Report to the Board June 2016

Transcription

1 Report to the Board June 2016 SUBJECT: Reviewed by: MALARIA VACCINE PILOTS Programme and Policy Committee Agenda item: 09 - Appendices 1 & 2 Category: For Decision Strategic goal: SG1 - Underused and new vaccines Board-2016-Mtg-1-Doc 09 - Appendices 1 & 2 1

2 Report to the Programme and Policy Committee May 2016 SUBJECT: Report of: Authored by: Malaria vaccine pilots Aurélia Nguyen, Director, Policy & Market Shaping Judith Kallenberg, Head, Policy Agenda item: 10 Category: For Decision Strategic goal: SG1 - Underused and new vaccines Section A: Overview 1. Purpose 1.1 The purpose of this report is to update the PPC on the Malaria Vaccine Pilot proposal developed by WHO following SAGE/MPAC 1 recommendations in October 2015, and to seek a PPC decision on potential funding for the implementation of these pilots. Executive Summary 2.1 WHO estimates that malaria causes over 400,000 deaths a year, primarily children in Gavi-eligible countries in Africa. 2.2 Insecticide-treated nets, anti-malarial medicines, and indoor residual spraying are the cornerstones of malaria control, but they are unable to drive down malaria in some areas despite good coverage. In addition, all recommended interventions are insecticide- or drug-based, and emerging resistance threatens their effectiveness. WHO states that coverage with existing interventions should be further scaled up, while new tools are urgently needed to reduce the continued, unacceptable burden of malaria and address the threat of resistance. 2.3 RTS,S is the first 2 Malaria Vaccine to have received approval for licensure. 3 The vaccine, developed by GSK, showed 39% efficacy against malaria in children vaccinated with four doses in trials in Africa, when added to existing malaria control and prevention tools. The very high burden of 1 The Strategic Advisory Group of Experts (SAGE) and the WHO Malaria Programme Advisory Committee (MPAC) 2 Other malaria vaccine candidates are at least 5-10 years behind RTS,S and their prospects are uncertain. 3 The European Medicines Agency (EMA) in July 2015 issued a positive opinion, reflecting the quality of the vaccine and favourable risk/benefit balance from a regulatory perspective 1

3 malaria disease in some African settings must be taken into account when assessing the public health value of a vaccine. Impact modelling predicts that while efficacy, in percentage terms, is modest, the vaccine could avert approximately 484 deaths per 100,000 fully vaccinated children, or 1 life saved per 200 children The Board shortlisted the Malaria Vaccine in the 2013 Vaccine Investment Strategy and asked for an updated investment case following WHO recommendations, as the vaccine was still being tested. Following the conclusion of the trials, in October 2015, WHO recommended an initial rollout of the vaccine in large-scale pilots. Vaccination of approximately 360,000 children across three countries will enable a comprehensive assessment of the risk/benefit balance of the vaccine in a real-life setting, and inform considerations of broader use across Sub-Saharan Africa. In particular, the pilots would enable a better understanding of the operational feasibility of delivering 4 doses, of vaccine impact on malaria mortality and morbidity, and of overall vaccine safety in the context of a routine immunisation programme. 2.5 In December 2015, the Board advised that Gavi should engage in the WHOled process to prepare for the pilots, together with other potential funders, and requested to be presented with new information and findings from this collaboration at its next meeting. 2.6 At present, WHO has finalised its plans for pilot implementation, which which would run from in two phases and would be overseen by a Programme Advisory Committee with SAGE and MPAC members. The estimated total budget for the pilots amounts to US$ 101 million. The Bill & Melinda Gates Foundation (through a grant to PATH) and WHO have committed to contribute approximately US$ 8 million and US$ 17 million respectively. WHO is seeking funding from Gavi and UNITAID to cover a remaining funding gap in the budget, estimated at US$76 million, with US$55 million needed for Phase 1 ( ) and US$ 21 million for Phase 2 ( ). 2.7 The 6-year timeframe of the pilots is driven mainly by the mortality impact assessment, which requires longer follow-up of children having received 4 doses. However, sufficient data on feasibility and safety should already be available by 2020, which marks the end of phase 1. Provided that findings on feasibility and safety are favourable, pilot implementation would continue as per the proposed plan to generate required additional data on mortality impact. Should the Programme Advisory Committee consider that feasibility, safety and severe malaria data (as a proxy for mortality) show a clear benefit at an earlier stage, SAGE/MPAC could be convened to make a decision already in Penny MA, Verity R, Bever CA, Sauboin C, Galactionova K, Flasche S, et al. Public health impact and cost-effectiveness of the RTS,S/AS01 malaria vaccine: a systematic comparison of predictions from four mathematical models. Lancet. 2016;387(10016):

