GlobAl HeAltH InnovAtIon QuotIent prIze

Transcription

Global Health Innovation Quotient prize
Point-of-Care Diagnostics for Differential Diagnosis of Fever in Children
donor proposal
April 2011
Global Health Innovation Quotient Prize: Point of Care
Diagnostics for Differential Diagnosis of Fever in Children
Copyright © 2011 BIO Ventures for Global Health
All rights reserved
This report was written by the team at BIO Ventures for
Global Health with contributions from Elizabeth R. Aden
and Dalberg Global Development Advisors.
Authors’ note:
We gratefully acknowledge the Bill & Melinda Gates
Foundation for its financial support. We are grateful
to Elizabeth R. Aden and the team at Dalberg Global
Development Advisors: Timothy Carlberg, Vicky Hausman,
and Wouter Deelder for their hard work and significant
contributions to this document. We also thank our
Industry Working Group for their feedback and support:
David Friedman, David Steinmiller, Doug Dolginow, Geoff
McKinley, John McDonough, Karen Hedine, Neil Butler,
Patrick Beattie, Susan Bromley, Una Ryan, and William
Rodriguez. We thank those at PATH and the Clinton Health
Access Initiative who provided valuable input throughout
the course of this work. Finally, thank you to all those
interviewed during the course of this project for their time
and effort to ensure the accuracy of the report.
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BIO Ventures for Global Health
Contents
1. Executive Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2. Project Objectives and Approach. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
3. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
4. Need for a POC Fever Diagnostic. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
5. Target Product Profile (TPP). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
6. Impact and Cost-Effectiveness of Proposed POC Fever Panel. . . . . . . . . . . . . . . . . . . 23
7. Guiding Principles for Incentive Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
8. Incentive Design and Structure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
a. Criteria of Each Milestone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
b. Number of Awards. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
c. Size of the Milestone Payment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
d. Selection of Awardees. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
e. Eligibility Criteria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
f. Intellectual Property Considerations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
9. Incentive Administration and Governance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
10. Monitoring and Evaluation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
11. Financial Requirements Over Time. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
12. Impact Considerations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
a. Access Provisions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
b. Supporting Interventions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Appendix A: Organizations and Individuals Consulted. . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Appendix B: Project Approach. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Appendix C: Disease Selection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
Appendix D: Integrating a Multiplexed Diagnostic into the IMCI Guidelines. . . . . . . 65
Appendix E: Definition of Terms Used in the Target Product Profile (TPP). . . . . . . . . . 68
Appendix F: Impact Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
3
The Need for Point-of-Care
Diagnostics in Developing Countries:
1. Executive Summary
many different infectious agents, some that are
Children brought to clinics in developing
countries frequently present with general
symptoms, including fevers that could be
caused by a wide range of diseases.
curable with currently available treatments and
Clinicians are often unable to isolate the root cause of
others that are not. It is the rainy season and malaria
illness and have difficulty making an accurate diagnosis
cases fill the wards as they do each year. The clinic
to determine the appropriate treatment needed to save a
recently received rapid diagnostic tests for malaria
child’s life. This presents an urgent threat to child health.
and the doctor orders this test. Thirty minutes later,
Each year more than 2 million children under the age of
when the doctor looks at the results of the test, it
five die from bacterial pneumonia infections; a further
is negative for malaria. However, because there is
700,0001 children die from malaria. The vast majority of this
no laboratory capability to test for other causes
burden — more than 97% of pneumonia episodes — is
of fever, and because the parents of this very sick
carried by the developing world and could be avoided
child are demanding treatment for malaria, the
with appropriate diagnosis and treatment.2
A child comes into a clinic in rural Africa with a
complaint of fever. That fever could be caused by
doctor orders antimalarials for the child in any case.
This scenario is repeated countless times across
poor countries, as doctors and nurses are forced
to deliver care without the benefit of modern
diagnostic technology.
However, there is currently no point-of-care
diagnostic that can distinguish bacterial
infections, such as bacterial pneumonia,
from other fever-causing pathogens.
The introduction of rapid diagnostic tests for malaria in
These clinicians desperately need diagnostics that
some regions has helped. But in the absence of differential
can be used at the point of care, enable clinically
POC diagnostic tests, clinicians are often unable to make
relevant decisions, and are rugged enough to survive
definitive diagnoses. A multiplex POC diagnostic for fever
the conditions found in developing countries.
would reduce mortality by providing earlier diagnosis to
more people, enabling significantly higher clinical accuracy
than currently unaided clinical diagnosis, and reducing
misdiagnosis of pneumonia as malaria. Furthermore, the
test would increase adherence to standard treatment
protocols by minimally trained health care practitioners.
1
2
4
World Malaria Report 2009. World Health Organization. 2009.
Pneumonia: The forgotten killer of children, The United Nations Children’s Fund (UNICEF)/World Health Organization (WHO), 2006.
The potential health and economic
benefits associated with a multiplex
POC fever diagnostic are significant.
To encourage development of a multiplex
POC fever diagnostic, a pay-for-success,
milestone-based prize is needed:
An analysis of the data suggest that timely and accurate
BIO Ventures for Global Health (BVGH) is committed to
diagnosis of bacterial infections such as pneumonia could
bringing the tools of biotechnology and the expertise of
reduce child mortality among the population tested by
the biopharmaceutical industry to bear on the problem
15-20%, saving more than 350,000 lives if universally adopted.
of neglected diseases. Despite the immense need for a
According to World Bank standards, such a diagnostic would
POC fever diagnostic, industry investments to develop
be considered cost effective in the developing world, in the
such products remain limited, largely due to a lack of
range of $80-160 per life-year saved in sub-Saharan Africa.
attractive markets and financial returns. This is not an
Beyond the direct impact on bacterial pneumonia mortality,
insurmountable barrier. The Global Health Innovation
the proposed diagnostic could have additional impact on
Quotient Prize (IQ Prize) described in this proposal will
the correct use of antimalarials and reduction of mortality
provide financial support to companies that develop novel
associated with other bacterial infections.
technologies leading to a multiplex POC diagnostic for
3
fever symptoms that can serve the poorest populations
Furthermore, universal adoption would
reduce inappropriate use of antibiotics
and delay the development of resistance
to antibiotic treatment.
affected by diseases such as malaria and bacterial
pneumonia.
Without the aid of modern diagnostic technologies,
The IQ Prize will help encourage private sector
investment in global health initiatives.
clinicians often indiscriminately prescribe antibiotics. This
Such a mechanism can reduce the amount of capital
has led to potentially dangerous increases in resistance,
investment required by the company and mitigate the
which has increased the cost of fighting infectious
technical, financial, and market risk associated with global
diseases and potentially undermines investments made
health research and development (R&D). Milestone-
to increase access to drugs. A POC diagnostic would
based prizes provide compensation in stages, linked to
reduce unnecessary use of antibiotics contributing to the
the successful achievement of key product development
development of antibiotic resistance.
milestones. This allows smaller, innovative companies
with limited access to capital to participate in the
development process, using interim payments to fund the
next stage of work.
3
5
The World Development Report for 1993 (World Bank, 1993), which reviewed many public health interventions, suggests that interventions costing
less than $150 per DALY saved are highly cost‐effective. These estimates are based on an assumed unit cost of testing ranging from $1.50 – 3.
The Global Health Innovation Quotient
Prize proposed in this document
would provide for the following:
From the donor perspective, the pay
for-success nature of the prize has
additional benefits.
Rather than a fully-funded contract arrangement, which
would require donors to ‘pick winners’ and technology
A Target Product Profile (TPP) to ensure the
resulting product meets the needs of developing
countries as the standard for achievement sought.
The TPP has been informed by 80 leading global
health and industry stakeholders and reviewed by an
industry working group of 12 potential developers;
An open competition among diagnostic developers
having the capability to achieve all or part of the
TPP and that are willing to participate and agree to
the rules of the competition;
A milestone structure that is familiar to industry
participants, rewarding successful completion
of key inflection points in the development of a
novel POC diagnostic, meeting the predetermined
requirements and providing adequate commercial
incentive to motivate industry participation;
Payment only for milestones achieved during
the competition, i.e., no payment for prior results,
although a competitor could enter midstream if
earlier milestones have been satisfied.
A fixed, maximum number of awards at each
milestone to cap the amount donors would have to
approaches at the outset of the work, a pay-for-success
incentive prize allows for the participation of a greater
number and broader range of diagnostic developers
and technology approaches – reducing the overall risk
to the donor of product development failure. Combined,
a milestone-based, pay-for-success approach would be
attractive to both industry and donors.
Donor support of approximately $150
million over 8 years would be required
to implement the proposed prize
for significant health impact in the
developing world:
The proposed Global Health Innovation Quotient Prize (IQ
Prize) was informed by interviews with more than 80 experts
in the fields of global health and diagnostics development.
It is estimated to cost approximately $150M over an 8-year
period and is expected to result in two novel POC diagnostic
products available to children (and adults) in the developing
world. The target product is designed to be low-cost,
portable, simple to use and durable enough to withstand
resource-poor environments. The impact of the IQ Prize
would be supported by a comprehensive access plan and
a number of supporting interventions to ensure successful
integration of the new diagnostics into established health
care systems.
reserve for payment;
Objective determination by an expert working
group as to whether each milestone is achieved
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2
Project Objectives and Approach
2. Project Objectives and Approach
At BVGH, we help for-profit companies find commercially
viable ways to participate in global health. It is essential
The Global Health Innovation Quotient Prize
proposed in this report has dual objectives:
to engage private-sector companies—particularly
document that follows is a proposal for a commercial
To spur R&D efforts to develop a new
POC diagnostic test for the differential
diagnosis of fever that can generate
significant health impact in the
developing world.
incentive structure that we believe will engage industry,
We propose in this document a milestone-based prize to
particularly small- to medium-sized diagnostic developers,
promote the development and launch of a POC diagnostic
in global health R&D.
test for the differential diagnosis of fever, targeted primarily
entrepreneurial biotechnology companies with a track
record of innovating new products—in the effort to
prevent, diagnose, and treat neglected diseases in the
developing world. In line with our overall objectives, the
at children less than 5 years of age. We believe that a POC
This proposal is informed by more than 80 consultations
diagnostic platform that meets our TPP has the potential
with a broad range of stakeholders, including: the
to lead to a significant reduction in child mortality from
executive teams and venture capital investors of diagnostic
pneumonia and other bacterial infections and to delay the
companies both large and small; global health experts
onset of antibiotic resistance. We further believe that the
working to support the development and introduction of
milestone-based prize proposed here is a cost-effective
new diagnostic tools; clinicians working in low-resource
intervention to achieve this result.
settings in developing countries; and academic experts
presented in this report. A full list of individuals and
To demonstrate the value of a
milestone-based, pay-for-success prize
structure in motivating key players along
the product development value chain.
organizations consulted in the report and participating on
We believe that a well-designed incentive should mitigate
the Industry Working Group can be found in Appendix A
the technical, financial, and market risk to companies
and more information on our approach and methodology
associated with developing world POC diagnostic platforms
can be found in Appendix B.
on a pay-for-success basis. We recognize that innovation
in incentive design. Additionally, a high-level Industry
Working Group was convened to validate the prize design
structure and key assumptions in the financial analysis
often thrives in small- and medium-sized enterprises that
lack sufficient resources and capacity to make multi-year
investments, as illustrated in the chart below.
8
Figure 1: Source of New Drugs Approved by U.S. FDA, 1998-20074
Therefore we have designed a milestone-based prize that
rewards attainment of clearly defined product development
milestones and that would ensure participation of a broad
range of companies. This prize structure could serve as a
platform for other incentive programs and could stimulate
innovation in fields outside of POC diagnostics. We believe
that this structure will resonate with both donors and
innovators and can be widely applied in order to advance
the prevention, diagnosis, and treatment of neglected
diseases in the developing world.
Kneller, Robert, “The importance of new companies for drug discovery: origins of a decade of new drugs.” Nature Review. Volume 9. November 2010.
4
9
3
Introduction
3. Introduction
Over the past decade, donor and government institutions
accurate, inexpensive, and portable; capable of operating
have invested billions of dollars in R&D to prevent and
without clean water or electricity; able to withstand high
treat neglected diseases — such as malaria and pneu-
temperatures and humidity; and simple enough to be used
monia — which primarily affect underserved people in the
by minimally-trained health care workers.
developing world. Unfortunately, only 4% of this annual
hundreds of thousands of lives each year by detecting
The Need for a POC Diagnostic to
Support Differential Diagnosis of
Children with Fever
diseases that can be treated effectively if caught in the
Globally, nearly 9 million children die each year before
early stages and by reducing the inappropriate use of
they reach the age of five.7 Of that number, approximately
medication due to misdiagnosis. Therefore, the small
2 million die from lower respiratory infection (LRI) due
percentage of investment in diagnostics relative to other
to pneumonia.8 As a result, Millennium Development
products is surprising and concerning.
Goal 4 was created to prioritize child mortality. Many of
spending has been directed towards diagnostics.5 New
forms of diagnostic technology have the potential to save
the primary causes of childhood mortality — including
It is essential to find avenues to spur increased investment
pneumonia, meningitis, malaria, and HIV/AIDS — present
in diagnostic development for the developing world—
with non-specific symptoms such as fever and cough.
to reduce mortality, improve health outcomes, delay
The Integrated Management of Childhood Illness (IMCI)
resistance to antibiotics, and improve the cost effectiveness
guidelines, developed jointly by the World Health
of current interventions.
Organization (WHO) and UNICEF, provide a tool to help
health care practitioners evaluate patient symptoms,
The Importance of POC Diagnostics
make presumptive diagnoses, and treat accordingly.
Private-sector innovation is driving improvements that
However, the absence of definitive diagnostic tools and
have primarily been implemented through central
tests to support these guidelines in low resource settings
laboratory testing in the developing world, a system
can lead to incorrect and delayed treatment, prolonged
which is consistent with developed world infrastructure,
illness, or overuse of unnecessary medications. A new
access, and treatment availability. Yet infrastructure-
multiplex POC diagnostic for differential diagnosis of
intensive laboratory-based solutions will never fully meet
fever presents an opportunity to have an immediate
the needs of patients in low resource settings. In the
impact on child health.
developing world, improved access to diagnostics depends
on developing POC diagnostic tools in the form of rapid
tests or small handheld devices that can be used in low
resource, minimal infrastructure settings. In order to reach
the majority of patients in developing countries, where as
many as 70% of individuals only have access to minimal
levels of health care infrastructure if any,6 diagnostic
tests must meet certain requirements. Tests must be
5
6
7
8
11
-Finder 2011. “Neglected Disease Research & Development: Is the Global Financial Crisis Changing R&D? Policy Cures.” 2011.
G
Girosi, F., S. Olmsted, et al (2006). “Developing and interpreting models to improve diagnostics in developing countries.” Nature 444 Suppl 1: 3-8.
UNICEF/WHO (2006). “Pneumonia: The forgotten killer of children.”
UNICEF/WHO (2006). “Pneumonia: The forgotten killer of children.”
