overview of the transition, progress so far and normative ...overview of the transition, progress so...
TRANSCRIPT
Overview of the Transition, progress so far
and normative guidance
Dr Raman Velayudhan
Coordinator
Vector Ecology and Management
Dept. of Control of Neglected Tropical Diseases
World Health Organization, Geneva, Switzerland
Outline
• Transition
• GLP accreditation
• Vector Control Advisory Group
• Equivalence
• Future work..
GLP accreditation
GMP & NTD
October 2016 – Geneva, Switzerland
WHO Criteria for selection of countries & research institutions
1. Existing WHO collaborating institutions engaged on pesticide product testing and other potential research institutions
2. Geographical representation of sites
3. Diversity of vectors to be tested
• Susceptible
• Resistant
4. Feasibility to evaluate a range of pesticide products
5. Institutional commitment and resources
I2I grant GLP accreditation
WHO & IVCC sites for GLP accreditation
Region Site Products Phases
America
s
Brazil & any other Latin American institution (TBD) SS Larv 2 3
Centro Regional de Investigación en Salud Pública, Tapachula, Mexico IRS 2 3
Western
Pacific
WHO CC - Centre for Disease Control, Beijing, China Larv 2 3
Institute for Medical Research, Kuala Lumpur, Malaysia LLIN 3
SEA
LLIN IRS 1
WHO CC - National Institute of Malaria Research (NIMR), Delhi, India LLIN IRS Larv 1 2 3
WHO CC - Vector Control Research Centre, Puducherry, India LLIN IRS 2 3
Current testing capabilities:
West
Africa
Institut de Recherche en Sciences de la Santé (IRSS) Centre Muraz, Bobo Dioulasso, B.F. LLIN IRS 1 2 3
CREC, Cotonou (in collaboration with LSHTM), Benin LLIN IRS 1 2 3
Institut Pierre Richet (IPR), Institut National de Santé Publique, Cote d’Ivoire 1 2 3LLIN IRS
Centre Suisse de Recherches Scientifiques en Cote d’Ivoire, CSRS, Cote d’Ivoire LLIN 1 2 3
East
Africa
Kilimanjaro Christian Medical University College, Moshi, Tanzania LLIN IRS 1 2 3
Ifakara Health Institute, Bagamayo Research & Training Centre, Tanzania LLIN 2 3
Vector Control Research Unit, Universiti Sains Malaysia, Penang, Malaysia 2 3SS
Larv
IVC
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o l
ea
dW
HO
to
le
ad
IRS 2
Europea
n Larv
SS
WHO CC – IRD, Montpellier, France
SS
STEPS VCRC NIMR CCDC IMR VCRU IRD
Baseline facility audit / onsite inspection, gap audit
C C C C C P
GLP Training Workshop C C C C C P
Development of SOPs and Quality Management Systems
O O O O O P
Off site mentoring O O O O O P
Progress reporting (email / Skype) O O O O O P
Infrastructure improvements for GLP compliance purposes
O O O O O P
Training of Quality Assurance Manager P P P P P P
Self-audit P P P P P P
Development of GLP Training Manual C C C C C P
Follow-up visit for facility audit P P P P P P
ACCREDITATION PHASE
Capacity building for GLP Inspectors (GLP CP)
Application for GLP accreditation
First visit of GLP Body
Follow-up visit by GLP Body
Accredation Granted
FULLY ACCREDITED 7C =completed O= ongoing P = planned
Vector Control Advisory Group (VCAG)
on New Tools for Vector Control
GMP & NTD & PQ
October 2016 – Geneva, Switzerland
• Revision of TOR – functions:
• To assess the evidence for new vector control tools / approaches;
• To advise WHO on proof of principle of such tools;
• To discuss and finalize the Target Product Profiles;
• To advise WHO on product development plans including data requirements for accelerated recommendations.
• Membership – comprising of 2 groups:
• A core group of 7, including chair, term of 3 years
• A flexible group of experts (max 8) invited as needed
VCAG repositioning and scheduled activities
• Special meeting on vector control pathways (19 Sept 2016)
• As multiple new innovative tools & approached have been reviewed, there is need to map out pathways for new vector control products and expected evaluation methods
• Selected VCAG, MPAC and STAG members, plus other experts with experience in public health product development and evaluation
• Output: expert advice to WHO on data requirements for new tools/approaches in Vector control
• 5th VCAG meeting (2-4 Nov 16)• Focus – gene drive system (two ideas) and SIT for vector
control
• Update on progress for other tools already reviewed by VCAG
VCAG repositioning and scheduled activities
Paradigm
• Paradigm in vector control is a category of
intervention that share a common entomological
mechanism of action to reduces infection/ vector
borne diseases. Paradigm is the same as a class of
product category. It requires evidence of
epidemiological efficacy as a proof of concept to
confirm the product claim has impact on disease.
• A new paradigm requires a tailor made or specific
set of evaluation and guidance for deployment.
