Independent Review of Medicines for Malaria Venture ...siteresources.worldbank.org/EXTGLOREGPARPROG/Resources/...channel through which the DCG can support malaria drug development.

INDEPENDENT REVIEW OF MEDICINES FOR MALARIA VENTURE Annexes 1 – 11 Alan FAIRLAMB

Keith BRAGMAN

Hassan MSHINDA

Adetokunbo LUCAS – Team Leader May 2005 DFID Health Resource Centre 27 Old Street London EC1V 9HL Tel: +44 (0) 207 251 9555 Fax: +44 (0) 207 251 9552

Title: Independent Review of Medicines for Malaria Venture – Annexes 1 -11 Author: Alan Fairlamb, Keith Bragman, Hassan Mshinda, Adetokunbo Lucas

DFID Health Resource Centre 27 Old Street London EC1V 9HL Tel: +44 (0) 20 7251 9555 Fax: +44 (0) 20 7251 9552

ANNEX 1: UNITED NATIONS MILLENNIUM GOALS.........................................1

ANNEX 2: TERMS OF REFERENCE..................................................................2

ANNEX 3: BIO DATA OF TEAM MEMBERS ...................................................11

ANNEX 4: LIST OF PERSONS INTERVIEWED IN THE COURSE OF THE MMV REVIEW..................................................................................25

ANNEX 5: BACKGROUND ON MALARIA ........................................................26

ANNEX 7: GOVERNANCE OF MMV .................................................................33

ANNEX 8: THE PRODUCT DEVELOPMENT PATHWAY MODEL ..................37

ANNEX 9: GLAXO SMITH KLINE (GSK) COLLABORATION WITH MMV.......38

ANNEX 10: THE OZ 277/RBX 11160 SYNTHETIC ENDOPEROXIDE (TRIOXALONE) ...............................................................................40

ANNEX 11 TEMPLATE FOR FUTURE REVIEWS OF PD PPP EVALUATIONS.........................................................................................................46

Independent Review of Medicines for Malaria Venture – Annexes 1 -11 1

DFID Health Resource Centre May 2005

ANNEX 1: UNITED NATIONS MILLENNIUM GOALS

By 2015, all 191 United Nations Member States have pledged to: 1. Eradicate extreme poverty and hunger

• Reduce by half the proportion of people living on less than a dollar a day • Reduce by half the proportion of people who suffer from hunger

2. Achieve universal primary education • Ensure that all boys and girls complete a full course of primary schooling

3. Promote gender equality and empower women • Eliminate gender disparity in primary and secondary education preferably by

2005, and at all levels by 2015

4. Reduce child mortality • Reduce by two-thirds the mortality rate among children under five

5. Improve maternal health • Reduce by three-quarters the maternal mortality ratio

6. Combat HIV/AIDS, malaria and other diseases • Halt and begin to reverse the spread of HIV/AIDS • Halt and begin to reverse the incidence of malaria and other major diseases

7. Ensure environmental sustainability • Integrate the principles of sustainable development into country policies and

programmes; reverse loss of environmental resources • Reduce by half the proportion of people without sustainable access to safe

drinking water • Achieve significant improvement in lives of at least 100 million slum-dwellers,

by 2020

8. Develop a global partnership for development

www.un.org/millenniumgoals



ANNEX 2: TERMS OF REFERENCE

Medicines for Malaria Venture (MMV) Review, 2005 1. Background

The World Health Organization (WHO) estimates that there are 300-500 million clinical malaria episodes per year, with more than 1.5 million deaths. Malaria remains second only to AIDS in the attributable disease burden (around 45 vs 80 million DALYs per year). Children under five and pregnant women are most at risk, and every 30 seconds a child dies of malaria. In Sub-Saharan Africa, malaria is the leading cause of death for children under five years, accounting for 20% of all deaths. Effective prevention methods for malaria include: insecticide treated nets (ITNs) which can reduce under five deaths by about 20% and clinical episodes of malaria by about half; provision of intermittent presumptive treatment (IPT) for pregnant women within antenatal services, and in certain well defined settings, Indoor Residual Spraying (IRS) of insecticides (including DDT) along with environmental measures to reduce mosquito breeding. Significant developments in malaria treatment include artemisinin-combination therapies (ACTs), which provide a rapid cure and are an immediate solution to the problem of drug resistance. However, the scaling up of ACTs is threatened by inadequate global production capacity, and the fact that artemisinins are more costly than existing drugs. Access to all malaria treatments is hampered where health systems are weak. The 2000 Abuja targets are central to the achievement of the several Millennium Development Goals (MDGs) that relate to malaria (refer to Annexe). The achievement of these MDGs, the further reduction of the malaria burden beyond 2015, requires new innovative products and approaches. The Product Development Public Private Partnerships Donor Co-ordination Group (PD PPP DCG) was established in April 2004. The focus of the group is product development through public private partnerships with focus on diseases associated with poverty including HIV/AIDs, Malaria, and TB.The DCG goals are to: facilitate improved decision making of individual donors in the PD PPP field; encourage an increased number of donors to support the PD PPPs, and monitor and ensure follow up to the April 15-16 2004 PD PPP Financing Strategies meeting and the donor consultation that took place following it. The DCG key areas of focus include information sharing, policy analysis and advocacy. The DCG is supported by DFID, Wellcome Trust, Gates Foundation, Rockefeller, the Dutch, Irish, and the Swiss Agency for Development and Co-operation, as well as NORAD, CIDA, USAID and the NIH. PPPs have been established for HIV and non-HIV (e.g. malaria) product development.

MMV is a non-profit foundation dedicated to reducing the burden of malaria in disease endemic countries by co-ordinating and managing drug discovery development and delivery. MMV is one of the most well established PD PPPs, and currently manages the largest global anti-malarial drug portfolio. The foundation was established in November 1999, is based in Geneva, and is managed by its Stakeholders through a Board, a Chief Executive Officer (Dr Chris Hentschel) and three senior managers. MMV aims to produce new, affordable and appropriate drugs (anti-malarial and treatment) to areas of greatest need in the shortest possible time through partnerships between the public and



private sector. The initial (2000) intention was to create a portfolio capable of registering about one new anti-malarial drug every five years from 2010. Achievements to date include a portfolio of 21 projects with seven in the development phase of the research and development value chain.

The Intellectual Property Rights (IPR) relating to individual products are assigned to MMV (through contract agreements with inventors/partners) though more typically MMV requires a license which gives it freedom to operate in a manner consistent with its mission. It is a condition of partnering agreements that MMV obtains rights to the new drug(s) for public health use at an affordable price when used in developing countries (although a higher price to the travellers market is allowed). Total funding to date (pledged and received) is USD 113 million, as can be seen below.

Funders need to consider the length of time they wish to continue to support MMV given that there is no final output, as products require constant updating. While there have been individual donor evaluations of MMV these were mainly related to its ‘start up’ phase which was more dominated by portfolio creation and management issues. After five years of operations there are now critical issues emerging for MMV. In particular there are many more projects in (or just about to enter) clinical development than had been anticipated in 2000. This raises issues related to prioritisation of projects, refinement of the thinking about what drugs (indications) are most valuable to the malaria control community and particularly how product development, which is the most expensive phase, is going to be financed. This is happening in the context of a wider generic need to determine how to evaluate progress towards product development within PPPs and how to value portfolio progression in a consistent manner. This process will need to recognise that the actual end product can take many years to develop, and that attrition happens in pharmaceutical research and development. 2. Purpose

2.1 To conduct an external review of progress made by MMV since its inception. The

review should provide a retrospective analysis of what has been achieved to date



(best practice and lessons learned), and a prospective component that will inform and make recommendations for the broader field of PD PPPs .

2.2 To develop a template for conducting future PD PPP evaluations including review

process and a framework of key areas for consideration (indicators and performance metrics will be covered in a separate study) . This will enable harmonisation of evaluation requirements for the different funders allowing for a single report to reduce the organizational burden for both funders and PD PPPs.

2.3 To test out the Pathways model. 2.4 To determine if MMV is an effective PPP for developing drug research and the best

channel through which the DCG can support malaria drug development. 3. Scope of Work

3.1 Strategic direction: provide an overview of how MMV is meeting its current

strategic goals and the current processes for determining the strategic direction of the organization. This is likely to include,

3.1.1 What is the current context in which MMV is operating and what developments

are taking place amongst the other actors in the architecture’ surrounding product development PPP’s - This includes: • the funders of the R&D (DCG members and others) • other research organisations including DNDI, TDR, EDCTP, Pfizer • those setting and implementing medicines policy at international level as well

as at country level (e.g. WHO, EU, Ministers of Health) • those marketing and buying MMV commodities • technical developments since MMV was formed (e.g. progress in the use of

artemisinins and combined therapies) 3.1.2 Is MMV, demonstrating sufficient commitment to global policy goals? , What is

MMV’s relevance in achieving these goals? For example: • contribution to meeting MDGs • focus on poverty reduction via affordable end products • alignment with country processes e.g. early discussions on ethics, trials,

registration, access • capacity building • open governance including representation from developing countries • articulation of added value

3.1.3 What achievements has MMV made in respect to the original goals laid out at the

time the organization was formed? Against the goals laid out in the revised 2002 business plan? What has contributed to or hindered progress to date? What are the major challenges ahead (within current remit and outside current remit)?

3.1.4 Has MMV been more or less successful because it is a public private partnership

vs. a public or a private organization? What if anything has this allowed MMV to achieve that could not have otherwise been achieved?



3.2 Scientific progress 3.2.1 Assess the scientific progress of MMV since its inception. What have been the

major achievements? As MMV plans to enter late stage trials are the appropriate clinical/governance processes in place? Do the plans as currently formulated have adequate stakeholder involvement? Could MMV be doing more to increase its rate of scientific progress? (e.g. how could/should they engage further to speed up the development of artificial artemisinins?)

Note: The team are not expected to undertake a technical/scientific assessment of each project within the portfolio, rather provide an overview of `science’ and MMV, highlighting areas of science, which may need further in-depth evaluation. 3.3 Achievements in Operational effectiveness 3.3.1 Assess the current organizational structure, governance and effectiveness,

including roles and responsibilities, financing processes, accountability and reporting lines (internal and external).

3.3.2 Assess the make up and effectiveness of:

� MMV Board � ESAC � MMV internal organization How are key stakeholders represented within the current organization (basic research, private sector, donors, country level representation) and to what extent do they (or should they) influence decision making by the MMV Board?

3.4 Achievements in key processes in product development 3.4.1 How effective are MMV’s portfolio management processes in lowering risks of

the portfolio and creating knowledge and cost synergies across projects. What role does the ESAC play in supporting this process? How does MMV balance the risk profile of its portfolio (e.g. risk of projects vs. level of innovation)? How does MMV make decisions about the relative priority of projects in a resource constrained environment?

3.4.2 How effectively does MMV manage its current portfolio of projects, in particular in

relation to MMVs specific goals of: - Rigorous project selection and review process, - Adherence to mission-driven project guidelines and protocols, and - Access to external expertise and technologies to drive the added value

gained through portfolio management. 3.4.3 How effective and efficient is MMV in managing the partnerships on which it

relies? What factors contribute to the successful management of the partnerships? What opportunities are there for improvement?