The Potential for
Technological Breakthroughs
preparation, and detect broad panels of analytes—
There are a limited number of POC diagnostics available
These new technologies have the potential to simplify
for use in low resource developing world settings,
the number of platforms required to address the needs of
primarily for malaria and HIV diagnosis. Their successful
the developing world.
including proteins, nucleic acids, and small molecules.
adoption in developing countries has begun to support
the shift in health care delivery from a clinically-based,
The rapid evolution of in vitro diagnostic technologies
presumptive treatment model towards a “test and treat”
offers realistic hope that products being created by both
paradigm. There is a need for POC tests that can detect
large and small companies could be adapted for the
an array of additional pathogens, such as multiplex tests
developing world. In our extensive interviews with
that span multiple diseases with related symptoms. Over
diagnostic companies, we found a strong interest in
time, this will better enable effective case management
exploring ways to assist in the fight against neglected
of individuals while at the same time inform population-
diseases. At the same time, companies reinforced their
level epidemiologic surveys that are critical indicators
position that they will be unable to commit their resources
of the overall effectiveness of interventions. Rather
to this goal in the absence of a financial model that makes
than developing new single pathogen tests or running
a compelling business case.
existing tests in parallel, development of multiplex tests
using a common sample type (urine, blood, saliva, etc.)
The Need for Incentives to Spur Diagnostic
Development for Neglected Diseases
to differentiate between illnesses with similar symptoms.
The hurdles to industry involvement in meeting the
This would allow healthcare workers to obtain differential
needs of the developing world are high. The commercial
diagnoses and would help them to identify and treat
prospects for the next generation of POC diagnostics in the
diseases that often occur simultaneously.
developed world are unproven due to uncertain market
to identify relevant panels of disease is needed, ideally
competitiveness with existing laboratory-based solutions.
Fortunately, technological innovations are emerging
While a clear need exists in the developing world, the lack
that could address many of the unmet diagnostic needs
of secure distribution channels along with the limited
for neglected diseases. These innovations were the
focus of BVGH’s 2010 report: The Diagnostics Innovation
Map: Medical Diagnostics for the Unmet Needs of the
Developing World. In that report, we highlighted the
potential of new and emerging POC diagnostic platforms.
These innovations hold the potential to dramatically
change the diagnostic paradigms in the developing
world. Some of these diagnostic technologies have the
capacity to run multiple tests in a variety of sample
types simultaneously, simplify process steps like sample
9
12
G-Finder 2011. “Neglected Disease Research & Development: Is the Global Financial Crisis Changing R&D?” Policy Cures. 2011.
ability of consumers to pay create barriers to industry
investment. Public and donor support will be needed
to initiate, and in some cases to sustain, private-sector
product development efforts, including market-based
incentives that provide downstream financial returns.
Non-governmental organizations and government
bodies are increasingly aware of the need for and value
of diagnostic products. A key example of this is the fact
that funding to purchase existing diagnostics and improve
training and laboratory facilities has increased dramatically
through programs such as the U.S. President’s Emergency
Plan for AIDS Relief (PEPFAR), the Global Fund to Fight
HIV/AIDS, Malaria and Tuberculosis, the World Bank, and
UNITAID. Yet the funding to support innovation of POC
diagnostics for the developing world has not received
comparable backing, despite the continued efforts of donors
and product development partnerships such as the Bill &
Melinda Gates Foundation, Grand Challenges Canada, PATH
and FIND Indeed, in 2009, diagnostics accounted for less
than 4% of total global health R&D spend.9 Developing
the next generation of POC platforms will enable effective
diagnosis in the developing world. Without market forces
to drive these developments, the global health community
will need to create financial incentives that will encourage
companies to invest in diagnostics for low resource settings.
The remainder of this proposal
presents what our analysis has
indicated to be an effective design for
such an incentive program — one that
would both motivate industry and
create impact for donors — and that
would attract the support necessary to
make it happen. The proposal includes:
• A
n initial analysis of the potential health impact of a
new POC diagnostic test for differential diagnosis of
fever in children under 5 in the developing world, in
terms of both lives saved and second-order benefits
such as delayed resistance to antibiotic treatments.
A perspective on the potential cost-effectiveness of
such a diagnostic intervention is also presented.
• A proposal for the Global Health Innovation Quotient
Prize that could be used to motivate diagnostic
companies to engage in developing new POC
diagnostics for use in differential diagnosis of fever
in children under 5. We propose a structure which
is informed by substantial stakeholder input and
relevant data, understanding that many of the design
elements of our structure could be modified based
on markets, industry perspectives, or funder needs.
• A quantification of the financial requirements
estimated to be associated with supporting such
an incentive program from the perspective of
potential donors.
• An overview of impact considerations that
are critical to the success of the incentive
program, including:
- a plan to ensure broad access to diagnostic
tests developed through this program
- a range of supporting interventions that will
support the ultimate impact of the program
- a proposal for an effective monitoring and
evaluation framework to measure impact
• A proposal for organizational structure, governance,
and administration of the incentive mechanism.
13
4
Need for a POC Fever Diagnostic
4. Need for a POC Fever Diagnostic
Disease Burden
Causes of childhood mortality presenting with non-specific
Millennium Development Goal 4 aims to reduce mortality
febrile symptoms account for more than 30% of total
of children under the age of 5 by two-thirds between
global childhood mortality12 (Figure 2). These diseases
2009 and 2015. Although this mortality rate is decreasing
are highlighted in the figure below. Please note that these
(between 1990 and 2008, there was a 28% reduction in
estimates may be conservative, as more recent data on child
annual mortality), the pace of decline is insufficient to
mortality due to malaria published in the 2009 World Malaria
meet the 2015 goal.10 Nearly 9 million children die each
Report are significantly higher than that cited by the WHO
year before they reach the age of five, and many of these
Global Burden of Disease report referenced in the table below,
children could be saved with access to accurate diagnosis
with estimates ranging upwards of 700,000 deaths per year:13
and effective treatment.
11
Many of the primary causes of childhood mortality —
including pneumonia, meningitis, malaria, and HIV/AIDS
— present with non-specific symptoms such as fever and
cough. The absence of definitive diagnostic tools and tests
to support clinical diagnostic guidelines in low resource
settings can lead to incorrect and delayed treatment,
prolonged illness, or overuse of unnecessary medications.
Figure 2: Global Deaths and DALYs Per Year in Children Under Five14
Disease
Deaths
Deaths, as percent of
total under 5 mortality
DALYs, in millions
Pneumonia
2,000,000
19.0%
33.0
Malaria
Meningitis
397,000*
82,000
7.3%
1.5%
15.0
3.2
TB
23,000
0.4%
0.8
HIV
131,000
2.4%
4.5
* As noted, these estimates are widely viewed as conservative, with more recent data on child mortality due to malaria published in the 2009 World Malaria
Report estimated at upwards of 700,000 deaths per year (World Malaria Report 2009; World Health Organization. 2009).
United Nations Millennium Declaration, September 2000; http://www.un.org/millenniumgoals/
Pneumonia: The forgotten killer of children, The United Nations Children’s Fund (UNICEF)/World Health Organization (WHO), 2006.
12
Diseases described here and in the subsequent figure exclude diarrheal diseases, measles, and other causes of childhood death that present with
specific symptoms (i.e. diarrhea, maculopapular rash, etc.) beyond the non-specific symptoms of fever and cough.
13
World Malaria Report 2009; World Health Organization. 2009.
14
WHO (2004) Global Burden of Disease; UNICEF/WHO (2006) “Pneumonia: The forgotten killer of children.”
10
11
15
The ability to confidently diagnose the cause of fever and
In contrast, in low resource settings in the developing world,
treat appropriately has the potential to make a significant
disease diagnosis and subsequent treatment are generally
impact on child mortality. A new multiplex POC diagnostic
made on a presumptive basis using only clinical evaluation.
for differential diagnosis of fever presents an opportunity
The majority of health care in these settings is provided
to make an immediate impact on child health.
by nurses, community health workers, informal health
practitioners, and family members with varying degrees
Current Diagnostic
and Treatment Algorithm
of training. Unlike the developed world, where laboratory
Differential diagnosis of diseases with related or
care practitioners in low resource settings rarely have access
overlapping symptoms is fundamental to the practice of
to the laboratory facilities needed to confirm a presumptive
medicine. In order to make a treatment decision in the
diagnosis. In order to help reduce deaths in children, WHO
developed world, medical professionals use a combination
in collaboration with UNICEF developed the Integrated
of clinical evaluation (including assessment of patient
Management of Childhood Illness (IMCI) as a training tool
symptoms, patient history, and physical exam findings)
and reference guide for health care workers in low resources
and laboratory diagnostics (including disease specific
settings. This treatment algorithm describes danger signs
tests, general blood chemistries, and serology) to narrow
and common symptoms to guide referral for urgent care or
down the list of possible diagnoses. The diagnosis that best
presumptive treatment of children. Please note that a full
accounts for both the clinical and laboratory findings is the
description of the need for definitive diagnostic tools and the
initial diagnosis for which the patient is treated.
potential impact of the proposed multiplexed POC diagnostic
testing can be used to supplement clinical diagnosis, health
on the IMCI guidelines are presented in Appendix D.
Figure 3: Treatment Guidelines for Febrile or Pneumonia-Like Illnesses Based on IMCI15
15
16
Presenting Symptoms
Signs Used for Diagnosis
Treatment
Danger signs/Severe disease
Convulsions, lethargic/unconscious,
unable to feed, continuous vomiting,
chest in drawing, stiff neck
Give antimalarial (usually IM quinine or
artemether) and antibiotic (IM ampicillin or
gentamicin), refer immediately
Cough/Shortness of breath
(SOB) and Fever
Fast breathing
High malaria risk area
Give antibiotic for pneumonia (oral
co-trimoxazole or oral amoxicillin) and
antimalarial (ACT)
Fever
No runny nose
No measles
No other obvious cause of fever
High malaria risk area
Antimalarial (ACT)
Cough/Shortness of breath
(SOB)
Fast breathing
Give antibiotic for pneumonia (oral
co-trimoxazole or oral amoxicillin)
UNICEF/WHO (2008) “Integrated Management of Childhood Illness.”
Introduction of Malaria
Rapid Diagnostic Tests (RDTs)
ACTs, was first detected.17 Definitive diagnosis of malaria,
Building on the groundwork laid by the IMCI guidelines for
in low resource settings, is now recommended prior to
clinical diagnosis, inexpensive lateral flow diagnostics that
giving ACTs in order to protect the efficacy of this valuable
provide rapid point of care diagnosis of malaria are now
medication.18 According to the 2010 World Malaria Report,
available to confirm or eliminate malaria as the underlying
outside of Africa around 80% of suspected malaria cases
cause of fever. The rationale for the development and use
are assessed with a microscopic or rapid diagnostic. In
of malaria RDTs is based on concerns about the high cost
Africa, the number of ACTs distributed is more than 2.4X
of artemisinin combination therapies (ACTs) and the risk
the number of microscopic or rapid diagnostics performed,
for the emergence of drug resistance to these medications.
suggesting there are still shortfalls in access to diagnostics
using either traditional laboratory techniques or RDTs
in the region.19
Due to increasing drug resistance to inexpensive existing
antimalarial treatments, the WHO recommended that ACTs
Although malaria RDTs provide numerous benefits over
replace chloroquine as the gold standard for the treatment
traditional laboratory diagnostic techniques in resource
of uncomplicated malaria in 2002. ACTs are significantly
poor settings, the limitations of malaria RDTs have been
more expensive (10 to 40X the price) than chloroquine
realized in the field. Health care workers using malaria
and other previous antimalarial treatments, therefore
RDTs in resource limited settings are not equipped to make
judicious use of ACTs is important to mitigate their relative
an alternative diagnosis when a patient with suspected
higher cost. Additionally, the prevalence of chloroquine
malaria tests negative. In some trials, this has resulted in
and other antimalarial drug resistance has raised concerns
administration of antimalarials despite a negative test
about the potential for ACT drug resistance to arise. In
result or the increased use of presumptive antibiotic
2009, resistance to artemisinin, a key active ingredient in
therapy.20 The benefits and limitations of these POC
16
diagnostic tests are summarized in Figure 4.
Figure 4: Benefits and Limitations of Malaria RDTs in Diagnosing Cause of Fever
Benefits
• Can be used in resource limited settings
with minimal training
• Results available quickly to guide treatment
and monitor disease spread
• Do not require specialized laboratory equipment
16
17
18
19
20
17
Limitations
• A negative individual malaria test does not provide
guidance or suggestions for alternative diagnosis
of the patient
• The presence of malaria, as determined by an
individual malaria test, does not rule out the
possibility that the patient’s symptoms are caused by
a co-infection such as pneumonia
MFm Task Force of the Roll Back Malaria Partnership (November 2007). “Technical Design for the Affordable Medicines Facility – malaria.”
A
Dondorp AM et al (2009) “Artemisinin resistance in Plasmodium falciparum malaria.” New England Journal of Medicine 361: 455-467; WHO (2010)
Global Report on Antimalarial Drug Efficacy and Drug Resistance: 2000-2010.
WHO (2011) Global Plan for Artemisinin Resistance Containment; The malERA Consultative Group on Health Systems and Operational Research
(2011) “A Research Agenda for Malaria Eradication: Health Systems and Operational Research.” PLoS Medicine 8: e1000397; The malERA Consultative
Group on Diagnoses and Diagnostics (2011) “A Research Agenda for Malaria Eradication: Diagnoses and Diagnostics.” PLoS Medicine 8: e1000396.
WHO (2010) World Malaria Report 2010.
Reyburn H et al (2006) “Rapid diagnostic tests compared with malaria microscopy for guiding outpatient treatment of febrile illness in Tananzia: randomized trial.” BMJ 334: 403.; Msellem MI et al (2009) “Influence of rapid malaria diagnostic tests on treatment and health outcome in fever patients,
Zanzibar: a crossover validation study.” PLoS Medicine 6: e1000070.
Benefits of a Multiplex POC Diagnostic Tool
“differential” through multiplexed assays rather than
In order to increase the utility of POC diagnostic tests in
through sequential test selection. Multiplex POC diagnostic
low resource settings, multiplex POC diagnostic tests that
tests therefore offer both medical and logistical benefits
evaluate panels (or groups) of symptomatically related
over single POC diagnostics.
diseases are needed, either in the form of rapid diagnostic
tests or small, portable devices. Although individual tests
In the case of fever, diagnosis of bacterial pneumonia
for each individual potential cause of fever could be
offers the opportunity to complement the current IMCI
developed in a form that can be used at the point of care,
guidelines for clinical diagnosis as well as build on the
it is not feasible or practical for a minimally trained health
advances in rapid POC diagnostics made in the malaria
worker to select, run, and interpret multiple individual
field. In 2004, pneumonia deaths made up the largest
tests. A multiplex POC diagnostic test would allow the
proportion of mortality for children under age 5 (see
minimally trained health worker to perform multiple tests
Figure 5). Development of a diagnostic that targets
simultaneously in one device, producing a single answer
multiple diseases with high under-five mortality, especially
with standardized readout and interpretation. This type
malaria and pneumonia, is a key step towards improving
of test offers a key tool to recapitulate the differential
appropriate treatment and reducing child mortality.
diagnosis performed in developed world health care
settings by allowing the test or device to perform the
Figure 5: Pneumonia is the Leading Cause of Mortality among Children under Five21
21
18
UNICEF/WHO (2006) “Pneumonia: The forgotten killer of children”
Unlike malaria, which is caused by a limited number of
related parasitic organisms, pneumonia can be caused
by a variety of bacterial or viral organisms. While no
specific treatment of viral pneumonia is available,
bacterial pneumonia is treatable with antibiotics, thus the
recommendation in the IMCI guidelines for presumptive
antibiotic treatment of those with pneumonia-like
symptoms. Although most antibiotics are inexpensive
relative to the ACTs used to treat malaria, drug resistance
to antibiotics is a growing concern. The two key benefits of
multiplexing pneumonia and malaria diagnostics are:
1) Increasing the diagnosis of bacterial pneumonia,
which previously may have been missed due to
a lack of pneumonia tests that can be used in
resource poor settings or due to positive malaria
RDT results in a person with multiple infections.