4 2.8 The PPC is asked to consider recommending a commitment for half of the required funding for the pilot phases 1 and 2 ( ), estimated at US$ 38 million; or for half of Phase 1 of the pilot ( ) only, estimated at US$ 27.5 million. These funding commitments would be contingent upon WHO securing funding from other sources to fully finance the pilot such as UNITAID.The Global Fund (GF) does not have a separate mechanism for this type of investment and therefore has not included the pilots in its replenishment ask. The GF has provided more than US$ 200 million for malaria control programs in the three pilot countries from Pending replenishment, the GF expects to continue these strong levels of support for the foundation of malaria control activities in the pilot countries. Gavi continues to engage with the GF in the pilot planning process. 2.9 WHO s detailed proposal is attached as Annex A. A letter of support from the external advisory group (including SAGE and MPAC members) 5 that oversaw the development of WHO s proposal is attached as Annex B Gavi support for the Malaria Vaccine pilots would be in alignment with its mission to accelerate the availability of life-saving new vaccines for children in developing countries. A joint investment with other agencies would reflect collective burden sharing for a public good, i.e. conclusive evidence of the value of a new malaria intervention, and would strengthen partnerships with other global health funders. According to WHO and supported by published literature on modelled impact estimates, the vaccine has the potential to prevent millions of cases of malaria. It also represents a scientific advance that can pave the way for the next generation of more effective vaccines. These benefits will need to be weighed against the opportunity cost of the investment, and risks, for example, relating to precedent-setting. A decision also requires consideration of the risk of inaction, such as potential termination of production if pilots remain unfunded and weakened incentives for public-private models aimed at product development for diseases that primarily affect low-income countries If the PPC recommends investment in the Malaria Vaccine pilots and requests an external review, this would be convened in late May - early June. The purpose of the review would be to provide an additional validation of the proposed implementation approach, focusing on organizational capacity, governance and management, and to confirm value for money. Separately, UNITAID will present the same WHO proposal to its Review Committee in May who will make a recommendation to the UNITAID Board in June External Advisory Group members: Prof. Peter Smith (London School of Hygiene and Tropical Medicine), Prof. Kate O Brien (Johns Hopkins Bloomberg School of Public Health ), Prof. Fred Binka (University of Health and Allied Sciences Ghana), Prof. Samba Sow (Center for Vaccine Development Mali), Prof. Nick Andrews (Public Health England), Prof. John Aponte (Barcelona Institute for Global Health) 3

5 Recommendations 3.1 The PPC is asked to consider to either (a) Recommend to the Board, subject to endorsement by the Audit and Finance Committee of any funds recommended for approval, using available resources from the current strategic period, and contingent upon WHO securing funding from other sources to fully finance the Malaria Vaccine Pilots, that it EITHER (i) Approve an amount of up to US$ 38 million (equivalent to half of the funding request) for the WHO-led Malaria Vaccine pilots to be implemented during , of which up to US$ 27.5 million is for Phase 1 of the pilots while the release of the remaining amount of up to US$ 10.5 million for Phase 2 is contingent upon successful completion of Phase 1. OR (ii) Approve an amount of up to US$ 27.5 million (equivalent to half of the funding request) for Phase 1 of the WHO-led Malaria Vaccine pilots to be implemented during AND (iii) Request the Secretariat to facilitate, in advance of the June 2016 Board Meeting, an external review of the Malaria Vaccine Pilot proposal, focusing in particular on organizational capacity, governance, management, and value for money. OR (b) Recommend to the Board not to invest Gavi funding in the Malaria Vaccine pilots at this time, but to continue to engage with WHO to monitor progress on pilot implementation. 4

6 Section B: Content The Malaria Vaccine 4.1 Dramatic scale-up of malaria control activities 6 in the past 15 years has significantly reduced the burden of disease, including a reduction of more than 50% in global malaria mortality. Despite this progress, malaria is still a leading cause of death. In 2015, WHO estimated that malaria caused 438,000 deaths, killing 1200 people per day, the far majority children in Gavi-eligible countries in Sub-Saharan Africa Existing tools, such as bednets and insecticide spraying, are highligy costeffective and have been the corner stone of progress achieved in the past 15 years. However, they are unable to reduce malaria in some areas despite good coverage. Moreover, all recommended interventions are insecticideor drug-based and emerging resistance threatens their usefulness. 8, 9 WHO states that coverage with existing interventions should be further scaled up, while new tools are urgently needed to reduce the continued, unacceptable burden of malaria and address the threat of resistance For decades, researchers and pharmaceutical companies have searched for a vaccine against malaria. The complex nature of this parasitic disease which enters the human body through mosquito bites, replicates in the liver and releases into the bloodstream where it can quickly cause organ failure, has created a formidable challenge in vaccine development. After many failed attempts over the past ~50 years, in 2004, for the first time, a vaccine candidate, the so-called RTS,S vaccine hereafter refered to as the Malaria Vaccine, demonstrated a measure of protection against malaria in children. In 2009, the manufacturer GSK in partnership with the PATH Malaria Vaccine Initiative with support from the Bill & Melinda Gates Foundation, began testing the vaccine in large-scale phase III clinical trials involving more than 15,000 children across seven African countries. 4.4 Trials concluded five years later and demonstrated that the vaccine was 39% effective in preventing malaria in children vaccinated with four doses. 11 When a child contracted malaria, whether vaccinated or part of the control group, they were promptly treated. Thus, because of the close follow up of the trial population and thanks to a high standard of care, mortality rates were low and the impact of the vaccine on malaria deaths could therefore not be assessed in the trials. It is critical to take into account the very high 6 Including widespread deployment of long-lasting insecticidal nets (LLINs), the use of indoor residual spraying (IRS) with insecticides, prompt diagnosis using quality-assured rapid diagnostic tests (RDTs) and treatment with artemisinin-combination therapies (ACTs). 7 World Malaria Report 2015, World Health Organization, Geneva Assessing the potential impact of artemisinin and partner drug resistance in sub-saharan Africa Slater HC, Griffin JT, Ghani AC, and Okell LC. 2016, Malaria Journal, 15:10 9 Imperial College analysis indicates that the spread of multi-drug resistance in sub-saharan Africa could result in anywhere from 10-70M additional malaria cases over a 5 year period. 10 Malaria vaccine: WHO position paper January 2016: The Lancet, Volume 386, No 9988, p31-45, 4 July