3.4.4 Product supply, marketing and access:



How has MMV made changes to its approach to increase the focus on the deliver component of its tag line “discover, develop and deliver”. Does this work encompass social perspectives and broader development issues? How effective have these changes been? Is there a plan for how to get products to the market place? What else could MMV reasonably do in this area?

3.5 Application of the Pathways Model to MMV

3.5.1 Based on the framework developed as part of the DIFD Pathways study confirms

the current role of MMV and how it maps to this pathway. Determine if the pathway is a useful tool for illustrating the current role of MMV. What are the perceived strengths and weaknesses of the pathway as currently defined?

3.5.2 Should MMV continue with its current mandate, or are there further opportunities

to improve the quality of science, gain economies of scale, improve management, increase co-ordination and enhance advocacy by engaging further in other areas of the pathway or adopting a different organisational structure?

3.5.3 How effective is MMV in managing its relationships within the sector? Are there

opportunities to improve this? Could/should MMV do more to collaborate with other organizations within the Malaria field? Or more broadly?

3.6 Relationship with donors 3.6.1 Determine whether or not MMV is an effective aid instrument in comparison/co-

ordination with other instruments, i.e. • Has the creation of MMV made it more likely that new, affordable products

will be made available to poor people, and will the intention of producing one new anti-malarial drug every five years by 2010 be met ?

• Has the creation of MMV increased the absolute volume of resources (financial and human) dedicated to the discovery and introduction of new drugs for malaria? Can this increase in research volume be quantified in relation to resources prior to the establishing of MMV, and can it be predicted in the future? What implications do such changes have for MMV and other organisations involved in malaria R&D?

• What added value has MMV given to the quality of research and development for malaria drugs.

3.6.2 How effective/efficient are MMV in supporting the needs of current donors? How effective/efficient are donors in consulting and communicating these needs and are they harmonised between donors? Is there more that donors could do today in terms of the support they provide the organization? What could/should be the role of the bilateral agencies and smaller donors? How else beyond funding can donors provide MMV with support? For example: • Advocacy or policy advice • Management and technical advice • Finance application and reporting • Communications with MMV



3.6.3 Would there be benefit from a single reporting structure to donors? Given the range of interest/focus of today’s donors would one reporting structure be feasible? What recommendations would this team have for such a structure?

3.7 Financing Assess the current sources and projected future funding needs for the organization based on its transition from discovery of new products to a product development organisation. How do the cost projections compare with other available benchmarks? How sustainable is this given the current base of funders? What plans are in place to address funding needs, including exploring the use of novel supplementary funding mechanisms for R&D, such as the IFF or use of IDA loans. 3.8 A template for future reviews of PD PPPs 3.8.1 Propose a template for future evaluations including the process for the

development of TORs and scope of reviews, team make up and selection, involvement of the PD PPPs and feedback and output from reviews.

3.8.2 The team should not focus specifically on key indicators or metrics (these will be

developed in a separate study) however they should identify those metrics they observe during the MMV review if they would be appropriate for reviews and ongoing assessment of the PD PPPs. This work should include a summary of key questions by common areas that could form part of a review for a PD PP (expectation that the team would consult with the metrics/indicators study currently underway)

3.8.3 Identify any areas of future work not included in the scope of this review. 4. Methodology 4.1 Review of documentation (MMV internal documents, other key donor documents

including the DFID Global Health Partnerships Review, the DCG Pathway work, and external publications)

4.2 Interview MMV staff in Geneva, a selection of the 21 projects supported through

MMV, donor representatives, others within the field of malaria (e.g. EMVI, MVI, and Roll Back Malaria), interview any teams working on studies of public private partnerships (e.g. study commissioned by DCI) and other key international agencies.

4.3 At least one member of the team will be requested to observe a minimum of the

last two days of the next Expert Scientific Advisory Committee (27-28th January 2005) to enable an objective view of the value of the advice given, and judgements made, by the ESAC in relation to MMV. A special session could be arranged following the ESACs regular business to answer specific questions arising.

4.4 Some of the team will need to undertake several in country visits to gain a better

understanding of the relationship between the country level operations and the central MMV organization. Initial discussions highlight the site in Tres Cantos, Madrid where there is a mini portfolio of discovery projects and Delhi India where



MMV is working with Ranbaxy. (Depending on budget and timing it may also be appropriate to visit one of the clinical sites in Thailand).

4.5 For the future template of reviews, donor representatives, selection of PD PPP

personal from other disease/technology areas ( e.g. HIV/AIDs, TB, vaccines, e.t.c.) and other project teams or organizations currently tracking PD PPPs or developing indications (e.g. IPPPH, Gates funded indicator project metrics) should be interviewed.

5. Outputs 5.1 A retrospective and prospective narrative review of MMV 5.2 A template for future PD PPP evaluations (including value of Pathways) 6. Reporting 6.1. Part A

A narrative report of the review of MMV suitable for a broad range of audiences. The primary audiences will be current and future donors, and MMV and its board. It may also serve as a useful reference tool for other PD PPPs. For current and potential donors of MMV this document will be used to support donors who are making the case for ongoing/new funding for MMV. As such this report should provide sufficient background and understanding for readers who are not familiar with the operations of MMV. Report should include: • Executive summary, including key recommendations for donors and MMV (2-3

pages) • Main report (not more than 20 pages) • Supporting appendices as required

6.2. Part B

• Overview of how to’ conduct future PD PPP evaluations (2-3 pages) • short PowerPoint presentation for communication to donors (not more than 10

slides) to facilitate further discussions on joint reviews for the PD PPPs. 7. Timing 7.1 Work should be started in sufficient time for one/some consultants to be available

to observe the ESAC meeting 27-28 January 2005 7.2 Review is expected to take place between January 2004- March 2005 7.3 Draft report ready by the end March 2005 8. Organisational Arrangements



8.1 DFID will take the lead on managing the review which would include responsibility for finalizing TORs and working with the DFID resource centre to coordinate applications for the review team (check CVs, bring team together) and ensure the production of a high quality final report.

8.2 The Rockefeller Foundation through their support of the DCG will make available

up to 3 days of support from DCG secretariat 8.3 Additional contributions from other DCG members contribute TO BE

DETERMINED 9. Expertise 9.1 It is anticipated that the scope of work will require four consultants with a mix of the

following expertise and experience: i. Institutional and organizational design and analysis ii. Technical expertise in Malaria research and development iii. Understanding of PD PPPs iv. Industry experience in the process of pharmaceutical product development

and regulation v. Monitoring and evaluation of clinical research programs vi. Social development, particularly poverty and access issues

9.2 Team should ideally include a developing country researcher to be mentored in the process of evaluation of PD PPPs, potentially a Malawian researcher from the on-going malaria research programme in Blantyre

9.3 Resource Centre Responsibilities

• Provide assistance with selection and recruiting team members • Appoint Team Leader who will have final responsibility for production of the

evaluation report. • Manage day to day administrative and logistical aspects of the review • Manage the overall budget for the review, in liaison with DFID CRD and

Contracts Branch, with specific responsibility for invoicing for and disbursing team member’s travel and subsistence costs.

ANNEX Malaria and the MDG’s Goal: 1. Eradicate extreme poverty and hunger There is a high geographic correlation between poverty and malaria. its unremitting impact both causes poverty and is enhanced by it. Goal 2: Achieving Universal Primary Education. In high transmission areas malaria is a leading source of illnesses and absenteeism in school age children and teachers. CNS damage due to severe malaria effects subsequent cognition and learning. It additionally adversely affects universal education by impeding school enrolment and attendance,



Goal 4: The reduction of child mortality Malaria constitutes as much as 20% of total childhood mortality in highly endemic areas Goal 5: The improvement of maternal health Malaria cases are particularly severe during pregnancy and are a significant cause of maternal mortality. Severe debilitating anaemia often leads to low-birth weight babies that fail to thrive. . Goal 6: The combating of HIV/AIDS, malaria & other diseases Where case management is poor and does not involve modern effective drugs malaria morbidity and mortality are increasing. This is particularly true in Sub Saharan Africa. Goal 8: Development of a global partnership for development, including as a target the provision of access to affordable essential drugs Significant problems with access to affordable effective drugs are a deep-seated yet very tractable barrier to lowering the malaria burden. Source: MMV, Dec 2004 THE ABUJA TARGETS FOR MALARIA CONTROL (2000) 1. At least 60% of those suffering from malaria/fever will have access to and are

able to use correct and appropriate treatment within 24 hours. 2. At least 60% households in targeted districts will have at least ONE ITN 3. At least 60% of those at risk from malaria, particularly children under five years of

age and pregnant women will sleep under an ITN. 4 At least 60% of all pregnant women who are at risk of malaria, especially those

in their first pregnancy, will have access to chemoprophylaxis or IPT 5. At least 60% of the epidemic prone countries will have capacity to detect early

and respond appropriately to malaria epidemics.



ANNEX 3: BIO DATA OF TEAM MEMBERS Keith BRAGMAN Expertise: Clinical Pharmaceutical Development Born: 26 April 1949 Nationality: British Summary of Experience: • More than 15 years experience in senior management and leadership positions in

clinical pharmaceutical development. Currently an advisor to the industry and government sponsored institutions. These activities cover internal medicine with a focus on infectious diseases, haemato-oncology, immune based disorders and policy initiatives.

• Interests include the issues associated with the conduct of global clinical research and healthcare practice. A member of the Ethical Issues Committee, Faculty of Pharmaceutical Medicine, Royal College of Physicians of London; the Scientific Research Committee, European and Developing Countries Clinical Trials Partnership (EDCTP) and Chairman of the Ethics Working Party, European Forum for Good Clinical Practice.

• An advisor to a number of not-for-profit institutions including the Africa Centre for Health and Population Studies, South Africa; NIH/NIAID, Division of AIDS and the Adult ACTG, Washington DC, USA; WHO and UNAIDS, Geneva, Switzerland. A faculty participant on the “Ethical Issues in International Health Research” course held at the Harvard School of Public Heath, (June 2000, 2001 and 2002).

• Pioneered the pharmaceutical development of combination antiretroviral therapy with HIV-Protease Inhibitors and also specialised in experimental cancer chemotherapy.

• Originally trained as a biochemist and then read medicine at the University of London. An accredited specialist in haematology and completed his postgraduate training at St. Bartholomew’s Hospital, London, United Kingdom and the Cancer Research Institute, University of California at San Francisco, USA, prior to holding consultant responsibilities in haematology at Addenbrooke’s Hospital, Cambridge, United Kingdom.

• Has published in the fields of experimental chemotherapy for infectious diseases, haemato-oncology and immunology.

