Global TB Research – as part of the new End TB
Strategy
Dr Dick Menzies
Research Methods course
McGill University – 6-10 July 2015
The Global Burden of TB - 2013
Estimated number
of cases
All forms of TB
9 million
126 per 100,000
• 550,000 in children
• 3.3 m in women
Estimated number
of deaths
1.5 million*
• 80.000 in children
• 510.000 in women
HIV-associated TB
1.1 million (13%)
360,000
Multidrug-resistant TB
480,000
210,000
Source: WHO Global TB Report 2014
* Including deaths attributed to HIV/TB
TB cases and deaths in slow decline, 1990-2013
All TB deaths
Incidence peaked at 9.5 million in 2004
9 million in 2013
Total mortality peaked in 2002 at 1.7 million
1.5 million in 2013
Full implementation of Global Plan: 2015 MDG
target reached but TB will not be eliminated by 2050
Current rate of decline
-1.5%/yr
China, Cambodia
-4%/yr
W Europe 1950-60s
-10%/yr
Elimination target:<1 / million/yr
-20%/yr
The End TB Strategy: Vision, goal, targets 2035
Vision: A world free of TB
Zero TB deaths, Zero TB disease, and Zero TB suffering
Goal: End the Global TB epidemic (<10 cases per 100,000)
Target 1
95% reduction in
deaths due to TB
(compared with
2015)
Target 2
90% reduction in TB
incidence rate
(compared with
2015)
Target 3
No affected
families face
catastrophic
costs due to TB
The End TB Strategy - Components
1. INTEGRATED, PATIENT-CENTRED CARE AND PREVENTION
A. Early diagnosis of tuberculosis including universal drug-susceptibility testing, and systematic
screening of contacts and high-risk groups
B. Treatment of all people with tuberculosis including drug-resistant tuberculosis, and patient
support
C. Collaborative tuberculosis/HIV activities, and management of co-morbidities
D. Preventive treatment of persons at high risk, and vaccination against tuberculosis
2. BOLD POLICIES AND SUPPORTIVE SYSTEMS
A. Political commitment with adequate resources for tuberculosis care and prevention
B. Engagement of communities, civil society organizations, and public and private care providers
C. Universal health coverage policy, and regulatory frameworks for case notification, vital
registration, quality and rational use of medicines, and infection control
D. Social protection, poverty alleviation and actions on other determinants of tuberculosis
3. INTENSIFIED RESEARCH AND INNOVATION
A. Discovery, development and rapid uptake of new tools, interventions and strategies
B. Research to optimize implementation and impact, and promote innovations
Projected acceleration of TB incidence decline to
target levels
Current global trend: -1.5%/year
Optimize use of current & new tools
emerging from pipeline, pursue UHC
and social protection
Average -10%/year
by 2025
Introduce new tools: a vaccine,
a new easier prophylaxis &
Average
treatment regimen, a PoC test -17%/year
-5%/year
Global TB diagnostics Pipeline - 2013
GLOBAL TB
PROGRAMME
Global TB Drug Pipeline 2013
Discovery1
Preclinical Development
Lead Optimization
Diarylquinoline
DprE Inhibitors
GyrB inhibitors
InhA Inhibitors
LeuRS Inhibitors
MGyrX1 inhibitors
Mycobacterial Gyrase
Inhibitors
Pyrazinamide Analogs
Riminophenazines
Ruthenium (II) complexes
Spectinamides
Translocase-1 Inhibitors
Preclinical
Development
CPZEN-45
DC-159a
Q201
SQ609
SQ641
Clinical Development
GLP
Tox.
Phase I
BTZ043
TBA-354
4 Repurposed Drugs
6 New Drugs
3 New Classes
Phase II
Phase III
AZD5847
Bedaquiline (TMC-207)
Linezolid
Novel Regimens2
PA-824
Rifapentine
SQ-109
Sutezolid (PNU-100480)
Delamanid (OPC-67683)
Gatifloxacin
Moxifloxacin
Rifapentine
Drugs currently in the regulatory
review process
Chemical classes: fluoroquinolone, rifamycin, oxazolidinone, nitroimidazole, diarylquinoline, benzothiazinone
1 Ongoing
projects without a lead compound series can be viewed at http://www.newtbdrugs.org/pipeline-discovery.php.