7 burden of malaria disease in some African settings when assessing the public health value of a malaria vaccine. Modest efficacy could lead to substantial impact in high transmission areas due to the high rate of malaria mortality in young children in these areas. Mathematical modelling by four independent groups suggests that in a real-life setting the vaccine may reduce child mortality from malaria by 10%-28%. 12 The vaccine could avert approximately 484 deaths per 100,000 fully vaccinated children, or 1 life saved per 200 children. 13 At a hypothetical price of US$5 per dose, this would put the vaccine in the category of highly cost-effective interventions 14, in the same range as other recently introduced vaccines such as pneumococcal and HPV vaccines. 4.5 In 2015, the Malaria Vaccine received a positive Scientific Opinion 15 from the European Medicines Agency (EMA) indicating that the quality of the vaccine and the risk/benefit balance are considered favourable from a regulatory perspective. As for any new vaccines approved by the EMA, post-approval studies are planned by the manufacturer to further characterise the safety and effectiveness of the Malaria Vaccine (see 6.2). 4.6 In October 2015, two independent advisory committees 16 advised that WHO lead the initial rollout of the vaccine in large-scale pilots in 3 to 5 settings. These pilots would enable the next step for the vaccine through an assessment of the operational feasibility of implementing a 4-dose schedule (3 doses of which are outside of the normal EPI schedule), and to evaluate the impact of the vaccine in a real life setting, as well as further characterise the safety profile of the vaccine. How has the Alliance been involved to date? 5.1 Individual Gavi Alliance partners, in particular the Bill & Melinda Gates Foundation (BMGF) have been closely involved in the development of the Malaria Vaccine. The BMGF has invested over US$ 200 million through PATH s Malaria Vaccine Initiative for activities up to the completion of Phase III clinical trials and an additional US$42 million thereafter, including ongoing support to PATH for activities related to the phase IV studies and for the 12 Source: For RTS,S/AS01: Penny MA, Verity M, Bever CA, et al. Public health impact and costeffectiveness of RTS,S/AS01 malaria vaccine: a systematic comparison of predictions from four mathematical models. Lancet All other vaccines: Estimated deaths averted per FVP over based on Gavi Strategic Demand Forecast v.11, 2014 impact analysis. 13 In comparison, HPV is estimated to avert 1600 deaths, HepB 972 deaths, pneumococcal 319 deaths, Hib 225 deaths, and rotavirus 153 deaths per 100,000 vaccinated persons. 14 The Commission for Macroeconomics and Health has classified interventions that gain a year of healthy life (i.e. a DALY averted) at a cost that is less than a country s GDP per capita as highly cost-effective. For a 4-dose schedule in moderate to high transmission intensity settings the cost per DALY would be less than US$ 100, well below the GDP p.c. of malaria-endemic countries. 15 The EMA provided this opinion under Article 58 of a European Community Regulation, which is a mechanism whereby the EMA may give a Scientific Opinion, in the context of cooperation with WHO, for the evaluation of certain medicinal products for human use intended exclusively for markets outside Europe. 16 The Strategic Advisory Group of Experts (SAGE) and the WHO Malaria Programme Advisory Committee (MPAC) 6

8 implementation of pilots. The Gavi Secretariat has been closely involved with GSK and PATH since 2012 to follow the development of the vaccine. 5.2 In 2013, the Gavi Board discussed the Malaria Vaccine for the first time, in the context of the 2013 Vaccine Investment Strategy (VIS). In the VIS, the Gavi Board considers the added value and cost of new vaccines for potential inclusion in Gavi s portfolio through a prioritisation exercise that is undertaken every five years. Impact estimates were highest for the Malaria Vaccine amongst 12 vaccines considered in 2013, and countries expressed strong demand for the vaccine in consultations. The Board shortlisted the vaccine, which at the time was still being tested, and asked the Secretariat to prepare an updated investment case following WHO recommendations after the trials. 5.3 Following the WHO recommendation for pilots 17, in November 2015, the PPC discussed options regarding Gavi s involvement in preparations for the pilots. Subsequently, in December 2015, the Board advised that Gavi should continue to engage in the process, led by WHO, in order to help design the pilots and to plan and coordinate next steps during the first half of It welcomed the collaboration with the Global Fund and suggested that Gavi also work in partnership with UNITAID. The Board requested to be presented with new information and findings from this collaboration at its next meeting. 5.4 Following the Board s guidance, the Gavi Secretariat s involvement over the past 5 months has been two-fold: (a) Jointly with UNITAID and the Global Fund, Gavi provided input to WHO on questions to be addressed in the pilots. In particular, the agencies suggested inclusion of an economic evaluation component to assess the incremental cost of delivering the vaccine, and an assessment of the effect of Malaria Vaccine administration on uptake of other recommended primary health care interventions. (b) Gavi and UNITAID provided guidance on the required information to be provided by WHO in its pilot proposal for review by their governance bodies. Malaria Vaccine Pilots overview Information in this section is extracted from the WHO proposal (Annex A) 6.1 The purpose of the pilots is to generate further evidence on the overall riskbenefit balance of the Malaria Vaccine to inform an updated WHO recommendation on potential wider use of this vaccine among children in sub-saharan Africa. 18 They will enable first-time use of the vaccine in real- 17 Malaria vaccine: WHO position paper January 2016, available at 18 Full information on the evidence base of WHO recommendations can be found in Malaria vaccine: WHO position paper January 2016, available at 7

