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The RTS, S/AS Malaria Vaccine Candidate at the Pivotal Phase III Evaluation Stage

Source: TropIKA

Title of the session: The RTS, S/AS Malaria Vaccine Candidate at the Pivotal Phase III Evaluation Stage

Date: 6th November, 2009

Agenda item: Symposium 42: GSK-PATH

Session theme: GSK-PATH

Meeting room: Amphitheatre

Chair(s):

• Christina Lour, Director of the PATH-GSK partnership, (PATH MVI)
• Sophie Biernaux, Head of the Malaria Vaccine Initiative, GSK Biologicals

Presenters:

• Dr. Joe Cohen, Vice President of GSK Biologics, Co-inventor of RTS,S/AS vaccine
• Dr. Patricia Njuguna, Principal Investigator, Kilifi, Kenya
• Vasee Moorthy, Technical Officer, WHO Vaccine
• Alan Brooks, Director, Policy and Access

TropIKA rapporteur: Faith Apolot Okalebo

Major topics:

• Results of Phase 2 trials of the malaria vaccine
• The design of the Phase 3 study
• Scientific and Public Health considerations for Phase 3 efficacy trials of malaria vaccines in Africa
• Planning ahead for the first malaria vaccine: The path form development to impacting health

Keywords:

• Vaccine
• malaria
• GSK
• PATH
• clinical trial

Scope: Translational research on the potential vaccine for prevention of malaria

REPORT ON ORIGINAL SESSION

Overview

Though very effective drugs, vaccines and new interventions are developed, there is often a considerable delay before they are adopted in the management guidelines of individual countries. This problem can be avoided by involving public health officials in the design of clinical studies as well as and planning well in advance strategies for implementation of new innovations.

RTS, S/AS is a malaria vaccine candidate that is currently undergoing Phase III clinical trials in 11 African countries. RTS,S/AS is one of world’s most clinically advanced malaria vaccine candidate. It was developed by GlaxoSmithKine Biological (GSK) which partnered with PATH Malaria Vaccine Initiative to carry out the clinical studies. The vaccine is primarily aimed at infants and children aged less than five years. Development of the vaccine started in 1987. It contains an antigen, RTS which is a fusion protein fused with an antigen form Hepatitis B. It is produced from yeast cells by co-expression of RTS and HBs antigen. Phase II clinical trials have been carried out.

The ongoing Phase III clinical trial is unique because it was designed in consultation with health policy makers to incorporate outcomes that are of interest to public health policy makers such as potential impact on the all cause mortality and malaria related admissions. In addition the Phase III trial will evaluate the plausibility of administration with the EPI immunization schedules for children. To avoid delays in adoption of the vaccine, issues related to its financing, licensing and distribution are under discussion by the relevant health agencies at international, regional and country levels.

In this session, first speaker discussed the finding of the Phase II on the safety and efficacy of the vaccine. The next speakers talked about the capacity building efforts and the consultative meetings that took in order to facilitate the Phase III studies. The last speaker discussed ongoing policy discussions to facilitate the quick adoption of the vaccine by National Malaria Programs of African countries.

CONTEXT AND ISSUE

There are sometimes considerable delays in adoption of management guidelines on new drugs, vaccines and other interventions by individual countries. Reasons for this delay include lack of evidence of the impact of new interventions; and of indicators that are of interest to health policy makers. Often these indicators are not included in the outcomes of clinical trials. A second reason for the delay is lack of finance to implement the new intervention by the country disease management guidelines as well lack of prequalified manufacturing facilities from which to source the products. To licence new agents, regulatory agencies at country and regional level often require information that is often not available at the end of clinical studies. Many African countries rely on recommendations of the WHO and therefore an understanding of the decision making processes within the WHO is key to the design of strategies that will fast track the uptake of new technologies.

RTS, S/AS is a malaria vaccine candidate that is currently undergoing Phase III clinical trials in 11 African countries. The Phase III clinical trial is unique because it was designed in consultation with health policy makers to incorporate outcomes that are of interest to public health policy makers such as potential impact on the all cause mortality and malaria related admissions. In addition the Phase III trial will evaluate the plausibility of administration with the EPI immunization schedules for children. To avoid delays in adoption of the vaccine, issues related to its financing, licensing and distribution are under discussion by the relevant health agencies at international, regional and country levels.

Results of the Phase II clinical study on RTS,S/AS

A total of 11 studies were carried out. The main objectives were to determine the safety and efficacy of the vaccine; to determine the feasibility of integrating the vaccine in the EPI immunization schedules of African countries and finally to determine the optimal dosing schedule. In addition these, studies compared the efficacy of two vaccine adjuvants called ASO1 and ASO2. Studies were carried out in two age groups: 1 to 4 year olds and 5-17 month old infants. The efficacy studies were carried out in Kenya and Mozambique while safety studies were done in South Africa, Tanzania, Ghana and Gabon. A total of 8000 doses were tested in 300 children. The vaccine was found to be partially effective and reduced parasite prevalence. It conferred protection for 42 months and reduced the severity of clinical attacks of malaria in children. It is immunologically compatible with vaccines in the EPI schedule. The ASO1 adjuvant was found to be superior and was carried forward to the Phase III clinical trials. The antigen induced induced a strong antigen response in all age groups but the response waned with time. The safety profile of the vaccine was found to be superior to the rabies and equivalent to EPI vaccine. Fever was the most common adverse effect. The vaccine has no reactogenicity.