2) Reducing the risk of antibiotic resistance by
ensuring that antibiotics are used only for bacterial
pneumonia rather than being overprescribed
presumptively for patients who actually have
malaria or viral pneumonia.
There may be additional benefits that we have not fully
modeled in this paper – including extending the life
of antimalarial treatments as they would be less often
prescribed when a child tests negative for malaria after
the introduction of the proposed diagnostic. In the
following sections, a specific Target Product Profile for a
multiplexed fever panel diagnostic is presented along
with a quantitative analysis of the potential impact of this
diagnostic on health and antibiotic resistance.
19
5
Target Product Profile (TPP)
5. Target Product Profile (TPP)
Introduction
Based on the unique requirements of developing world
Operational Requirements
for Minimal Infrastructure Settings
settings, we have developed both “minimal” and “optimal”
Beyond the biological specifications outlined in the TPP,
TPPs that lay out our “must have” and “nice to have”
additional criteria that ensure the test is appropriate for
recommendations for the minimally acceptable and optimal
use in minimal infrastructure developing world settings are
requirements for the diagnostic test for this incentive
outlined. These are adapted from WHO ASSURED criteria
program. The minimal and optimal TPPs are in Figure 6.
for diagnostic tests for resource poor settings.22 The need
for smaller, more resource-efficient diagnostics is great in
The preliminary TPP is designed to outline requirements for
Africa—where more than 70% of the population is located
a diagnostic device that can guide differential diagnosis and
in settings with minimal or no infrastructure.23 These
treatment of febrile illness, including in children under 5 years
criteria are designed to increase the usefulness of a device
old. The goal of the TPP is to ensure that the diagnostic:
in the field, thus facilitating uptake and integration of a
• Is clinically useful to endemic country
successful device into standard health practices.
health care providers;
• Is both ambitious and technologically feasible; and
Technology Focus
• Fosters innovation to increase health impact.
The TPP does not specify which type of technology should
be the basis of the minimal and optimal diagnostic platform.
Additional TPP details and definitions of key terms can be
It is desired that a full range of technologies, including
found in Appendix E: Target Product Profile.
immunoassay-based, molecular/nucleic acid- based, and
novel innovative detection systems, will be explored
Product Focus
through the proposed incentive program. Please also note
The diagnostic tool outlined in the TPP is designed
that the TPP currently provides only guidelines for target
to identify malaria, bacterial pneumonia, and other
ex-works price of the diagnostic test. The target prices
bacterial infections at the point of care such that patients
provided will be refined based on additional analysis prior
receive antimalarial or antibiotic treatments only when
to the launch of the milestone-based prize, as part of the
appropriate. A more detailed account of the disease
process of validating the TPP. Please also note that these
selection for the fever panel can be found in Appendix
prices are for the assay only and do not take into account
C: Disease Selection Criteria. The test should give
the cost of the device itself, should one be required.
confidence to health care workers either to treat according
to appropriate clinical practice standards for any disease(s)
identified through diagnosis, or to withhold antimalarial
or antibiotic treatment for patients with no additional
defining clinical symptoms and who test negative for all
diseases included on the panel.
22
23
21
The World Health Organization (WHO) has suggested criteria for ideal diagnostic tests for resource-poor settings using the acronym ASSURED: Affordable by those at risk of infection, Sensitive, Specific, User-friendly (simple to perform with minimal training), Rapid (enabling treatment at first visit) and
Robust (does not require refrigerated storage), Equipment-free, and Delivered to those who need it. Urdea M, et al (2006) “Requirements for high impact
diagnostics in the developing world.” Nature. 23;444.
Girosi, F., S. S. Olmsted, et al. (2006). “Developing and interpreting models to improve diagnostics in developing countries.” Nature 444 Suppl 1: 3-8.
Figure 6: Target Product Profile
Fever Panel Target Product Profile
Disease / Pathogen
•Malaria: definitive and distinct diagnosis of Plasmodium falciparum and P. vivax.
• Bacterial pneumonia: diagnosis of bacterial pneumonia by either definitive diagnosis of each of the
three major pathogens causing bacterial pneumonia or diagnosis as a group of organisms through novel
biomarkers: Streptococcus pneumonia, Staphylococcus aureus, Haemophilus influenzae B.
• Supplemental pan-bacterial marker: One or more known general biomarker(s) for bacterial infection24 to
provide “rule-in” diagnosis of other bacterial infections that should receive antibiotic treatment or suggest
referral for further testing even without definitive diagnosis, including atypical bacterial pneumonia and
bacterial meningitis. A single biomarker or multiple biomarkers that comprise a signature are acceptable.
• (Optimal) Supplemental pan-viral marker: general biomarker or multiple biomarkers that comprise a
signature for common viral causes of fever, to confirm in patients who are entirely negative by the fever
panel diagnostic that antibiotics should not be given.
• (Optimal) Active tuberculosis: definitive and distinct diagnosis of Mycobacterium tuberculosis.
• (Optimal) HIV: definitive and distinct diagnosis of human immunodeficiency virus.
Goal of Test
Differential diagnosis of the cause of fever for treatment, including in children <5
Reference Test
Culture and microbiologic testing for bacterial diseases and microscopy for malaria
Sensitivity
•
•
•
•
•
•
P. falciparum – 95%
P. vivax – 95%
Streptococcus pneumoniae – 95%
Staphylococcus aureus – 95%
Haemophilus influenzae B – 95%
Supplemental pan-bacterial marker(s) that, in
combination with pathogen-specific markers
above, can identify all bacterial pneumonia with
an overall sensitivity of 95%.
• Supplemental pan-viral marker(s) – Best in class
• Tuberculosis – Best in class
• HIV – Best in class
Specificity
Each individual pathogen above, 85%
Each individual pathogen above, 80%
Reproducibility
>95%
>85%
Optimal
Minimal
Biological Principle
Sample preparation
Special Handling/
Equipment
Refrigeration requirements
Power requirements
Stability
Water requirements
Training Required
Time to result
Duration of valid result
Precautions
Steps to Test Result
Patient Record
Test/Platform size
Target Ex-Works Price25
24
25
22
P. falciparum – 90%
P. vivax – 90%
Streptococcus pneumoniae – 90%
Staphylococcus aureus – 90%
Haemophilus influenzae B – 90%
Supplemental pan-bacterial marker(s) that, in
combination with pathogen-specific markers
above, can identify all bacterial pneumonia with
an overall sensitivity of 90%.
Not pre-determined
Quality Control
Test Result & Interpretation
Interfering Diseases
Specimen / Sample
•
•
•
•
•
•
Positive and negative control required
Visual readout that directs treatment without manual data interpretation
None
One of the following sample types: blood, saliva,
sputum, mouth swab, or urine
One or more of the following sample types collected
in a single patient visit: blood, saliva, sputum, mouth
swab, urine
None required (sample preparation/processing internal to device acceptable)
None required
None required
Prefer none, renewable battery power (e.g., solar recharger) acceptable
24 months at 55°C and 90% humidity
18 months at 45°C and 80% humidity
No running water required
Minimal: visual and intuitive interface and instructions; no language requirements to operate instrument;
no more than 1 page of instructions
<10 minutes
<30 minutes
>72 hours
>24 hours
Safe specimen / sample management
5 or less steps to result
Patient identification required
Handheld device; <5 lbs / 100 tests
Portable device; <10 lbs / 100 tests
$2-5, plus cost of device if one is required
$2-5, plus cost of device if one is required
Such as procalcitonin
Target ex-works price provided here should be considered a guideline. These target prices will be refined based on additional analysis prior to the launch of the incentive, as part of the process of validating the TPP. These prices are for the assay and do not take into account the cost of the device itself, should one be required.
6
Impact and Cost-Effectiveness
of Proposed POC Fever Panel
6. Impact and Cost-Effectiveness
of Proposed POC Fever Panel
This section presents the results of a preliminary
systematic immunization of children could significantly
analysis to quantify the impact and cost-effectiveness
reduce child mortality due to lower respiratory infections.
of the proposed POC fever panel.26 While a multiplex
Still, given that the vaccine has not yet been widely
POC diagnostic for fever has the potential to replace
adopted and data on expected penetration rates are not
standalone malaria diagnostics in a clinical setting, the
yet available, we have estimated the potential impact of
modeling described in this proposal focuses primarily on
the proposed diagnostic test based on the best currently
the additional impact of the multiplex test on bacterial
available data of child mortality.
pneumonia mortality. Impact on malaria mortality is
assumed to be comparable to previous estimates for
As shown in Figure 7 below, the overall global mortality
existing diagnostics.
due to pneumonia would drop an estimated 15%-20%
27
among the population treated as a result of introducing
Preliminary estimates suggest that the fever panel
the proposed POC diagnostic. If the aggressive goal of
could reduce mortality among the population served
universal adoption were achieved, this implies that the
by 15-20% (saving more than 350,000 lives if rolled out
proposed diagnostic has the potential to save between
globally), reduce inappropriate use of antibiotics, and
355,000 and 460,000 children per year. The number of lives
delay resistance to antibiotic treatment. Further, at the
saved would be especially high in sub-Saharan Africa and
assumed target price of $2-5, the intervention would be
India. The impact would of course be significantly lower until
cost effective in the developing world by widely accepted
high levels of adoption are achieved, which may take several
World Bank standards, in the range of $106-271 per life-
years following product introduction.
year saved in sub-Saharan Africa.
28
The proposed multiplex POC diagnostic will have
Impact on Health:
significant impact at all infrastructure levels, but will make
The impact of the proposed multiplex POC diagnostic on
the most noticeable impact in rural areas. In settings with
disease burden was analyzed using children under age 5
minimal infrastructure, the new diagnostic will provide
(excluding neonates) and for bacterial pneumonia only. The
earlier diagnosis to more people, have significantly higher
benefit of the proposed diagnostic is directly correlated
accuracy than current unaided clinical diagnosis, and
with the increased treatment of bacterial pneumonia and
reduce misdiagnosis of pneumonia as malaria.
initial estimates suggest that the new diagnostic could
contribute to a significant reduction in the mortality from
this disease. However, it should be acknowledged that the
potential for reducing child mortality may be mitigated
by parallel health interventions, such as the roll-out of
the pneuomoccal vaccine that is currently underway.
The introduction of the pneumococcal vaccine and the
26
27
28
24
Dalberg Global Development Advisors supported BVGH to help determine the impact of the fever panel. These estimates should be interpreted as
preliminary. Due to on-going validations with external experts, and due to the strong sensitivity to the final characteristics of the new diagnostic and
ongoing changes in wider health systems, results are not absolute.
Uzochukwu BS et al. (2009) “Cost-effectiveness analysis of rapid diagnostic test, microscopy and syndromic approach in the diagnosis of malaria in
Nigeria: implications for scaling-up deployment of ACT” Malaria Journal 8: 265.
less than $150 per DALY saved are highly cost‐effective. These are based on an assumed unit cost of testing ranging from $2-5.
Figure 7: Lives Potentially Saved Due to Fever Panel
Pneumonia Deaths
(<5 years)29
Potential Reduction in
Pneumonia Mortality (%)30
Potential Lives Saved
(universal roll-out)
1,100,000
15-20%
165,000 – 220,000
India
700,000
20-25%
140,000 – 175,000
China
100,000
20-25%
20,000 - 25,000
Latin America
50,000
15-20%
7,500 – 10,000
N. America and Europe
<2,000
5-10%
100 – 200
150,000
10-15%
22,500 – 30,000
2,100,000
15-20%
355,000 – 460,000
Region
Sub-Saharan Africa
Rest of World
Global
Maximizing the impact of the proposed diagnostic will be
a supplemental pan-bacterial biomarker on the fever
aided by integrating a successful product into the WHO/
panel increases the likelihood that additional bacterial
UNICEF IMCI guidelines. A more detailed analysis of the
infections beyond bacterial pneumonia, such as bacterial
potential role and impact of the proposed diagnostic on the
meningitis, strep throat (the underlying cause of rheumatic
IMCI guidelines is included in Appendix D: Integrating a
heart disease), or sepsis, will be detected. The proposed
Multiplexed Diagnostic into the IMCI Guidelines.
diagnostic has the potential to reduce mortality associated
with these other bacterial infections, but this potential
Beyond the direct impact on bacterial pneumonia
impact has not been quantified here. However, while we
mortality in children under the age of five, the proposed
feel our estimates are conservative in these aspects, the
multiplex POC diagnostic could have additional health
roll-out of the pneumococcal vaccine, as noted, would
impact. The test would not be restricted to use in children
decrease the incidence of bacterial pneumonia and will
under the age of 5 and therefore would have additional
therefore reduce to an uknown extent these estimates of
impact on other age groups. Furthermore, inclusion of
lives saved through use of the proposed diagnostic.
29
30
25
The Race against Drug Resistance, A report of the Center for Global Development’s Drug Resistance Working Group.
The Center for Global Development (June 15, 2010), Press release “When Medicines Fail”
Figure 8: Reduction in Antibiotic Prescription for Bacterial Pneumonia
Region
SubSaharan
Africa
India
China
Latin
America
North
America,
Europe
Rest of
World
Reduction in antibiotic
prescription (%)
5 -10%
10-15%
15-20%
15-20%
5-10%
10-15%
Reduction in inappropriate antibiotic prescriptions per year
20-25M
30-35M
25-30M
25-30M
10-15M
50-55M
Impact on Antibacterial Resistance
The resulting impact of delayed antibiotic resistance from
In the developing world, millions of children die annually
improved diagnoses has not been included in either the
from drug resistant disease strains.31 While donors have
mortality or the cost-effectiveness calculations presented
spent more than $1.5 billion on advanced drugs to treat
in this document, and should therefore be considered
resistant diseases, since 2006, few interventions have
an additional improvement to these estimates. More
specifically targeted reducing the use of antibiotics.
information on antibacterial resistance is presented in
Another key benefit of the fever panel would be its impact
Box 1: The rising concern of antibacterial resistance.
32
on delaying the onset of antibiotic resistance through
more accurate diagnosis of bacterial infection and the
resulting reduction of inappropriate use of antibacterial
medication. Figure 8 provides the anticipated reduction in
antibiotic usage resulting from universal adoption
of a multiplex POC diagnostic for fever.
31
32
26
The Race against Drug Resistance, A report of the Center for Global Development’s Drug Resistance Working Group.
The Center for Global Development (June 15, 2010), Press release “When Medicines Fail”
Box 1: The Rising Concern of Antibacterial Resistance33,34,35,36,37
For many years, respiratory infections were inexpensively
In 2009, the United States and the European Union
cured with penicillin, one of the world’s first antibiotics.
established a transatlantic task force to address antibiotic
Today, penicillin effectively treats only half of the S.
resistance. One of the primary objectives for this group was
pneumoniae strains circulating in many developed and
the promotion of appropriate therapeutic use of antibacterial
developing countries, and less than a quarter of strains in
medication. To highlight the severity of the problem, the WHO
certain regions. In 1987, only 2% of patients infected with
has issued a clear call to action to halt the spread of antibiotic
S. aureus failed to respond to methicillin, an inexpensive
resistance, adopting Combating Antimicrobial Resistance as
antibiotic that had been used effectively against these
the theme for World Health Day 2011.
infections since the 1960s. By 2004, more than 50% of
patients with S. aureus failed to respond to methicillin.
