Rheumatoid Arthritis - Biologics battle up the treatment algorithm

About the CNS, Arthritis and Pain pharmaceutical analysis team 2
CHAPTER 1 EXECUTIVE SUMMARY 3
Scope of the analysis 3
Datamonitor insight into the rheumatoid arthritis market 4
CHAPTER 2 INTRODUCTION AND SCOPE 12
What is rheumatoid arthritis (RA)? 12
How is it treated? 13
Coverage of the Stakeholder Insight Survey 13
Country level "treatment trees" 15
Supporting data sets 15
CHAPTER 3 COUNTRY TREATMENT TREES 17
US 18
Japan 21
France 24
Germany 27
Italy 30
Spain 33
UK 36
CHAPTER 4 EPIDEMIOLOGY AND PATIENT SEGMENTATION 39
Definition of the disease 39
Epidemiology of rheumatoid arthritis 39
Key patient segmentations 42
Disease severity shows an even split among mild and moderate disease, with fewer severe patients 42
Early active RA should be defined as less than one-year duration for maximum patient benefit 43
Co-morbidities, complications and risk factors 46
Hypertension, elevated cholesterol and, to a lesser extent, heart attacks are common in RA patients 48
Osteoporosis is also common, but likely to be due to long-term steroid use 50
Depression is two to three times greater in RA patients than in the general population 50
Other co-morbidities include additional autoimmune diseases and stomach ulcers 51
CHAPTER 5 DIAGNOSIS AND TREATMENT OPTIONS 52
Presentation and diagnosis lower than in previous Datamonitor surveys 52
Treatment types 54
Pharmacological and non-pharmacological therapy is often used in combination for moderate and severe patients 54
Use of combination drug therapy also increases with severity 55
NSAIDs, analgesics and traditional DMARDs are the most commonly prescribed drug classes 57
Treatment options 60
Treatment guidelines 61
Referral patterns 63
Direct consultation, or referral, for rheumatologists? 64
The next referral move 64
CHAPTER 6 PRESCRIBING TRENDS 68
NSAID prescribing trends 68
The most commonly-used NSAID molecule is diclofenac 68
Use of NSAIDs and COX-2s since the withdrawal of Vioxx 69
High, and possibly inappropriate, co-prescription of a gastro-protective agent with NSAIDs 75
Use of NSAIDs before and in combination with DMARDs 78
Traditional DMARD prescribing trends 80
Methotrexate most commonly used as first-line therapy 85
Infection and inadequate response are the main reasons for switching 85
CHAPTER 7 BRAND ASSESSMENT 88
Factors influencing physician decision making 88
Disease modification and side-effects are the most important factors to prescribing physicians 88
Disease modification 91
Side effects 94
Speed of action and pain relief 95
Formulary or reimbursement status 99
Dosing frequency and delivery method 100
Ability to combine 101
Ability to treat co-morbidities 102
Compliance 102
Biologic DMARD brand assessment 104
Biologic DMARD overview shows Enbrel leads in terms of total brand sales for all indications 104
Interpreting a brand map 107
As the gold standard traditional DMARD, methotrexate is used to benchmark the biologic treatments 109
The three available anti-TNFs are perceived to be similar 110
Brand comparison shows Humira and Enbrel lead the group 112
Enbrel (etanercept) 112
Remicade (infliximab) 115
Humira (adalimumab) 118
Kineret (anakinra) 121
Orencia (abatacept) 123
Rituxan/MabThera (rituximab) 125
CHAPTER 8 IMPROVING TREATMENT OUTCOMES 129
Treatment outcomes 129
Outcome measure definitions 129
American College of Rheumatology 20, 50 and 70 129
Disease activity scale 130
Visual analogue scale 131
Erythrocyte sedimentation rate 131
C-reactive protein 132
Global Assessment 132
Health assessment questionnaire 135
Medical outcome short form 36 (SF-36) health survey 136
Physician patient conversation is the most commonly used outcome measure in the clinic 136
Expected outcome measures before and after anti-TNF treatment don't always correlate with published data 138
Expectation versus published results 138
Compliance rates improve with disease severity 143
Unmet needs 146
Efficacy and side-effects are key, but other challenges should also be addressed by the pharmaceutical industry 146
APPENDIX A 152
Bibliography 152
Other sources and websites 156
APPENDIX B 157
Physician research methodology 157
Physician sample breakdown 157
US 157
Japan 157
France 158
Germany 158
Italy 158
Spain 159
UK 159
Contributing experts 159
APPENDIX C 160
The survey questionnaire 160
Section 1: Epidemiology 160
Section 2: Treatment classes and disease severity 164
Section 3: Prescribing factors 169
Section 4: Prescribing patterns 171
Section 5: Treatment outcomes 177
Disclaimer 181
List of Tables
Table 1: RA patient population, 2006 40
Table 2: Point prevalence of RA, by age and sex, per 100 patients in Norfolk UK study, 2002 41
Table 3: Estimated RA population based on population aged >60: CAGR for each country, 2005-2030 42
Table 4: RA disease severity as a percentage of total diagnosed RA population, by country 43
Table 5: Physician-estimated proportion of patients defined has having early active RA, by country 44
Table 6: Proportion of patients defined has having early active RA, by physician specialty 45
Table 7: Percentage of RA patients with each co-morbidity, by country 48
Table 8: Diagnosed RA patients, physician-estimated, by country 52
