David Alnwick Project Manager, Roll Back Malaria, WHO, Geneva Enriqueta Bond President, Bourroughs Wellcome Fund, USA
Louis Currat Executive Secretary, Global Forum for Health Research, Geneva
Winston E. Gutteridge former head of Product Research and Development, UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR)
Trevor Jones Director-General, Association of British Pharmaceutical Industries, UK R.A. Mashelkar Director General, Indian Council of Scientific and Industrial Research
Graham Mitchell Chairperson, Scientific and Technical Advisory Committee, UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR)
Francis Nkrumah Director, Noguchi Memorial Institute for Medical Research, University of Ghana Leon Rosenberg Professor, Department of Molecular Biology, Princeton University, USA
Christopher C. Hentschel Chief Executive Officer, MMV
Insert 8.5.2 MMV Stakeholders
Bill & Melinda Gates Foundation Exxon Mobil Corporation Global Forum for Health Research
International Federation of Pharmaceutical Manufacturers Associations Netherlands Ministry for Development Cooperation
Rockefeller Foundation
Swiss Agency for Development and Cooperation
United Kingdom Department for International Development World Bank
World Health Organization: TDR and Roll Back Malaria
(c) Stakeholders
MMV receives funding and support from the organizations shown in Insert 8.5.2.
3. Strategies and objectives
M M V ’s virtual R&D approach comprises several modules. It competitively selects and then actively manages projects that, with its partners, contain all the scientific and project-management expertise normally found in both public and private sectors. Thus a key strategy is to link compatible academic and industry groups to optimize access both to the technologies associated with drug R&D, and to the mindset and thinking that is required to generate real world products. In some cases these links may already be established and in others it may be necessary to bro k e r partnerships. MMV managers, together with the Expert Scientific Advisory Committee, then closely monitor the projects against defined milestones. Continued funding will be dependent on success and progress toward the goal of discovering and developing an appropriate drug.
The virtual drug R&D managed by MMV implies that all laboratory processes are o u t s o u rced. This is a model pioneered in the bio-pharmaceutical industry to re d u c e capital expenditure. However, the paradigm envisaged by MMV is not only to utilize cost e ffectively cutting-edge science where it a l ready exists, but also to integrate this with cutting-edge managerial approaches facilitated by the IT and communications re v o l u t i o n . A key advantage offered by MMV to potential donors and stakeholders is the p o rt f o l i o management aspect operating within MMV.
By developing a portfolio approach, assessed by competitive scientific and sustainability criteria, MMV provides a considerably greater chance of achieving success than by the n a rrowly targeted investment in a single project or single institutions.
MMV has developed a strategy that utilizes existing and emerging scientific opportunity to meet both short-term and long-term drug R&D needs.
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In the short term, great hope is attached to the development of existing drug classes such as the artemisinin derivatives, drugs derived f rom a Chinese herb A rtemisia annua.
However, these drugs currently have to be administered over five to seven days when given alone. In poor countries, where cost of treatment is a major concern and health care infrastructure is poor, the full course is often not completed and re c rudescence of the disease can occur. To counter this problem, and in an attempt to reduce the likelihood of d rug resistance, some scientists have p roposed that these drugs should be combined with other drugs for the treatment of malaria. Examples of such combinations can be found in the current MMV portfolio.
In the medium to longer term, MMV seeks to bring forward entirely new classes of drugs, both singly and in combination, to meet the future challenges of drug resistance and to improve compliance. The availability of the malaria genome sequence, expected to be finalized in the near future, will generate a substantial amount of valuable new i n f o rmation that will be a wonderf u l additional asset to this long-term goal.
H o w e v e r, drug discovery is a long and complex process. It takes many years of dedicated biology allied to cutting-edge medicinal chemistry to convert ideas and
“leads” into drugs. The chemical compounds have to be designed not only to inhibit the molecular target against which they are directed, but to be stable, to be non-toxic, to be absorbed into the blood stream and to c ross from the blood plasma into the component is competition. MMV seeks the best projects possible, both in terms of science and in terms of the teams that can be
assembled around the projects. A stro n g competitive process is generated initially t h rough an open, public and widely communicated call for project proposals. This is coupled with more proactive research and networking on a global scale.
There remains a strong competitive element to the process after selection. The project teams are made aware at the outset that continued MMV support is dependent on both progress against milestones and on the p roject remaining competitive with other projects in the MMV portfolio. Therefore, all major projects have to be reviewed annually by the Expert Scientific Advisory Committee.