Education: 1999 FFPM, Fellow, Faculty of Pharmaceuticals Medicine, RCP, London, UK 1997 FRCP, Fellow, Royal College of Physicians (RCP) of London, UK 1995 FRCPath, Fellow, Royal College of Pathologists, UK 1984 MD Doctorate in Experimental Heamato-Oncology, Faculty of Medicine,

University of London, UK 1975 MBBS, Bachelor of Medicine and Surgery, University of London, UK 1970 BSc (Hons), Biochemistry, University of London, UK



Professional Accreditation and Licensure: • General Medical Council, UK, 1975 • Specialist Registrar, Haematology, General Medical Council, 1984 • European Union Specialist Medical Order in Haematology, 1996 Employment Record: Non-Executive Director/Independent Director, BruCells SA, 2003 – to date A biotechnology company developing cellular vaccines for the treatment of cancer

Biodevelopment Ventures, LP, New York, USA, 2003- to date Member of business and product development board

Member of Advisory Board, DiagnovIS, 2003 – to date A start up company developing diagnostics for infectious diseases recently formed from the Cambridge MIT Institute Limited. Head of R&D (Japan)/Director, Global Clinical Development, UCB SA, 2002 - 2003 Responsible for global clinical drug development, Phases I-IV, for the CNS (neurology and psychiatry) and Allergy therapeutic groups, clinical pharmacology, regional operations (Europe, USA, Asia-Pacific) and “R&D” Japan, a total of 220 people, managing a budget of approx �90M Chairman, Clinical Development Committee; Chairman, Concord Group (Pharmaceutical Development). Major Achievements: • Implemented benchmarking practices across the organisation to align UCB’s

development goals with world-class standards and simplified operating practices. • As Interim Head of the CNS Therapeutic Group, ensured the continuing support of

Keppra and implemented programmes for new compounds entering the clinic. • Re-organised the “R&D” group in Japan with improved efficiency and more highly

motivated teams with clearly defined responsibilities and goals. • Provided strategic support for business/licensing activities and identified new

therapeutic opportunities. Vice President/Senior Partner, Anti-infective Strategic Business Unit, Quintiles, Transnational Corporation, 1996 – 2002 Vice President and Senior Partner for Biotechnology, 2000 – 2002 Responsible for the biotechnology business across all therapeutic areas, focusing on oncology, haematology, infectious diseases and immunology. Consultant in pharmaceutical medicine to industry, advising on drug development programmes for regulatory purposes in the USA and European Union. Major achievements: • Provided expert guidance on drug development to Biotechnology companies • Advised Quantiles on strategic alliances with Biotechnology companies Vice President, Anti-Infectious Strategic Business Unit, 1996 – 2000 Responsible for building a specialised anti-infectious business unit. Consultant to pharmaceuticals and biotechnology companies in Europe, USA and Japan, with “P&L” reasonability for Europe. Member of the Quintiles Senior European Management Team.



European Head of Clinical Virology (Therapeutic Group Leader), Hoffmann-La Roche, 1989 n- 1995 Leading the global clinical development of the first HIV-Protease Inhibitor, InviraseTM

Responsible for building the European team for the development of HIV-protease and reverse transcriptase inhibitors for the treatment of HIV-infected individuals. Major achievements: Successfully developed the first HIV-protease inhibitor, invarase, from ‘proof of principle’ to market approval; leading the global clinical team and obtaining FDA (USA) and CPMP (European union) approvals in 1995 – 1996 respectively. Pioneered combination antiretroviral therapy with invirase Represented Roche with institutions including who, Geneva, Switzerland; MRC UK and ANRS France; adult aids clinical trials group, USA and patient advocacy groups

Director and European Head of Clinical Oncology, Bristol-Myers Squibb, 1986 – 1989 Responsible for the management of clinical programmes in oncology and haematology in Europe. Major Achievements: • Developed novel cytotoxic drugs in collaboration with the EORTC Early Drug

Development office at the Free University of Amsterdam, Netherlands. • Successfully completed the European Phase III work and presented the results of

the Paraplatin programme to the FDA Oncology Advisory Committee in 1988. Other Professional Activities: • Chairman of the Ethics Working Party, European Forum for Good Clinical

Practices, 2004 – to date • Member of the Ethical Issues Committee, Faculty of Pharmaceutical Medicine,

Royal College of Physicians of London, 2001 – to date • Faculty Member, “Ethical issues in International Health Research” course, Harvard

School of Public Health, 2000, 2001 & 2002 Advisor to not-for-profit institutions:

- Africa Centre for Health and Population Studies, Mtubatuba, South Africa, 2004

- European & Developing Countries Clinical Trials Partnership (EDCTP Scientific Research Committee, HIV Section, 2004

- National Institute of Allergy and Infectious Diseases (NIH/NIAID), Division of AIDS, Bethesda, Smart Clinical Trial Programme Review, 2004

- The Adult AIDS Clinical Trial Groups (ACTG), Washington DC, USA, 2001

- World Medical Association, University of Pretoria, South Africa, 2001 - WHO, 2000, and UNAIDS, Geneva, Switzerland, 1999 - Fogarty International Centre for Advanced Healthcare Studies, NIH, USA,

1999 Languages: Speak Read Write English Mother tongue Excellent Excellent



Alan FAIRLAMB Expertise: Drug Research Born: 30 April 1947 Nationality: British Summary of Experience: • Career Research primarily devoted to the development of better treatments for tropical

parasitic diseases through a comparative study of the biochemistry and molecular biology of parasites and their hosts.

• Studies on the mode of action of existing drugs and experimental compounds and the mechanisms by which parasites acquire resistance to these agents resulted in the discovery of trypanothione (N1, N8-bis(glutathionyl)spermidine). This metabolite is unique to trypanosomes and leishmania and represents an attractive validated target for rational drug design.

• Current research aims to elucidate the roles and functions of trypanothione in trypanosomatid metabolism and to validate other potential chemotherapeutic targets using a variety of molecular genetic and chemical approaches.

• Also has an interest in bioinformatics applied to parasite genomics, particularly in the construction of 'metabolomes' as a tool for the discovery of new potential drug targets for drug discovery against malaria, African trypanosomiasis, Chagas’ disease and the leishmaniases.

• Particular Malaria experience includes: o Development of improved cultivation techniques for Plasmodium falciparum o Isolation and characterization of haemozoin (malaria pigment) o Carbohydrate metabolism, electron transport and energy metabolism o Mode of drug action (chloroquine, artemisinin and cyclosporin A.) o Measurement of intracellular pH in malaria infected red blood cells by 31P

NMR o Molecular structure and reaction mechanism of cyclophilin o Fatty acid metabolism in the apicoplast o Regulation of gene expression by histone acetylation

Education & Qualifications: 1975, PhD in Biochemistry, University of Edinburgh Medical School, UK 1971, MB, ChB, Medicine, University of Edinburgh Medical School, UK 1968, BSc (Med Sci) Hons, Biochemistry, University of Edinburgh Medical School, UK

Scientific Advisory Boards & Committees 2003 WHO/TDR Chemotherapy Portfolio Review Steering Committee (Chair) 2003 DNDi Scientific Advisory Committee (TDR representative) 2003 RSE Sectional Committee A4, Cell and Molecular Biology (member) 2001 - WHO/TDR SWG Genomes to Drugs (member) 2000 E.C. INCO-DEV grant committee (expert adviser) 1999-2002 WHO/TDR Drug Discovery Research Steering Committee (Chair)



1998 WHO SWG: Strategies for Drug Discovery Research (temporary adviser) 1996-1999 MRC, Physiological Medicine and Infections Board (member) 1995-1999 Burroughs Wellcome Fund Advisory Committee (member) 1994 WHO Stimulating R&D into Medicines for Developing Countries (temporary

adviser) 1993-1996 Wellcome Trust, Genetics Interest Group (member) 1993 WHO Immal Task Force on Antigens as Vaccine Candidates (temporary

adviser) 1991-1996 Wellcome Trust, Infection and Immunity Panel (member) 1991-1994 Wellcome Trust, Tropical Medicine Interest Group (member) 1991 WHO Macrofil SWG: Targets for New Macrofilaricides (temporary adviser) 1990-1993 WHO Steering Committee on Integrated Chemotherapy for

Trypanosomiasis, Leishmaniasis and Chagas' Disease (member) 1989-present Member, Kenneth S. Warren Laboratories, New York, USA (formerly Drug

& Vaccine Development Corporation) 1987-1991 WHO Joint Steering Committee on Chemotherapy and Immunology and

Pathology of the SWG on African Trypanosomiasis (member and chair)

Current Research Funding: WELLCOME TRUST (042368/Z/94), 1996 – 2006 (£2,533,583) Biochemistry and chemotherapy of parasites Principal Research Fellowship: salary support for 10 years; programme grant support for 1996-2001 WELLCOME TRUST (042368/Z/97/B), 2002 – 2006 (£1,125,356) Identification, molecular characterization and validation of metabolic drug targets in protozoan parasites Programme support for Principal Research Fellowship WELLCOME TRUST / BURROUGHS WELLCOME FUND (059056/Z/99/Z), 2001 – 2005 (£173,939) Clinical response and resistance to antimonial drugs in Leishmania This is part of a larger collaborative grant (Infectious Disease Initiative) to Dr N G Saravia (PI: Mexico) with co-applicants Prof G H Coombs (Glasgow), Prof M Ouellette (Canada), Prof P M Rainey (USA) and Prof B Rosen (USA). WELLCOME TRUST (065523/Z/01/A), 2002 – 2005 (£42,468) Fatty acid biosynthesis as a chemotherapeutic target in malaria parasite 4-year studentship programme for Sasala Wickramasinghe DRUGS FOR THE NEGLECTED DISEASES INITIATIVE, 2004 – 2005 (£45,821) Validation of DHFR-TS as a drug target in African trypanosomes Collaborative grant with Professor S. Beverley (Washington University, St Louis, USA) and Dr J.K. Stiles Morehouse School of Medicine, USA) DRUGS FOR THE NEGLECTED DISEASES INITIATIVE, 2004 – 2005 (�120,000) HTS against trypanothione reductase for new drug-like molecules Collaborative grant with Professor J. Clardy (Harvard University



Recent Seminars / Conferences 2004 09-10/01/04 TriTryp Genome Annotation Meeting, Hinxton Hall Conference Centre, Cambridge 22-23/01/04 Target Validation Conference, Royal Garden Hotel, London. Conference

Chair. Lecture: Drug Discovery for Tropical Diseases at WHO 02-06/02/04 WHO - SWG Meeting on Leishmaniasis, Geneva. Expert advisor. 12 -14/03/04 School of Life Sciences Annual Retreat, Crieff. Session Chair. 24/03/04 London School of Hygiene and Tropical Medicine. Meeting with Simon Croft

and Susan Thomas to discuss DNDi research projects. 28/03-02/04/04 WHO/CPRC meeting in Geneva. Meeting Chair. 06-07/05-04 DNDi Scientific Advisory Committee meeting in Geneva. 08-10/07-04 Fifth meeting of the Working Group on Genome to Drugs and Diagnostics,

Boston USA. Committee member. 13-16/09/04 Scientific Advisory Committee – TriTryp Genome Meeting, Seattle, WA 4-5/10/04 DNDi Scientific Advisory Committee meeting in Geneva. Member 2003 12-14/01/03 Enzyme Mechanism - A structural Perspective. University of St Andrews.

Participant. 16-17/01/03 WHO/TDR Screeners Meeting in Geneva. Committee member. 23-24/02/03 Structural Genomics and Target Selection Meeting - Hinxton Hall

Cambridge. Advisor. 17/03/03 Royal Society of Chemistry Meeting, Edinburgh. Research and the

Biology/Chemistry Interface. Invited participant. 28- 31/03/03 School of Life Sciences Annual Retreat, Pitlochry, Perthshire. Lecture:

Trypanothione metabolism as a chemotherapeutic target in trypanosomes and leishmania.

