STRAMA, the Swedish Strategic Programme Against Antibiotic

224 Pages·2010·2.21 MB·English

high levels of pathogen resistance are,
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antibiotics obsolete. Coupled with antibiotics we will be facing a public health disaster. Informed ie
insufficient investment in discovering discussion on how to address the need for drugs against s
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new treatments, multidrug-resistant priority, multidrug-resistant infections must take place at the n
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infections pose an increasingly urgent highest level of national government and within the appropriate
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To curb the growth of antibiotic both new and old ideas that lay the groundwork for the tiv
complex biological and market-specific considerations that will e
resistance and prevent major morbidity s Policies and incentives
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bacterial infections we must address p
Otto Cars, Professor of Infectious Diseases, Department of
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overuse and actively promote research Medical Sciences, Uppsala University, Sweden; Chair of m for promoting innovation
and development for antibiotics with STRAMA, the Swedish Strategic Programme Against Antibiotic o
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novel mechanisms of action. This must Resistance; Director of ReAct, Action on Antibiotic Resistance in
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be done through appropriately designed in in antibiotic research
incentives for health and regulatory n
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systems in addition to economic “Society has reached a crisis in infectious diseases. Antibiotic va
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incentives to attract academic interest resistance is skyrocketing while new antibiotic development is io
and industry investment. dying. The thought leaders at the London School of Economics n
understand these intertwining problems like few others. This in