According to Rachel Nugent, chair of the expert working
group formed by the Center for Global Development (CGD)
The onset of antibacterial resistance is causing an
to prepare the report, The Race Against Drug Resistance, “drug
enormous burden; increasing global health care cost by
resistance is a natural occurrence, but careless practices in
as much as $100B annually. A recent U.S. Senate report
drug supply and use are hastening it unnecessarily.” In June
indicated that antibiotic resistance costs more than $40B
2010, Nugent stated that “we can no longer afford to be
in the U.S. alone. Separate studies have estimated direct
indifferent to the spread of drug-resistant diseases. For the
costs of increased hospital stay due to resistant S. aureus
sake of all people who seek effective health care, now and in
infection in the E.U. and the U.S. at $14B.
the future, drug resistance must be addressed urgently and
aggressively as a global health priority.”
Over-prescription of antibiotics is widely accepted
as a primary cause of resistance and there is a clear
relationship, as shown in graph 1, between antibiotic
usage and resistance in the community level. Emerging
evidence shows that even individual antibiotics prescribed
in primary care can contribute to antibacterial resistance
on an individual basis for up to 12 months following
treatment.38 While documented evidence is limited,
many global health experts anticipate that the burden
of antibiotic resistance in the developing world will be
particularly severe, especially in areas where access to
secondary, non-resistant medication is unavailable.
33
34
35
36
37
38
27
The Race against Drug Resistance, A report of the center for Global Development’s Drug Resistance Working Group.
111TH CONGRESS, 1ST SESSION H. R. 2400. To amend the Public Health Service Act to enhance efforts to address antimicrobial resistance.
Effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: systematic review and meta-analysis, BMJ
2010;340:c2096doi:10.1136/bmj.c2096.
Extending the cure: policy responses to the growing threat of antibiotic resistance / by Ramanan Laxminarayan and Anup Malani; with David Howard and David L. Smith.
BVGH expert interviews.
Antibiotics prescribed to an individual in primary care were consistently found to be associated with resistance of urinary and respiratory bacteria
to those antibiotics in that individual antibiotics prescribed in primary care may impact on bacterial resistance in a patient for up to 12 months. The
greater the number or duration of antibiotic courses prescribed in the previous 12 months, the greater the likelihood that resistant bacteria would
be isolated from that patient.
The problem of antibiotic resistance requires a multi-
Cost Effectiveness
faceted, multi-stakeholder solution. While discussing
Analysis suggests that the fever panel would be cost
the potential for a multiplex POC diagnostic for fever,
effective in the developing world in comparison to
expert interviewees acknowledged that while overuse
commonly used standards for cost effectiveness. As shown
of antibiotics is extremely difficult to model and the
in the table below, assuming a per unit diagnostic test cost
implications are not entirely understood, delayed
of between $2 - 5, excluding any cost of the base unit, the
development of resistance is clearly an added benefit
cost effectiveness would especially be high in sub-Saharan
of reduced antibiotic usage. The proposed incentive
Africa and India, and aligned with the commonly used
program aims to contribute to this solution through the
cut-off point for cost effectiveness (as used by the World
development and roll-out of better diagnostics to address
Bank) of $150 per life-year saved.39
inappropriate use of antibiotics.
Figure 9: Cost-Effectiveness of POC Diagnostic for Pneumonia 40
39
40
41
28
Region
SubSaharan
Africa
India
China
Latin
America
North
America,
Europe
Rest of
World
Costeffectiveness
($ per life-year
saved)41
$106-$271
$89-$228
$181-$471
$368-$973
$30,000$77,000
$834-$2,134
less than $150 per DALY saved are highly cost-effective.
The cost-effectiveness calculation should be seen as preliminary. It takes into account the volume and costs of the diagnostic, the volume and costs
of drugs prescribed/saved, and the estimated number of lives saved. It does not yet include estimates on other cost categories, such as the time and
costs of health care providers or the differences in cost of care at different levels and/ different disease stages. In addition, the cost-effectiveness is
calculated on life-year (LY) saved, a measure that does not include the morbidity component in the DALYs (making it more conservative than an estimate incorporating DALYs). Interestingly, the cost effectiveness of a POC diagnostic for pneumonia varies dramatically by region. The differences in
cost-effectiveness are influenced in the differences in absolute mortality of bacterial pneumonia between the regions. For example, in North America
and Europe there is a lower mortality burden associated with bacterial pneumonia so the absolute number of lives saved are fewer, which impacts
the cost-effectiveness of the fever panel in these regions. Another obvious consideration for cost-effectiveness is the cost of the diagnostic. The
cost-effectiveness of this intervention is directly correlated to the final cost of the diagnostic. A doubling of the cost of the diagnostic would roughly
halve the cost-effectiveness, and vice versa.
Preliminary analysis shows that sensitivity and specificity of the target diagnostic will have a significant impact on the cost per life year saved. For
example in Sub-Saharan Africa, cost effectiveness nearly doubles where sensitivity and specificity change from 70% - 70% to 95% - 95% respectively.
7
Guiding Principles for Incentive Design
7. Guiding Principles for Incentive Design
There are numerous barriers that must be addressed in order to enable access to needed POC diagnostics for patients in
the developing world. Our proposed Global Health Innovation Quotient Prize (IQ Prize) addresses key barriers that today
limit investment in R&D for these products — in particular, the lack of a commercial market, lack of funds for R&D, limited
knowledge of required test characteristics, and limited access to clinical samples and trial sites that limit effective product
development and performance evaluation of developing world diagnostic tests. The focus of the proposed IQ Prize is
illustrated in Figure 10 below.
Figure 10: Focus of Proposed Incentive Program by Product Development Stage
Pay-for-Success “Pull” Incentives
The majority of funding for global health diagnostics
development has taken the form of “push” funding:
upfront research grants and contracts from donors- such
as the Bill & Melinda Gates Foundation, Grand Challenges
Canada, Rockefeller Foundation, Wellcome Trust and other
foundations, governments, and private donors- most often
directed through product development partnerships
(PDPs) to selected development firms. There are notable
exceptions, such as the ongoing Grand Challenges that
seek to engage industry directly.
30
While many of these efforts have successfully reduced the
In designing an incentive that would be attractive to smaller
burden caused by neglected diseases, other approaches are
diagnostic companies, we considered the ways in which
needed. The absence of substantial pull incentives that reward
these companies are financed—primarily by raising equity
companies for creating global health products has left many
capital via the sale of stock, and by licensing product rights to
small- to medium-sized innovators on the sidelines. Push
large companies to secure interim compensation and share
funding, even if it covers 100% of the cost of a global health
risk during the product development process. Our analysis
project, isn’t necessarily sufficient to drive companies to shift
suggests that an appropriately sized milestone-based prize
limited resources to global health R&D. In addition to direct
that would reward success at notable inflection points in
costs, there is an opportunity cost associated with diverting
diagnostic development would meet the needs of both
time and resources away from profitable developed world
funders and diagnostic innovators. The benefits of milestone-
projects towards global health R&D. For innovative companies
based structures include:
to put global health on a par with their priority developedworld research programs, this opportunity cost must be
overcome through market-based incentives that are in line
with reasonable commercial returns.
• Industry familiarity with the approach, based on a long
history of clearly definable end points that can trigger
payments, especially in partnership relationships;
• Smaller up-front investments by innovators, which
are more likely to be within the financial capacity of
Further, push funding requires donors to ‘pick winners’
and place bets in advance of results. Such a structure does
smaller diagnostic companies and lowers their risk;
• The potential to attract a larger cross-section of
not necessarily reward success, as funding is most often
organizations, including not only large diagnostic
provided in advance, in anticipation of work completed.
companies but also start-ups, small or medium-sized
This carries with it a risk that the program may not yield
venture-backed companies, and innovative emerging
the desired results. By contrast, “pull” incentives of the kind
proposed here do not require donors to “pick winners” in
market diagnostic developers; and
• Improved monitoring and evaluation of progress
advance, instead creating a competitive structure in which
toward targeted interim goals, as opposed to incentive
donors pay for successful product development.
structures where only the end result is compensated.
Milestone-Based Incentives
Summary of IQ Prize
Existing pull mechanisms typically provide funding after
More than 80 interviews with stakeholders confirmed our
a drug or vaccine has received regulatory approval and is
initial hypothesis: a milestone-based, pay-for-success prize
ready for market launch (e.g., Advance Market Commitment;
would help motivate diagnostic developers/innovators,
Priority Review Voucher, X Prize). Often, large companies
particularly small- to medium-size companies. This would
have the revenue and typically profitability, lower cost of
also provide a results-oriented structure which has the
capital, and staying power to make multi-year investments
potential for traction with potential donors and represents
without interim compensation. Yet small, pre-profit diagnostic
an alternate (and complementary) approach to current
companies, which are most often the source of innovation
push-based funding.
in the field, cannot afford to make such long-term bets, even
if the ultimate reward were to be substantial.42 To address
the financial timelines and constraints of such diagnostic
developers, a nearer-term incentive is required.
42
31
BVGH interviews and research.
Figure 11: Milestone-Based Prize Concept
The IQ Prize
would provide for the following:
• A TPP, confirmed through a consensus-based process
by a group of independent experts, as the standard for
achievement sought;
• An open competition among diagnostic developers
having the capability to achieve all or part of the TPP
and who are willing to participate and agree to the
rules of the competition;
• A milestone structure rewarding successful
completion of key inflection points in the
development of a novel POC diagnostics meeting the
TPP requirements and providing adequate commercial
incentive to motivate industry participation;
• Payment only for milestones achieved during
the competition, i.e., no payment for prior results,
although a competitor could enter midstream if earlier
milestones have been satisfied.
• A fixed, maximum number of awards at each level;
• Objective determination by the same or another
expert working group as to whether each milestone is
achieved, with donor representation if desired
32
IQ Prize Design Principles
Our proposed prize structure, therefore, is based on the following principles.
Figure 12: IQ Prize Design Principles
IQ Prize Design Principles
33
Prize should be a
“pull” mechanism
that rewards results
“Pull”-based financial incentives reward results rather than funding inputs.
Advantages include allowing donors to pay only for success, to solicit and access
the broadest pool of technical knowledge and expertise, and to reap the benefits of
market competition.
Successful achievement of interim
milestones should be
rewarded for work
completed during the
competition
Milestone-based rewards for performance divide product development into successive parts, set at industry-recognized inflection points. Advantages include: the ability to craft milestones tailored towards donor goals, to more accurately determine
the appropriate milestone size relative to the task, and to engage a diverse range of
participants by providing interim payments.
Transparency and
objectivity must
be maintained
Credibility of the incentive, both in terms of sponsorship and criteria for selection
of awardees, is critical. Tying milestones to specific, objective criteria for each milestone, pre-identifying the number and amount of each award, and creating and
consulting with a carefully selected independent group of experts at every level will
ensure transparency and objectivity of the prize program and enhance the credibility
of the program in the eyes of industry.
Milestone award
amounts should be
set to motivate serious engagement on
the part of industry
Milestone awards must cover at least the cost of product development incurred for
achievement of that milestone and provide an additional premium to compensate
for risk, opportunity cost, and cost of capital. The premium provided should be greatest where the greatest risk is incurred.
Milestone structure
should pursue the
final product
Multiple awards will be provided for each milestone. The number of awards issued
at each level is pre-determined based on typical attrition rates from one stage to
the next, and with the aim of commercializing more than one successful product.
Likewise, a bonus premium can be applied for those developers who satisfy not just
the minimal but the optimal TPP, to incentivize these beneficial improvements.
Milestone structure
should fairly balance
intellectual property
considerations
Developers will retain ownership and control of their pre-existing and newly developed intellectual property. Donor investment must be protected, however, if the
developer is unable or unwilling to proceed in the competition or to supply an
approved product. In these cases, technology transfer provisions would be established
through intellectual property licenses to donors or their designees. These licenses
could be limited both geographically to the developing world and to the specific field
of use for neglected tropical diseases.
A successful program
should promote
widespread access in
endemic countries,
without which innovation would not
reach those in need
Access and distribution of the final product(s) must also be assured through an
access plan addressing issues such as affordability, supply, and distribution. Prize
design and access plans should be structured to maintain affordability, ensure
adequate supply, and support in-country manufacture and distribution.
8
IQ Prize Design and Structure
8. IQ Prize Design and Structure
a. Criteria of Each Milestone
BVGH’s Global Health Innovation Quotient Prize (IQ
Prize) is designed to lead biotech developers toward
developing a critically needed POC fever diagnostic.
More than 80 stakeholders contributed to the design.
The IQ Prize uses interim rewards for reaching key
milestones along the product development process,
the achievement of which are tied to specific, objective
metrics for each milestone level. Each milestone in turn
will advance innovation towards the final TPP. Selection
of awardees at each milestone will be determined by
an independent expert advisory group (EAG). The EAG
will be comprised of recognized scientific, medical,
commercial, and global health experts, selected by the
donor(s). Membership of the EAG will be adjusted as
appropriate to reflect the different technologies used at
each milestone.
This milestone structure reflects key inflection points
in diagnostic test development and the requirements
of the TPP outlined in Section 4. The milestones to be
rewarded and initial perspectives on the criteria for
successful achievement are laid out in Figure 13. Four
clearly defined milestones were developed in pursuit
of reaching the TPP – 1) proof of concept, 2) prototype
creation and clinical evaluation, 3) clinical validation
in the field, and 4) regulatory approval. The milestones
are intended to describe the performance standards a
developer must meet in order to receive a milestone
payment. These milestones are intended to reflect the
product development process for diagnostics, but have
been grouped together so as to reward steps where
performance can clearly be evaluated. These milestones
have been vetted with a wide range of stakeholders as well
as a panel of diagnostic company executives.
35
Figure 13: Milestones and Descriptions
Milestone Description
Proof of Concept of Platform Technology: Individual Pathogen Tests (Milestone #1)
•
Demonstration that the platform technology can be used to detect each of the five pathogens43 identified in the
TPP as well as a single or multiple (signature) known pan-bacterial biomarker(s)44 in a small number of relevant clinical samples equaling or improving upon the sensitivity and specificity requirements defined in the TPP.
Prototype Build and Initial Clinical Performance Evaluation: Fever Panel (Milestone #2)
•
•
•
•
•
Demonstration that, when an optimized alpha prototype device is used to diagnose the cause of fever in clinical samples45, the device meets or improves upon the sensitivity and specificity requirements defined in the TPP. Note that the
number of clinical samples to give 90% powered statistics will be determined pending the input of a biostatistician.
Demonstration of inter- and intra-laboratory reproducibility across a minimum of two laboratory sites as defined in the TPP.
Demonstration that device and relevant assay materials meet or improve upon accelerated stability testing criteria
determined to be representative of the minimum stability criteria46 defined in the TPP.
Demonstration that the device meets or improves upon the minimum time to result criteria as defined in the TPP.
Determination of bill of materials as checkpoint to ensure that cost is consistent with final test meeting target
price guidelines.
Clinical Validation in the Field (Milestone #3)
•
•
Demonstration that, when the beta device is used to diagnose the cause of fever in patients in the field, the device
meets or improves upon the sensitivity and specificity requirements defined in the TPP at multiple independent field
sites when operated by local health care staff. Note that the number of clinical samples to give 90% powered statistics
and that the number of independent field sites required will be determined pending the input of a biostatistician.47
Demonstration that all other specifications of at least the minimal TPP are met or exceeded.
Regulatory Approval (Milestone #4)
• Primary approval through the EU CE mark48
Milestone 1: To receive milestone payment 1, the
developer must complete basic proof of concept tests of
infected with Streptococcus pneumoniae, Staphylococcus
its technology. The ability of the technology to diagnose,
aureus, or Haemophilus influenzae B. Proof of concept at
at a minimum, the relevant pathogens specified in the
this stage of development is defined as correct detection
TPP using existing biomarkers will be the key criteria for
of positive and negative clinical samples for each
evaluation. Access to clinical samples will be facilitated:
pathogen, while meeting or exceeding TPP sensitivity and
presently contemplated to be blood from patients infected
specificity qualifications.