2
Combination regimens: first clinical trial (NC001) of a novel TB drug regimen testing the three drug combination of PA-824,
moxifloxacin, and pyrazinamide was initiated November 2010 and completed in 2011 with promising results. The second
clinical trial (NC002) of this regimen was launched in March 2012 and will test the efficacy of the regimen in drug-sensitive
and multidrug-resistant patients. The third clinical trial (NC003) will evaluate PA-824, TMC-207, pyrazinamide and
clofazimine in combinations and is scheduled to begin September 2012.
www.newtbdrugs.org
Updated: June 18, 2013
Global TB Vaccine Pipeline 2013:
Phase II
Ad5 Ag85A
McMaster CanSino
ID93 + GLA-SE
IDRI, Aeras
Hyvac 4/ AERAS-404
+ IC31
SSI, sanofi-pasteur,
Aeras, Intercell
H56 + IC31
SSI, Aeras, Intercell
MTBVAC
TBVI, Zaragoza,
Biofabri
Hybrid-I + CAF01
SSI, TBVI
VPM 1002
Max Planck, VPM,
TBVI
Hybrid-I + IC31
SSI, TBVI, EDCTP,
Intercell
RUTI
Archivel Farma, S.L
Phase IIb
Phase III
MVA85A/AERAS485
OETC, Aeras
AERAS-402/ Crucell
Ad35
Crucell, Aeras
M72 + AS01
GSK, Aeras
M. Vaccae
Anhui Longcom,
China
Viral vector
rBCG
Protein/adjuvant
Attenuated M.tb
Immunotherapeutic:
Mycobacterial – whole cell
or extract
10
Implementation, and research - need financing
IMPLEMENTATION
$2 billion
Funding gap
RESEARCH
$ 6 billion available
$1.32 billion
Funding gap
$8 billion funding required for
TB prevention, diagnosis and treatment
$677 M
$2 billion funding required for
research and development
TAG TB R&D report 2013
Total TB R&D Funding, 2005-2013: flat line
$675,328,887
$700,000,000
$643,360,390
$636,979,349
$676,656,323
$638,783,272
$494,576,235
$525,000,000
$478,343,421
$418,928,300
$358,476,537
$350,000,000
$175,000,000
$0
2005
2006
2007
2008
2009
2010
2011
2012
2013
but receives
TB has killed more people…
less funding
$43 BILLION
HIV/AIDS
GLOBAL FUNDING
Malaria
1813-2013
30,000,000 $7 Billion TB
HIV/AIDS deathGlobal Funding
Source: Nature Vol 502, No. 7470
Suppl, S2 (2013)
Tuberculosis
1990-2010
Source: Financing Global Health 2012,
IHME; Aeras
Global Consultation on Research for TB Elimination
Stockholm, Nov 2014
Meeting objectives:
•To review the existing mechanisms, funding and capacity for TB
research, identify gaps and propose new mechanisms of
collaboration, capacity building and resource mobilization,
•To outline a global framework to operationalize pillar 3 that
addresses TB research planning, capacity-strengthening and
research funding in all countries
GLOBAL TB
PROGRAMME
14
Global Consultation on Research for TB Elimination
Stockholm, Nov 2014
Main Output:
Development of a Global Action Framework for TB Research aimed at the
operationalization of research for TB elimination, with:
→ a 10 year vision (2025) towards reaching the 2035 targets of the End TB
Strategy
→ a 5-year strategic plan to implement Pillar 3 of the End TB Strategy
→ a 1-year operational plan with specifics at global and national levels:
- enhance use of current resources,
- strengthen country specific research programs,
- strengthen research capacity,
- identify mechanisms for innovative financing of research.
GLOBAL TB
PROGRAMME
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The Global Action Framework for TB
Research
The Global Action Framework for TB Research sets the principles for
action on TB research and recommends the roles, responsibilities and
deliverables of major stakeholders at global and national levels.
Four main parts:
- Part I: Strengthening TB research in low and middle-income countries
most affected by TB.
- Part II: Supporting and facilitating research at global level.
- Part III: Supportive role of WHO
- Part IV: Next steps.
Supporting and facilitating research at global level
Aim: to support and reinforce the efforts invested at national level through
the development of strong research partnerships and networks,
accompanied by reinvigorated funding for TB research and development.
1. Mobilizing increased resources for TB research:
- Expand international funding sources to support research in low
and middle income countries
- Hold regular TB research donors’ forum
- Stimulate the development of innovative funding mechanisms
- enhance advocacy globally and nationally
Supporting and facilitating research at global level
2. Enhance international collaboration on TB research.
- Pursue an international mapping of TB research
- Compile an international compendium of funding opportunities
- Stimulate the creation of international networks and thematic hubs
- Encourage large scale, cross-cutting multi-disciplinary multi-site
collaborative research projects
Role of WHO
1. Provide Technical Assistance to countries.
2. Develops guidance tools and documents (e.g. “How to
form a TB research network”, “How to develop a National
TB Research Agenda”, etc.).
