Table of Contents

7 EXECUTIVE SUMMARY
7 Orphan drug coverage is beginning to test payer budgets
7 Some P&R frameworks are ill-equipped to deal with orphan drugs
7 Payers have begun to take evasive action
8 Some orphan manufacturers have learnt expensive lessons

10 THE ORPHAN DRUGS EXPLOSION
10 Incentivizing investment in orphan drug R&D
11 From backwater to boom
16 Time for a rethink of orphan drug rules?
18 Payers are looking for ways to rein in orphan drug costs
19 Bibliography

22 ORPHAN DRUG COVERAGE, FUNDING, AND PRICING
22 Established systems reflect a benign approach to orphan coverage
26 Raising the orphan P&R bar
34 Bibliography

40 US
40 Still few constraints on orphan coverage or prices
40 Orphan-specific P&R rules are notable by their absence
44 Rising orphan costs begin to prompt closer scrutiny
49 Bibliography

54 UK
54 Orphan coverage reflects fragmented regulatory framework
59 Payers turn the screw as NHS funding crisis bites
62 Bibliography

65 FRANCE
65 New pressures on orphan drug prices emerge
65 Orphan-specific rules focus on pricing, not reimbursement
68 Payers seek increased leverage over orphan prices
73 Bibliography

75 GERMANY
75 Payers toughen stance on orphan prices
75 Orphans are reimbursed widely, but price is an issue
79 Calls for a tighter line on orphan P&R are growing
83 Bibliography

86 ITALY
86 MEAs will remain the key to orphan access
86 Most orphans benefit from special provisions for “innovative” drugs
89 Payers may shift the focus of MEAs as orphan spend rises
93 Bibliography

95 SPAIN
95 Orphan coverage hit by healthcare funding crisis
95 National decisions determine orphan P&R status
96 Orphan P&R approval rates plunge as funding crisis bites
100 Bibliography

102 JAPAN
102 P&R overhaul will have implications for orphans
102 Reimbursement is comprehensive, but prices are tightly regulated
104 Spending surge prompts new P&R reform drive
106 Bibliography

108 ORPHAN DRUG CASE STUDIES
108 Experience, and lessons learned
108 Data limitations pose a challenge for regulators, as well as payers
109 Payers crave certainty, where often there is none
110 Maximizing prospects for positive P&R outcomes
113 Case studies
113 Glybera and Strimvelis – salutory lessons for gene therapy pioneers
115 Orkambi – offering less to more proves a hard sell for Vertex
117 Exondys 51 – Sarepta works hard to win over skeptical payers
119 Imbruvica – highlighting the P&R gulf between Europe and the US
121 Kymriah and Yescarta – CAR-T pioneers break the US pricing mold

LIST OF TABLES
122 Translarna – efficacy queries plague commercialization efforts
124 Jakafi/Jakavi – strong data the platform for commercial success
127 Bibliography

134 APPENDIX
134 About the author
134 Scope
134 Methodology

LIST OF TABLES
11 Table 1: Orphan drug definitions and development incentives
12 Table 2: Orphan drug indication approval numbers in the US, EU, and Japan
14 Table 3: Lenalidomide orphan designations, marketing authorizations, and indications in the US
15 Table 4: Global sales of Revlimid (lenalidomide)
17 Table 5: Orphan status of oncology drugs approved by the FDA in 2016
25 Table 6: Overview of approaches to orphan drug P&R in the US, Japan, and Europe
27 Table 7: Turning the screw on orphan drug reimbursement
30 Table 8: Potential solutions to the orphan drug funding challenge
32 Table 9: Leveraging pressure on orphan drug prices
43 Table 10: Relative exposure of marketplace plan holders to orphan drug costs
54 Table 11: Access to orphan drugs in the five major EU markets
57 Table 12: NICE appraisal outcomes
58 Table 13: Positive ultra-orphan drug appraisals by NICE
59 Table 14: Patient access schemes for orphan drugs recommended by NICE
62 Table 15: Ultra-orphan drugs in the NICE appraisal queue
67 Table 16: ASMR scores for new orphan drugs reviewed recently by HAS
71 Table 17: Change in ASMR rating following orphan drug reassessment
77 Table 18: Comparison of G-BA benefit assessment outcomes for orphan and non-orphan drugs*
89 Table 19: Orphan drug monitoring programs linked to performance-based MEAs
90 Table 20: Orphan drug spending and consumption trends in Italy
91 Table 21: Orphan drugs being bankrolled by AIFA’s new innovative drug funds
92 Table 22: Benefits conferred on innovative drugs by AIFA’s new algorithm
98 Table 23: Main contributors to hospital spending on orphan drugs in Spain
99 Table 24: Decline in P&R approval rates for non-cancer orphan drugs in Spain
108 Table 25: Flexible approach to the regulatory review of orphan drugs in the US
116 Table 26: Orkambi takes off in the US, but struggles elsewhere
126 Table 27: Global sales of ruxolitinib