43
44
45
46
47
48
36
with P. falciparum or P. vivax, and sputum from patients
Five pathogens: P. falciparum, P. vivax, Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae B
Such as procalcitonin
Evaluation to be performed by contracted laboratory services that will ensure consistent and objective evaluation across incentive participants. As
many fully validated clinical samples as possible will be used; however, additional clinical samples that require further testing with reference tests
may be needed.
The stability criteria defined in the TPP are designed to mimic the extreme storage and operation temperatures of the developing world where the
devices will be used. The device and associated reagents should have shelf lives that meet or exceed these criteria. As actual shelf life evaluation will
depend on final packaging and other local conditions, these TPP criteria will be evaluated using accelerated stability testing whereby the device and
associated materials or reagents will be evaluated for performance both before and after storage at the temperature and humidity specified in the TPP.
In order to validate performance against current gold standard tests, portions of clinical samples will be transported to centralized laboratory facilities for validation by gold standard reference assays.
Unlike the approval of drugs, where the International Conference on Harmonization (ICH) has clearly defined certain organizations a “stringent regulatory authorities” (including the U.S. FDA; the Japanese Ministry of Health, Labor, and Welfare; the European Agency for the Evaluation of Medicinal
Products/EMEA centralized procedure; the European Free Trade Area - represented by the Swiss Medic; and the Canadian drug regulatory authority,
the Therapeutic Products Directorate, Health Canada) no such definition of “stringent regulatory authorities” for the evaluation of diagnostics has
been developed nor is the definition necessarily directly equivalent to that established for the evaluation of drugs. Therefore, milestone 4 will require
primary approval by the EU CE mark program as the minimum standard for achievement of this milestone as a proxy. This milestone may need to be
adjusted in the future as the diagnostic community moves towards harmonization of regulatory processes as has been done for therapeutics.
Milestone 2: Between Milestones 1 and 2, the respective
achievement of Milestone 3 is defined as correct pathogen
developers will need to build and optimize alpha prototype
detection in patient samples as determined by comparison
devices to prove the “fever panel” test concept. Optimization
to results obtained with gold standard reference tests and
will likely take several rounds of device modification and
meeting or exceeding all the requirements of the minimal TPP.
validation on a relatively small number of clinical samples.
Lack of interference in the identification of all pathogens on
Milestone 4: To satisfy the fourth and final milestone,
the panel must be demonstrated if different sample types
developers will need to obtain approval through the
are to be analyzed simultaneously. When the developer
European Union CE mark process. As the laboratory and
decides optimization is complete, devices will need to
field clinical validations described in Milestones 2 and
be submitted by the developer to a contract research
3 will be designed to meet the majority of regulatory
organization (CRO) or other laboratory contracted by the
requirements, the burden on the developer for this step
prize administrators for independent evaluation, paid for by
should primarily be on completion of paperwork. Any
the developer. Successful achievement of this milestone is
country-specific additional evaluations that may be
defined as meeting or exceeding key requirements defined
required will be addressed separately by the developer, but
in the TPP, including: test sensitivity, specificity, inter-site
will not be the subject of a milestone payment.
reproducibility, time to result, and duration of valid result.
The results of the independent evaluation will be used as
the criteria for the milestone reward.
Core Package of Product
Development Interventions
There is a core package of product development
The criteria for this milestone have been designed to
interventions that are required to facilitate product
minimize failure in subsequent milestone steps. At this
development efforts by participating innovators and
point in development, a tally should be taken of the costs
to support the effective evaluation of these efforts at
of test materials to confirm that they are consistent with
each milestone. These interventions are directly linked
the production of a final diagnostic test that is affordable
to product development and milestone evaluations and
to the developing world and consistent with the target
would be funded within the scope of the incentive.
price per the TPP.
Interventions are needed to facilitate evaluation of
Milestone 3: Devices that achieve Milestone 2 will then
innovator development at each of the milestones.
be further developed and submitted for performance
Materials, contracted laboratory facilities, and/or clinical
evaluation in the field by local health care staff. Aliquots
field tests will be required to allow for accurate comparison
of each patient’s sample will be analyzed using gold
of devices at each of the first three milestones. Although
standard reference tests for each of the pathogens on
analysis of regulatory processes for diagnostics has been
the panel and for the pan-bacterial biomarkers. This
undertaken as part of the prize development process,
represents the second component of clinical validation.
additional country-specific information must be gathered
While the TPP criteria are designed to minimize failure in
during Milestone 4 to ensure each device meets the
the field by outlining strict criteria at Milestone 2, devices
regulatory requirements for each country targeted for
that are too complex, difficult to transport, unstable, or
distribution. As noted above, these are core interventions
difficult to maintain are all likely to fail at this stage. As the
that will be funded and administered within the scope of
developer will also pay for these clinical validations, it will
the incentive program.
be in the developers’ best interest to ensure all minimum
TPP requirements are met before submission. Successful
37
Figure 14: Core Product Development Interventions to Facilitate Milestone Evaluations
Activity
Description
Milestone 2: Contract
CRO for independent
evaluation
As part of Milestone 2, initial clinical validation of the prototype devices will
be performed using fee-for-service evaluation through a contract research
organization (CRO) or academic research groups as appropriate, paid for by
the developer. An appropriate CRO (or other group) will need to be selected
and relevant, standardized evaluation and reporting protocols established.
Milestone 2: Access to
validated clinical samples
In order to minimize the cost of evaluation in Milestone 2, validated clinical
samples are required. New samples can be obtained and evaluated by gold
standard techniques at the CRO, or donations or access to validated clinical
samples can be obtained through organizations with sample banks, such as
WHO/TDR or CDC.
Milestone 3: Establish
sites for field evaluation
Performance of diagnostics can vary geographically due to differences in climate, local variations in infectious organisms, differences in level of training of
operators, etc. In order to fairly compare devices to the TPP performance, field
evaluation of tests will be performed using fee-for-service contractors (paid
for by the developer). To facilitate this, multiple relevant field sites capable of
conducting evaluation of the devices must be identified and engaged through
either contracted services or collaborations.
Milestone 4: Survey of
relevant governments
to establish regulatory
requirements
In Milestone 4, regulatory approval must be obtained for the POC diagnostic
test in the form of the EU CE mark. In preparation for this, government officials
from low resource countries likely to use the new test must be consulted to
determine what might be required of the developer beyond CE Mark approval
for use in their country.
b. Number of Awards
A critical element in the IQ Prize design is determining the
number of awards to be made at each milestone. From the
innovator’s perspective, increasing the number of awards
helps reduce risk in competing for the incentive, as it will
increase the odds that they will be selected as a recipient.
From the donor’s perspective, and in the case of milestonebased prizes, awarding a larger number of innovators also
increases the pool of innovation that can be promoted to
the next stage of the competition. However, the tradeoff is
that the overall prize becomes more expensive to fund.
We propose that the number of awards at each milestone
be informed by expected attrition rates associated with
advancing to the next product development milestone. We
the final TPP. We believe that having multiple successful
end-products will help promote market competition that
will drive prices down, allow for alternate supply sources,
and support the dual objectives of affordability and access
to the final POC diagnostic.
Our initial assumptions presented here are based on the
input from a panel of 12 industry executives representing
10 diagnostic companies, ranging from small, privately held
venture-backed companies innovating a single technology
to large, publicly traded multinational diagnostic
companies employing a variety of technologies with a
portfolio of products. The likelihood of technical success
at each milestone and the proposed number of milestone
awards are presented in the table below.
have used initial estimates of likely attrition gathered from
industry executives to determine the number of awards
proposed here, keeping in mind our ultimate aim of the IQ
Prize to support two new diagnostic products that meet
38
Figure 15: Number of Awards
Milestone 1:
Proof of Concept
(Technology)
Milestone 2:
Prototype Build
/ Initial Clinical
Performance
Evaluation
Milestone 3:
Clinical Validation in
the Field
Milestone 4:
Regulatory
Approval
Estimated
Attrition Rate49
20%
80%
25%
Nominal
Required
Participants
Based on
Attrition Rate
19
15
3
2
Target Number of
Milestone Awards
15
3
2
2
c. Size of the Milestone Payment
milestone (Milestone 3). We have assumed that of the
A key challenge in establishing pull incentives is
two products developed through this incentive program,
determining the appropriate size of the prize. The specific
one will meet the minimal TPP and the other will achieve
balance is in setting the prize high enough to attract
the optimal TPP (and therefore receive a higher award
innovators, but not so high as to overpay for an innovation.
payment at Milestone 3).
After initial consultation about the proposed TPP and
milestones with a panel of industry experts, we believe
Such a milestone award structure, which compensates for
that milestone awards must reflect both costs and amount
costs incurred by the developer and rewards a premium
of risk incurred by the developer at that particular stage
where significant risk is incurred, works well in the area
of development. In other words, where milestones are
of POC diagnostics for differential diagnosis of fever.
associated with limited risk to the innovator, milestone
Our research indicates that the proposed TPP for fever
awards should roughly reimburse the costs incurred by
diagnosis fulfills an unmet need in developing countries,
the developer during the particular phase of development
and that there is real market potential for such a product
in question, as approximated using industry standard
in the developing world. However, difficulty accessing
estimates. Where achievement of milestones requires
patient samples, lack of familiarity with navigating
significant innovation and carries significant technical risk,
developing world distribution channels, and uncertainty
a risk premium will be applied to milestone awards.
about consumer ability to pay for the test have prevented
significant industry engagement to date. Our consultations
Another important issue is that of motivating developers
indicate that the proposed milestone-based incentive,
to strive for achievement of the optimal TPP through
combined with the potential for a sustainable market,
the size of the milestone payments. We propose that an
would motivate real investment on the part of innovative
additional premium be paid to developers successfully
diagnostic developers.
achieving the optimal TPP at the Clinical Validation
49
39
Expected attrition rates are based on aggregating the results of an Industry Working Group meeting of 13 diagnostic company executives held in
Cambridge, MA on December 17, 2010.
Using estimates gathered primarily from a panel of industry experts and the assumptions outlined in Figure 15, we have
approximated the cost, time, and likely attrition rate associated with achieving each milestone. Based on these estimates,
we have proposed an award size, including a risk premium where appropriate, at each milestone. The payments that would
be awarded to a successful developer at each milestone are outlined in the figure below:
Figure 16: Size of Milestone Payment Awarded to a Successful Developer
Additional secondary benefits to the developer from
participation in the program include:
• Non-dilutive funding for product development:
Successful developers will access non-dilutive funding
for product development.
• Benefits to other commercial programs: Successful
developers will be able to fund R&D efforts through this
program that could have significant benefits outside the
particular product application proposed here.
• Leveraging possible developed world commercial
opportunity: A test that could differentiate broadly
• Achieving proof of platform: Early stage companies
may achieve proof of platform through participating in
this incentive program, making them more attractive
to venture investors.
• Learning how to operate in key emerging markets:
The test that is the focus of the incentive program is
one that has high potential for key emerging growth
markets such as India and China.
• Positive publicity: Successfully developing a multiplex
fever panel that achieves the proposed TPP would
garner significant positive attention.
between viral and bacterial infection may have
commercial potential in the developed world as well.
40
Assumptions around milestones, number of awards, and size of the award payments lead us to believe that the IQ Prize will
take approximately 8 years and cost approximately $150M to yield two new POC diagnostic tests for fever that meet the
requirements outlined in the TPP. These estimates are outlined in Figure 17 below, which identifies the probability of technical
success (PTS), likely timing and cost associated with each proposed milestone, along with the proposed milestone award level
and number of milestone awards at each milestone:
Figure 17: Snapshot of Proposed Incentive Program
* Probability of Technical Success
d. Selection of Awardees
incentive. As described above, milestone awards will be
As noted, the IQ Prize utilizes interim rewards for reaching
confirmed by an independent expert advisory group
key milestones along the product development process,
comprised of recognized scientific, medical, and global
the achievement of which are tied to specific, objective
health experts selected by the donor. This group will
metrics for each milestone level. Milestone awards will
determine whether or not a potential awardee has met
be determined based on a “race to finish” approach
the minimum technical requirements specified at each
that grants awards to the first contestant(s) to meet the
milestone.
minimum requirements set by the administrators of the
41
This approach carries two significant benefits. First, it
e. Eligibility Criteria
encourages faster innovation to meet the technological
The IQ Prize is designed to encourage the participation of
challenge of each milestone. This premium placed on
a wide range of innovators and technological approaches.
speed is particularly ideal in situations such as this one,
However, we propose that a basic set of eligibility criteria
where technological innovation is desperately needed,
be used to screen participating diagnostic innovators.
and time saved can be translated into a real-world benefit
In order to ensure that we do not unduly limit the
in terms of lives saved. Second, the race-to-finish model
competition through these requirements, we propose that
provides a transparent set of rules for developers. The
the bar for qualification be set relatively low, requiring only
concept of “race to finish” is straightforward and easily
that developers demonstrate a reasonable chance of being
understood by developers. This is particularly important in
competitive.
centralized incentive models, such as a milestone-based
Proposed eligibility requirements include:
pull prize, since the administrators and donors must be
• Demonstrated expertise in diagnostic research,
trusted and the rules must be understood in order to
development, or commercialization, as represented
encourage participation by developers.
by either company history or senior management
experience; and
However, this strategy does carry a particular drawback.
• Sufficient resources to engage in the prize
Specifically, while there is a time-saved benefit to this model,
competition, either directly or through identified
it means that the first developers meeting the minimal TPP
contractor/subcontractor/partner relationships, as
requirements will be awarded, even if others that cross the
measured by:
finish line later have potentially better products. In order to
• Funds adequate to reach the first level
mitigate this risk, we have proposed that the technological
milestone, with a stated plan to fund
hurdles outlined in the minimal TPP are sufficiently high
subsequent levels (which could include receipt
to ensure quality end-products that will meet user and
of incentive payment);
purchase needs, and we have also provided for two final
awards as well as the optimal profile opportunity.
• A facility or facilities logically capable of
housing that work, licensed or certified as
needed to conduct relevant work; and
• Staff with adequate background and
experience to demonstrate capability of
completing the incentive program work.
Our belief is that the eligibility process will help donors
monitor the progress of the incentive in terms such as
number of competitors, quality of developers, types
of technology being developed, and progress that the
developers are making. This type of information may be
invaluable to predicting administrative costs and ensuring
that the end-goals of each milestone are met.
42
f. Intellectual Property Considerations
in seeking some value for their investment, and to facilitate
Access to intellectual property (IP), including know-how, is
continued innovation, if the participant receives a certain
potentially a more complex discussion for diagnostics than for
level of funding from IQ Prize. Companies and their investors
therapeutics. In the case of therapeutics, the most important
will certainly resist, however, any approach to IP which
single piece of IP is often the composition of matter patent
jeopardizes their core IP or technology.
on the active pharmaceutical ingredient used in a treatment.
Occasionally, manufacturing process or method of use
Our program would therefore provide that each developer
patents can be important in an IP portfolio for a therapeutic.
will continue to own all IP generated through the prize
In contrast, for diagnostics there are often multiple patents
program, subject to the following conditions:
supporting sample acquisition, sample processing, assay
configuration and chemistry, and manufacturing, as well
• If the company receives payment for one or more of
as materials, reagents, software, and instrument design.
