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

C t

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