Table 9: Number of months from symptom onset to presentation to physician 53
Table 10: Percent of patients receiving pharmacological versus non-pharmacological treatment, by country 54
Table 11: Pharmacological versus non-pharmacological treatment, by physician specialty and percentage of diagnosed patients 55
Table 12: Percentage of patients on each number of drugs, by severity and by country 56
Table 13: Percentage of patients receiving each drug class, by severity 57
Table 14: Number of physicians using each set of guidelines, by physician specialty 61
Table 15: Percentage of mild, moderate and severe RA patients referred on to another physician, by specialty 65
Table 16: Percentage of physicians referring to each specialty, by country 67
Table 17: Percentage of patients receiving each NSAID molecule, by severity 68
Table 18: Action taken on traditional NSAID prescribing, percentage of physicians, by country, 73
Table 19: Action taken on COX-2 prescribing, percentage of physicians, by country 74
Table 20: Average length of time RA patients are given only an analgesic/ anti-inflammatory before being prescribed a DMARD, in months, by severity and country 79
Table 21: Percentage of RA patients taking analgesic or anti-inflammatory treatment in addition to a DMARD, by severity and country 80
Table 22: Percentage of patients on traditional DMARDs receiving key molecules, by country and severity 83
Table 23: Number and percentage of physicians able to rate each brand 91
Table 24: Comparative erosion and joint space narrowing (JSN) scores after 12 months, found in prescribing information, by brand 92
Table 25: Efficacy comparison among key brands 97
Table 26: Key biologic brand characteristics 105
Table 27: Methotrexate's attribute scores, by country 109
Table 28: Enbrel's attribute scores, by country 113
Table 29: Remicade's attribute scores, by country 116
Table 30: Humira attribute scores, by country 119
Table 31: Kineret attribute scores, by country 122
Table 32: Orencia's attribute scores, by country 124
Table 33: Rituxan/MabThera's attribute scores, by country 128
Table 34: Healthy ESR values 132
Table 35: Commonly used outcome measures, by country 137
Table 36: Average expected outcome measures before and after anti-TNF therapy 138
Table 37: Published anti-TNF impacts on key outcome measures 139
Table 38: Average VAS before and after anti-TNF therapy 141
Table 39: Rheumatologist estimates of 28 tender and swollen joint counts before and after anti-TNF therapy 143
Table 40: Compliance estimates by disease severity 145
Table 41: Importance of challenges facing the RA market, by country 148
Table 42: US physician sample breakdown, 2006 157
Table 43: Japan physician sample breakdown, 2006 157
Table 44: France physician sample breakdown, 2006 158
Table 45: Germany physician sample breakdown, 2006 158
Table 46: Italy physician sample breakdown, 2006 158
Table 47: Spain physician sample breakdown, 2006 159
Table 48: UK physician sample breakdown, 2006 159
List of Figures
Figure 1: Overview of the coverage of Stakeholder Insight: Rheumatoid Arthritis survey, 2006 14
Figure 2: US RA patient population, split by physician-estimated diagnoses, disease severity, drug-treated population and drug-class usage 18
Figure 3: Key NSAID, traditional DMARD and biologic DMARD molecules used in the US, by disease severity 19
Figure 4: US treatment algorithm from onset of symptoms to percentage reaching desired outcome, for NSAIDs and first- to fifth-line DMARDs, by disease severity 20
Figure 5: Japan RA patient population, split by estimated diagnoses, disease severity, drug-treated population and drug-class usage 21
Figure 6: Key NSAID, traditional DMARD and biologic DMARD molecules used in Japan, by disease severity 22
Figure 7: Japanese treatment algorithm from onset of symptoms to percentage reaching desired outcome, for NSAIDs and first- to fifth-line DMARDs, by disease severity 23
Figure 8: France RA patient population, split by physician-estimated diagnoses, disease severity, drug-treated population and drug-class usage 24
Figure 9: Key NSAID, traditional DMARD and biologic DMARD molecules used in France, by disease severity 25
Figure 10: France treatment algorithm from onset of symptoms to percentage reaching desired outcome, for NSAIDs and first- to fifth-line DMARDs, by disease severity 26
Figure 11: Germany RA patient population, split by physician-estimated diagnoses, disease severity, drug-treated population and drug-class usage 27
Figure 12: Key NSAID, traditional DMARD and biologic DMARD molecules used in Germany, by disease severity 28
Figure 13: Germany treatment algorithm from onset of symptoms to percentage reaching desired outcome, for NSAIDs and first- to fifth-line DMARDs, by disease severity 29
Figure 14: Italy RA patient population, split by physician-estimated diagnoses, disease severity, drug-treated population and drug-class usage 30
Figure 15: Key NSAID, traditional DMARD and biologic DMARD molecules used in Italy, by disease severity 31
Figure 16: Italy treatment algorithm from onset of symptoms to percentage reaching desired outcome, for NSAIDs and first- to fifth-line DMARDs, by disease severity 32