7-11/04/03 WHO/CPR and DNDi Committee Meetings in Geneva. Meeting Chair. 15-16/05/03 Eimeria Genome Consortium Meeting in Wantage, Oxon. Lecture: Utilizing genomes for drug discovery. 2-4/06/03 Tri-Tryp 2003 Meeting on Genome Sequencing at Hinxton Hall,

Cambridge. Lecture: Discovery of drug targets in the post-genomic era. 2-3/10/03 DNDi Scientific Advisory Committee meeting in Paris. Advisor 5-6/10/03 MRC Workshop, Royal College of Physicians, London. Participant Workshop on Translation of Academic Malaria Research into New

Products 3-6/12/03 ASTMH 52nd Annual Meeting in Philadelphia Lecture: The mode of action of antimonials against Leishmania donovani

– a double-edged sword Most Recent Publications Hamilton, C.J., Saravanamuthu, A., Eggleston, I.M. and Fairlamb, A.H. (2003) Ellman’s

reagent mediated regeneration of trypanothione in situ: Substrate economic microplate and time-dependent inhibition assays for trypanothione reductase. Biochemical Journal, 369: 529-537.



Chibale ,K., Visser ,M., van Schalkwyk, D., Smith, P.J. Saravanamuthu, A. and Fairlamb, A.H. (2003) Exploring the potential of xanthene derivatives as trypanothione reductase inhibitors and chloroquine potentiating agents. Tetrahedron Letters, 59: 2289-2296. Aliberti, J., Valenzuela, J.G., Carruthers, V.B., Hieny, S., Andersen, J., Charest, H., Reis e Souza, C., Fairlamb, A., Ribeiro, J.M. and Sher, A. (2003) Molecular mimicry of a CCR5 binding-domain in the microbial activation of dendritic cells. Nature Immunology, 4: 485-490. Zani,C.L. and Fairlamb, A.H. (2003) 8-Methoxy-naphtho[2,3-b]thiophen-4,9-quinone, a non-competitive inhibitor of trypanothione reductase. Memorias do Instituto Oswaldo Cruz, 98: 565-578. Sarkar, M., Hamilton, C.J. and Fairlamb, A.H. (2003) Properties of phosphoenolpyruvate mutase, the first enzyme in the aminoethylphosphonate biosynthetic pathway in Trypanosoma cruzi. Journal of Biological Chemistry, 278: 22703-22708. Alphey, M.S., Gabrielsen, M., Micossi, E., Leonard, G.A., McSweeney, S.M., Ravelli, R.B., Tetaud, E., Fairlamb, A.H., Bond, C.S. and Hunter, W.N. (2003) Tryparedoxins from Crithidia fasciculata and Trypanosoma brucei: photoreduction of the redox disulfide using synchrotron radiation and evidence for a conformational switch implicated in function. Journal of Biological Chemistry, 278: 25919-25925. Ariyanayagam, M.R., Oza, S.L., Mehlert, A. and Fairlamb, A.H. (2003) Bis(glutathionyl)spermine and other novel trypanothione analogues in Trypanosoma cruzi. Journal of Biological Chemistry, 278: 27612-27619. Oza, S.L., Ariyanayagam, M.R., Aitcheson, N. and Fairlamb, A.H. (2003) Properties of trypanothione synthetase from Trypanosoma brucei. Molecular and Biochemical Parasitology, 131: 25-33. Hamilton, C.J., Saravanamuthu, A., Fairlamb, A.H., Eggleston, I.M. (2003) Benzofuranyl 3, 5-bis-polyamine derivatives as time-dependent inhibitors of trypanothione reductase. Bioorganic & Medicinal Chemistry, 11: 3683-639 Vickers, T.J. and Fairlamb, A.H. (2004) Trypanothione S-transferase activity in a trypanosomatid ribosomal elongation factor 1B. Journal of Biological Chemistry, 279: 27246- 27256 Saravanamuthu, A., Vickers, T.J., Bond, C.S., Peterson, M.R., Hunter, W.N. and Fairlamb, A.H. (2004) Two interacting binding sites for quinacrine derivatives in the active site of trypanothione reductase – a template for drug design. Journal of Biological Chemistry, 279: 29493-29500 Vickers, T.J., Greig, N. and Fairlamb, A.H. (2004) A novel trypanothione-dependent glyoxalase I with a prokaryotic ancestry in Leishmania major. Proceedings of the National Academy of Sciences USA, 101, 13186-13191.



Wyllie, S., Cunningham, M.L. and Fairlamb, A.H. (2004) Dual action of antimonial drugs on thiol redox metabolism in the human pathogen Leishmania donovani. Journal of Biological Chemistry, 279, 39925-39932 Vickers, T.J., Wyllie, S. and Fairlamb, A.H. (2004) Leishmania major elongation factor 1B complex has trypanothione S-transferase and peroxidase activity. Journal of Biological Chemistry,. 279, 49003-49009 Oza, S.L.., Shaw, M.P., Wyllie. S. and Fairlamb, A.H. (2005) Trypanothione biosynthesis in Leishmania major. Molecular and Biochemical Parasitology, 139, 107-116. Garnelis, T., Athanassopoulos, C.M., Papaioannou, D., Eggleston, I.M., Fairlamb, A.H. (2005) Very short and efficient syntheses of the spermine alkaloid Kukoamine A and analogs using isolable succinimidyl cinnamates. Chemistry Letters, in press



Hassan MSHINDA Expertise: Malaria, Parasitology, Entomology, Research, Epidemiology,

Drug Trials Born: 21 September 1959 Nationality: Tanzanian Summary of Experience: • Currently Director, Ifakara Health Research and Development Centre, Tanzania and

manager of various research programmes. • Parasitologist/Epidemiologist with extensive experience in research in Malaria in

Africa. • Author of numerous publications on malaria research including treatment, control,

vaccinations, bed nets, drug resistance, drug trials and DNA fingerprinting analysis of malaria parasite.

Education & Qualifications: 1981 Certificate in Medical Laboratory Technology, Faculty of Medicine, University of

Dar es Salaam 1985 Diploma in Medical Laboratory Technology (Parasitology and Entomology),

Faculty of Medicine, University of Dar es Salaam 1991 Pre-MSc Course, University of Liverpool 1992 MSc in Applied Parasitology and Medical Entomology, University of Liverpool 2000 PhD Epidemiology, University of Basel, Switzerland Employment Record: Director, Ifakara Health Research and Development Centre, 1998 - date Grants for research include: • Molecular epidemiology and Modelling of antimalarial drug resistance US$150,000

Multilateral Initiative for Malaria in Africa. • Kilosa School Health Research Project £80,000 Irish aid. • Markers of Morbidity for S.haematobium infections US$100,000 European Union. • Markers of Morbidity for S.haematobium infections. New non-invasive tools for

morbidity assessment in research and control US$100,000 European Union. • Ifakara Health Research and Development Centre, US$400,000 Swiss Agency for

Development and Cooperation • Molecular genotyping of samples from WHO combination - therapy trials US$30,000

WHO/TDR • Diagnostic support for communicable disease US$40,000 International Atomic

Energy Agency. Research Scientist, Head Medical Parasitology and Diagnostics Unit, Ifakara Health Research and Development Centre, Tanzania, 1992 - 1997



Laboratory Supervisor, Swiss Tropical Institute Field Laboratory (presently, Ifakara Health Research and Development Centre), Tanzania, 1987 - 1990 Makutopora National Service, First appointment Ilala District Hospital, Dar City Council, Tanzania, 1981 - 1982 Consultancies: Tanzania Evaluation of Laboratory services in Tanzania supported by DANIDA. Tanzania Health Impact Assessment of Lower Kihansi Hydro Power Project supported by TANESCO / NORPLAN. Tanzania OPR Review of Adult Morbidity and Mortality Project supported by DFID. Tanzania Roll Back Malaria External Evaluation supported by DFID. Languages: Speak Read Write Swahili Mother tongue Excellent Excellent English Excellent Excellent Excellent Publications: Schellenberg D., Menendez C., Kahigwa E., Aponte J., Vidal J., Tanner M., Mshinda, H., Alonso P (2001). Intermittent treatment for malaria and anaemia control at time of routine vaccinations in Tanzanian infants. A randomised, placebo/controlled trial. Lancet 357, 1471/.1477. Armstrong Schellenberg JRM, Abdulla S, Nathan R., Mukassa O, Marchant TJ, Kikumbih N., Mushi A, Mponda H., Minja H., Mshinda H., Tanner M., Lengeler C (2001) Effect of large scale social marketing of insecticide treated nets on child survival in rural Tanzania. Lancet 357 Mshinda, H (2000). The challenge of drug resistance in malaria: Studies in an area of intense perennial transmission, Kilombero district, Tanzania.PhD thesis University of Basel, Switzerland. Menendez C, Sanchez-Tapias JM, Alonso PL, Gimenez-Barcons M, Kahigwa E, Aponte JJ, Mshinda H, Navia MM, Jimenez de Anta MT, Rodes J, Saiz JC. 1999. Molecular evidence of mother-to-infant transmission of hepatitis G virus among women without known risk factors for parenteral infections. J.Clin. Microbiol.37:2333-6

Schellenberg DM, Acosta CJ, Galindo CM, Kahigwa E , Urassa H, Masanja H, Aponte JJ, Schellenberg JR, Fraser-Hurt N, Lwilla F, Menendez C , Mshinda H, Tanner M,



Alonso PL. 1999. Safety in infants of SPf66, a synthetic malaria vaccine, delivered alongside the EPI. Trop. Med Int. Health 4:377-82

Hatz CF, Vennervald BJ, Nkulila T, Vounatsou P, Kombe Y, Mayombana C, Mshinda H, Tanner M. 1998. Evolution of Schistosoma haematobium-related pathology over 24 months after treatment with praziquantel among school children in southeastern Tanzania. Am. J. Trop. Med Hyg. 59:775-81

Edoh D, Mshinda H, Jenkins J, Burger M. 1997. Pyrimethamine-resistant Plasmodium falciparum parasites among Tanzanian children: a facility-based study using the polymerase chain reaction . Am. J. Trop. Med Hyg. 57:342-7

Schellenberg DM, Abdalla S, Mshinda H. 1997. Malarial drug trials [letter; comment]. Trans. R. Soc. Trop. Med Hyg. 91:727

Wang P, Lee CS, Bayoumi R, Djimde A, Doumbo O, Swedberg G, Dao LD, Mshinda H, Tanner M, Watkins WM, Sims PF, Hyde JE. 1997. Resistance to antifolates in Plasmodium falciparum monitored by sequence analysis of dihydropteroate synthetase and dihydrofolate reductase alleles in a large number of field samples of diverse origins. Mol. Biochem. Parasitol. 89 :161-77.