Milestones 2 through 4, and after a reasonable period
Moreover, some of the most important intellectual property
of time50 is either unable or unwilling to continue
is not the patents themselves but know-how, such as
in the competition, the sponsor can, within a stated
manufacturing expertise. The know-how to make a high
period of time and at the sponsor’s option, require the
quality product at the lowest possible cost is often the most
company to provide a non-exclusive license, with right
important component of a diagnostic company’s IP portfolio,
of sub-license, to the IP generated in the competition
and can be subject to trade-secret protections.
and any pre-existing company IP necessary in order
to practice the newly generated IP, in order to make,
In order to retain the desired motivation of developers, the
use, or sell the subject product. That license would be
IQ Prize is designed so that the developers retain all rights
limited by territory and field-of-use consistent with
to their pre-existing and newly developed IP. However,
the parameters and objectives of the competition, and
sponsor interests would be protected if a developer
would be subject in turn to due diligence and quality
receives significant milestone payment(s) and withdraws
requirements by the licensee and any sub-licensee.
from further competition; or is unable to follow through on
supply if their product is one of the final products chosen.
• We suggest that receipt of payment for Milestone 1 alone
Technology transfer of a product to another company for
would not trigger the license requirement described
ongoing development or manufacture is a complicated
above, for two reasons: the IP generated at that point
endeavor full of delays and outright failures. Thus the prize
would not likely be highly useful to others, given the
design is based on incentivizing the ongoing involvement
relatively low probability of technical failure to reach
of the developer.
that milestone; and the sponsor funding at that point
is not significant enough to risk deterring company
It stands to reason that requiring a company to transfer its
participation. Only after the much higher technical
know-how and manufacturing expertise to a third party in
standard of Milestone 2 is reached (and a more significant
the developing world will be met with resistance by many
amount paid) would the license requirement apply.
potential program participants. However, under certain
circumstances, donors who pay for the prize have good
• A company would not be subject to the license
reason to insist on access to intellectual property that is
provisions above if it continued in good faith in
developed through incentive funding. Sponsors are justified
the competition despite not having received an
50
43
“Reasonable period of time” is to be determined by the sponsor for each milestone, with industry input.
intervening milestone. For example, a company
or to out-license manufacturing immediately after
receives payment for Milestones 1 and 2, does not
administration of the award. These plans would be held
receive Milestone 3 because of the limited number of
confidential by the sponsor. To the extent possible,
payments, but continues to compete for Milestone 4.
sponsors should assist in developing pre-negotiated
purchase agreements with purchasing agents in
• If a company goes through the competition and
developing countries. The plan for manufacturing, or
receives one of the final awards (Milestone 4), but is not
out-licensing technology to one or more third parties for
able or willing to provide ongoing supply at scale, the
manufacturing, will be subject to review and validation
company would also be required to provide the license
by the sponsor or its delegate of the ability to produce
described above, along with adequate technology/
at the scale projected. Requiring the submission of this
know-how transfer to reasonably enable effective use of
plan at Milestone 3 not only acts to verify the competitor’s
the license by a third party manufacturer. The same due
planning and good faith effort, but will give the sponsor
diligence, quality, and expiration rules would protect the
the ability to engage in the validation and review process
company in this setting.
prior to the final milestone payment, and thus prevent
delay if that product is successful.
The effect of the foregoing would be for the company to
continue to own all IP generated: its own core IP, as well
as IP generated in the competition. The sponsor receives
assurance, however, that if the competitor exits following
receipt of at least two milestone payments, the sponsor
retains some benefit via the non-exclusive license. The
sponsor is further protected by the license requirement
if a company receives an award for an approved product
but cannot or will not manufacture and supply the
product. The company is protected by due diligence and
quality requirements in the license arrangement, which
itself would expire if the sponsor or sub-licensee does
not progress the subject IP toward product approval or
manufacture. Requiring a license only after receipt of
Milestone 2 creates a floor for the requirement which
will give comfort to companies without significantly
compromising sponsor interests.
For receipt of payment for Milestone 3, we recommend
that awardees be required to either submit a good-faith
(confidential) strategy to scale-up manufacturing and
distribution of the POC diagnostic, including plans to
obtain regulatory approval, maintain pricing consistent
with the target product profile and product approval,
and a willingness to negotiate and enter into purchase
agreements or tenders with foreign Ministries of Health,
44
9
IQ Prize Administration and Governance
9. IQ Prize Administration and Governance
In this section we have outlined a potential administration
To support the secretariat, we propose convening a
and governance structure which is built around a program
panel of industry experts familiar with all aspects of
secretariat, likely imbedded within a host organization.
the development and manufacture of POC diagnostics,
The proposed secretariat will be responsible for managing
including expertise in the developing world. Throughout
the Global Health Innovation Quotient Prize (IQ Prize) on
the course of the program, the EAG will meet to objectively
behalf of donors, performing the following activities:
determine whether a participating developer has satisfied
milestone requirements and would therefore be eligible to
• Directing the flow of funding from donors to developers;
receive a milestone award.
• Managing contractual relationships with developers;
• Facilitating the work of the expert advisory group
(EAG); and
• Maintaining communication links amongst
Figure 18 provides a more detailed summary of the
proposed administration and governance structure as well
as the roles and responsibilities of key stakeholders.
stakeholders and with the general public.
Figure 18: Overview of Program Governance
46
To ensure a lean architecture for the IQ Prize, with minimal
overlap with existing institutions in the global health
community, the secretariat should be embedded within
an existing organization. The secretariat will require an
estimated 2-3 full-time-equivalent (FTE) staff members to
administer the program. Actual staffing will depend on the
degree to which the secretariat functions are outsourced
or provided by the organization managing it, which
will depend on the competencies of the selected host
organization.
The core operational areas of the secretariat are
outlined below:
Operational Area
Activities
Governance and oversight
•
•
•
Strategic and general management support functions
Performance measurement
Financial management
•
•
•
Determining eligibility of innovators
Establishing and managing the expert advisory group
to evaluate successful achievement of milestones
Payment processing
•
•
Managing all communications with innovators and the public
Transparent information sharing/management of online resources
Administration
Communications
Final administration and governance structures will be
designed with input from donors in order to determine
voting rights and oversight procedures, create an objective
and consistent milestone judging mechanism, and finalize
the ongoing role of the program secretariat.
47
10
Monitoring and Evaluation
10. Monitoring and Evaluation
It will be critical for the Global Health Innovation Quotient
Prize (IQ Prize) to have a comprehensive monitoring
Key components of the M&E framework
• A baseline study to determine the point of comparison
and evaluation (M&E) framework to assess the progress
for future M&E, including the development of
achieved in attaining its goals and objectives. Please note
counterfactuals.51
that the cost associated with M&E has been included in the
overall overhead costs associated with the IQ Prize.
• Annual monitoring of both the IQ Prize and the
complementary activities required to support the
public health goal of the prize.52
M&E of the IQ Prize and its impact will be essential to
• A process evaluation about two years after the launch
(1) demonstrate progress toward achieving the program
of the IQ Prize to assess whether the mechanism is
objectives, (2) inform any refinement of the prize
working as expected and to obtain information on any
design required, and (3) guide the use of supporting
outstanding design issues.
interventions. These M&E activities will be critical to
• Outcome evaluations every 3 years.53 The outcome
ensuring the effectiveness of the IQ Prize and must be
evaluations will focus on assessing the extent
completed as outlined below.
of achievement of IQ Prize objectives, as well as
addressing design issues, as required. They will
The following M&E principles should apply to
the IQ Prize:
52
53
49
outcome evaluation is expected approximately 3
• Routine monitoring and evaluation of whether the
years after the launch of the program, provided that
prize is efficient and effective in achieving its goals;
sufficient developers have joined the program. It will
• Integration, where possible, into existing tools
51
include an analysis of the counterfactuals. The first
be up to the donor whether or not to attempt to
and activities to obtain the necessary information,
measure the impact of the IQ Prize on overall health
minimizing the burden on endemic countries and
in the developing world as part of these outcome
existing investments in M&E; and
evaluations. Linking the IQ Prize directly to reductions
• Collation, analysis, and feedback of data collected
in mortality, morbidity, and delayed antibiotic resistance
and a clear strategy for feeding back information
would be important and informative, but would require
to stakeholders in endemic countries and the
significant effort to collect data and appropriately
international global health community.
attribute results to the prize.
Counterfactuals are a simulation of what would have happened without intervention, or if the intervention had taken a different (but specified)
form. Assessing the difference between the situation under the existence of the milestone-based incentive program, and the counterfactuals contributes to the assessment of impact of the incentive.
Monitoring is the process of collecting and analyzing information to track the efficiency of the project in achieving its goals, in order to provide
regular feedback that helps to track costs and timeliness to compare what was planned to actual results.
Evaluation is the systematic process of collecting and analyzing information to assess the effectiveness of the project in achieving its mission. Evaluation will provide regular feedback to help analyze the consequences, outcomes, and results of project team activities.
M&E Structure
Specific structures and dedicated resources are required to
ensure satisfactory implementation of the M&E activities.
It is proposed that the prize secretariat be responsible for
monitoring, including:
• Managing the monitoring activities, with
accountability to the donor for these activities;
• Managing the independent contractors required for
the implementation of the baseline study; and
• Producing annual reports, as identified in the
requirements for annual monitoring.
To ensure the independence, objectivity, and credibility of
the outcome evaluations, it is proposed that an external
body be responsible for evaluation, including:
• Managing the evaluation activities, with accountability
to the donor for these activities;
• Conducting the outcome evaluations every 3 years,
comparing the extent of achievement of the prize
objectives relative to the baseline study/
counterfactual assessment.
50
11
Financial Requirements Over Time
11. Financial Requirements Over Time
Building on the assumptions outlined in Section 7 of this document, it is estimated that the total donor funding
requirement for the Global Health Innovation Quotient Prize (IQ Prize) is approximately $150M (including $500K per year for
administration and overhead costs as shown in Figure 19 below).54 To llustrate donor costs over the life of the project, we
have assumed that milestone payments will be made in equal amounts at the end of each year across the duration of each
milestone. For example, Milestone 1, which is anticipated to take a developer on average 1.7 years to complete and require
a total of $58.5M in award payments, is shown with donor payments in years 2 and 3 of $29.3M.
Figure 19: Summary of Total Donor Cost over the Project Timeline ($M)
Milestone payments have been rounded to nearest $100k at each milestone. Individual milestone lengths rounded up to
the next full year to calculate number of payment years per milestone.
The illustration shown above represents the base case
base case scenario discussed in this document provides for
scenario based on average estimates of R&D cost, time,
a high likelihood of achieving two successful diagnostic
and risk received from a panel of industry experts. Donor
developments using a range of technological approaches,
funding levels are likely to dictate many of the final IQ Prize
including innovative molecular platforms which carry
characteristics including the number of awards given at
added future benefit of addressing a potentially wider
each milestone, the type of companies likely to participate,
range of diseases.
and the range of technology pursued by developers. The
54
52
Administration and overhead costs assume (1) the cost of two fully-loaded administrator FTE salaries of $150k and (2) general operating expenses
incurred by the host organization of $200k per year. Limited additional costs associated with the expert working group and milestone evaluations
have not been included. Further refinement of these figures will be required prior to project launch.
12
Impact Considerations
12. Impact Considerations
a. Access Provisions
We have organized the access proposal into four
Access is an important part of the Global Health Innovation
broad categories:
Quotient Prize (IQ Prize), because having an impact on the
• Appropriateness
health of people in poor countries is the motivation for
• Regulatory approval
this project. Unlike the developed world markets, access is
• Affordability
often a hugely challenging aspect of delivering a medicine
• Manufacturing, supply, and distribution
or diagnostic tool where it is needed in the developing
There are numerous potential approaches that could be
world.
taken to support the ultimate aim of ensuring access in the
developing world. As the IQ Prize is focused on product
development, rather than on access interventions, we have
limited our proposal to those interventions that we believe
to be most essential. These are outlined in the table below:
Figure 20: Access Proposal
Goal
Access Proposal
Appropriateness
• The Target Product Profile was developed to specifically meet the health needs of
developing countries and to meet the particular product requirements for use in low
resource settings.
Regulatory
Approval
• POC diagnostics must satisfy regulatory requirements before commercial use in a given
country. The prize program requires approval by the EU CE Mark as the requirement for
achieving Milestone 4. CE Mark is an appropriate regulatory standard that will enable
registration in high-burden developing world countries.
• Price has an inherent impact on access. Our TPP will have a target ex-works price target built
in13, to ensure the ultimate uptake of the product. This price will be determined based on cost
to produce, expected volume, country demand, priority, and other relevant factors.
Affordability
• The IQ Prize has the end goal of commercializing two products that meet at least the
minimal TPP. This will ensure post-prize competition that is expected to drive prices down
even further (and may be preferred in order to address regional or country differences in
manufacturing requirements and capabilities). Further, by incentivizing the development of
multiple products, donors can help protect against unanticipated obstacles, for example, in
the event the developer discontinues work, shifts their market focus, or decides to sell their
technology to a third party who cancels the project.
• We should not overlook the possibility of third party subsidies as a method of reducing
price to public purchasers in the developing world, but these approaches would need to
be considered outside the scope of the proposed prize program.
Manufacturing,
Supply and
Distribution
54
• Developers are encouraged to meet developing world demand and will be required to
submit a plan for manufacturing and distribution to do so. Donors will also take an active
role in facilitating market access. A developer unable or unwilling to supply a relevant
market will provide an enabling out license of its IP to a third party supplier, to allow the
market to be served. There may be additional requirements on the developer to ensure
that the product is distributed in developing countries. For example, donors may require
developers to agree to supply a specified, mutually agreed volume of the product, based
on forecast of effective demand , either through direct manufacture and distribution of
the diagnostic, or through licensing the technology to a third-party manufacturer. This
and other potential approaches would need to be carefully developed and vetted with
industry in advance of the launch of the IQ Prize.
b. Supporting Interventions
The IQ Prize focuses on accelerating product development
Secondary Package
of Supporting Interventions
efforts for the proposed POC diagnostic test for fever. In
Supporting interventions that do not directly impact the
addition to awarding milestone payments to successful
milestones outlined in the IQ Prize but are essential to
diagnostic developers that successfully achieve each of the
developing a sustainable platform include:
identified product development milestones, it is important
to recognize that there are a variety of other important
factors that contribute to effective case management and
1. Measuring demand for a multiplex fever diagnostic and
ensuring sufficient supply for the developing world;
2. Promoting adoption by developing country
rational treatment use in endemic countries. These factors
governments and multilateral organizations who
include patient treatment-seeking behavior, product
manage health care systems, especially in low
availability, the national regulatory environment, provider
resource settings; and
knowledge, local distribution capacity and supply-chain
3. Encouraging continued innovation to incorporate
efficiency, patient demand and education, and product
optimal parameters and integration of additional
efficacy.
biomarkers in subsequent product developments.
A secondary package of supporting interventions has
been developed based on a broader assessment of supply-
As noted above, these would be funded and administered
chain challenges. These interventions will help companies:
outside the scope of the IQ Prize.
• Effectively measure and meet demand for the
diagnostic test
• Promote country-level adoption
• Encourage continued product innovation
This secondary package of supporting interventions could be
supported by the prize donor if desired, or funded outside of
the scope of the prize by other donors and/or organizations
that are already focused on these types of activities.
In summary, the broader package of supporting interventions
has not been included in estimates of overall funding
requirements of the IQ Prize, as they would be funded outside
the scope of the prize
55
Measuring and Meeting Demand
As devices progress through the IQ Prize, it will be necessary to begin preparing for scale-up and delivery of successful
devices. Although the potential health impact and utility of the fever panel have been analyzed in the context of
developing the IQ Prize, more information is needed to understand the demand for such a device and to design supporting
interventions to meet this demand as outlined below.