9 life settings and thereby bridge the knowledge gaps currently inhibiting wider scale use of a tool with considerable potential public health impact. 6.2 Pilots would enable an assessment of a) programmatic feasibility of delivering a 4-dose Malaria Vaccine schedule requiring new immunization contacts; b) vaccine impact on malaria mortality and morbidity; and c) vaccine safety in the context of a routine immunization programme. (a) Programmatic feasibility. Pilots will assess what coverage can be achieved with the required 4-dose schedule; what is the effect on uptake of other vaccines, and of other recommended malaria interventions (coverage and behavior change); what is the incremental cost of delivery and budgetary impact for Ministries of Health. 19 Data will be collected through routine monitoring, household surveys, cost of delivery and budget impact studies and behavior change studies together with other assessment tools. (b) Impact of the Malaria Vaccine will be assessed by measuring its effect on all-cause mortality, malaria mortality, and hospitalisation for malaria. Data will be collected by village reporters and trained health workers who will conduct verbal autopsies to classify cause of death and through enhanced in-patient surveillance in sentinel and other hospitals. (c) Safety. As for any new vaccine approved by EMA, separate postlicensure ( Phase IV ) studies are planned by GSK to further characterise the safety of the vaccine. These studies will be about 10 times smaller than the pilots in terms of numbers vaccinated, and are likely to occur in the same countries as the pilots. Active surveillance, including home visits, increase the chances of detecting potential (rare) adverse events, which would not be possible in the routine-use settings of the pilots. The information generated in the pilots and Phase 4 studies will therefore be complementary and provide additional insight on whether this vaccine is associated with increases in meningitis, cerebral malaria and/or other adverse events following immunization. 20 In the pilots, safety data will be collected through routine pharmacovigilance reporting by vaccinating facilities and through enhanced in-patient surveillance in sentinel hospitals with advanced diagnostic tools. 6.3 Design. A parallel cluster-randomized design will be used. In each pilot country, 120,000 children are included in the Malaria Vaccine cluster and 120,000 in the comparison arm. The vaccine is introduced into Malaria Vaccine clusters at the start of the programme while introduction into comparison (control) areas is delayed. 19 The Malari Vaccine is expected to incur costs associated with vaccine introduction, while also averting costs associated with treatment that is no longer necessary. Understanding overall budget impact is critical to understand the value for money of this vaccine. 20 A higher number of meningitis and cerebral malaria episodes occurred in vaccine recipients in the Phase 3 trial compared with the control group. No causal relationship with the malaria vaccine has been established. 8

10 6.4 Pilot countries. WHO launched a public call for expressions of interest from Ministries of Health in sub-saharan Africa in December By January, ten countries had formally submitted written expressions of interest. SAGE/MPAC recommended pilot implementation in 3-5 settings. To minimise cost, WHO has selected the lowest possible number of countries that allows for a robust evaluation. Based on a range of selection criteria and following discussions with the relevant Ministries of Health, Ghana, Kenya and Malawi have been selected. 6.5 Implementation. Pilot vaccination will occur in the context of the routine EPI programme with Ministry of Health oversight. Doses 1, 2, 4 are new visits while the 3rd dose could potentially be administered together with measles vaccine. Different vaccination schedules and outreach strategies will be tested. Coverage will be monitored through standard administrative methods and household surveys. Pharmacovigilance systems will be strengthened in health facilities and sentinel hospitals. 6.6 Programme management. WHO would take the overall technical and scientific lead supported by PATH who would also be in charge of specific activities. 21 Within WHO, the programme would be managed jointly by the Directors of the Global Malaria Programme and of the Immunization, Vaccines & Biologicals Departments, with input from GSK and a Funders Forum, in which Gavi would participate should it become a funder. A Programme Advisory Committee (including SAGE and MPAC members) will monitor progress, and a Programme Safety Committee (comprised of safety experts, National Regulatory Authority representatives and others) will review all safety data on an on-going basis. In-country Co-Coordination Groups based in the Ministries of Health in pilot countries, will include: 1) a country coordinator appointed by the MoH, 2) the implementation team (including EPI, National Malaria Control Programme), 3) the in-country evaluation partner(s) contracted to execute evaluation activities, and 4) representatives from the National Regulatory Authority (NRA). These Co- Coordination groups would be supported by a dedicated WHO staff member in the WHO country office and by PATH staff on the ground. 6.7 Timelines. According to the WHO proposal, the total duration of the Malaria Vaccine pilots will be approximately 6 years, with two phases of approximately 4 and 2 years. If fully funded, preparations for the pilot rollout would take place throughout Vaccination and follow-up would start in 2018 and end by 2021, followed by a period of analysis and reporting which would end by Safety and feasibility results would be reported on an ongoing basis, while (mortality) impact data would only be available at the end of the pilots. The 6-year timeframe is thus driven mainly by the mortality impact assessment, which requires longer follow-up of children having received 4 doses. Sufficient data on feasibility and safety should already be available by 2020, which marks the end of phase 1. Provided that findings on feasibility and safety are favourable, pilot implementation 21 PATH will take the lead on Economic Assessments, Qualitative Assessment of Behaviour Change and external communications. 9