Steps
Pathway : LLIN Extension of claim to efficacy against insecticide resistance populations:
New types of mixture/combination LLINs NOT previously reviewed (WHOPES & VCAG) Outcome expected
1 Manufacturer undertakes pre-submission meeting
(participants: GMP, NTD and PQ)
2 Standard LLIN Efficacy (WHOPES Efficacy I / II), Safety and Specifications
3 Demonstrate claims of efficacy against resistant populations (Laboratory and small scale field
testing of IR claims – VCAG guidelines)
VCAG/ERG to assess the data
and the claim
4 Full demonstration of IR efficacy claims through field trials in areas of moderate to high
pyrethroid resistance. The end points will be:
1. Community RCT with epidemiological endpoints (comparing standard LLIN vs new
LLIN (PY + new AI) one season trial and
1. Entomological end points,
Proof of concept will require one trial, to validate the product does biologically what it claims
to do
VCAG recommendation on IR
efficacy
(PQ listing on product claim.)
5 Full demonstration of LLIN efficacy through large scale field trials (WHOPES Efficacy III ) PQ Dossier Review and
Listing (procedures and timing
defined by WHO PQ)
Potential Outcome Pathway
(1) VCAG endorses the proven efficacy claims against insecticide resistance (qualification of the claim, type of resistance mechanism
required); publication of assessment via VCAG report
(2) PQ listing and public assessment report leading to registration of products by countries
(3) WHO Disease programmes (GMP) recommends where and how such LLINs can be used / deployed and develops operational
guidance. Additional trial data may be needed for policy recommendation (gradual process)
(4) Final Step:- Policy recommendation to be considered by MPAC.
(5) Subsequent products in same category with resistance management claim will go through PQ for review
StepsPathway 3: New Intervention Concept – Biological
Wolbachia infected Mosquitoes specific for dengue/zika,
Outcome so far for
Wolbachia and Oxitec
1 Pre-submission meeting / Review LOI Completed
2 VCAG Initial Concept Review (Advice on any needed data for disease
programme policy making)
Completed
3 EAG/ERG to assess risk / safety and guide efficacy trials Completed
4 Entomological and Epidemiological efficacy data generated –
manufacturer generates data and dossier
Reviewed
5 Specifications / Quality control criteria developed In progress
6 VCAG Data Review for Concept (answers the question: is the
intervention effective against vectors? Against disease?)
(CRT starting in 2017)
Pilot deployment (with
conditions)
7 EAG for disease programme policy making (answers the question:
what (if any) place does the intervention have in vector borne disease
programmes?)
EAG/NTD
8 Policy Decision by WHO (advised by STAG)
Potential Outcome Pathway
(1) VCAG endorses the proven efficacy claims for the new intervention concept, publication of VCAG report
(2) WHO Disease programme (VEM/NTD) recommends where and how these interventions can be used /
deployed and develops operational guidance. Additional trial data and assessment via EAG may be
needed for policy recommendation.
(3) Final Step:- Policy recommendation to be considered by STAG.
StepsPathway :
New types of IRS AI previously not reviewed (WHOPES & VCAG) Outcome expected
1 Manufacturer undertakes pre-submission meeting
(participants: GMP, NTD and PQ)
2 Standard IRS Efficacy (WHOPES Efficacy I / II), Safety and Specifications
3 Demonstration of claims of efficacy against resistant populations
(Laboratory and small scale field testing of IR claims – VCAG guidelines)
ERG to assess the data and the claim
4 Full demonstration of IR efficacy claims through field trials in areas of
moderate to high pyrethroid resistance. The end points will be:
1. Community RCT with epidemiological endpoints (comparing
standard IRS vs new IRS and
1. Entomological end points (proof of concept),
Proof of concept will require one trial, to validate if the product does
biologically what it is supposed to do, based on which guidance on
deployment conditions will be issued
VCAG recommendation on IR efficacy
5 Full demonstration of IRS efficacy through large scale field trials
(WHOPES Efficacy III )
PQ Dossier Review and Listing (full)
Potential Outcomes
(1) PQ Interim Review, Listing and Public Assessment Report leading to country registration
(2) VCAG endorses the efficacy claims for the AI, publication of VCAG report
(3) PQ full review including efficacy against IR
(4) WHO Disease programmes (GMP) recommends where and how IRS can be used / deployed and develops guidance
(5) Final Step:- Policy recommendation to be considered by MPAC.
New Category Prototype
POLICY DEVELOPMENT PIPELINE
Step 1: Concept
Step 2: Efficacy (Ento)
Step 3: Efficacy
(Epi)
Risk Assess.
