.080.052 Chr illnessNo Yes1.320.052 Swine flu vaccineNo Yes4.49<0.001 Seasonal flu vaccineNo Yes0.890.481

75. Subject participates “Buy-in” Enrols “Buddy” Feedback on outcome Engaged for next year “Viral Transmission” Subject + Buddies + “Virals” The Virtuous Cycle

76. Delivery at home Compliance with drug still low Understand agency effectiveness, reasons for drop outs Understand real life prescribing vs guidelines Evaluate and then implement ways of improving outcomes Measures – AEs, compliance, QOL – disease specific and generic EQ5D Enbrel Project 76

77. Enbrel - Process 77 Patient group recruited through leaflets with hospital clinic or HaH nurse visit to train on injection Initially 6 month follow up at 1 month intervals Recently extended to 2 year follow up at 3 month intervals

78. Enrolled 344 patients Out of ~1000 leaflets distributed 284 patients by web site 60 patients by telephone 93-100% completion of questions at baseline 140 patients have reached month 6 Enbrel – First 6 months 78

79. If you are experiencing problems with the website or any of the questions please contact the following number and we will endeavour te help you: 0800 731 2647

80. Age of Participants

81. Baseline Use of Methotrexate

82. Examples – MS, epilepsy, gout, infectious illness, depression Pre programmed questionnaire – timing ?? Baseline then every month/ 2 weeks - recall? Simple email – yes or no Rely on people saying when they have “event” Intermittent events- data gathering 82

83. Capture QoL changes when worst time of cycle Variation within and between women Compare to “normal” time Intermittent Condition – Problem Periods 83

84.  2699 respondents  Age – good range from 49 (61% < 30)  Absenteeism – 3+ days/mth 6% 1-2 days/mth 16% Results – Screening survey 84

85.  Significant impact on ALL Quality of Life Scales  Significant change between the different times of period cycle Results – Main Outcomes 85

86. Main outcomes – EQ5D 86

87. SF 36 utility score 87

88. Routinely gather PRO on All Medication related to condition Doctor visits (Primary & Secondary care) Nurse visits Pharmacy visits Telephone calls (if relevant) Hospital In/ Out Patient visits and number of days Resource utilisation 88

89. A real world study using Patient Reported Outcomes to assess the consequences associated with the forced switching of asthma medication/device in stable adult asthma patients Data to be captured from Patients themselves: baseline patient reported level of Asthma control/satisfaction with device Reasons for switch (if known) (prospectively) Outcomes of switch: Clinical (FEV1, Control) Health resource use (GP visits, hospitalisations) lifestyle impact (days off work) (prospective) The questionnaires would be administered monthly (prospectively) so that any changes are captured 89

90. Unmet need Gathering information on children/ adolescents/ parents Adherence, satisfaction, burden of illness Cystic Fibrosis 90

91. If you need real world PRO data in Europe/US Databases don’t collect info you need Patients Direct can collect the data, directly from the patient Quick, efficient, cost effective solution Conclusion 91

92. Burden Of Illness Study – Depression Management Understanding Patients ability to monitor their own condition – Heart Rate survey Disease treatment pathway mapping – CVA Study Mapping new EQ5D Are QALYs appropriate across EU ? Market Access 92

93. Socio-demographics, PMHx, Resources use – Client Service Receipt Inventory QOL - EuroQoL Productivity – WHO Health & Productivity Questionnaire Depression – HAM-D, MADRS Burden Of Illness - 300 pts depression 93

94. Utility weights UK population data and EQ5D → QALYs Burden Of Illness 94

95. Depression severity - cost Depression severity - QALYs Burden Of Illness 95

96. Medical pathway of ischaemic stroke until 1 year acute episode Cost of stroke management Cost drivers Comparison between UK, France, Germany Disease Pathway and Management 96

97. Socio-demographic Pre hospital management – PMHx, 1 st contact, transport Hospital management – treatments, investigations Post hospital management - rehabilitation Disease Pathway and Management 97

98. New 5 level questionnaire (from 3 level) 500 pts UK Different levels disability CV disease, Respiratory, Neurological, RA EQ 5D Mapping 98

99. FP 7 grant Pan European – UK arm (with A Walker) University of Lyon Identification of different methods in HTA Review of different methods Alternatives to QALY Use of QALY across EU 99

100. Involved in questionnaire mapping Gathered data via various QoL scales Gathered data on inputs and outputs - costs, diseases, outcome Individuals involved in SMC and NICE submissions and Advisory Boards Access and use of UK experts – Robertson Centre HE and OR 100

101. Bespoke Innovative solutions Professional Quality Assurance /control History of delivering results –On time –Value for Money Tailored to sponsor brief Multiple Applications Summary 101

102. Source Randomised Controlled Trials PMS Studies Physician driven Patient registries Prescribing data Database/physician input Focus groups Patient organisations Patients Current data sources