Mshinda H, Font F, Hirt R, Mashaka M, Ascaso C, Menendez C. 1996. A comparative study of the efficacies of chloroquine and a pyrimethamine-dapsone combination in clearing Plasmodium falciparum parasitaemia in school children in Tanzania. Trop. Med Int. Health 1:797-801

Guyatt HL, Smith T, Gryseels B, Lengeler C, Mshinda H, Siziya S, Salanave B, Mohome N, Makwala J, Ngimbi KP. 1994. Aggregation in schistosomiasis: comparison of the relationships between prevalence and intensity in different endemic areas. Parasitology 109 ( Pt 1):45-55

Lengeler C, Mshinda H, Morona D, deSavigny D. 1993. Urinary schistosomiasis: testing with urine filtration and reagent sticks for haematuria provides a comparable prevalence estimate. Acta Trop. 53:39-50

Huber W, Hurt N, Mshinda H, Jaquet C, Koella JC, Tanner M. 1993. Sensitivity of Plasmodium falciparum field-isolates from Tanzania to chloroquine, mefloquine and pyrimethamine during in vitro cultivation. Acta Trop. 52:313-6

Mshinda, H (1992). Severe malaria: DNA fingerprinting analysis of malaria parasite in relation to cytoadherence. Msc dissertation,Universtiy of Liverpool.

Koella JC, Hatz C, Mshinda H, de Savigny D, Macpherson CN, Degremont AA, Tanner M. 1990. In vitro resistance patterns of Plasmodium falciparum to chloroquine--a reflection of strain-specific immunity? Trans. R. Soc. Trop. Med Hyg. 84:662-5

Lengeler C, de Savigny D, Mshinda H, Mayombana C, Tayari S, Hatz C, Degremont A, Tanner M. 1991. Community-based questionnaires and health statistics as tools for the cost-efficient identification of communities at risk of urinary schistosomiasis. Int. J. Epidemiol. 20:796-80



Lengeler C, de Savigny D, Mshinda H, Mayombana C, Tayari S, Hatz C, Degremont A, Tanner M. 1991. Community-based questionnaires and health statistics as tools for the cost-efficient identification of communities at risk of urinary schistosomiasis. Int. J. Epidemiol. 20:796-80

Lengeler C, Mshinda H, de Savigny D, Kilima P, Morona D, Tanner M. 1991. The value of questionnaires aimed at key informants, and distributed through an existing administrative system, for rapid and cost-effective health assessment. World Health Stat. Q. 44 :150-9

Mshinda H, Lengeler C, Hatz C, de Savigny D. 1989. Field diagnosis of urinary schistosomiasis by multiple use of nuclepore urine filters. J. Parasitol. 75:476-8



Adetokunbo LUCAS Expertise: Tropical Disease Research

Nationality: Nigerian Summary of Experience: • Currently Adjunct Professor of International Health, Harvard University,

CAMBRIDGE, USA • Has served on the expert committees and advisory boards of various national

organisations and international agencies -- Rockefeller Foundation, Edna McConnell Clark Foundation, Carter Center, Wellcome Trust, Bill and Melinda Gates' Children's Vaccine Programme and the Governing Board of the Centre for Agriculture and Biosciences International

• Chaired the Global Forum for Health Research, for four years when the new entity was established to promote international health research.

• Represented West and Central African countries on the Governing Board of the Global Fund for Fighting AIDS, Tuberculosis and Malaria.

• Was awarded various academic honours including the Harvard Medal, the Mary Kingsley Medal of the Liverpool School of Tropical Medicine, the Honorary Fellowship of the London School of Hygiene and Tropical Medicine, and the Harvard School of Public Health Alumni Award of Merit

• Has served as an external examiner at various institutions in Africa and in Europe. • Publications include papers on clinical and epidemiological aspects of tropical

parasitic and infectious diseases -- schistosomiasis, malaria, African histoplasmosis, etc.

• Received the Prince Mahidol Award 1999 in recognition of his contribution in the development of the Special Programme for Research and Training in Tropical Diseases, WHO.

• Served as the first honorary President of the Alumni Association of the London School of Hygiene and Tropical Medicine for 11 years

• Was elected to the Institute of Medicine of the United States National Academy of Science as one of the first eight persons in a new category of membership -- foreign associate

Education & Qualifications: BSc. (Durham) MD (Newcastle) DPH (Belfast) SM Hygiene (Harvard) DTM&H (England) FRCP (London.) FFPHM (UK) FMCPH (Nig.) FWACP (West Africa) FRCOG (UK) FUI (Ibadan) FIC (London)



Hon. DSc (Emory) Hon. DSc (Tulane) Hon. DSc (Newcastle) Employment Record:

Cambridge, USA, Current Role

Adjunct Professor of International Health, Harvard University Cambridge, USA, 1990 Professor of International Health at the Harvard School of Public Health 1986 – 1990 Chair of Carnegie Corporation's grant programme concerned with Strengthening Human Resources in Developing Countries. WHO, Geneva, 1976 – 86, Director Special Programme for Research and Training in Tropical Diseases based at the World Health Organization in Geneva. Ibadan, Nigeria, 1965 – 1976 Professor and Head of the Department of Preventive and Social Medicine Taught clinical and community medicine. Honorary Memberships: Elected an honorary member of various professional organisations including:

• American Society of Tropical Medicine and Hygiene • British Society of Parasitology • International Epidemiological Association • Swiss Society of Tropical Medicine • Society of Gynaecology and Obstetrics of Nigeria • Royal Society of Tropical Medicine and Hygiene • Ghana College of Physicians and Surgeons • Ghana Academy of Arts and Sciences



ANNEX 4: LIST OF PERSONS INTERVIEWED IN THE COURSE OF THE MMV REVIEW MMV Board Dame Bridget Ogilvie FRS, University College London, United Kingdom (Chair of MMV Board) Dr Jack Chow, Assistant Director-General, HIV/AIDS, TB and Malaria, World Health Organization, Switzerland Mr Louis Currat, Executive Secretary, Global Forum for Health Research, Switzerland (retired from Board in October 2002) In his capacity as the Executive Secretary of the Global Forum for Health Research, he chaired the crucial meetings that led to the final agreements about the founding of MMV. MMV Team Dr Chris Hentschel Chief Executive Officer, Medicines for Malaria Venture (MMV),

Switzerland J. Carl Craft Chief Scientific Officer Peter Potter-Lesage Chief Financial Officer Diane Cottran Human Resources and Management Services Officer P.V. Venugopal International Operations Director Apart from the formal interviews, the team members interacted with these and other members of the MMV team and obtained useful insights into the functioning of MMV. ESAC Dr Win Gutteridge, former Chief, Product R&D, Special Programme for Research and Training in Tropical Diseases (TDR), World Health Organization, Switzerland Professor Robert (Bob) William Snow, Head, Malaria Public Health Group, KEMRI/Wellcome Trust Programme, Nairobi, Kenya Dr Simon Campbell FRS, Chemist , former Senior Vice-President, Worldwide Discovery and Medicinal R&D, Europe, Pfizer; (served as founding Chair of ESAC from 1999, retired in 2003) WHO Dr. Bob Ridley, Director, WHO Tropical Diseases Research Programme Nafo Traore WHO Roll Back Malaria Department Alan Schapira WHO Roll Back Malaria Department Maryse Dugue MMSS Donors and stakeholders Dr. Olusoji Adeyi World Bank, Washington, DC Sue Kinn, DFID Central Research Department Dr David Carr, Wellcome Trust Dr Hannah Kettler, Bill and Melinda Gates Foundation Katherine White, Donor Co-ordination Group Others Dr. Broun Management Sciences for Health Simon Croft Drugs for Neglected Diseases Initiative (DNDi) Christopher J. Gingerich Consultant to the Bill & Melinda Gates Foundation Marc Pfizer Foundation Strategy Group, Geneva Office Roy Widdus Global Forum for Health Research, IPPPH Professor Peter Winstanley University of Liverpool



ANNEX 5: BACKGROUND ON MALARIA Malaria is a leading cause of morbidity and mortality in the world particularly among pregnant women and children under five years old in tropical and sub-tropical countries mainly in Africa and in Asia. According to WHO, 300 to 500 million cases with 1.1 to 1.3 million deaths occur each year. Professor Rob Snow, a member of ESAC, and his colleagues have presented new estimates of the malaria disease burden. From their model which used a combination of epidemiological, demographic and geographical information systems, their analysis indicated that 2.2 billion people are at risk of P. falciparum infection with 300 to 660 million of clinical attacks each year. It is estimated that malaria causes a loss of 1.3% in the annual per capita economic growth rate of malaria endemic countries and long term impact of this could be a reduction of Gross National Product to a half. Therecent worsening of the malaria situation has been attributed to various factors: • climatic and environmental conditions; • civil unrest and poor economic conditions contributing to the collapse of already

weak health systems; and • the emergence of the parasites and their vectors that are resistant to drugs and

insecticides respectively. Roll Back Malaria In 1998, the former Director General of WHO Dr Gro Bruntland launched a new initiative to Roll Back Malaria. The goal is to reduce malaria deaths by half by 2010. The initiative is based on early detection and effective treatment of malaria, intermittent preventive treatment in pregnancy, malaria prevention by use of insecticide treated bed nets or other methods of vector control. The Roll Back Malaria initiative received political support from African Heads of State and endorsed as the Abuja Declaration to roll back malaria. The emphasis of the declaration is on creating an enabling environment to increase coverage of malaria control tools. To date it is still difficult to assess the impact of Roll Back Malaria in terms of reduction of malaria morbidity and mortality, but clearly there is greater political commitment to control malaria as stated in both the Abuja and Millennium Declarations. The establishment of the Global Fund to Fight AIDS, Tuberculosis and Malaria provides additional financial resources for malaria control. There is some progress in terms of increased coverage of interventions but not yet at a level of demonstrating substantial public health impact. Although promising progress has been reported, no effective malaria vaccine is currently available for the control of the disease. Antimalarial Drugs Antimalarial drugs play a vital role in the current strategy for malaria control, both for populations resident in endemic areas as well as tourists and short term visitors. Drugs are used for the effective treatment of mild and complicated cases and for various preventive strategies. Trials are in progress to determine the efficacy of intermittent preventive treatment in infants and children as a new “chemo vaccination” approach for malaria control.



