Co-ordinated malaria research for better policy and practice: the role of research consortia

David SchellenbergProfessor of Malaria & International HealthACT Consortium Director

9th European Congress in Tropical Medicine & International HealthBasel, Switzerland

Tuesday 8th September 2015

Improving health worldwidewww.lshtm.ac.uk

A Common Goal“Novel approaches for clinical trial design”

• Typical aims in research proposals:– “This study seeks to improve the health of [Country] children by controlling malaria

….”– “will increase the number of sub-Saharan African countries in which malaria

prevention and control efforts rapidly reduce malaria incidence and ultimately … deaths.”

– “a solid evidence-base for choosing the best ACT deployment strategies to gain optimal impact on malaria morbidity and mortality does not exist”

• Can research consortia facilitate attainment of the ultimate goals?

Working as a Consortium• Two examples: IPTi Consortium & ACT Consortium• Co-ordinated approach to produce reliable, policy- or

practice-relevant outputs– Involves academics, policy makers & programme managers – Standardisation of methodology, endpoints, quality

assurance• Robust safety and effectiveness data: pooled analyses

Intermittent Preventive Treatment (IPT)

The delivery of a treatment dose of an anti-malarial at a pre-specified time, regardless of the presence of symptoms or P falciparum parasitaemia

IPTi = IPT in infants

0 3 6 9 12 15 18 Age (months)

DTP

/OP

V-1

DTP

/OP

V-2

DTP

/OP

V-3

Mea

sles

Tanzanian EPI Schedule

IPTi IPTi IPTi

IPTi in Ifakara, Tanzania

Randomised placebo-controlled double-blind safety and efficacy trial of IPTi with sulphadoxine-pyrimethamine (SP)– 701 children – SP/placebo at 2, 3 & 9 months of age

Schellenberg D, Menendez C, Kahigwa E et al. Lancet 2001;357:1471-7.

Summary Results– Well tolerated & safe– Efficacious

• 59% (41,72) reduction in clinical malaria• 50% (8,73) reduction in incidence of PCV<25%• 13% (0,24) reduction in febrile episodes• 30% (8,47) reduction in admissions to hospital

– No interactions with EPI vaccines– No ‘rebound’ effect.

If it looks too good to be true – it probably is!

Developing a Research Agenda• Research collaborations interested in further evaluation self-

identified; covered their own costs to meet informally– Included WHO and UNICEF

• Groups aligned on main research questions and work needed to address them

• Secure funds for a portfolio of projects

Timely information for policy

Efficacy & safetyin several

transmission settings

Work with policy makers

Operational issues & Effectiveness

studies

POLICY

POLICY

Efficacy & safetyin several transmission

settings

Operational issues & Effectiveness studies

Work with policy makers

Time

EFFICACY

EPI INTERACTIONS

COMMUNITY EFFECTIVENESS

COSTING / ACCEPTABILITY

REBOUND / IMMUNOLOGY

SAFETY

DRUG RESISTANCE

Availability of Data to Inform Policy

Time

2006 SP

2008Other drugs

Time

www.IPTi-malaria.org/

Safety

Efficacy Morbidity

Mortality

EPI interactions

Delivery strategies

Acceptability

Feasibility

Costs

Proof of Principle Public Health Action

Effectiveness

Platform for Policy Discussions

The IPTi Consortium

Consortium Committee

Southern Tanzania Kisumu ManhicaKili Gabon UNICEF 6 studies

DSMB DSMBDSMB DSMB

Consortium Safety Panel

Gates Foundation

Clinical Monitoring

ExecutiveCommittee

Core Administration

WHOPolicy

Platform

DSMB – Data and Safety Monitoring Board

Cost Effectiveness

WG

Acceptability WG

StatisticalWG

Drug Resistance

WG

PNGDSMB

Applicability of IPTi WG

Evidence Available 2006Malaria incidence up to age 12m

Predicting public health impact

http://ipti.lshtm.ac.uk/

When the policy process is inadequate...• Researchers may need to become advocates

– Not appropriate, but may be unethical not to?– Potential for unnecessary polarisation within Consortium

IPTi – where are we now?

• 2009: WHO policy recommendation• 2012: Policy adopted in 1 country - Burkina Faso• 2012: Eight nations met to discuss IPTi implementation

PolicyResearch Implementation

• 2001: Early discussions following WHO recommendation to use

ACTs to treat malaria

• 2003/4: Researchers, policy-makers and implementers identify

key barriers & design studies. – NMCPs, WHO, WHO-AFRO, RBM, Global Fund inputs

• 2005/6: Research portfolio refined

• 2007: Consortium funded: further revision & review

• 2008/9: Operationalisation of projects

The ACT ConsortiumGoal: Develop and evaluate mechanisms to improve ACT delivery

ACCESS

TARGETING

SAFETY

QUALITY

Formative research, cluster randomised trials, cohort and

descriptive studies, impact evaluations, economic and

anthropological studiesACT Consortium 2007-2016

25 projects 10 countries

17 institutions

Four Research Themes• ACCESS: Poorest have worst access to malarial drugs

– How can this be improved ?

• TARGETING: Many ACTs used by people without malaria. – Implications for ACT cost-effectiveness, drug resistance, non-malaria

case management– How can ACTs be used more efficiently?

ACT Consortium 2007-2016

Four Research Themes• ACCESS: Poorest have worst access to malarial drugs

– How can this be improved ?

• TARGETING: Many ACTs used by people without malaria. – Implications for ACT cost-effectiveness, drug resistance, non-malaria

case management– How can ACTs be used more efficiently?