11 would continue as per the proposed plan to generate additional data on mortality impact. Should the Programme Advisory Committee consider that feasibility, safety and severe malaria data show a clear benefit at an earlier stage, SAGE/MPAC could be convened to make a decision in 2020 or earlier The Malaria Vaccine Pilot funding gap 7.1 The total budget of the WHO proposal for Malaria Vaccine pilot implementation for the period amounts to US$ 101 million (see Annex A). The cost of vaccines is excluded from this budget as GSK will donate all necessary doses to cover the needs of the pilot. In-kind contributions by pilot countries are also not included (e.g. frontline health workers, supply chains, supervision and information systems). Other estimated co-funding of the pilots by BMGF and WHO amounts to US$ 8 million and US$ 17 million respectively. This results in a pilot funding gap of US$ 76 million. 7.2 The malaria vaccine pilots are the last step in the process towards deploying the first malaria vaccine. Figure 1 below presents an overview of all investments in the Malaria Vaccine to date and planned future investments. Figure 1 RTS,S/AS01 malaria vaccine cumulative investments since 1984 Cumulative investments are illustrative and may not reflect precise cash flows. *Some co-funding contributions are not reflected, such as vaccine donations by GSK and in-kind contributions by pilot countries (e.g. frontline health workers, supply chains, supervision and information systems) Pre-clinical Clinical development Post-approval Pilot implementations funding gap: $76 million : BMGF funds for RTS,S (including interest) $237 million Co-funding contribution to pilots*: WHO: $17 million BMGF: $8 million $1bn $900m $800m $700m $600m $500m : ExxonMobil Foundation funds for RTS,S $1.3 million $400m : USAID funds for RTS,S $1.9 million $300m : GSK has invested over $365 million 1984 GSK team set up to find a malaria vaccine Start of the first research studies in adults in Africa Partnership established by GSK and PATH Proof of concept demonstrated in African children Phase 3 trials begin First results of Phase 3 trials published Source: WHO RTS,S/AS01 Malaria Vaccine Pilot Implementation Proposal; GSK; PATH; updated 26 April 2016 Additional future investment by GSK: >$ million* *excludes manufacturing investments $200m $100m Pilot implementations Phase 4 post-approval studies 2016 Decision on funding of pilots 2015 April: Final results of Phase 3 efficacy and safety trial published. July: EMA positive opinion. October: SAGE/MPAC recommendation for pilot implementations. 10

12 Rationale for investment This section discusses the rationale and other considerations for a potential Gavi investment, while section 11 outlines the risks of a potential investment. 8.1 Primary rationale: alignment with mission. A Gavi investment, jointly with other funders such as UNITAID, would enable the next step for a potentially life-saving new vaccine, by supporting the implementation of WHO-recommended pilots in Sub-Saharan Africa. If these pilots confirm the value of the vaccine, this would open the door for further scale up of a new preventative intervention against malaria, which remains one of the biggest killers of children in low-income countries. Modelling groups have predicted that the vaccine could avert approximately 484 deaths per 100,000 fully vaccinated children, or 1 life saved per 200 children. 8.2 Collective burden sharing and fostering R&D for diseases of the poor. As described in paragraph 5.1, the BMGF and PATH have funded part of the development costs of the Malaria Vaccine and continue to provide substantial financial support to ongoing activities. To date, GSK has invested over US$360 million and is expected to invest another US$ million to complete post-licensure studies as agreed with the EMA. Further, GSK will donate all doses of vaccine required for the Malaria Vaccine pilot. The manufacturer has announced publicly that it will not make profit off the Malaria Vaccine. 22 Thus, through an investment to support pilot implementation, Gavi, and potentially UNITAID, would join a range of public and private global health actors that have jointly invested to develop, test and pilot the first malaria vaccine for low-income markets. Such global commitments are necessary to sustain industry s willingness to engage in R&D for diseases that mainly affect the developing world. Other potential considerations include: 8.3 Strengthened partnership with global health funders. Collaboration benefits for the Alliance could include the opportunity to work in a unique partnership with UNITAID and potentially other funders, joining forces to advance the fight against a disease of shared concern. Funding agencies would be convened in a Funders Forum and, together with technical advisory groups, would provide critical guidance to WHO as the Malaria Vaccine pilots are implemented. The benefits of this collaboration could in future extend beyond malaria as agencies become more familiar with their respective systems and processes, and are able to identify areas of complementarity. 8.4 Evidence generation for coverage and equity. The Malaria Vaccine pilot could generate lessons with applicability beyond the three pilot countries and beyond the Malaria Vaccine. For example, as part of the feasibility assessment of delivering vaccine doses outside the current schedule, in 22 In 2010 GSK announced that it would make the vaccine available, upon widespread use, at cost plus a 5% mark-up with any profits being reinvested in research and development for next generation malaria vaccines and vaccines against other neglected diseases. 11