3. Work with international and bilateral agencies that are
providing support to countries for various forms of
research
4. Foster support for dissemination of research outputs and
uptake by countries (eg Xpert, new TB drugs, etc)
5. Enhance data sharing
6. Convene meetings and facilitate communication
7. Establish a Global TB Research Task Force that will
assist in implementation of the Global Action Framework
Strengthening TB research in low and middleincome countries most affected by TB – Key steps
1. Development/reinforcement of a national TB research network,
2. Development of a country-specific TB research strategy and priorities
based on the characteristics of the TB epidemic and the mapping of
resources and activities at country level,
3. Plan for relevant training and capacity building on (TB) research from
an early stage,
4. Ensure sustained national TB research funding mechanism for
training, infrastructure and research operations,
5. Establish mechanisms for on-going monitoring and evaluation of the
implementation of the TB research action framework,
6. Advocate for public support and funding of TB research.
Strengthening TB research in low and middle-income
countries most affected by TB – Key steps
1.
Establish/Strengthen an integrated national TB research network
1.
Members:
- NTP/MoH and other Ministries. A “Focal point in research” within NTP
is often a successful linkage
- University based researchers (a focal point for NTP can be appointed)
- NGO’s / international organizations
- Civil society
2.
Funding – modest funding for meetings/secretariat needed – long term
3.
Leadership – ideally rotates between members
4.
Functions: Regular meetings
- Scientific meetings
- Set national research agenda
- Help coordinate projects
Strengthening TB research in low and middle-income
countries most affected by TB – Key steps
2.
Establish/update National strategic plan for TB research
1.
This should be developed by all stakeholders
Could be a responsibility of the TB Research Network
2.
Based on the needs and capacity of the country
- Assessment of the TB epidemic – incidence, HIV-TB, DR-TB, etc.
- Inventory of current TB research and research capacity
(Research teams/institutes/universities)
3.
Development of country-specific TB research priorities.
4.
Needs to be part of a National TB Strategic plan
Strengthening TB research in low and middle-income
countries most affected by TB – Key steps
3.
Publicly Funded Plan to build and maintain capacity for TB Research
1.
Training in Research at several levels
- Under-grad – medical schools and others
- Post-grad – Master’s and PhD levels
- Methodologies – include the spectrum of research (basic to
operational)
2.
Salaries – for researchers
- Through competitive mechanisms
- Through universities or research institutes
3.
Infrastructure
- Labs – for basic research, or to support clinical research (RCTs)
- Personnel – research coordinators, data analysts, etc
Strengthening TB research in low and middle-income
countries most affected by TB – Key steps
4. National funding for TB Research.
1. This should be part of general plan for health research funding
2.
Funding should come from national Government
- Ministries of Health, or Science & Technology …
3.
Other sources could include
- Industry (Pharmaceuticals, Diagnostics)
- Donors/NGOs (eg. Global Fund, USAID)
4.
Commitment should be long-term
- smaller funds that are stable more likely to affect career choices
5.
Mechanism – suggested based on best model in high income countries:
- open and transparent process
- peer reviewed
Model countries – roles and expected
outcomes
• Objective: develop models for implementation of “Pillar
3” within low/middle income countries that have high TB
burden.
• Selection criteria: ad hoc process - self-identified.
• Role: Partner with WHO to produce examples of
successful implementation that other LMIC may follow in
next 10 years
• Outcomes:
– Achieve within one year (by June 2016) the
milestones outlined above for low-middle countries
– Evaluate and document major roadblocks as well as
key factors in success
Potential 'path-finder' or Model countries
•
•
•
•
•
•
Brazil*
India
Indonesia*
Peru
South Africa
Vietnam
Brazil
•
•
•
Status at end 2014:
– Functioning TB research network (REDE-TB since 10 years)
– Very well funded research training (Science without Borders)
– Well funded peer-reviewed research funding
– Substantial international collaborations (NIH, Gates)
Progress in 2015:
– Survey (investigator, health system managers, industry and NGO) to identify
Gaps and Research Priorities
– Joint meetings of REDE-TB, Government, NTP, Fiocruz
– Updated the Brazil national TB research strategy/Research Agenda
– Formulated plans for immediate action in new tools
Plans up to June 2016:
– Fiocruz – develop a new Tuberculin. NTP & Universities – will test
– Industry/REDE TB – impact of new Diagnostic for MDR-TB (replace liquid
culture).