• SAFETY: Drugs may be licensed with data in ~6,000 people – Rare but important adverse events may not be detected pre-licensure– Need to consolidate safety profile eg repeat dosing, subgroups (eg

HIV), interactions (eg antiretrovirals)

• QUALITY: Substandard and fake ACTs– Weak systems for quality assurance in endemic countries

ACT Consortium 2007-2016

V E R Y D I V E R S E

NEED TO ENSURE RELEVANCE

Medicine

The ACT Consortium

R O SP J E TC

Social Science

Health Economics Statistics EpidemiologyC o r e S c i e n t i s t s

Secretariat

P R O J E C T S

Ad hocScientific Review

panel

The ACT Consortium

C o r e S c i e n t i s t s

Secretariat

P R O J E C T S

Review panel

Steering Committee

Directorate

Expert Oversight Committee

The ACT Consortium

C o r e S c i e n t i s t s

Secretariat

P R O J E C T S

Review panel

DS M

Bs

Steering Committee

Directorate

Expert Oversight Committee

The ACT Consortium

C o r e S c i e n t i s t s

Secretariat

P R O J E C T S

Review panel

D S M B s

SCALE

Synthesising & Communicating ACTc study results, Liaising with stakeholders, to produce Evidence-based policy and programmes

Quality Assurance

Steering Committee

Directorate

Expert Oversight Committee

The ACT Consortium

C o r e S c i e n t i s t s

Secretariat

P R O J E C T S

Review panel

D S M B s

SCALESafety Working Group

RDTs in Context Working Group Complex Interventions

Working Group

Non-Malaria Febrile Illness Working Group

Quality Assurance

Steering Committee

Directorate

Expert Oversight Committee

ACT Consortium 2007 – relevant today?

3 pillars:1. Ensure universal access to malaria prevention, diagnosis and treatment.2. Accelerate efforts towards elimination and attainment of malaria-free status.3. Transform malaria surveillance into a core intervention.

WHO Global Technical Strategy for Malaria 2016-2030 Endorsed by 2015 World Health Assembly

Action and Investment to defeat Malaria 2016-2030 (AIM) – for a malaria-free worldApproved by Roll Back Malaria Partnership board

Concrete targets to accelerate progress towards a malaria-free worldEncourages the development of tailored country programmes

‘Strategic Reserve’• Helps to maintain relevance & responsiveness of

consortium• Ring-fenced funding to:

– Tackle critical emerging needs – Enable rapid response to opportunities to add value to

existing projects e.g. ancillary studies of referral, new lines of work

Mapping the causes of non-malaria fever

www.wwarn.org/surveyor/NMFIInforming the development of guidelines for the

management of non-malaria fevers

Process Evaluations in Operational Research

Onwujekwe O, et al. Effectiveness of Provider and Community Interventions to Improve Treatment of Uncomplicated Malaria in Nigeria: A Cluster Randomized Controlled Trial. PLoS ONE 10(8): e0133832. doi:10.1371/journal.pone.0133832

If a strategy doesn’t work, make sure the evaluation can show where it broke down.

If it does work, identify

components critical to success!

A

B L A C K

B O X

31

Cross-consortium analysesHarmonised approaches, facilitated by a consortium data

repository, enable cross project, sector & country analyses:

- Explaining variation in RDT* uptake and compliance with results

- Understanding RDT impact on patient care including subsequent treatment-seeking, household costs and health outcomes

- Modelling cost-effectiveness of RDT introduction in private sector

- RDTs and malaria care in the peripheries of the Ugandan health system - comparison of RDT introduction in public, private and community health care settings

* RDT – Rapid Diagnostic Test for malaria

32

Emerging broad findings, and new questions

RDTs improve the targeting of ACTs* In all settings, fewer patients without malaria received an ACT Wide variation in the level of improvement across settings – analyses

ongoing

Not all patients with a positive RDT receive an ACTHow to balance reduced wastage of ACTs against missed treatments?

No evidence that RDTs improve individual health outcomesIntroducing RDTs does not appear to be harmful

Introducing RDTs increases the use of antibiotics

* ACT – Artemisinin-based Combination Treatment

CROSS-CUTTING FINDINGS DESPITE

DIVERSITY OF PORTFOLIO

Needs when starting a Consortium

• Experienced PIs sharing a common goal– Keep sight of the goal: don’t let academic/institutional rivalry get in the way!– Not just a funding mechanism

• Trust-based collaborations– Give credit where credit’s due

• Agree the decision-making mechanism from the outset• Co-ordinator, supporting an engaged executive committee

of senior investigators, or a directorate model

Needs when starting a Consortium (2)

• Invest in adequate, time-limited formative research• Build in adequate time & finance for analysis and writing• Build in capacity strengthening activities

– Good capacity strengthening requires good research • Ring-fence resources for strategic needs • Agree communications strategy - advocacy?

Policy Makers & Research Consortia• Involve them! Especially for operational research

– Challenge to get their time & thoughts, and to anticipate future operational challenges

– Essential first-hand experience of implementation issues and what will make a scalable strategy

• Important they are aware of the Consortium’s activities and ready to consider its results

• Beware - short half-life - may not be around for results! – Core group of policy-making stakeholders– Consider deputies rather than heads/directors – better availability

What’s needed for better policy, and for better practice?

• Good policy should consider robust evidence presented in a timely and unbiased way to an independent, mandated, decision-making mechanism

• Good research to improve practice should recognise– Operational challenges vary between settings: local research – involving local

implementers – is essential– A variety of approaches needed to develop & evaluate strategies– Potential for common truths to emerge despite diversity across contexts and countries

Know when to stop