Simplifying and clarifying vector control product listing and policy guidance. May 14th, 2018

Transcription

1 Simplifying and clarifying vector control product listing and policy guidance May 14th, 2018

2 Context Last October, MPAC recognized recent progress, but requested that WHO continue to simplify the definitions and processes underlying its evaluation of new vector control products and product classes 2's aim is to share suggestions on how to incorporate this feedback, specifically as it relates to three questions: How could use of preferred product characteristics strengthen the evaluation process? How might doing so make product classification clearer, simpler and more consistent? How might WHO roles & responsibilities evolve with this type of approach? To prepare, we have gathered an array of perspectives from SRAs, developers, procurers, countries and donors, and synthesized them into a set of high-level findings The viewpoints expressed in this presentation are those of the i2i leadership team only and are not intended to represent specific opinions or endorsement of those consulted throughout this process 2

3 Confusion from external stakeholders around Class definitions, inclusion criteria, and epi requirements Roles and responsibilities across WHO for listing, policy and implementation activities Precedents set now may have far reaching implications for future product development 3

4 Preferred product characteristics How could use of preferred product characteristics strengthen the evaluation process? How might doing so make product classification clearer, simpler and more consistent? How might WHO roles and responsibilities evolve with this type of approach? 4

5 How How Why Why What What Should we be talking about target product profiles (TPP) or preferred product characteristics (PPC)? TPP owned and used by developer PPC owned by WHO's regulatory and normative bodies Technical, product-specific tool that summarizes a development program using labeling concepts High-level and "upstream" target and desired efficacy and safety thresholds for a new product class Focus and add stage gates to development efforts; structure interactions with regulators Help guide development of products within a class based on best available information at the time Dynamic summary predicated on developer's desired claims that changes along with knowledge of product Uses public health need and existing data; iterated on using trial results and modeling Focus of this section Source: Stakeholder interviews; BMGF materials; FDA materials 5

6 Example PPC for ivermectin Efficacy - Clinical & ento efficacy Efficacy related - Target population - Dosage and schedule - Formulation Safety - Safety profile Feasibility - Manufacturability - Shelf life Cost effectiveness - Cost per year of protection Registration - PQ evaluation Minimum" and "desired" thresholds for each category E.g., for ivermectin's desired ento efficacy: "n high to moderate transmission settings, at least 80% reduction in the entomological inoculation rate in intervention arm compared to control " Thresholds are preferred, not mandatory, and are intended to start dialogue and help inform applicant's TPP Meeting thresholds is not automatically grounds for a WHO policy recommendation Source: Stakeholder interviews; BMGF materials; GMP information note on endectocide for malaria transmission control 6

7 The case for using PPCs in vector control Stakeholder Developers and PDPs Potential benefits throughout the development process Clarifies data requirements and thresholds ncreases overall transparency and avoids moving targets Regulators Provides framework for early listing discussions Provides concrete decision criteria Policymakers Provides framework for early policy discussions Provides concrete decision criteria Funders dentifies trial requirements for appropriate and timely funding Provides concrete decision criteria Procurers and Countries Gives oppty to provide input on criteria informing purchasing Guides post-market analysis 7

8 Product classification How could use of preferred product characteristics strengthen the evaluation process? How might doing so make product classification clearer, simpler and more consistent? How might WHO roles and responsibilities evolve with this type of approach? 8

9 Main components of product evaluation Does product meet standards for safety, quality and efficacy? Pathway for new product class 1 2 Entomological efficacy, safety and quality thresholds for product listing Epidemiological thresholds to validate public health value of product class 1 st registration WHO PQ WHO policy guidelines NRA registrations Planning and Procurement Delivery and Access Surveillance and mpact Does product class have public health impact? s product worth paying for? How should it be implemented? Source: Adapted from BMGF E2E initiative 9