13 particular the 4 th dose during the second year of life, coverage optimisation strategies would be implemented (e.g. reminders through a community outreach system, the use of locally appropriate incentives, and other tools). This experience could enhance understanding of effective approaches to optimise vaccine coverage and equity, and of reaching children in their second year of life, which is relevant for example for measles and Meningitis A vaccination. 8.5 Benefits for research into improved malaria vaccines. In the medium term, learnings from the pilots will be directly beneficial to the assessment of a so-called fractional 3rd dose of RTS,S which showed promising results in early studies. 23 If confirmed, the greater efficacy could benefit the same population (young children), and contribute to the achievement of longer-terms goals for malaria elimination and eradication. As the fractional dose would build off the current RTS,S product, the development pathway and risks associated with approving this next generation version of the Malaria Vaccine would be substantially reduced. In addition, the new data from the pilots would provide critical data and information to help with the design of a larger scale fractional dose study, should proof of concept be achieved in Phase 2B. In the longer term, the experience gained during the pilots will benefit future malaria vaccines facing similar questions with regards to feasibility of a new dosing schedule and integration with other malaria interventions. Timelines for effective uptake could thereby be reduced. 8.6 Capacity building in pilot countries. As per the WHO proposal, the pilot is designed to sustainably contribute to capacity building and health system strengthening in pilot countries, which includes a PEF Tier 1 country 24. The the pilots would generate several benefits for the three countries involved in line with Gavi s strategic focus areas. For example 25, the pharmacovigilance systems in pilot countries would be evaluated and strengthened as necessary through support to the National Pharmacovigilance Center, trainings for health care workers and support to sentinel hospitals would be given, routine health information systems would be strengthened to improve information flow from health facilities to central level, and cold chain assessments would be updated in each pilot country and upgrades made as required. Relevant past experience. 9.1 Gavi has previously invested in implementation research and other pre- and post-licensure studies for new vaccines ahead of inclusion in Gavi s portfolio. To date, Gavi has invested approximately US$ 200 million in vaccine-related studies and pilots. This sections highlights key examples. 23 A delayed fractional 3rd dose of RTS,S showed a significant ~2/3 increase in efficacy in a small controlled human malaria infection challenge study in the United States and is currently entering a Phase 2 field trial. 24 Tier 1 represents countries with the highest numbers of under immunised children. 25 A full list of additional benefits for pilot countries is included in the WHO Proposal in section 1.2.a. 12

14 More details can be found in the December 2015 Board document on the malaria vaccine. 9.2 Gavi supports HPV demonstration programmes in countries wanting to introduce this vaccine. The demo, typically implemented in 1-2 districts over 2 years, serves to test implementation feasibility of delivering a vaccine to adolescent girls outside the routine immunisation schedule and to gain experience with effective delivery strategies to prepare for a national rollout. 9.3 Gavi invested over US$ 75 million in the Accelerated Development and Introduction Plans (ADIPs) for pneumococcal and rotavirus vaccines. At the time, these two vaccines were not yet recommended for use in developing countries and not part of Gavi s vaccine portfolio. The ADIPs supported clinical trials of rotavirus vaccines and effectiveness studies to assess the immunogenicity, safety, efficacy and effectiveness of pneumococcal and rotavirus vaccines in developing countries. Rotavirus vaccine had previously only been tested in and recommended for use in North America, Latin-America and Europe. Data from Gavi-supported trials in Africa and Asia informed WHO recommendations for use of the vaccine in the rest of the world, paving the way for the roll out of the vaccine in lowincome countries. In 2009, Gavi committed an additional US$60 million for assessments of the risk of pneumococcal serotype replacement, and assessments of safety related to rotavirus (intussusception), 26 amongst other studies. Gavi also supported the pilot rollout of a new pneumococcal vaccine, PCV10, in Kenya and Ethiopia, in conjunction with Phase IV studies funded by the manufacturer, to test the operational feasibility of delivering a new vaccine with different characeristics In 2013, the Gavi Board approved an investment in a learning agenda for cholera and rabies vaccines, which are not currently in Gavi s portfolio 28. The objective of the learning agenda investment (around US$6 million) is to address evidence gaps and inform consideration of potential Gavi support for these vaccines in the next VIS. Section C: Financial implications and Risk implication and mitigation Financial implications 10.1 The Malaria Vaccine Pilot would be implemented in two phases. The estimated costs of the first phase ( ) is US$ 55 million. If favorable data on safety and feasibility become available during Phase 1, this would 26 Rotavirus vaccines are associated with an increased (up to 6-fold) risk of a potentially fatal condition called intussusception after the first dose of vaccine in some populations. Initially, WHO recommended an age restriction for administration of rotavirus vaccines, given a potentially higher risk beyond the recommended age. Ultimately, in 2012, WHO removed the age restriction since the benefits of providing rotavirus vaccine to more children (including those that present beyond the recommended age range) far outweighed the risks. WHO recommends active surveillance of intussusception in countries that plan to introduce rotavirus vaccines. 27 PCV10 lacked a preservative and existing policies on the use of multi-dose vials did not apply 28 Gavi supports the global Oral Cholera Vaccine Stockpile for outbreak response but does not offer support for routine use of this vaccine through a country funding window 13