Figure 21: Supporting Interventions to Measure and Meet Demand
Activity
Description
Demand
forecasting
In order to ensure that a product developed through the IQ Prize is produced in sufficient
quantities to meet demand in the developing world, in-depth analysis and forecasting of the
potential demand for a successful product must be conducted. This forecasting will:
 Inform potential volume and therefore manufacturing costs of a product;
 Inform developer participation choice by defining the market potential of the device
in the developing world; and
 Guide the development of additional supporting interventions to optimize uptake in
the developing world market.
Purchasing
agreements
Develop purchasing agreements with multilateral organizations and national governments
thus developing the market for the new POC diagnostic and driving cost of production down
through increased volumes.
Identify potential distributors and connect potential distributors with developers and purchasers.
Distribution
channels
56
Regulate economic operators of the diagnostic-distribution chain involved in distributing lowcost tests, including treatment prices and alignment of incentives to enable an appropriate
price/margin structure, through mechanisms such as:
 Wholesaler volume rebates
 Suggested/recommended retail pricing
 Maximum suggested retail price
Promoting Adoption and Utilization
Beyond developing an environment to maximize availability of the fever panel, supporting interventions that will create an
environment to foster uptake and utilization within developing countries and among multilateral organizations that guide
global health policy are outlined below.
Figure 22: Supporting Interventions to Promote Adoption and Utilization
Activity
Description
National policy
and WHO preparedness
Work with WHO and national policy makers including Ministries of Health to integrate
into IMCI guidelines or other national treatment guidelines.
Public education
and awareness
(IEC)
Build awareness of availability, efficacy, pricing, and rational use of fever panel diagnostic through media campaigns directed at patients and by packaging and labeling
products appropriately.
Provider training
Train health professionals and other health workers to promote appropriate use of the
diagnostic, including operation, maintenance, interpretation of results, and data reporting.
Operational
research
Conduct additional field-based operational research to explore the full utility of the POC
Dx in conjunction with current WHO IMCI guidelines for fever in different levels of health
infrastructure across multiple countries and geographic regions.
Data reporting
An added value of the fever panel POC Dx is the ability to gain new epidemiological
information on the origin of fever in a given area. Data reporting plans for public health
purposes should be developed with Ministries of Health or other users/purchasers of
the devices.
Encouraging Continued Innovation
Mechanisms to support and promote the development of biomarkers and diagnostics for active TB and HIV are ongoing
independent of the IQ Prize. As best in class biomarkers emerge, they can be integrated into the fever panel, either during
or after the prize program. However, improving upon pan-bacterial and developing pan-viral biomarkers to enhance
the capabilities of the fever panel are not currently an area of focus. Therefore, to encourage innovation in this area an
additional intervention may be needed as outlined below.
Figure 23: Supporting Interventions to Encourage Continued Innovation
57
Activity
Description
New pan-bacterial
and pan-viral biomarker discovery
Create parallel incentives with other prize programs (e.g., InnoCentive) to stimulate new
biomarker discovery for pan-bacterial or pan-viral detection and future integration into
the POC diagnostic test for fever
A
Appendix A:
Organizations and Individuals Consulted
Appendix A: Organizations and Individuals Consulted
Academics / Global Health Clinicians:
David Mack, PhD, Alta Partners
Brian D. Wright, PhD, University of California, Berkeley
David Steinmiller, PhD, Claros Diagnostics
David Brown, PhD, Independent Consultant
Doug Dolginow, MD, Ignite Institute
Doreen Ramogola-Masire, MD, Botswana-University
of Pennsylvania Partnership
Elizabeth Bailey, MPP, Commons Capital
Elizabeth Molyneux, MD, World Child Cancer
Jack B. Wilkins, MBA, GeneEx
George W. Rutherford, MD, University of California,
San Francisco
James A. Geraghty, JD, Genzyme Corporation
Gerald J. Kost, PhD, University of California, Davis
John Clarkson, PhD, Atlas Genetics Ltd.
Groesbeck Parham, MD, University of Alabama
Medical Center
Kara Palamountain, Northwestern University
Julia Gage, PhD, National Cancer Institute
Lynette Denny, MD, University of Capetown
Madhukar Pai, PhD, McGill University
Malcolm Molyneux, MD, Liverpool School of Tropical
Medicine and Malawi-Liverpool-Wellcome T
rust Clinical Research Programme.
Geoff McKinley, PhD, Independent Consultant
Jean-Francois de Lavison, MBA, Ahimsa Partners
John A. Hurvitz, JD, Covington & Burling LLP
John McDonough, T2 Biosystems
Karen Hedine, Micronics
Knut Seifert, Roche Diagnostics
Krista Thompson, MBA, Becton Dickenson
Leighton Read, MD, Alloy Ventures
Chandrasekhar Nair, MCE, bigtec Labs
Natarajan Sriram, Tulip Group
Mark Schiffman, MD, MPH, National Cancer Institute
Neil Butler, Independent Consultant
Paul Yager, PhD, University of Washington
Patrick Beattie, Diagnostics for All
Paul A. Wilson, PhD, Columbia University
Peter Chun, PhD, EASE-Medtrend Biotech Ltd.
Philip Castle, PhD, MPH, National Cancer Institute
Peter Dailey, PhD, Cepheid
Rebecca Richards-Kortum, PhD, Rice University
Robert Schueren, PhD, Agilent Technologies
Rosanna Peeling, PhD, London School
of Hygiene and Tropical Medicine
Robert Wallis, ME, Pfizer
Samuel Sia, PhD, Columbia University
Shama Bhat, PhD, Bhat Biotech India
Serigne Mbaye Diene, PhD, Academy
for Educational Development (AED)
Susan Bromley, PhD, Novartis AG
Sarah Smiley, AdvaMed
Talha Syed, JD, University of California, Berkeley
Syd Daftary, Bharat Serums & Vaccines Ltd./
Advy Chemical
Temina Madon, PhD, University of California, Berkeley
Thomas Lowry, PhD, T2 Biosystems
Industry Executives
and Investment Community:
Alex Rubido, PhD, Independent Consultant
Anthony P. Lakavage, JD, Becton Dickinson
Bala S. Manian, PhD, ReaMetrix
Teva Rothwell, Independent Consultant
Una Ryan, OBE, PhD, DSc, Diagnostics for All
Wendy Woods, MBA, Boston Consulting Group
William Rodriguez, MD, Daktari
Blessed Okole, Technology Innovation Agency
Candice Pillay, PhD, Technology Innovation Agency
(South Africa)
Chris Colwell, MPP, Becton Dickinson
Daryl Pritchard, PhD, Biotechnology Industry Organization
David Friedman, Ativa Medical
59
Non-Profit Organizations and
Government Representatives
Alan Magill, MD, Walter Reed Army Institute of Research
Amy P. Wong, Clinton Health Access Initiative
Bernhard Weigl, PhD, PATH
David Wholley, MA, Foundation
for National Institutes of Health
Hellen Gelband, Resources for the Future
Jane Rowley, Independent Consultant
Kevin Kain, PhD, McLaughlin-Rotman
Centre for Global Health, University of Toronto
Mark Perkins, MD, The Foundation
for Innovative New Diagnostics (FIND)
Maurine Murtagh, JD, The Murtagh Group
Patrick Lammie, PhD,
U.S. Centers for Disease Control (CDC)
Peter A. Singer, MD, McLaughlin-Rotman
Centre for Global Health, University of Toronto
Rachel Nugent, PhD, Center for Global Development
Richard M. Thayer, MBA, The Catalysis Foundation
and Halteres Associates
Robert Hecht, PhD, Results for Development Institute
Ruth Levine, PhD, .S. Agency for International
Development (USAID)
Tala de los Santos, MBA, PATH
Ted Roumel, PhD, Independent Consultant
Tido von Schoen-Angerer, MD, MSc,
Médecins Sans Frontières (MSF)
Travis Carley, CCS
Trevor Peter, PhD, Clinton Health Access Initiative (CHAI)
Francis Moussy, PhD, World Health Organization
Special Programme for Research
and Training in Tropical Diseases (WHO/TDR)
60
B
Appendix B:
Project Approach
Appendix B: Project Approach
This report is informed by more than 80 interviews
in the fields not only of diagnostics, but therapeutics
conducted with a broad range of stakeholders, including
(drugs) and vaccines as well. The financial model we have
the executive teams of diagnostic companies – both large
commissioned for this proposal provides a framework
and small and in both the developed world and emerging
which should be readily adaptable to those tools, and with
markets, global health experts working to support
proper inputs, other disease states as well. Our hope is that
development and introduction of new diagnostic tools,
this structure resonates with funders and innovators across
global health clinicians working in the field in low-resource
all of these sectors in order to advance the prevention,
developing country settings, academics, and venture
diagnosis, and treatment of neglected diseases in the
capital investors. A full list of individuals and organizations
developing world.
consulted can be found in Appendix A.
The analyses performed to date have resulted in our
Primary research was supported with reviews of relevant
framing design principles for a prize structure to promote
clinical, technical, and global health research literature as
the development, launch, and distribution of a multiplex
well as information provided on company websites. We
panel for the differential diagnosis of fever in children
have reviewed relevant data sources on disease burden,
under age 5, as resulting from malaria or lower respiratory
epidemiology, standards of care in both diagnostics
infection of bacterial origin, as distinct from viral infection.
and therapeutics, and related topics such as antibiotic
Statistics cited elsewhere demonstrate the significant need
resistance. We have also undertaken a survey of currently
for improved treatment methods for these diseases, which
available diagnostic tools, both point of care and
have a substantial impact on the world’s poorest children.
otherwise, in the developing world, in order to determine
We believe that a point of care diagnostic platform which
the degree of unmet need. Our analysis has considered
meets our Target Product Profile has the potential to
potential innovations in diagnostic technologies and
have a significant positive impact on global health, and
platforms which could have application in the developing
specifically the reduction of mortality in children under
world. We have investigated the potential costs to
age 5 from pneumonia and other bacterial infections.
innovators of developing a multiplex panel capable of
satisfying the objectives of the target product profile
We look forward to refining our analysis based on specific
(TPP). We have also reviewed other prize structures, both
funder needs and priorities, as well as further industry
as to point of care diagnostics specifically, and financial
consultation and deeper analysis.
incentives generally.
In conducting this research, we identified similar published
work and tried to leverage, rather than duplicate, prior
efforts. We acknowledge that there are many other
organizations and efforts directed at designing and
promoting effective R&D incentives for global health, and
we have attempted to consult with these groups and align
our efforts with theirs.
Our background work before preparing this specific
proposal is intended to serve as the platform for a
milestone-based prize which could stimulate innovation
62
C
Appendix C:
Disease Selection
Appendix C: Disease Selection
Disease Selection Criteria
Viral pneumonia and viral meningitis were excluded as
The criteria we used to evaluate possible panels
no treatment is available for these diseases. If a patient
of diseases included:
is negative for both malaria and the bacterial tests listed
above, the patient will be assumed to have a viral infection
• Diseases characterized by shared but
non-specific symptoms.
and treated with paracetamol and other supportive
therapy only.
• The syndrome, or the predominant diseases
encompassed by that syndrome, has a significant
health impact.
• If untreated, the disease has a high mortality and/or
morbidity rate.
• When treated, there is a success rate ≥75% and/or ≥10
year improvement in life expectancy with
a high quality of life.
• Treatment is acute, of short duration, and selfadministered, or results from a single intervention
by a clinician/health care worker.
Other considerations included:
• Preference to have a potential impact on maternal
or child health.
• Likelihood for developed world application to create
a diagnostic that is cost effective and practical
for long term use.
• Level of technical “innovative” step towards developing
an effective product.
• Level of active diagnostics research and development
within each respective disease area.
Using these criteria, “fever” was
identified as a symptom that can
encompass multiple diseases of
significance, including malaria,
pneumonia and other respiratory
infections, meningitis, diarrhea,
tuberculosis, and HIV. Further
refinement using the criteria described
above resulted in identification of our
suggested minimal fever panel:
To supplement the minimal panel,
the following components would
add significant value but may
require significant new innovation to
identify biomarkers and are therefore
included in the optimal TPP only:
• Pan-viral marker (viral pneumonia, viral
meningitis, and other viral infections):
Although treatments are rarely given for viral
infections, inclusion of pan-viral marker would
serve as a control to support a health care
worker’s decision not to give an antibiotic
when the bacterial tests are all negative.
• Active tuberculosis (TB): Active tuberculosis
is often confused with pneumonia when
diagnostics are not available. Unlike bacterial
pneumonia, tuberculosis treatment requires
long courses of expensive antibiotics. Delayed
or improper treatment of TB can be fatal, and
can also contribute to a worsening problem of
drug resistance.
• HIV: HIV is a complicating factor for diagnosis
of disease. HIV positive status can alter a
patient’s immune response causing false
negatives in an immune-based diagnostic. HIV
positive patients are also more susceptible to
atypical infections that may not be captured
by common causes of diseases included on the
proposed panel.
• Malaria (Plasmodium falciparum and P. vivax)
• Bacterial pneumonia (Streptococcus pneumoniae,
Staphylococcus aureus, and Haemophilus influenza b)
• Supplemental pan-bacterial marker (bacterial pneumonia,
bacterial meningitis, other bacterial infections)
64
D
Appendix D:
Integrating a Multiplexed
Diagnostic into
the IMCI Guidelines
Appendix D: Integrating a Multiplexed
Diagnostic into the IMCI Guidelines
An overview of the WHO/UNICEF IMCI guidelines is present-
• Definitive diagnosis of malaria and/or pneumonia in
ed in Figure 3 of the “Need for New Diagnostics” section.
patients with fever and respiratory symptoms: Rapid
Here, a summary of the need for definitive diagnostic tools
breathing is a danger sign in children with severe
and the potential impact of the proposed multiplexed POC
malaria as well as a sign for the presence of pneumonia.
diagnostic on the IMCI guidelines are presented.
Without a diagnostic, health care practitioners must
presumptively treat both conditions or make a guess as
Unmet Diagnostic Needs
in Low Resource Settings
to which disease the patient has. A diagnostic that can
Within the IMCI treatment algorithm, there are several
help a health care practitioner make a correct decision
areas where improved diagnostic methods would increase
and avoid unnecessary treatment.
screen for malaria and pneumonia simultaneously would
the quality of care:
• Diagnosis of severe disease: When a child is unconscious
• Alternative diagnosis of patients with suspected malaria
or severely ill, s/he is presumptively treated for malaria and
who test negative: There are now POC diagnostics
bacterial infection (possible pneumonia, meningitis, or
available for malaria. Although these tests are not
sepsis) and referred to a hospital. However, in many rural
yet widely used, initial introduction has identified a
areas, transportation to hospitals or skilled medical facilities
few challenges. One challenge is that in patients with
is not possible. Without a definitive diagnosis at the point
suspected malaria, but who test negative, health care
of care, the health care provider is unable to ensure the
workers are not equipped to make an alternative
appropriate treatment has been administered.
diagnosis. In small trials, this has resulted in administration
of antimalarials despite a negative test result or the
• Definitive diagnosis of bacterial pneumonia: Pneumonia
increased use of presumptive antibiotic therapy.57 A
is primarily diagnosed by observing rapid breathing.
diagnostic that provides alternative diagnoses for patients
However, breathing rate is not entirely indicative of
without malaria would help overcome the challenges
whether the person has bacterial pneumonia. Across all
faced by malaria-only diagnostics.
cases, accurate clinical diagnosis of pneumonia is less
than 60%.56 Viral pneumonia, asthma, and the common
cold can also cause changes in breathing rate but will
not be affected by antibiotic treatment. Although a
POC diagnostic for S. pneumoniae bacterial pneumonia
is available in the developed world, it is not widely
used in the developing world and would miss bacterial
pneumonia caused by other bacterial species.