10 Regulatory function based around validating the label llustrative label categories Basic background info Efficacy Active ingredient(s) Mode of action Precautionary statements Physical and chemical hazards Directions for use nfo on label Target vectors and genera Entomological efficacy Efficacy against resistant strains Time to impact Duration nfo not on label Target disease(s) Epidemiological efficacy Cost effectiveness Class inclusion criteria generally based on entomological endpoints Developer can use claims to differentiate product from others in the class e.g. efficacy against resistant strains Label can be updated based on post-market data Source: Stakeholder and expert interviews; adapted from EPA Label Review Manual 10

11 Key to also distinguish between information needed for policy versus implementation guidelines llustrative questions during policy process Does the product class have demonstrable epidemiological impact and under what conditions? What is the anticipated public health value? At a high-level, do these data tell us anything about how and where class can be used most effectively? s there relevant evidence already available? llustrative questions during implementation How and where can product class be implemented cost effectively? How does it perform against different resistance profiles and transmission settings in the field? s the product performing as per its label claims? How does this impact procurement decisions? How does this impact use of other interventions? Pre-market (largely WHO/VCAG) Post-market (largely procurers, countries, PQ and VCTEG) 11

12 Potential go-forward guiding principles For product listing Claims and label should reflect entomological efficacy, safety and quality and be managed by PQ Applicants can use claims to differentiate a product within a class, e.g., efficacy against resistant strains Listing process should happen in in parallel to policy process PQ should have an active role in post-market lifecycle mgmt. For policy Epi data should validate public health value of new class or ento effect Products meeting class safety, quality and ento endpoints should be included under that class irrespective of specifications Policy guidance should be structured as pragmatically as possible; can be amended based on post-market data Cost effectiveness should be post-market and largely driven by implementers. Country-specific implementation questions should not bottleneck initial policy guidance Key to encourage collection of relevant data early on Potential for VCTEG to collate data across countries Need to assess where effectiveness trials will suffice post-market vs. RCTs 12

13 mportant to first align on key variables and their definitions Variable Delivery mechanism Our working definition How product delivers insecticide or makes contact with vector Examples Net, spray, fog, mosquito Entomological effect Nature, extent and speed of product's primary impact on vector Adult mortality, blood feeding rate Use case mplementation sites Forest, in home, outside of home Disease target Disease against which product is effective Malaria, dengue, filariasis Resistance Efficacy claims against resistant strains Efficacy in areas of pyrethroid resistance Mode of action How pesticide interferes with vector biochemistry Nerve and muscle or growth targets Active ingredient One or multiple chemicals that drive ento effect Pyrethroid, carbamate formulations Design specs ncorporation method, concentration levels, life of product PBO on surface of net vs. throughout 13

14 We propose using delivery mechanism and entomological effect to define a new product class Variable Delivery mechanism Entomological effect Use case Disease target f delivery mechanism and/or ento effect are novel, epi testing required to show public health value Novel use cases may require epi testing, but key to anticipate different use cases in advance and design TPP/PCC and first-in-class ento and epi trials accordingly (e.g., ATSBs inside vs. outside of house) Epi testing to assess impact on transmission of a new disease also may be helpful when practical Even if other variables are novel, they are superseded by delivery mechanism and ento effect With the need for new products increasing, we should accept initial policy guidance based on the "strength of predictability" rather than having to go "beyond any reasonable doubt" There may be unanswered questions about how a product actually works (e.g., sub-lethal effects, lack of ento-epi correlation) but they can largely be addressed post-market 14

15 Proposed algorithm begins to address MPAC feedback around simplifying and clarifying definitions and processes Variable Delivery mechanism Current approach (nets) Current approach (RS) Proposed approach SRA-style approach Entomological effect Use case Disease target Resistance Mode of action Active ingredient Design specs Must share in order to be considered part of existing class 15