15 open the door for phase 2, during which the impact of the malaria vaccine on morbidity and mortality would be further evaluated. The remaining costs in phase 2 are estimated at US$ 21 million. A detailed breakdown of the budget provided by WHO can be found in Annex A While malaria has been flagged to the Board as a potential future investment for some time, an investment in malaria vaccine pilots was not included as part of the replenishment ask. Risks implications and mitigations 11.1 Opportunity cost. There is a risk that investment in the Malaria Vaccine pilots would limit Gavi s ability to make other future investments not currently included in Gavi s budget. To mitigate this risk, the burden of pilot funding would be shared with other funders, including potentially UNITAID, thereby limiting the amount that Gavi would invest to no more than US$ 38 million. It is expected that this amount can be absorbed in Gavi s overall budget for , subject to endorsement by the Audit and Finance Committee at its meeting on 4 May Setting a precedent. There is a risk that investment in the Malaria Vaccine pilots raises expectations about Gavi s engagement in other upstream work on (non-gavi) vaccines. This risk is mitigated by clearly communicating the rationale for Gavi s involvement in the Malaria Vaccine pilots, and by ensuring thorough assessment of any future requests for funding of similar implementation pilots Vaccine-related risk. Gavi s engagement in initial vaccine roll-outs that also aim to further characterize the safety profile of a vaccine could be perceived as high-risk. This risk is mitigated by clear communication of the relevant authoritative assessments: (a) The vaccine received a positive opinion from the European Medicines Agency (EMA), reflecting the quality of the vaccine and favourable risk/benefit balance from a regulatory perspective. 14

16 (b) Reviews by WHO s Global Advisory Committee on Vaccine Safety (GACVS) confirm that no serious or fatal adverse events have been related to malaria vaccination. 29 Although a higher number of meningitis and cerebral malaria episodes occurred in vaccine recipients in the Phase 3 trial compared with the control group, no causal relationship with the malaria vaccine has been established. The WHO proposal notes that the RTS,S safety profile will be considered in the context of overall vaccine benefit. Vaccines with serious associated adverse events have been licensed and implemented when those vaccines were considered to have benefits that substantially outweighed risks (e.g. rotavirus vaccine induced intussusception). The safety evaluation, together with the analysis of feasibility and impact will be considered in a comprehensive risk benefit analysis of RTS,S/AS01 vaccine. (c) As agreed with the EMA, GSK will further assess the vaccine s safety profile in the post-licensure period in studies that are being conducted concurrently to the pilots. Any data emerging from these studies will be shared on a regular basis with the relevant bodies involved in the conduct and oversight of the pilots. (d) Finally, the pilots have been designed to identify potential safety concerns early on, thereby minimising the risk for children in the pilot areas as well as for funding agencies and implementers. 30 The Programme Safety Committee will receive safety reports from both the pilots and the GSK Phase 4 studies on an ongoing basis. National pharmacovigilance centers in pilot countries will formally liaise with the Programme Safety Committee to ensure effective communication around country specific safety concerns and the Malaria Vaccine pilotwide safety review Expectations about a future Gavi funding window. There is a risk that investment in the Malaria Vaccine pilots raises expectations about future engagement in further scale-up of the vaccine, if recommended by WHO. This risk is mitigated by clearly communicating the time-limited and ringfenced nature of Gavi s support for Malaria Vaccine pilots, and that future Gavi support for a broader rollout would require separate Board decisions in 4 to 6 years time Premature transition from pilot to scale-up. In light of the high profile of malaria in many Sub-Saharan countries, there is a risk that political pressure for new malaria interventions could lead to a rush into broader scale-up. This risk is mitigated through clear and consistent communication around WHO s current recommendation. In addition, GSK has no plans to pursue 29 GACVS reports published in WHO s Weekly epidemiological records July 2015 and December 2015, 30 The vaccine will first be introduced in areas with highly capable sentinel hospitals where clinically significant safety signals can be assessed early and with a greater range of diagnostic tools. The routine pharmacovigilance system will be strengthened at health facilities located within the pilot implementation programme areas in order to capture any spontaneously reported vaccine-related adverse events. 15