Antimalarial drug resistance Malaria case management is the cornerstone of malaria control. The emergence and spread of parasite resistant to most commonly used antimalarial drugs has become a major problem that is seriously compromising the effectiveness of this strategy. There is epidemiological evidence of increasing morbidity and mortality associated with increasing incidence of drug resistance in malaria. Chloroquine resistance in P.falciparum was first reported in Colombia and South East Asia, and Amodiaquine resistance in P.falciparum has been reported in Papua New Guinea, East Africa and Amazon Basin. The drug is still efficacious in West and Central Africa and the Pacific Coast of South America. Resistance to suphadoxine-pyrimethamine (SP) in P.falciparum was reported in South East Asia and Amazon region. Recently, since countries in East Africa adopted the drug as a first line drug, resistance has emerged and spread to reach 50% in some areas. SP resistance is still low to moderate in the rest of Africa (WHO 2001, 2003). Decreasing sensitivity to quinine has been reported in South East Asia and South America. This been associated with wide use of quinine, and cross resistance with Mefloquine has been reported in South East Asia and Brazil. Mefloquine has not been used widely in Africa but there are reports of isolates with reduced sensitivity to the drug. The first reports of P. vivax resistance to chloroquine came from Irian Jaya and Papua New Guinea in 1989. Drug resistance in these areas has spread so that nearly 50% of infections are resistant. Treatment failures have been reported in Brazil, Guatemala, India, and Myanmar. Artemesinin derivatives and their use in Combination Therapy The introduction of artemisinins, drugs derived from the Chinese traditional herbal remedy, is the most important development in the chemotherapy of malaria in recent years. Derived originally from the plant Artemesia annua, the active principle is an endoperoxide compound. It is fast acting but with its short half life, treatment has to be continued for several days to achieve complete cure. To date there is no report of artemesinin resistance in field conditions. Current global policy is to use drug combinations that include an artemisinin drug, artemisin combination therapy (ACT), as the first line treatment of malaria. Combination therapy is the simultaneous use of two or more drugs, active against the blood stages of the infection, which have independent modes of action and different biochemical targets in the parasite. The concept of combination therapy is based on synergistic or additive potential of two or more drugs to improve therapeutic efficacy and delay development of resistance to the individual components. Combination therapy is preferably artemesinin based and co-formulated in order to increase compliance. This concept is based on the experience in South East Asia where a combination of artesunate and mefloquine was shown to be more efficacious in delaying development of resistance and in reducing malaria transmission. The following combination therapies are currently recommended by WHO; artemether / lumefantrine, artesunate plus amodiaquine, artesunate plus sulphadoxine pyrimethamine, artesunate plus mefloquine. The recent report on lumefantrine resistance by the malarial parasite in Zanzibar needs further investigation.



Although the concept of artemesinin combination therapy (ACT) is therapeutically convincing, cost remains a major obstacle for most governments to adopt this as a standard approach to malaria treatment. A few countries have moved to combination therapy after receiving financial assistance from The Global Fund. However, given that the current cost of combination therapy exceeds more than 60% of the entire drug budget of ministries of health in some countries, it is not clear how this will be sustained in the long term. The adoption of combination therapy as the way forward for malaria treatment still needs further scientific evidence to document the advantage of such combination therapy in Africa as in Asia. Conclusion The malaria problem is massive and growing. Chemotherapy, the main control tool, is of declining efficacy because of the emergence of drug resistant strains of P. falciparum. Current therapy is largely based on combinations of artemisinin based compounds with other anti-malarial drugs. There is an urgent need for new drugs that can be effectively used for treatment and prophylaxis.



ANNEX 6: MMV BOARD AND ESAC This appendix contains notes about the MMV Board and the Expert Scientific Advisory Committee (ESAC) MMV Board The Medicines for Malaria Venture (MMV) is governed by a Board of a maximum of twelve members, chosen for their scientific, medical and public health expertise in malaria and related fields, their research and management competence as well as their experience in business, finance and fundraising. The MMV Board meets twice a year, usually in Geneva at MMV headquarters. It is the highest policy and decision-making body of the Foundation. Its main duty is to ensure that the management, through the annual budget and workplan, is efficiently executing the objectives of MMV. It establishes the policies and principles followed by the Foundation and also appoints the Chief Executive Officer. The Chair of the MMV Board is Dame Bridget Ogilvie, a former head of the Wellcome Trust. Following a distinguished career in pharmaceutical research, Dame Bridget currently serves on the faculty of University College London. She was elected as a Fellow of the Royal Society in 2003. The Members of the MMV Board are:

1. Dame Bridget Ogilvie FRS, University College London, United Kingdom (Chair of MMV Board)

2. Dr Enriqueta Bond, President, Burroughs Wellcome Fund, USA 3. Dr Jack Chow, Assistant Director-General, HIV/AIDS, TB and Malaria, World

Health Organization, Switzerland 4. Dr Chris Hentschel, Chief Executive Officer, Medicines for Malaria Venture

(MMV), Switzerland 5. Prof. Trevor Jones, Director General, The Association of the British

Pharmaceutical Industry (ABPI), United Kingdom 6. Dr R. A. Mashelkar, Director General, Council of Scientific and Industrial

Research (CSIR), India 7. Dr Pascoal M. Mocumbi, High Representative of the European and Developing

Countries Clinical Trials Partnership (EDCTP); former Prime Minister of Mozambique

8. Prof. Francis Nkrumah, Former Director, Noguchi Memorial Institute for Medical Research, University of Ghana, Ghana

9. Prof. Leon Rosenberg, Department of Molecular Biology, Princeton University, USA

Observers: Dr Winston E. Gutteridge, former Chief, Product R&D, Special Programme for Research and Training in Tropical Diseases (TDR), World Health Organization, Switzerland; served as full MMV Board Member from 1999-2003; took over Chair of MMV Expert Scientific Advisory Committee (ESAC) in 2003.



Former MMV Board Members include:

a) Mr David Alnwick, Director, Malaria Control Department, World Health Organization, Switzerland (retired from Board in 2003).

b) Mr Louis Currat, Executive Secretary, Global Forum for Health Research, Switzerland (retired from Board in October 2002)

c) Dr Tore Godal, Executive Secretary, GAVI Secretariat, Switzerland (retired from Board in 2001)

d) Dr Graham Mitchell, Chair, Scientific and Technical Advisory Committee, Special Programme for Research and Training in Tropical Diseases (TDR), WHO, Switzerland (retired from Board in October 2002)

e) Dr David Nabarro, Executive Director, World Health Organization, Switzerland (retired from Board in 2001)

Expert Scientific Advisory Committee (ESAC) The function of this body is to advise on the selection and review of projects for funding by MMV and to provide more general advice and information on appropriate technical strategies for the Foundation to achieve its goals. The members of the ESAC come from both industry and academia and cover the full range of expertise required to assess projects in the extremely complex process of drug research and development. For more on the project selection process go to MMV Projects. The first Chair of ESAC was Dr Simon Campbell FRS, who was formerly Head of Worldwide Drug Discovery and Development, Europe, Pfizer. MMV appointed Dr Win Gutteridge as the new Chair for ESAC in Summer 2003. The ESAC Secretary is Dr Solomon Nwaka, Scientific Officer at MMV. The members of the Expert Scientific Advisory Committee (ESAC) include: Chair: Dr Win Gutteridge, former Chief, Product R&D, Special Programme for Research and Training in Tropical Diseases (TDR), World Health Organization, Switzerland Members: Dr George Aynilian, PhD Pharmacist with expertise in clinical research (Phase I – IV), international regulatory affairs and 15 years' drug development experience in leadership roles of strategic operations and project management in pharmaceutical and hospital product divisions Dr David Floyd, Chief Scientific Officer and Executive Vice-President, Pharmacopeia Drug Discovery, USA; former Vice-President, Discovery Chemistry, Bristol-Myers Squibb Dr Alan Hudson, Chemist, former Head of Cancer Research, Wellcome plc (UK) with additional expertise in parasitology and malaria chemotherapy Dr Zulfiqarali Gulamhussien Premji, Clinical Parasitologist with over 25 years of experience in teaching, research and clinical work combined with extensive experience in laboratory work involving diagnosis and molecular biology techniques



Dr David Roos, Professor of Biology and Director, University of Pennsylvania Genomics Institute. Expertise in the cell biology of apicomplexan parasites and joint coordinator of the Plasmodium genome database, USA Dr John A Salmon, Senior Pharmaceutical Research Scientist with expertise in bioanalysis, drug metabolism and pharmacokinetics. Consultant in biopharmacy to the pharmaceutical Industry and visiting lecturer at King's College, London and the University of Greenwich Dr Dennis Schmatz, Biologist with expertise in parasitology, including malaria. Vice President, Infectious Disease and Immunological Research, Merck Research Laboratories, USA Professor Robert (Bob) William Snow, Head, Malaria Public Health Group, KEMRI/Wellcome Trust Programme, Nairobi, Kenya Dr Henrietta Ukwu, Vice President, Global Regulatory Policy, Merck & Co., Inc. Over 10 years of senior pharmaceutical industry and regulatory experience Dr Thomas E. Wellems, Biologist with expertise in cell and molecular biology of malaria and mechanisms of drug resistance. National Institute of Allergy and Infectious Diseases/National Institutes of Health, USA Dr Kitima Yuthavong, Clinician/Paediatrician; former Medical Director, Aventis Pharma Thailand; currently, Vice President, Thailand Center of Excellence for Life Science (TCELS) Distinguished former members of ESAC include: Dr Simon Campbell FRS, Chemist , former Senior Vice-President, Worldwide Discovery and Medicinal R&D, Europe, Pfizer; (served as founding Chair of ESAC from 1999, retired in 2003) Dr Tanjore Balganesh, Biologist with expertise in infectious diseases. Head, Research and Development, AstraZeneca, India (served on ESAC from 1999, retired in 2003) Dr Simon Efange, Chemist, Professor of Chemistry, University of Buea, Cameroon (served on ESAC from 1999, retired in 2003) Professor Gilbert Kokwaro, Pharmacologist with expertise in malaria, University of Nairobi, Kenya (served on ESAC from 1999, retired in 2004) Professor Sornchai Looareesuwan, Clinician with experience in malaria, Dean, Faculty of Tropical Medicine, Mahidol University, Thailand (served on ESAC from 1999, retired in 2004) Dr Yves Ribeill, Chemist with experience of malaria through earlier work as Head of Anti-infective Chemistry Research with Rhône-Polenc Rorer France, currently President and CEO, Scynexis Chemistry and Automation Inc., USA (served on ESAC from 1999, retired in 2004)



Dr David Wesche, Clinical pharmacologist with expertise in malaria from previous experience with Walter Reed Army Institute of Research, currently with Pfizer Global Research and Development – Ann Arbor, USA (Served on ESAC from 1999, retired in 2004)



ANNEX 7: GOVERNANCE OF MMV

This annex contains summary descriptions of the following: • MMV Governance Model • Functional Chart • Current organization of MMV management • Core Functions of MMV Team • MMV International Operations

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Leg

MMV Management

Project Teams & Support Staff

Outsourced Support

Reporting Direction

Board of Directors

Key Committees

Chief Executive

Fund Fund

Fund I.

MMV Geneva

Geographic Spread

Fund Raising MMV Europe

Fund Raising New Delhi Support Office

Fund C.R.O

Fund Consultants-

Stakeholders

Fund Communication

Remuneration

Audit

Expert Scientific Advisory Committee

Nominations



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• Exploratory/Discovery Projects

• Development Projects

• Regulatory Affairs

• Clinical Trials

• Contractual/Legal Agreements (Science)

• Administration Support

• Recruitment & Selection

• Performance Appraisal

• Compensation & Benefits

• Development

• Payroll

• Work Permits / Residencies

• Taxes

• Governance/Board & Stakeholders Meetings

• Office Administration (Suppliers, travel,…)

•

• Development of relationships with Ministries of Health

• Bi-Lateral Development

• Fundraising (Asia, Africa)

• Negotiating low cost manufacturing options

• Distribution & delivery of drugs

• Relationships with International Organizations (TDR & RBM)

• Relationships with

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• Budget

• Financial Planning

• Financial Reporting

• General Accounting

• Cash Management & Banking

• Audit

• Fundraising (Europe)

• Stakeholders Reporting

• Donors Relations

• Proposals for New Donors

• External Communication

•



Core Functions of the MMV Team R&D Activity: Portfolio and Project Management

• Translate global health priorities into research priorities • Launch requests for proposals • Select projects • Manage projects on the basis of contractual agreement process including

intellectual property rights (IPR), drug discovery and development plans workplan, standard protocols, key milestones, funding requirements

• Review project progress • Mobilize and share external expertise, resources and technologies across

projects • Regularly assess project viability at the end of each phase of discovery and

development • Select new partners for drug discovery and development, and drug synthesis

and manufacture1 • Review projects with regulatory bodies • Confirm affordability • Control the quality of scientific reports • Selectively (Effectively) interface and collaborate with downstream partners

Augment the work of project officers through contracting out either specific management or technical activities for example by selecting a contract project management partner in the few cases when MMV requires such capacity

E.S.A.C.