56
57
66
Lynch et al “A Systematic Review on the Diagnosis of Pediatric Bacterial Pneumonia: When Gold is Bronze.” PLoS One 2010; Ebell, M., “Clinical Diagnosis of Pneumonia in Children” American Family Physician, 2010.
Reyburn H et al (2006) “Rapid diagnostic tests compared with malaria microscopy for guiding outpatient treatment of febrile illness in Tananzia: radomised trial.” BMJ 334: 403.; Msellem MI et al (2009) “Influence of rapid malaria diagnostic tests on treatment and health outcome in fever patients,
Zanzibar: a crossover validation study.” PLoS Medicine 6: e1000070.
Impact of a New POC Diagnostic for Fever on
Treatment Algorithm
presented in the figure below. Integration of the diagnostic
provides the following benefits:
A multiplex POC diagnostic test that can identify bacterial
• Definitive diagnosis to guide treatment in severe disease
infections, especially bacterial pneumonia, would reduce the
A multiplex
POC diagnostic
that can identify
bacterial patients
infections,
bacterial
withespecially
danger signs;
number
of treatments
given basedtest
on presumptive
diagnosis
pneumonia, would reduce the number of treatments given based on presumptive diagnosis and
educed excessive
usedifferential
of antibiotics or antimalarials
and
increase
theability
ability of
health
workers
to
increase
the
of minimally
minimallytrained
trained
health
workers
to• R
perform
successful
diagnosis
of disease.
caused by presumptive treatment in patients with fever
perform
successful
differential diagnosis of disease.
and cough that may have only one infection;
A summary of how a new diagnostic could complement the IMCI treatment algorithm when it
Abecomes
summaryavailable
of how a is
new
diagnostic
complement
• Identification
of co-infections
that may require dual
presented
in could
the figure
below. Integration
of the diagnostic
provides the
following
benefits:
the IMCI treatment algorithm when it becomes available is
treatment; and
¥
¥
¥
¥
• Epatients
mpowerment
of health
care workers to provide
Definitive diagnosis to guide treatment in severe disease
with danger
signs;
Reduced excessive use of antibiotics or antimalarials caused
by
presumptive
treatment
supportive therapy rather than presumptive antibiotics
in patients with fever and cough that may have only one infection;
or antimalarials if all tests are negative.
Identification of co-infections that may require dual treatment; and
Empowerment of health care workers to provide supportive therapy rather than
presumptive antibiotics or antimalarials if all tests are negative.
Figure 24: Integration of New Minimal Fever Panel Diagnostic into IMCI Guidelines
Figure 25: Integration of New Minimal Fever Panel Diagnostic into IMCI Guidelines
57
67
E
Appendix E:
Definition of Terms Used
in the Target Product Profile (TPP)
Appendix E: Definition of Terms Used
in the Target Product Profile (TPP)
Definition of terms for TPP:
at the temperature and humidity specified in the TPP.
Sensitivity: Sensitivities are defined in absolute terms
Regulatory requirements will also be taken into account.
for organisms where positive diagnosis would result in
treatment. In clinical validation, the performance of the
Steps to test result: The numbers of steps to test result
fever panel diagnostic will also be compared to the gold
includes the total number of steps needed for sample
standard assays listed under “reference test.”
collection, performance of assay protocol, and reading of
test results. There should be no steps required for sample
Specificity: Specificity will be determined for each
preparation, which if needed at all will be internal to the
individual component assay/organism. As the specificity
device.
requirement for each organism will be set at the same
level, this section has been condensed to a single value.
Time to result: The time to result is the time from
application of the patient sample to the device through
Reproducibility: Reproducibility will be evaluated in the
the time of readout.
laboratory clinical validation by performing assays by multiple
technicians in a single lab and by technicians in different labs.
Duration of valid result: Current POC diagnostics based on
Reproducibility will further be evaluated by examining test
lateral flow often have a narrow window of time where the
performance across multiple clinical trial sites.
visible result is valid. If a health care worker proceeds to see
other patients before the test result is read or would like to
Quality control: The device should contain positive or
record the test result several hours later, the result is no longer
negative controls to allow the operator or the test itself to
valid. Therefore, the duration of the valid result, either through
report if the test readout is valid.
maintained visual accuracy, data capture, or data storage
should ensure that the result remains valid for 24 – 72 hrs.
Interfering diseases: Ideally the diagnostic will not have
limitations in terms of co-morbidities that will interfere with
the test results. For instance, if a patient on a particular
medication or with a particular viral disease not diagnosed
by this panel always appears as a false positive for a
particular assay, this would constitute an interfering disease.
Stability: The stability criteria defined in the TPP are
designed to mimic the extreme storage and operation
temperatures of the developing world where the devices
will be used. The device and associated reagents should
have shelf lives that meet or exceed these criteria. As
actual shelf life evaluation will depend on final packaging
and other local conditions, these TPP criteria will be
evaluated using accelerated stability testing whereby
the device and associated materials or reagents will be
evaluated for performance both before and after storage
69
F
Appendix F:
Impact Model
Appendix F: Impact Model
Overview
• Current and estimated future number mortality due
The section outlines the potential health impacts of the
to bacterial pneumonia infection
new POC diagnostic for fever symptoms proposed by
• Estimated current and future utilization of antibiotics
the Global Health Innovation Quotient Prize. Given the
to treat bacterial pneumonia infections
current availability of POC diagnostics for malaria, the
• Estimated cost effectiveness of the new diagnostic
outputs calculated by this impact model were focused on
test (measured as cost per life and life year saved)
improvements in testing for bacterial pneumonia in order to
The model distinguishes between six regions- Sub-Saharan
demonstrate potential health impact.
Africa, India, China, Latin America, North America/Europe,
Input assumptions around target population
and the rest of the world (ROW)- in order to calculate
demographics, disease characteristics, testing and
similarly disaggregated outputs. Where appropriate, impact
treatment parameters, and diagnostic user requirements
has also been rolled-up to the global level.
were used to calculate key outputs including:
A summary of the modeling and logic is shown
• Estimated current and future number
in Figure 25 below.
of accurate diagnoses and treatments
of bacterial pneumonia infection
Figure 25: Impact Model Overview 25: Impact Model Overview
Calculations (outputs)
Assumptions (inputs)
Demographic Outputs
• Target population (under 5 - 000s)
• Fever cases per year (under 5 - 000s)
Demographic Inputs
• Total population, by country/region
• % at risk (population under 5), by country/region
1
2
Treatment and Testing Outputs
• Change in accurate number of bacterial
pneumonia diagnoses
• Change in accurate number of bacterial
pneumonia treatments
• Change in total antibiotic use
5
Disease Inputs
• Fever case data (fever cases /child /yr; % seeking treatment),
by country/region
• Disease incidence (% of fever cases), by country/region
• Bacterial pneumonia mortality, by country/region
Testing and Treatment Inputs
• Access to infrastructure, % by country/region
• Current treatment paradigm, by infrastructure access level and
country/region
• Cost of testing and treatment, by country/region
2,3,4
Mortality and Cost Effectiveness Outputs
• Change in bacterial pneumonia mortality
• Cost per life saved
• Cost per life year saved
71
Diagnostic Inputs
• Infrastructure requirements for the future diagnostic
• Diagnostic accuracy for both current and future diagnostic
methods
Summary for Model Logic
(4) Using both the infrastructure accessibility and accuracy
Referring to Figure 25, the calculation of key outputs listed
requirements defined in the Target Product Profile for
above is described in the following 5 steps:
the proposed diagnostic, a new treatment paradigm was
modeled for each segment and resulting post-intervention
(1) In order to calculate demographic outputs, regional/
(future) levels of accurate diagnosis and treatment of
country data on population and the percent of the
bacterial pneumonia were calculated. These resulting
population under the age of five58 was combined with disease
figures were compared with the baseline diagnosis and
incidence and treatment seeking behavior data . These inputs
treatment data calculated in step 3 to calculate the
were used to calculate the target population for the proposed
treatment and testing outputs. These outputs included
diagnostic as well as the number of fever and bacterial
the change in accurate number of bacterial pneumonia
pneumonia cases per year in each region/country.
diagnoses, in accurate number of bacterial pneumonia
59
treatments, and in total antibiotic use.
(2) Region/country specific access to health care
infrastructure data60 was used to disaggregate the
(5) Mortality and cost effectiveness outputs were
demographic outputs described in step 1 between those
then calculated using the demographic outputs (step
with access to no, minimal, and moderate/advanced health
1), treatment and testing outputs (step 4), bacterial
care infrastructure. From this point forward, all modeling
pneumonia mortality rates (disease inputs), and cost
calculations remained disaggregated by both region/
assumptions for testing and treatment (testing and
country and access to infrastructure level (henceforth
treatment inputs).62
“segment”) and were only combined to summarize region/
country outputs.
(3) Assumptions around the current testing and treatment
paradigm and current diagnostic accuracy61 were used
to determine the number of individuals currently being
tested and accurately treated for malaria, and the
subsequent accuracy of current diagnosis and treatment of
bacterial pneumonia.
58
59
60
61
62
72
Population Reference Bureau (2009), “World Population Data Sheet”
UNICEF/WHO (2006), “Pneumonia: The forgotten killer of children”
RAND Corporation / Gates Foundation (2006), “Developing and interpreting models to improve diagnostics in developing countries”
Assumptions were informed by over 80 interviews with global health and diagnostic industry experts conducted by BVGH in the second half of 2010
Based on industry standards and consultation with over 80 global health and industry experts
Input and Assumption Detail
The Table below provides a comprehensive summary of inputs variables and assumptions used to model the health
impact of the proposed diagnostic. Highly sensitive input variables, which have significant impact on mortality and cost
effectiveness estimates include bacterial pneumonia mortality rates, testing and treatment costs, and future diagnostic user
requirements including accuracy rates and infrastructure accessibility.
Input Variable
Assumption
Sensitivity (10%
increase in the
input variable)
Delineation aligned with UNICEF data on bacterial pneumonia incidence and mortality. Source: Population Reference Bureau 2009
World Population Data Sheet
N/A
Demographic Inputs
Population, by
region/country
% at risk (population under 5), by
region/country
- Mortality: +8%
- Cost effectiveness:
marginal increase
Calculated based on Population Reference Bureau
2009 World Population Data Sheet statistics
Note: this impact due to
the increased number of
cases available to be tested by the diagnostic
Disease Inputs
Fever case data
(fever cases /child
/yr), by region/
country
73
- Mortality: +10%
- Cost effectiveness: n/a
Source: UNICEF/WHO (2006), “Pneumonia:
The forgotten killer of children”
- Mortality: +5%
- Cost effectiveness: n/a
Fever case data
(% of cases seeking treatment), by
region/country
Disease incidence
(% of fever cases),
by region/country
- Mortality: +10%
- Cost effectiveness: +8-9%
Bacterial pneumonia mortality, by
region/country
Calculated based on total number of cases and guidance from
UNICEF/WHO (2006), “Pneumonia: The forgotten killer of children”9
(see Figure 26 below).
- Mortality: +10%
- Cost effectiveness: +10%
Input Variable
Assumption
Sensitivity (10%
increase in the
input variable)
Testing and Treatment Inputs
Source: RAND Corporation / Gates Foundation (2006), “Developing
and interpreting models to improve diagnostics in developing countries” (see Figure 27 below).
Infrastructure levels defined as:
Access to
infrastructure,
% by country/
region
No infrastructure: medical care within a village or community; no or
very limited access to electricity, clean water, physical health care
infrastructure, and medical care professionals
N/A
Minimal infrastructure: medical care within rural health clinics; limited
access to electricity, clean water, basic medical facilities, and minimally trained medical care professionals
Moderate/Advanced infrastructure: medical care in urban health clinics and hospitals; access to electricity, clean water, laboratories, and
medical care professionals
Current treatment
paradigm, by
infrastructure
access level and
country/region
Cost of future
testing, by
country/region
Assumptions of the current and future use of antimalarial medication
following accurate test results by malaria prevalence and infrastructure
level (see Figure 28 below). Based on consultations with over 80 global
health and industry experts conducted by BVGH in 2010.
Note: assumptions held constant in both current and future scenarios in
order to allow for a comparison in health outcomes based on improved
diagnosis and not subject to any changes in treatment procedure.
Assumption of $2.00-5.00 per unit, depending on region, based
design requirements for the proposed diagnostic.
NOTE: currently does not include the cost of distribution and administration or the potential cost of a base unit.
Assumption of $1.00 per treatment
Cost of antibiotic/
antimalarial
treatment, by
country/region
Note: held constant in both current and future scenarios as well as
consistent in all regions. This will ensure that the cost of treatment
does not impact cost-effectiveness calculations as treatment costs
will be unaffected by the proposed intervention.
Significant impact
on both mortality
and cost effectiveness
- Mortality: n/a
- Cost effectiveness: -10%
- Mortality: n/a
- Cost effectiveness:
marginal increase due
to increased antibiotic
cost savings
Diagnostic Inputs
Infrastructure
requirements
for the future
diagnostic
Diagnostic accuracy
for both current
and future
diagnostic methods
74
Assumption based on the target product profile. Current modeling
assumes that the future diagnostic will be accessible in minimal,
moderate, and advanced infrastructure levels.
Significant impact
on both mortality
Current diagnostic method: following malaria treatment- sensitivity
of 40%; specificity of 80% and not following malaria treatment- sensitivity of 60%; specificity of 60%
Future diagnostic: assumption based on the target product profile.
Significant impact
on both mortality
Note: current clinical diagnosis assumes that individuals are more likely to
receive an accurate diagnosis for bacterial pneumonia if the cause of fever
is assumed to be cause by an illness other than malaria.
Figure 26: Modeling Assumptions: Bacterial Pneumonia Mortality, by Region/Country
SubSaharan
Africa
India
China
Latin
America
N. America
and EU
ROW
Treated bacterial
pneumonia mortality
0.22%
0.14%
0.05%
0.05%
0.03%
0.25%
Untreated bacterial
pneumonia mortality
2.21%
1.43%
0.46%
0.45%
0.33%
2.50%
Figure 27: Modeling Assumptions: Access to Infrastructure, % by Country/Region
SubSaharan
Africa
India
China
Latin
America
N. America
and EU
ROW
No infrastructure
25.0%
25.0%
10.0%
5.0%
3.0%
5.0%
Minimal infrastructure
47.0%
30.0%
20.0%
5.0%
5.0%
5.0%
Moderate/Adv
infrastructure
28.0%
45.0%
70.0%
90.0%
92.0%
90.0%
Figure 28: Modeling Assumptions: Access to Infrastructure, % by Country/Region
75
Current
paradigm:
AM for Positive
Test Result (%)
Current
paradigm:
AM for Negative
Test Result (%)
Future
paradigm:
AM for Positive
Test Result (%)
Future
paradigm:
AM for Negative
Test Result (%)
High malaria prevalence:
Mod/Adv infrastructure
100%
0%
100%
0%
Low malaria prevalence:
Mod/Adv infrastructure
100%
0%
100%
0%
100%
100%
100%
100%
0%
0%
0%
0%
No infrastructure
100%
100%
100%
100%
No infrastructure
0%
0%
0%
0%
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Suite 1600
San Francisco, CA 94105 USA
Phone/Fax: +1 415-446-9440
www.bvgh.org

GlobAl HeAltH InnovAtIon QuotIent prIze

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