17 registration countries that are not part of the pilot programme or Phase IV studies. Risk of inaction 11.6 Pilots do not proceed due to lack of alternative funding. To date, WHO has not identified alternative funding options beyond potentially Gavi and UNITAID. In the proposal, WHO explains that this vaccine highlights the fact that no well-established funding model exists yet for a vaccine developed primarily for low-income countries that has achieved a positive regulatory assessment but for which certain questions remain before widespread introduction in these countries can occur. WHO states that new vaccines and other interventions will increasingly need to demonstrate their added value in the context of a range of existing vaccines and disease specific control measures, often with implementation feasibility and safety questions remaining Termination of RTS,S vaccine production. It is unlikely that GSK would be able to maintain support for the manufacture of the Malaria Vaccine, including retaining a designated manufacturing facility, without assurance that the vaccine will be utilized in pilots in the near future Public-private product development model may lose momentum. Should manufacture of the vaccine end, the public-private partnership that brought this vaccine through phase 2 and 3 trials may be considered a failed exercise, and could be a disincentive to those companies and researchers engaged in or considering such partnerships to develop products aimed at resource-poor areas Related research for Malaria Vaccine follow-on products may end. Should the manufacture of the Malaria Vaccine be stopped, efforts that build on the RTS,S platform, including the promising use of a fractionated dose (see paragraph 8.5), will likely also be stopped Reputational risk. In 2014, the Board adopted a risk appetite statement in relation to Gavi s four strategic goals (SG1-4) and key functional areas. With regard to accelerating the uptake of new vaccines in lower-income countries Gavi has a higher risk appetite relative to other areas of work. Achieving rapid access to new, life-saving vaccines is at the heart of Gavi s mission. The Alliance is willing to be bold and take some risk in pursuing this important goal. If the Alliance decides not to invest in the malaria vaccine pilots this could be seen as inconsistent with its risk appetite in this area. According to the WHO proposal, no new malaria vaccine is anticipated to become available in the next 5-10 years, while all existing interventions are under threat by increasing drug and insecticide resistance. Failure to implement the pilot implementation programme, particularly in light of the 31 New vaccines are normally assessed in the post-licensure phase through surveillance systems in North America and Europe. The resulting post-licensure data provide country experience of implementation which is often critical for global policy-making. Those evaluations are typically funded by governments of high-income countries as a component of their on-going vaccine safety surveillance. 16

18 EMA positive opinion and the WHO recommendation, may be perceived by African heads of state, Ministries of Health, the media, and the general population as an indication of a lack of commitment to one of the most serious public health problems of African nations. Next steps 12.1 If the PPC recommends investment in the Malaria Vaccine pilots and requests an external review, this would be convened in late May - early June. The purpose of the review would be to provide an additional validation of the proposed implementation approach, focusing on organizational capacity, governance and management, and to confirm value for money. Scientific and technical elements will not require review as WHO has worked closely with an Expert Advisory Group 32 who have provided regular input during the proposal development. A letter of support from this group is attached as Annex B A report of the Gavi external review would be annexed to the Board document on Malaria Vaccine Pilots for its meeting on June. Due to the timing of the submission of the WHO proposal to Gavi and UNITAID on the 25 th of April it was not possible to convene the External Review Panel prior to the PPC meeting Separately, in mid May 2016, UNITAID will present the same WHO proposal to its Review Committee who will make a recommendation to the UNITAID Board in June Although these processes are set up separately by UNITAID and Gavi, the Secretariats of both agencies are closely coordinating and aligning their approach whenever possible. UNITAID and the Global Fund will be invited as observers to the malaria vaccine session in the Gavi PPC meeting Following the Gavi external review, the Secretariat would work with WHO and other funders to agree on a final budget amount for presentation to the Gavi Board in its meeting on June and the Boards of other funding agencies as relevant. Section D: Implications Impact on countries 13.1 Pilot countries Ghana, Kenya and Malawi are among the countries with the highest malaria burden worldwide despite relatively high coverage of bed nets. 33 All three countries have gained experience with the Malaria Vaccine through involvement in the earlier RTS,S Phase III trial. The burden of 32 The mandate and composition of this group, comprised of SAGE and MPAC members are detailed in the Terms of Reference available on MyGavi 33 World Malaria Report 2015, World Health Organization, Geneva,

19 malaria is highest in Ghana 34, followed by Malawi 35, while in Kenya malaria is concentrated in the area around Lake Victoria The Malaria Vaccine will be delivered through an expanded EPI schedule building on the routine EPI programme under the supervision of the Ministry of Health in the pilot countries. Prior to introduction of the Malaria Vaccine, pilot countries would receive technical support in order to strengthen data systems, cold chain logistics and overall country readiness to introduce the new malaria vaccine. Country programme managers, supervisors and health workers involved in pilot implementation would receive training While pilots would be limited to three countries, the benefits of generating the necessary evidence for a WHO policy recommendation on wider-scale use would extend to all countries in sub-saharan Africa where malaria continues to be a burden. Potential market impact 14.1 According to WHO the pilots are expected to provide insights into patterns of likely demand, uptake, programmatic requirements, etc. and therefore allow improved estimates of potential market size should the vaccine be recommended for broader use. This will enable more efficient planning of production which directly affects the future price of the vaccine given that GSK remains committed to offer RTS,S/AS01 at cost of production plus 5% mark-up. Impact on Gavi stakeholders 15.1 WHO, supported by PATH, would have technical and scientific leadership over the Pilot Programme. Additionally, PATH would lead on health economics evaluations and qualitative aspect of behaviour change evaluations Under a joint funding arrangement, Gavi would closely coordinate with other funders, potentially including UNITAID. Impact on Secretariat 16.1 The Secretariat would manage the grant to WHO alongside its other grants for special studies currently ongoing (e.g. Gavi s investment in studies to assess the programmatic feasibility of rabies vaccination). Additional resource needs are not currently foreseen for the Secretariat but would need to be re-assessed on an ongoing basis. 34 ~60% of infants live in areas with a malaria prevalence rate >30%, while all children live in areas with prelavance rate >10% 35 All children live in areas with a malaria prevalence rate between 10 and 30%. 36 three regions with a malaria prevalence rate between 15-25% and the remainder of the country <10% malaria prevalence rate. 18