BBooaarrdd OOff DDiirreeccttoorrss Current Organization MMV Management

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Christopher Hentschel Chief Executive Officer

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MMV International Operations

The International Operations of MMV are directed by Dr P V Venugopal from offices in New Delhi, India. Dr Venugopal is former Executive Director of Dr Reddy's Laboratories Limited (India), with 10 year’s experience in key areas related to drug development and marketing in the developing world, including intellectual property rights etc. Through his extensive network of contacts within government and industry in many disease endemic countries in Asia, Africa and Latin America, he plays an important role in advocacy of MMV’s mission to discovery, develop and deliver new drugs for the malaria. He maintains regular contact with Dr Chris Hentschel (CEO, MMV) and is ideally placed to interface with Ranbaxy Laboratories Ltd and deal with issues relating to development of OZ277/RBx 11160. He is highly aware of the downstream issues relating to cost of goods and effective marketing and distribution of new drug products. He has been instrumental in identifying Unimark as a bulk supplier of intermediates for the synthesis of OZ277/RBx 11160 and its proposed partner drug piperaquine.

Comment As Director of International Operations, Dr Venugopal plays an important role in actively promoting and facilitating MMV’s mission from his base in New Delhi. This location is ideal for representing MMV within disease endemic countries so that he can exercise his considerable talents in leveraging the partnership with industry, clinicians and local and regional government.



ANNEX 8: THE PRODUCT DEVELOPMENT PATHWAY MODEL

ScaleCapacity

for Market

ComparativeEfficacy:Phase III

InitialCapacityfor Trials

InitialEfficacy:Phase II

Safety:Pre-Clinical& Phase I

DiscoveryResearch

In-CountrySupply ChainPreparation

OutreachActivities &Local POS

PoliticalDemand

HouseholdChoice toConsume

In-CountryProduct

Marketing

ProductAccess byTarget Pop

ProductLicensure

TargetProductProfile

NGO / CSOApproval

PrototypeCapacity

Post-Marketing

Surveillance

Malaria

Monitoring&

Evaluation

AffectedPopulationDemand

AffectedPopulation

Health Need

BasicScience

HealthWorkerTraining

CountryEvaluation& Approval

SustainableDemand

Procurement&

Contracting

EstablishDiseaseBurden

UptakePlanning &Forecast

TargetPopulation

Trials

EconomicDemand

EstablishEconomicBurden

• Basic Science and Discovery Research especially challenging due to multi-stage nature of Malaria infection.

• Target product profile – especially with regard to price – critical as many Malaria health products are traditionally paid for by end users.

- Product Demand- Product Development- Product Supply, Marketing & Access- Product Monitoring, Evaluation & Approval

Process Groups= 2 GHPs= 2 PPPs

GHP / PPP Mapping

= 1 GHP & 1 PPP= 1 GHP

= 1 PPP

Barriers & Linkages- Potential Barrier / Difficult Process

- Important Process (Often Overlooked)- Key Dependency

SpecifyTarget

Population

DESIGN DETAILS • Cells – Each cell identifies a specific “step” in a sub-path. Cells can represent one or more processes or a specific outcome. • Cell Color – Colors are used to distinguish major process groupings from one another. • Cell Borders – Colored cell borders represent potential barriers (red) or notably critical (green) processes or outcomes. • Arrows – Arrows represent key linkages or dependencies, in which the initial process is critical for successful progress in the dependent process. • Shaded and Un-Shaded Circles – The circles represent the number of GHPs (shaded) and PPPs (un-shaded) that have activities, programs or funding relevant to the cell. For this diagram, each full circle represents 2 of the specified organization type. • Cell Position – This diagram emphasizes the sequencing of events. Time flows from left to right, cells are positioned along the diagram in observed sequence. Note however that cell width and pace along the x axis is not proportional – i.e. the diagram representing sequencing only



ANNEX 9: GLAXO SMITH KLINE (GSK) COLLABORATION WITH MMV Introduction This centre was selected for review as it is representative of MMV’s partnership with the drug discovery unit of a major global pharmaceutical company with considerable expertise in infectious diseases. GSK has established a mini-portfolio of drug discovery projects in malaria. GSK’s research into Diseases of the Developing World (DDW) is centred on dedicated R&D facilities in Tres Cantos, Spain. Through the activities of DDW, GSK is committed to investing in research and development in the discovery and development of new antimalarial drugs and to providing drugs to disease endemic countries at preferential prices. This is a unique partnership between a major pharmaceutical company and MMV. It has clearly demonstrated that such a relationship can be synergistic in terms of shared commitment and both parties receiving mutually complimentary benefits. Furthermore the breadth of MMV’s overall relationship with GSK across drug discovery, late stage preclinical and clinical development must be unprecedented. Mini-portfolio with MMV GSK collaborates with MMV in a mini-portfolio of discovery and development projects. Currently there are three discovery projects (fatty acid biosynthesis inhibitors [FabI I]; cysteine protease inhibitors [falcipains]; and a backup series for the pyridone preclinical candidate GW844520) and three development projects (chlorproguanil / dapsone / artesunate (CDA); GW844520; and isoquine). Since 2002 two projects have been discontinued either due to failure to progress in lead potency (lactate dehydrogenase (LDH) inhibitors) or due to issues concerning cost of goods, rate of parasite clearance and resistance potential (peptide deformylase (PDF) inhibitors). GSK’s input GSK entirely funds 50 permanent staff with expertise in all aspects of drug discovery in Tres Cantos (bioinformatics; high throughput screening; hit to lead optimization; efficacy in vitro and in vivo; toxicology and pharmacology). A further 25 staff are funded 50% by GSK and 50% by MMV. The team has access to 8,500 m2 of research facilities, including two P3 facilities for in vitro (220 m2) and in vivo (4,000 m2) experimental work. Furthermore MMV has indirect access to GSK’s vast organization and scientists throughout the company. The DDW team frequently collaborate with other departments as particular expertise is sought to supplement their own discovery efforts. MMV’s input In addition to funding and managing the mini-portfolio, see MMV’s Drug Discovery and Development Portfolio, MMV identifies and fosters partnerships between academics with specific expertise in various aspects of malaria with GSK. MMV also helps define the choice of indications for further study in collaboration with GSK.



Management of the mini-portfolio GSK defines the criteria for prioritisation and day-to-day management of the research portfolio, with quarterly project meetings between the project leaders and MMV staff, a steering committee meeting every six months and annual review by ESAC. In order to reassure donors that they are receiving good value for money, GSK has instituted a tracking system to record the percent effort on each project in the mini-portfolio. Comments: This is a unique collaborative partnership between MMV and GSK that has been built up on mutual trust over the last 5 years of partnership. GSK has no issues relating to their relationship with MMV and feels very positive about the collaboration. However, it is important that MMV keeps GSK fully informed about downstream issues raised by TDR/RBM (WHO). Critical pathways for development with clearly defined milestones and go / no go decision points are in place, as would be expected for a professional organisation such as GSK. GSK’s commitment arises primarily through the company’s corporate and social responsibility, recognising that the financial returns and market potential are at best minimal or even non-existent. GSK is fully aware of issues of cost of goods and this is a driving factor in their selection of preclinical candidates. MMV receives excellent value for money through this partnership. GSK provides a complete infrastructure for drug discovery that would be difficult, if not impossible, to replicate in an academic setting. Flexibility and continuity are key advantages, since scientists can be readily redeployed onto other projects at short notice. This is one particular advantage of working with a large commercial partner as the sudden discontinuation of a development project in an academic institution could be highly disruptive to both the affected individual and/or department. If MMV for any reason were to decide to discontinue funding the mini-portfolio, GSK would strive to continue their efforts in malaria drug discovery, although at a slower pace. In addition GSK will likely absorb unspecified development costs and assure the distribution of new antimalarials at least within their own commercial markets.



ANNEX 10: THE OZ 277/RBX 11160 SYNTHETIC ENDOPEROXIDE (TRIOXALONE) Introduction This project was selected for detailed review and is representative of a partnership including academia and a mid-sized pharmaceutical company that currently specialises in the development and manufacture of generic medicines. The artemesinin products are critical to current malaria control programmes because of their activity against drug resistant strains of P. falciparum. OZ 277/RBx 11160, a synthetic endoperoxide, is thought to have a similar mechanism of action to the aremesinins. OZ 277/RBx 11160 is the flagship project of MMV. OZ 277/RBx 11160 may be more efficacious and a substitute for artemesinin, a natural product requiring more than a year between cultivation and harvesting. The success of this programme is critical to the assured provision of treatment. The product has entered Phase II clinical development and the next twelve months will be critical in confirming activity in human subjects, see Figure 1. MMV has planned for a total capital investment of approximately $30 M USD up to the time of product approval. This sum will not include the costs of scaling up drug manufacture that will be needed around the time of product launch. If MMV meets this development goal, the programme will represent exceptional value relative to a modest investment in drug development terms. The programme is representative of a Public Private Partnership with a commercial partner, Ranbaxy (New Delhi, India), whose transition from a generic producer to an R&D based firm is at a relatively nascent stage. This contrasts with the MMV collaboration with GSK, a highly experienced developer of novel chemical entities. Ranbaxy is highly committed to assuring the success of the project and the company has a number of important attributes that makes it an ideal partner for MMV. All things being equal, the MMV/Ranbaxy partnership should be a “win-win” opportunity for both parties leading to the development of an important new antimalarial. It is expected that OZ 277/RBx 11160 will be used in combination therapy because of concerns related to the parasite acquiring resistance to antimalarial drugs prescribed as single agents. Although it is possible to generate drug resistant parasites to artemesinin in the laboratory, fortunately this is not yet a problem in the field despite the widespread use of artemesinin as a single agent in China. Also combination therapy with OZ 277/RBx 11160 may be equally important in preventing parasite resistance to the partner drug(s) prescribed in the cocktail. Ranbaxy Laboratories Ltd., India Ranbaxy is best known for the production of generic medicines and the company has enjoyed exceptional growth over the last ten years. In the year 2004, global sales exceeded $1 Billion USD. OZ 277/RBx 11160 is the first time that Ranbaxy has embarked upon a full development project. Their expertise is very much in the areas of late stage preclinical development in support of the clinical pharmacology and pharmacokinetics required to gain the regulatory approval of generic products. Ranbaxy does not yet have experience of Phase III clinical development.