Specifi-cations
Policy Review
Opera-tional
Guidance
Resistance targeting
productsPermaNet 3.0 LN X X not applicable X X
MPAC
3 / 2015
ERG
9 / 2015
Microbial Control Wolbachia X X In progress ongoing ongoing 2017 2017
Spatial RepellentsTransfluthrin
passive emanatorX X In progress planning 2017 2017
Vector traps for disease
management
A LOT / TNK / AGO
/ In2TrapX X In progress planning 2018 2018
Systemic insecticides Rodent bait X X In progress 2018 2018
Lethal House LuresEave tubes and
bricksX X in progress 2019 2019
Genetic manipulationOX513A Aedes
aegyptiX X in progress ongoing ongoing 2017 2017
Attract and kill baitsAttractive Toxic
Sugar BaitX X
in progress
(IVCC)2019 2019
Insecticide treated
materials for specific risk
groups
none Xstalled due to
prototype
Overview: new vector control tools in process and predicted
timelines for policy development
Operational
Presubmission Guidance
(GMP/NTD/PQT)
• Based on LOI
– What is the label claim
– Data requirement
– Trial diversity (Geographic, vectors)
– QA assessment
– PQ dossier
– Does it need an ERG
– New paradigms –REFER to VCAG
– Robust and complete guidance including time line
Equivalency
October 2016 – Geneva, Switzerland
Objectives:
• To discuss outcomes of the WHO informational
session on determination of equivalence for
pesticide-based vector control products, 1–2
February 2016;
• To further understand the perspectives of pesticide
manufacturers on the current FAO/WHO
equivalence criteria and procedures; and
• To advise on the FAO/WHO criteria, procedures and
data requirements for determination of equivalence
for public health pesticide products.
LLINEvaluation parameters for reference
LN
Evaluation parameters for generic LN
Current criteria Changes proposed
1. Human exposure risk
assessment (HRA)
1. No HRA
requiredNone
1. Regeneration time
2. Wash resistance index (WRI)
for at least 20 laboratory
washes
3. Active ingredient chemical
content (within ±25% tolerance
limit of the specification)
4. For new AI with
knockdown/killing action:
- Intrinsic insecticidal activity
(lethal dosage; lethal
concentrations)
- Excito-repellent or irritant
properties
- Cross-resistance to other
insecticide classes/
mechanisms
- Discriminatory
concentration.
1. Regeneration time
2. WRI for at least
20 laboratory
washes
3. Chemical
content
1. The regeneration time
must be shorter or equal to
that of the reference LN.
2. The wash resistance index
should be same, as for the
reference LN.
3. Same specification for
chemical content (±25%) –
this involves parallel
comparison between
innovative versus generic
LN.
4. Conduct cone, and if
required tunnel test, on nets
washed at least 20 times
following the same wash
procedure as for
experimental hut trials. Use
existing efficacy criteria for
cone/tunnel test.
IRS
Evaluation parameters for reference IRS
products
Evaluation parameters for
generic IRS products
Current criteriaChanges
proposed
1. Human exposure risk
assessment (HRA)
1. HRA not
required1. None
Tests for the new AI with
knockdown/killing actions:
1. Intrinsic insecticidal activity
(lethal dosage; lethal
concentrations)
2. Excito-repellent or irritant
properties
3. Cross-resistance to other
insecticide classes/ mechanisms
4. Discriminatory concentration.
5. Efficacy and residual activity of
the formulated product on
relevant substrates (e.g. mud,
cement, wood).
6. Quality control testing of the
formulated product for
compliance with WHO/
manufacturer's specification.
2. None of
the tests
are
required
1. Comparative insecticidal
efficacy and residual activity of
the formulated product on
relevant substrates (generic
versus reference products).
Residual activity and efficacy of
generic products should be
same or longer than the
reference product.
2. Quality control testing of the
formulated product for
compliance with WHO/
manufacturer's specification.
Larvicides
Evaluation parameters for reference
mosquito larvicides
Evaluation parameters for generic mosquito
larvicides
Current criteria Changes proposed
1. Human exposure risk
assessment (HRA)
1. HRA not
required
1. None
1. Biopotency of the technical
material (lethal dosage and
concentrations)
2. Diagnostic concentration of
technical material
3. Cross-resistance to other
insecticide classes
4. Biological activity of
the formulated product.
5. Assessment of cross-resistance
1. No test
required
1. None
1. Efficacy under different
ecological settings
2. Method and rate of application
3. Initial insecticidal and residual
activity
4. Effect on non-target organisms
1. No test
required
1. Simulated efficacy
evaluation under
laboratory condition
2. Test 2, 3 & 4 not
required for generic
products
Thank you!
“Wolbachia could be a revolutionary form of protection against
mosquito-borne disease. It’s affordable, sustainable, and appears to
provide protection against Zika, dengue, and a host of other viruses.
We’re eager to study its impact and how it can help countries,” said Dr
Trevor Mundel, president of the global health division of the Bill and
Melinda Gates Foundation.
There are great hopes for Wolbachia but it is too soon to suppose this is the answer to the Zika and dengue epidemics. I’m in equipoise. I really hope it will work, but I’d like to see the evidence at scale.”
Jeremy Farrar, director of the Wellcome Trust
https://www.theguardian.com/international
26 October 2016