– Industry /REDE TB – impact of TB eXiST for XDR-TB diagnosis.
– International – collaboration with China in Translational research
– International – Promote cost sharing model of NIH-MoH-Brazil (Report Brazil)
Indonesia
• Status at end 2014:
– Functioning TB research network - TORG (Tuberculosis
operational research group) since 10 years
– Several university based research groups with well trained
researchers (largely through Netherlands)
– Challenge TB country
• Progress in 2015:
– Expansion of TORG – involve NTP manager, WHO country rep,
others
– Involvement of TORG in Global Fund concept note
• Plans up to June 2016:
– Recent meeting of TORG – consensus to push forward as
‘model country’
– Meeting of all stake-holders re National TB research strategy –
September 2015
Model countries: Milestones and deliverables – 1 year
Specific One-year Objectives for Model countries
1. Establish/Strengthen an integrated national TB research
network, linked with regional and international collaborations
2. Establish/update a National strategic plan for TB research,
as part of National Strategic plan for TB.
3. Plan to build and maintain capacity for TB Research –
part of a national plan to build/maintain capacity for all health
research.
4. Establish mechanisms for public funding for TB Research
- part of a national plan for all-health research funding
Model countries: Milestones and deliverables – 5 year
Specific Five-year Objectives for Model countries
1. Will have established mechanisms for national
funding for TB research with regular (e.g. annual)
national competitions for research operating funds.
2. Will have established mechanisms to review and
finance the research and development components of
the Stop TB Partnership’s Global Plan 2016-2020.
All other LMIC: Milestones and deliverables – 5 year
All other low and middle income countries with
substantial TB burden will have (at minimum):
1. established a National TB Research Network that
includes at least researchers, academia, the National TB
Programme and other relevant stakeholders.
2. developed and started implementing a national TB
Research Strategic Plan with clear TB research priorities.
3. initiated in-country research training with national faculty
(minimum – have the capacity within the country to deliver
operational research training).
All LMIC: Milestones and deliverables – 10 years
1) Implemented a national TB research strategic plan with a TB specific
prioritized research agenda within a larger health research agenda;
2) Established sustained national TB research funding mechanism(s):
- based on the national research priorities;
- Funds a broad spectrum of research efforts on TB (from basic to
operational as appropriate to country settings and resources).
3) Created/strengthened TB research capacity:
- including training, mentoring and career support.
- well-defined roles for governmental agencies and national TB
programmes (NTP), universities/medical schools/research
institutions, private sector, and NGOs.
4) Empowered a strong and self-sustaining TB research community (i.e.,
a critical mass within the country), which is productive, addressing
national priorities, and linked with regional hubs and international
networks of research.
The 10 year vision
- by 2025
1. Greatly increased capacity and leadership for TB Research in high
TB-burden countries. This means a strong and self-sustaining TB
research community in these countries,
2. Major increase of government and industry financing for TB
Research – especially in middle-income high TB-burden countries,
including the BRICS,
3. Further increased commitment and financing for global TB R&D in
high-income countries,
4. Enhance international collaboration within the larger context of
health research.
Next steps
1.
Post STAG Workshop:
- Training WHO country/regional staff on Pillar 3 - Global Action
Framework
- Up-date operationalization documents – “how-to” initiate/strengthen TB
research in LMIC.
2.
Global TB Research Task force:
- Initial meeting - Q4 of 2015
- Evaluate progress, refine indicators, suggest actions
3.
International Union Conference, Cape-town:
- Symposium on “End TB Strategy - Pillar 3”. Speakers from “model
countries” (researchers and NTP) – describe process, obstacles and
lessons learnt
4.
Continue work with Model countries:
- Update Framework – with various new models that have worked
"The struggle [against tuberculosis]
has caught hold along the whole line
and enthusiasm for the lofty aim
runs so high that a slackening is no
longer to be feared. If the work goes
on in this powerful way, then the
victory must be won".
Robert Koch, Nobel Lecture
December 12, 1905.
Acknowledgements – ideas, input, (and ppt slides)
Christian Lienhardt (slides)
Knut Lonnroth
Mario Raviglione (slides)
Mukund Uplekar
Diana Weil
… All Stockholm meeting attendees
…. And all those who are taking research
forward in Model countries
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