Public health expectations of a vaccine clinical trial and Regulatory approval process for clinical trials on vaccines

Planning for the Phase III clinical studies took 2 years in accordance with the WHO Policy Recommendations in the planning of Phase III trials a decision was made to consult a wide range of policy makers especially those involved in procurement and finance. Wide consultative meetings and consensus too place. Twenty five organizations were involved and the result of this process was a document on the Technical Guidance for the clinical trial (Vaccine, 2007). In addition to the scientific requirements for clinical studies, the requirements of policy makers, potential funders and procurement agencies were incorporated in the design of the clinical study. Monitoring and Evaluation Indicators of the impact of preventive strategies were incorporated in the study. Some of these indicators include all cause mortality, malaria related mortality and prevalence of severe malaria. The duration of follow up was prolonged and it was agreed that data analysis would be divided into time period of follow up. Issues such as a case definitions and extrapolation o f the funding were also considered.

A Joint Technical Expert Group (JTEG) was formed to advise WHO on clinical trial data required for registration of the vaccine in member countries. Since many countries rely heavily on WHO for treatment guidelines, the Group evaluated the Decision Making process in WHO, regional bodies and member countries in order to identify all the information requirements at all stages. The funding requirement of GAVI and UNICEF requirements for procurement of medicine were considered. The Group produced recommendations data that should come from the Phase III study that will accelerate pre- and post- licensure.

To fast track the process of obtaining regulatory approval in African countries where the trails were to be held, a WHO-led African Vaccine Regulators Forum was formed. The outcome of this initiative was the submission of a single regulatory application of the Phase 3 study. Since one of the objectives of the WHO Vaccine Department aimed at strengthening the capacity of African regulatory agencies to regulate clinical trials, a component of capacity building was added at this stage.

The Design of the Phase III study

The objectives of the Phase III study are to determine if the vaccine can protect from clinical disease especially for one year after administration. The secondary objectives are to determine the ability of vaccine to protect children from anemia and to reduce the rates of hospitalization. The effective duration of a vaccine will be determined and the role of a booster will be evaluated. Sub group analysis will be done to determine the effects of the vaccine on HIV positive and/or malnourished children. In addition the interaction will the rotavirus and pneumococcal vaccines will be evaluated.

The study design is a double blind randomized control trial. The studies will be carried out in 11 sites in Africa with different transmission patterns. Children will be divided into two age groups: 12 to 16 weeks old and 5 to 17 months old. Each age group will be divided into 3 study arms. One arm will receive a booster 20 months after the first vaccine is administered. A total of 16000 children will be recruited. At all sites the principal investigator is from the host country paired up with an international collaborator.

Capacity building was carried out before the studies. This involved upgrading of the diagnostic facilities, training investigators in GCP and GCLP and advance pediatric emergency care. Efficacy monitoring will be carried out.

Planning to promote access and implementation of malaria vaccines

The plan to fast track the malaria vaccine depended on the 30 years of experience of PATH (Program of Appropriate Technologies in Health). In summary, the quick adoption of any malaria vaccine is critical dependent on the following 5 principles:

1. START EARLY planning at the latter part of Phase II clinical trials. The clinical studies should be aligned with public health policies.
2. Planning ON WHAT? Planning should address all issues that are critical to the successful adoption of the new innovation. In the context of the malaria vaccine, these issues include:
   1. Commencement of formulation of Global Health Policies
   2. Regulatory requirements
   3. Sourcing for funding from relevant agencies such as GAVI and the Global Fund
   4. Identification of a WHO pre-qualified manufacturer who should have access to forecasted supply and demand information. A plant with capacity to manufacture the vaccine has already been identified in Belgium
3. WORK SYSTEMATICALLY by identifying issues that one has no control over and identify issue one can begin working on immediately. In this regard, action has been initiated with regard to Regulatory issues and global level policies.
4. WORK AT THE RIGHT LEVEL by involving all players in the following levels: Global, Regional and Country level. All decision makers have been identified and Malaria Vaccine Decision Making Frame Work (DMF) has been developed that involved all players. This framework has the support of African countries and there are ongoing efforts to sustain interest in DMF
5. BE TRANSPARENT by building bridges, sharing roles and maintaining mutual respect.

Some of the likely challenges to the implementation of the Malaria Vaccine policy are: the decreasing burden of the disease which may make the need of a vaccine obsolete; lack of knowledge on the incremental benefit partially effective malaria vaccine on currently preventive efforts; lack of Phase IV data on rare adverse effects; and the theoretical risk of increased delayed burden of disease.

Collaborating agencies

Very many agencies are involved and some of these include: JTEG, MALVAC, IVR Colleagues, EPI and QSS and IVB, WHO Global Malaria Programme and WHO AFRO

Public health Implications

The vaccine has potential to save life and to be adopted by National Malaria Control and Preventive programs. It is likely to reduce the malaria burden

Policy Impact

This approach in advance planning of implementation is likely to influence future policy processes and scientific innovation. The need of early planning for new interventions cannot be overemphasized. This is also likely to influence the conduct of clinical trials.

Translational Research Impact

This is likely to be great

From open discussions/debates

A participant asked why a partially effective vaccine is being promoted. The response was that there are many partially effective vaccines in the market and these still have some public health benefit.

Secondly someone asked why the implantation of this vaccine is being fast tracked yet there is lack of a lot of information of the immunological issues such as strain specificity and genomic issues. The participant was informed that parallel studies are going on to gain more inspect into action of the vaccine.

Personal observations from rapporteur

This session is a classical case of the scientist and policy makers working together and a paper should be written on this collaborative effort.

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