Figure 17: Spain RA patient population, split by physician-estimated diagnoses, disease severity, drug-treated population and drug-class usage 33
Figure 18: Key NSAID, traditional DMARD and biologic DMARD molecules used in Spain, by disease severity 34
Figure 19: Spain treatment algorithm from onset of symptoms to percentage reaching desired outcome, for NSAIDs and first- to fifth-line DMARDs, by disease severity 35
Figure 20: UK RA patient population, split by physician-estimated diagnoses, disease severity, drug-treated population and drug-class usage 36
Figure 21: Key NSAID, traditional DMARD and biologic DMARD molecules used in UK, by disease severity 37
Figure 22: UK treatment algorithm from onset of symptoms to percentage reaching desired outcome, for NSAIDs and first- to fifth-line DMARDs, by disease severity 38
Figure 23: Percentage of physicians with RA patients who have at least one co-morbidity 47
Figure 24: Prevalence of hypertension in US RA patients, 2004 49
Figure 25: Treatment algorithm for RA 60
Figure 26: Percentage of physicians using each set of guidelines, by country 61
Figure 27: Number of physicians using different guidelines, by specialty 63
Figure 28: Percentage of patients consulting a rheumatologist directly or via referral, by country 64
Figure 29: Percentage of mild, moderate and severe RA patients referred on to another physician, by specialty 65
Figure 30: Percentage of physicians that refer to each specialist type, split by PCPs and rheumatologists 67
Figure 31: US NSAID/COX-2 quarterly prescriptions (Rx), 2003-2005 70
Figure 32: Percentage of drug-treated RA patients receiving celecoxib and etoricoxib, by country 71
Figure 33: Trend in prescribing of NSAIDs and COX-2s after the withdrawal of Vioxx 72
Figure 34: Results of Jack Cush's US physician survey, November 2005 75
Figure 35: Decision tree for physicians treating arthritis patients developing GI complications with NSAIDs 76
Figure 36: Percentage of NSAID-treated patients also receiving a gastro-protective agent, by country and by physician specialty 77
Figure 37: Co-prescription of a PPI with an NSAID, comparing RA to all indications, % RX-Days, 2005 78
Figure 38: Percentage of RA patients using NSAIDs (including COX-2s), by physician specialty and by disease severity 79
Figure 39: Most commonly used traditional DMARD molecules, by disease severity 82
Figure 40: Number of months a patient will be continued on DMARD therapy before moving to the next line of therapy, by country and by physician specialty 84
Figure 41: Percentage of physicians using DMARD molecules at each line of therapy 85
Figure 42: Percentage of patients on biologics switching or terminating therapy, and key reasons 86
Figure 43: Average influence on prescribing decision: weightings assigned by surveyed physicians to key attributes for biologic and traditional DMARDs 89
Figure 44: Biologic and traditional DMARD attribute weightings assigned by physicians, by country 90
Figure 45: Comparative erosion and JSN scores, by brand 93
Figure 46: Physicians' scores of disease-modification efficacy, by brand 93
Figure 47: Importance of side effects to prescribing of biologic and traditional DMARDs, by country and by physician specialty 94
Figure 48: Physicians' scores of side effects, by brand 95
Figure 49: Comparative ACR 20, 50 and 70 scores for biologic therapies based on their prescribing information 98
Figure 50: Physicians' scores for therapeutic efficacy attributes, by brand 99
Figure 51: Importance of reimbursement/formulary status to prescribing of biologic and traditional DMARDs, by country and by physician specialty 100
Figure 52: Importance of dosing frequency and delivery method to prescribing of biologic and traditional DMARDs, by country and by physician specialty 101
Figure 53: Total biologics brand sales, seven major markets, $m 104
Figure 54: Comparison of total scores for all brands rated, by country and specialist 106
Figure 55: Total score for each brand across the seven major markets 107
Figure 56: Overview brand map of attributes versus brand perception 108
Figure 57: Physician perception of the anti-TNF inhibitors 110
Figure 58: Enbrel map, country preference to prescribing attributes 114
Figure 59: Remicade map, country preference to prescribing attributes 117
Figure 60: Humira attribute scores 119
Figure 61: Kineret attribute scores 121
Figure 62: Orencia attribute scores 123
Figure 63: Rituxan/MabThera attribute scores 126
Figure 64: Patient assessment form, American College of Rheumatology 134
Figure 65: Physician's global assessment 135
Figure 66: Commonly used outcome measures, by specialist 136
Figure 67: Comparison between survey results for expected improvement in disease activity measures after anti-TNF and prescribing information data 140
Figure 68: Average VAS before and after anti-TNF therapy 141
Figure 69: Swollen and tender joint count assessment 142
Figure 70: Compliance estimates by disease severity 144
Figure 71: Reasons why patients do not fill prescriptions or comply with drug regimes, 2002 146
Figure 72: Importance of challenges facing the RA market 147
Figure 73: IFPMA clinical trials portal 150