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This book analyses many of the book is of breathtaking scope, analysing the problem from both n
proposed policies and incentive a broad and in-depth perspective. Of greatest importance, the tib Elias Mossialos, Chantal M. Morel,
mechanisms that are on the table and authors propose very specific, meaningful economic solutions io Suzanne Edwards, Julia Berenson,
to the antibiotic crisis with a real-world perspective. This book tic
sheds light on the key issues that can
will serve as a blueprint for setting effective national policy for r Marin Gemmill-Toyama, David Brogan
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help policy-makers reach informed,
countries all over the world to deal with the antibiotic crisis.” s
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concrete decisions on how to avert this Brad Spellberg, MD, Associate Professor of Medicine at the a
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elias Mossialos, Professor of health Policy, Lse health ill-Tlos
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Marin Gemmill-Toyama, research Fellow, Lse health rord
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David Brogan, resident Physician, Department of orthopedic surgery, Mayo Clinic, rochester MN, an, B
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Policies and incentives for promoting innovation
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Policies and incentives
for promoting innovation
in antibiotic research
Elias Mossialos, Chantal M Morel, Suzanne Edwards,
Julia Berenson, Marin Gemmill-Toyama, David Brogan
This study was commissioned and financed by the
Swedish Government
Keywords:
ANTI-BACTERIAL AGENTS
DRUG RESISTANCE, BACTERIAL
MOTIVATION
HEALTH POLICY
DRUG INDUSTRY – economics – manpower
DRUG DISCOVERY
BIOMEDICAL RESEARCH
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ISBN 978 92 890 4213 0
Printed in the United Kingdom
Contents
List of tables, figures and boxes vii
List of abbreviations xi
Glossary xiii
Foreword ixx
Acknowledgements xxi
10 key messages xxiii
Introduction 1
Chapter 1 Background on antibiotics 9
1.1 What are antibiotics? 9
1.2 Why antibiotics are important 10
1.3 Externalities of antibiotics and AR 11
Chapter 2 Background on AR 15
2.1 What is AR? 15
2.2 Severity of AR 16
2.2.1 AR trends in developed countries 16
2.2.2 AR trends in developing countries 20
2.3 Clinical and economic impact of AR 21
2.3.1 Clinical outcomes 21
2.3.2 Costs of resistance 23
Chapter 3 Causes of AR 27
3.1 Misuse of antibiotics 27
3.1.1 Physicians and health-care providers 28
3.1.2 Livestock and agriculture 31
3.2 Role of diagnostics in AR 32
3.3 Role of vaccines in AR 36
3.3.1 Examples from Europe 37
3.3.2 Examples from the United States 37
3.4 Lack of new antibiotics 37
3.4.1 The antibiotic market 38
3.4.2 Areas of unmet need 43
Chapter 4 Reasons for limited innovation 49
4.1 Antibiotic restrictions deter pharmaceutical investment in R&D 49
4.2 Challenges in the antibiotics market – NPV 50
vi Policies and incentives for promoting innovation in antibiotic research
4.3 Regulatory environment 53
4.4 Estimated cost of drug development 54
4.5 Scientific challenges 57
Chapter 5 Health system responses to AR 59
5.1 Examples from Europe 61
5.2 Examples from the United States 63
Chapter 6 Analysis of opportunities and incentives to stimulate R&D 67
for antibiotics
6.1 Push incentives 67
6.1.1 Increasing access to research 68
6.1.2 Scientific personnel 71
6.1.3 Direct funding of research 71
6.1.4 Translational research 77
6.1.5 Tax incentives 79
6.1.6 PDPs 83
6.2 Pull incentives 89
6.2.1 Monetary prizes 89
6.2.2 Advance market commitments 95
6.2.3 Patent buyout 100
6.3 Lego-regulatory mechanisms 100
6.3.1 Clinical trials 101
6.3.2 Intellectual property mechanisms 106
6.3.3 Expedited regulatory review 117
6.3.4 Pricing and reimbursement 121
6.3.5 Liability protection 126
6.3.6 Antitrust laws 127
6.3.7 Sui generis rights 127
6.4 Combined push-pull incentive models 128
6.4.1 Orphan drug designation 128
6.4.2 Call options for antibiotics model 129
Chapter 7 Conclusions 137
7.1 Rationale for intervention in the antibiotics market 137
7.2 Preserving the effective life of existing and new antibiotics 139
7.3 Key concepts in incentive design 141
7.4 Conclusions on individual incentives 147
7.4.1 Direct public subsidy for basic research 147
Appendix A. EU Council conclusions on innovative incentives 159
Appendix B. US-EU joint declaration on creation of transatlantic 161
taskforce on antimicrobial resistance
Appendix C. Global vaccine research 175
Appendix D. Possible funding mechanisms for a COA scheme 177
References 179
List of tables, figures
and boxes
Tables
Table 3.1 Features and performance characteristics of commercial
molecular assays for detection of MRSA 34
Table 3.2 Antibiotic launches since 2000 41
Table 3.3 New systemic antibacterial agents with new target or new MoA
and in vitro activity based on actual data or assumed based on
known class properties or MoA against the selected bacteria
(n=15, as of 14 March 2008) 46
Table 4.1 Risk-adjusted NPV (US$ millions) for project therapeutic classes 51
Table 4.2 Top 13 oral drugs: patent expiry dates and 2007 revenues 54
Table 5.1 Susceptibility (S)/Resistance (R) results for S. aureus isolates in 62
a selection of European countries, 2007
Table 6.1 Differences between EMEA accelerated review mechanisms 118
Table 6.2 Products with conditional and exceptional circumstance EMEA 118
approvals to date
Table 6.3 Comparison of United States and EU orphan drug legislation 129
and processes
Table 6.4 Length of time and estimated success per development phase 133
Table 7.1 Merits of push and pull mechanisms 144
Table A New vaccines against infectious diseases: R&D status as of 175
February 2006
Figures
Fig. 2.1 S. pneumoniae: proportion of invasive isolates nonsusceptible to
penicillin, 2007 …….............................................…. See colour section
viii Policies and incentives for promoting innovation in antibiotic research
Fig. 2.2 S. pneumoniae: proportion of invasive isolates resistant to
erythromycin, 2007 …......................................……. See colour section
Fig. 2.3 S. pneumoniae: proportion of invasive isolates with dual
nonsusceptibility to erythromycin and penicillin, 2007
…….....................................................................…. See colour section
Fig. 2.4 S. aureus infections in ICUs in the NNIS system, 1987–1997
…….....................................................................…. See colour section
Fig. 3.1 Total outpatient antibiotic use in 25 European countries, 2003
…….....................................................................…. See colour section
Fig. 3.2 Correlation between penicillin use and prevalence of penicillin
nonsusceptible S. pneumoniae …....................……. See colour section
Fig. 3.3 ROC curve based on laboratory-based evaluation of 19
commercially available RDTs for TB (all patients = 355)
…….....................................................................…. See colour section
Fig. 3.4 Timeline of the rapid rate of resistance ……….......... See colour section
Fig. 3.5 Discovery of new classes of antibiotic …........…..…. See colour section
Fig. 3.6 Ten-year trend in drug and biological submissions
to the FDA ……...................................................…. See colour section
Fig. 3.7 New systemic antibacterial agents ……...............…. See colour section
Fig. 4.1 Antibiotic restrictions and the regulatory environment: 52
impact on NPV
Fig. 6.1 8+2(+1) arrangements in the EU 112
Fig. 6.2 Call option price (US$ millions) as a function of development 134
stage and Q
Boxes
Box 3.1 Coordinating prescribing practices with policies – lessons from the 30
Medicare Product Quality Research Initiative in the United States
Box 3.2 Current status of diagnostic tests for detection of MRSA 33
Box 3.3 Case study – pneumococcal conjugate vaccine 36
Box 3.4 Main findings from the EMA/ECDC Joint Technical Report: 42
The Bacterial Challenge –Time to React
Box 4.1 Regulatory experiences of five antibiotics recently reviewed by 55
the FDA
Box 5.1 Literature on policies to guide appropriate antibiotic use 60
Box 6.1 The Structural Genomics Consortium 70
List of tables, figures and boxes ix
Box 6.2 The Wellcome Trust 72
Box 6.3 The Innovative Medicines Initiative (IMI) 73
Box 6.4 Project Bioshield 76
Box 6.5 Examples of promising drugs developed through PDPs 83
Box 6.6 Wellcome Trust: Technology Transfer division 85
Box 6.7 Institute of OneWorld Health (iOWH) 87
Box 6.8 Example of a prize for a diagnostic test, X PRIZE Foundation 90
Box 6.9 Ex-ante award calculation 92
Box 6.10 Stockpiling 99
Box 6.11 Using IP mechanism to inhibit development of resistance 113
Box 6.12 Broadening IP protection 114
Box 6.13 Health technology assessments (HTAs) 122
Box 6.14 ACE Programme proposal 124
Box 6.15 Health impact fund (HIF) 125