Driving down the costs of goods (drug substance) is a critical activity in the drug development process and essential to the provision of affordable medicines. Ranbaxy’s chemists do have considerable experience in identifying novel ways to simplify the route of synthesis and manufacturing. Substantial progress has already been made in reducing the cost of bulk substance. In addition to marketing its generic products throughout the world, Ranbaxy has a marketing presence in India, Africa, Asia and Latin America which would support and dovetail with the distribution needs of antimalarial drugs. The OZ 277/RBx 11160 provides Ranbaxy with a unique opportunity to transition from being a manufacturer of generic medicines to a pharmaceutical company developing and marketing novel medicines. Even if the financial value of the product is small, the success of OZ 277/RBx 11160 would be of significant strategic value to Ranbaxy, since the project would demonstrate improved innovative capabilities to Ranbaxy investors. The global market for antimalarials is currently approximately $375 M USD/annually and Ranbaxy estimate that the target market for OZ 277/RBx 11160 is $160 M USD. Ranbaxy are satisfied that they will achieve a reasonable return on investment. At this time the final cost of goods is not known. However Ranbaxy is confident that the price target of less than $1 USD/treatment will be met. Planned Development of OZ 277/RBx 11160 The project team is working under the assumption that OZ 277/RBx 11160 will only be used in combination therapy and that the most likely drug candidate for combination use is piperaquine. MMV has received expert guidance on the choice of drugs for combination use. This takes into consideration the anticipated efficacy of drug combinations and cost of goods. Piperaquine has been used extensively in China for the treatment of malaria and is thought to be safe. However it has not yet been formally evaluated in clinical trials and has not been subject to regulatory scrutiny. This may represent a significant risk to the programme. Product launch of the combination is planned for 2009 and with an additional two years to optimise patient access to the drug. Furthermore Ranbaxy’s pre-existing marketing infrastructure places it in an ideal position to limit future capital investment and assure distribution of OZ 277/RBx 11160 in the relevant commercial markets. Ranbaxy’s limited experience in drug development will necessitate MMV spending additional time monitoring and supporting their activities. MMV and Ranbaxy have complimentary skill sets and with additional guidance from ESAC, the project should be more than adequately supported. MMV and Ranbaxy have developed a good working relationship, strongly supported by Dr. P. V. Venugopal (Director of International Operations, MMV, and New Delhi), see below. The clinical programme is further strengthened by Prof. Sornchai Looareesuwan, Faculty of Tropical Medicine, Mahidol University, Bangkok, see below, and Quintiles, a major international corporation and provider of expert drug development services. Recommendations: It is understood that current malaria treatment strategies focus on combination therapy and the prevention of drug induced resistance. However the development of two experimental drugs in combination does represent significant challenges. Even if



piperaquine is considered to be an “accepted” antimalarial, the team should assure themselves that the regulatory authorities will take a similar view. Drug development is an inherently risky process and it would be unfortunate for this important programme to founder because of unanticipated efficacy or toxicity issues with this combination. Recommendations: A Phase II dose ranging study is being planned to evaluate the anti-parasitic activity of three days of treatment with OZ 277/RBx 11160 alone. The possibility exists that patients with P. falciparum infection will be cured in this monotherapy study. Despite the accepted wisdom that OZ 277/RBx 11160 should only be developed in combination therapy, this outcome could bring into question the overall development strategy for the product in combination use. Although it is agreed that in principle combination therapy is a more sensible approach because of the fear that the parasite may eventually become resistant to the artemesinins. Also developing OZ 277/RBx 11160 as a monotherapy might be expected to reduce the time to an approvable product by up to two years whilst combination therapy is further evaluated. This would reduce the risk of depending upon one strategy for the development of OZ 277/RBx 11160 in combination with piperaquine, a drug for which only limited information on efficacy and safety is currently available. Recommendation: Previously Ranbaxy experienced problems in the quality of work conducted by other service organisations. There is no reason to assume that this is still the case and development problems are not unique to small or medium sized companies, or indeed, to firms in emerging markets. MMV is implementing a quality approach to management. However the project team should ensure that plans are in place to audit key service providers, research and clinical trial sites during the course of the programme. (For a description of MMV International Operations see Annex 6) Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand Professor Sornchai Looareesuwan is an internationally renowned expert on the treatment of malaria and is responsible for clinical trials at Mahidol University. In the past he has served as a member of ESAC. The unit has had 30 years experience in the management and treatment of malaria. Under his leadership, Mahidol has become a research based facility which treats up to 1500 patients each year with malaria. Approximately 50% of cases are falciparum infections and the majority of patients are admitted for observation and treatment. As Bangkok is free of malaria, patients must be recruited from hospitals and clinics in the malaria endemic areas adjacent to the Thai–Myanmar border. Mahidol has established excellent working relationships with the Thai government and has received substantial funding to build clinical research and training facilities in the malaria endemic region to the west of Bangkok. The unit is extremely well versed in Good Clinical Practice (ICH GCP). Clinical study files are maintained in good order with the help of Quintiles (Thailand), an international



service provider which has specialised in clinical trial practice within the region. Quintiles has worked with Prof. Sornchai for almost ten years. For MMV projects, Quintiles will conduct the data management and bioanalytical work in South Africa and the United Kingdom, respectively. The working relationship between Mahidol and Quintiles appeared to be very professional and collegial. One would expect clinical trials to be conducted to a very high standard through this partnership. Mahidol undertakes 2-4 sponsored and 2 unsupported clinical trials in malaria each year. Prof. Sornchai has collaborated closely with MMV and is currently evaluating Artemisone (Bayer, BAY 44-9585) in a Phase II clinical trial. The department is now preparing to begin a Phase II monotherapy dose ranging study evaluating OZ 277/RBx 11160 in collaboration with Ranbaxy, New Delhi, India. Patients have the choice of being treated locally, where they are expected to pay for their treatment, or receive free treatment and care at Mahidol University. Prof. Sornchai emphasised that patients are free to choose and informed consent for entry to a clinical trial does not take place until the patient is admitted to Mahidol. At this stage, patients are still free to choose conventional therapy. However the unit’s philosophy is to encourage all patients to participate in research. Also family members are encouraged to travel and stay with the patient at Mahidol. Patients who are too ill to travel will receive immediate treatment and care at their local clinic or district hospital. Phase III clinical research is conducted in district hospitals. Phase II studies are only conducted at Mahidol where the team has the facilities to intensively investigate and monitor patients during treatment. Also Mahidol is equipped to efficiently collect and process specimens required by pharmacokinetic drug disposition studies. Clinical research is forbidden by the Thai government in the clinics close to the border. Also it is especially difficult to conduct clinical research in the border areas where patients may not be easily observed and where follow-up may be unpredictable. There remains the ethical question of conducting research on refugees which should by definition be in the interests of the patient. Also conducting high quality clinical research in Laos and Cambodia will most probably be difficult because of the lack of experience and limited exposure to GCP practices. Comments: Mahidol University provides excellent facilities for the conduct of Phase II and III clinical studies. The Faculty of Tropical Medicine would appear to have all of the necessary ingredients to conduct high quality clinical research. MMV has an excellent working relationship with Prof. Sornchai’s department and there is no reason to believe that this collaboration will not continue to be fruitful. Regarding the planned Phase II dose ranging study in P. falciparum, MMV and Ranbaxy are currently considering the inclusion of additional study sites in both Africa and India. This poses a number of practical questions, see below. Recommendations: It might be tempting to assume that Mahidol will have sufficient numbers of patients to conduct the Phase II dose ranging trial solely at this one site. MMV and Ranbaxy should assure themselves that the timing of this trial will coincide with the peak incidence of



infections in Thailand and that there will not be studies competing for patients at Mahidol. To ensure the timely completion of this trial, consideration should be given to including an additional study site(s) within the region. The Phase II dose ranging trial need only recruit 150 patients. Ideally any trial should include a minimal number of study sites but still needs to ensure patient recruitment and standardised practices across the sites. The addition of sites in both Africa and possibly India will add to the cost and complexity of the trial. There may be variation in the experience and ability of sites in Africa to work to the same standards in Thailand. The need to include African sites should be reviewed as this trial will be critical. Furthermore there may be significant differences in the biology and response to treatment across the regions. Hence it may be appropriate to eventually consider complementary studies in these regions as part of the overall drug development plan for OZ 277/RBx 11160 rather than conducting one study which is unlikely anyway to answer all questions. If the first dose ranging study is conducted in Thailand, it could be followed by a smaller confirmatory trial in Africa.



Figure 1: Development plan and projected budget for OZ 277/RBx 11160



ANNEX 11 TEMPLATE FOR FUTURE REVIEWS OF PD PPP EVALUATIONS Organisational issues for future reviews • Selection of consultants for the review process should be planned well in advance of

the proposed review.

• Review team should comprise a broad range of expertise to cover all aspects of the review with strong representation from disease endemic countries with an appropriate gender balance.

• The review team should meet in person prior to the review, to design the study, to

identify additional information that they may require, to plan site visits and to select individuals for interview and allocate specific tasks to members of the team.

• Background documents and other information should be provided in a timely fashion.

• Realistic budgets and time required to perform the tasks should be agreed early on.

• Meetings and travel arrangements should be scheduled as far as possible in advance,

particularly where special arrangements are required for a visit (e.g. visas, medical prophylaxis, travel and medical insurance).

Identify and Quantify Health Requirements Define:

• current disease situation • economic and health burden • currently available tools / products for control interventions • unmet needs of the population versus the target profile(s) of the future

product(s), e.g. affordability, acceptability and availability. Quantifiable objectives

• Define scope and goals of organisation in relation to disease focus and target product profiles (e.g. drugs, vaccines, diagnostics, insecticides, and microbicides).

• Identify key deliverables, milestones and timelines (e.g. one new product every 5 years; cost of success versus cost of failure)

Management and organisation Assess composition, size and effectiveness of:

• Governing board • Expert scientific advisory committee • Internal organization (human resources, finance, legal and ethical policies,

procedures (systems, processes and quality management))



Project selection and assessment

• Initial selection process – is it proactive, passive or both? • Evaluation process – for different stages in discovery and development, what

standard templates are used to assess scientific merit and relevance to PPP goals?

• Standardised project management tools and development plans? • Have the most appropriate partners been identified? • Is there an appropriate reporting and review process? • Are there clear decision points and Go / No Go criteria?

Portfolio management

• Evolution of portfolio: additions and project terminations • Progress towards stated goals • Balance of innovation (high risk) versus well established pathways (low risk) • Identify and assess tools used for portfolio management

Financial management

• Financial reports, audit procedures and financial controls • Balance between operational costs and project costs • Cost of failed projects • Current and future financial projections based on different scenarios • Fundraising

Legal Aspects

• Patent protection and intellectual property rights • Charitable status under national and international law • Human Rights and Medical Ethics • Contractual obligations

Communications

• Press releases • Annual reports • Advocacy (website, press, TV, radio and public meetings)

Relationship with other agencies

• Define context in which PPP is operating in relation to other agencies • Identify upstream and downstream partners; their roles and responsibilities;

overlaps and gaps; conflicts and synergies. • Define relationship to donors and how this could be improved.

Independent Review of Medicines for Malaria Venture ...siteresources.worldbank.org/EXTGLOREGPARPROG/Resources/...channel through which the DCG can support malaria drug development.

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