16 Example: First-in-class ATSB Using current criteria Using proposed option Delivery mechanism? First-in-class (bait and kill) Delivery mechanism? First-in-class (bait and kill) Ento. effect? First-in-class Ento. effect? First-in-class Use case? First-in-class Use case? First-in-class Disease target? First-in-class Disease target? First-in-class Claims? Active ingredients? Design specs? First-in-class First-in-class First-in-class Considered new class Considered new class first-in-class already exists 16

17 Example: Second-in-class ATSB with different A and specs Using current criteria Using proposed option Delivery mechanism? Bait and kill Delivery mechanism? Bait and kill Ento. effect? Kill adult mosquitoes Ento. effect? Kill adult mosquitoes Use case? Outdoor Use case? Outdoor Disease target? Malaria Disease target? Malaria Claims? Active ingredients? Design specs? Resistance New A Different specs Considered existing class Considered new class first-in-class already exists 17

18 Example: Extending ATSB claims to a new use case and disease Using current criteria Using proposed option Delivery mechanism? Bait and kill Delivery mechanism? Bait and kill Ento. effect? Kill adult mosquitoes Ento. effect? Kill adult mosquitoes Use case? Disease target? ndoor Zika Use case? Disease target? ndoor Zika Evaluated on case-bycase basis Claims? Active ingredients? Resistance New A Potentially same class based on ento effect Design specs? Different specs Considered new class Key to anticipate scenarios in advance and design first-in-class product's TPP/PCC and ento and epi trials accordingly so as to avoid new rounds of epi testing, where possible first-in-class already exists 18

19 Example: PBO nets Using current criteria Using proposed option Delivery mechanism? Nets Delivery mechanism? Nets Ento. effect? Kill adult mosquitoes Ento. effect? Kill adult mosquitoes Use case? ndoor Use case? ndoor Disease target? Malaria Disease target? Malaria Claims? Active ingredients? Design specs? Resistance PBO added Diff incorporations Considered existing class Considered new class Procurers want to see efficacy against resistant populations, which should only require ento testing; 19 for PBO nets, epi testing helped PBO policy given paucity of ento data, but need to avoid this situation in future first-in-class already exists

20 Example: GR nets Using current criteria Using proposed option Delivery mechanism? Nets Delivery mechanism? Nets Ento. effect? First-in-class Ento. effect? First-in-class Use case? ndoor Use case? ndoor Disease target? Malaria Disease target? Malaria Claims? Active ingredients? Design specs? Resistance First-in-class (GR) First-in-class (GR) Considered new class Considered new class VCAG would assess public health value of the product class, not the specific product itself. GR + pyrethroid nets could be considered non-inferior to the pyrethroid only variant. first-in-class already exists 20

21 Roles and responsibilities How could use of preferred product characteristics strengthen the evaluation process? How might doing so make product classification clearer, simpler and more consistent? How might WHO roles and responsibilities evolve with this type of approach? 21

22 Post-market Pre-market Stakeholders need clarity on who does what PQ GMP/NTD MPAC/ STAG VCAG VCTEG Applicants Procurers/ mplementers Determine pathway R,A R,A C Validate ento thresholds R,A C, C, C, C, Listing Generate data C R,A Assess data; generate label R,A Validate epi thresholds A R C Policy Generate data C, C, R,A Assess data; make policy rec A R C Delivery Evaluate cost effectiveness Amend label (PQ) / policy (GMP/NTD) R,A R,A C, C, C, C R,A Key clarification / reallocation 22

23 Potential next steps Begin pursuing "quick wins" where there is alignment Clarify roles and responsibilities between PQ and GMP/NTD/VCAG nvestigate possibility using PPCs for vector control product classes Update terms of reference accordingly Similarly, where there is alignment, begin working on longer-term opportunities Clarify criteria for product classification, potentially by organizing stakeholder roundtable Define endpoints for each class and resistance parameters Update guidelines and test methodologies to reflect new tools and modes of action Clarify roles and responsibilities with respect to cost effectiveness Ensure that VCAG's collective thinking, where appropriate, feeds into broader GMP policy harmonization work 23