4. Results over the past two years and perspectives over the next two years MMV has built up a project portfolio over the past two years that is already the largest portfolio in malaria drug R&D since the Second World War. By 2002, MMV’s portfolio had grown to include eight projects: three exploratory projects, three discovery projects and two development projects; and funding had reached US$6 million a year, compared with US$2.4 million spent in 2000.
M M V ’s first call for proposals was focused on d rug discovery which, while high risk, has the advantage for a young organization of being less management-intensive than dru g development. This focus also provided an early test of the willingness of companies to engage in projects for which the chances of success and commercial re t u rn were very limited. Six projects from more than 100 original letters of interest were finally selected.
They consisted of three major pro j e c t s that each contained a link with major p h a rmaceutical companies, and thre e e x p l o r a t o ry projects based in academic laboratories. All of these projects were initiated under agreements that give MMV the rights to any compounds that are selected for entry into development. All of MMV’s legal agre e m e n t s
a re case-by-case and attempt to produce win-win scenarios for all the partners.
MMV is committed to and now has the capability to take on management-intensive d rug development projects. One of the challenges over the next two years will be to continue expanding the portfolio while simultaneously driving forward projects into the development phase.
By the end of 2002, MMV hopes to have up to 14 projects in its R&D portfolio while still containing R&D costs to the levels projected in its business plan. By 2004, MMV hopes to have about 20 projects in the pipeline, a number that should meet the challenge of delivering one new antimalarial every five years. To achieve this, funding will need to increase to about US$30 million a year, plus an equivalent of “in kind” support from industry.
Other challenges also need to be addressed over the coming years. Malaria chemotherapy is far more complex than the sole issue of combating the spread of drug re s i s t a n c e , important though that is. The drugs MMV helps develop must also address the full range of unmet medical needs associated with malaria. These include:
• Medicines and appropriate formulations for paediatric use
• Medicines that are safe for use in pregnancy, including intermittent use to p revent serious malaria infection in pregnancy and thus enhance the health of the newborn
• Medicines that are appropriate for use in complex emergency situations such as refugee camps, where healthcare i n f r a s t ru c t u re is minimal and where e x t remely short-course treatments are required
• Medicines that address needs of severe (comatose) malaria patients
• Medicines that address the needs resulting
from P. vivax infection and infection from other species of malaria parasites in addition toP. falciparum
• Medicines that are appropriate for malaria prevention.
MMV will manage the development of its p o rtfolio to ensure that these needs are addressed. Regular consultations, particularly through the Roll Back Malaria Partnership, will ensure that the drugs under development continue to be directed principally towards meeting priority medical needs, as data on these needs are refined at the country level.
5. Indicators of success
Ultimately, MMV’s value will be measured in terms of the number of patients treated with antimalarial drugs as a result of its work and that of its many partners. Shorter term indicators of success are the size and quality of MMV’s pipeline and the rate of pipeline p ro g ression compared to industry norm s . Such ‘surrogate’ indicators are required for drug R&D because it takes so long to deliver real products.
Unless the drugs discovered and developed by MMV are widely available to patients in disease-endemic regions, the whole venture will be of little practical use. Therefore, MMV is working at several levels in an effort to e n s u re optimal uptake of its pro d u c t s downstream:
• MMV has set as a goal the discovery of agents that have low intrinsic costs. Thus, p rojects will be identified in which manufacturing costs can be kept as low as possible.
• By taking on a large portion of R&D costs and also by taking on the responsibility for managing the projects and assessing their viability as sources of new drugs, MMV is substantially lowering both the cost and the risk for companies wishing to c o m m e rcialize MMV products downstream.
• Because of this engagement by MMV and the fact that it will actively seek IPR p rotection, MMV is in a position to negotiate appropriate arrangements for the out-licensing of its products for commercialization.
• MMV is a partnership supported by several organizations (e.g. WHO, IFPMA, World Bank) that are actively engaged in addressing the issue of improving access to products in developing countries. These discussions are maturing and it is anticipated that as MMV pro d u c t s approach the stage of commercialization,
MMV will be able to avail itself of the new initiatives that are likely to be developed over the coming years.
6. Conclusion
By engaging in antimalarial drug R&D within a not-for-profit, yet business-like framework, and by aligning itself constructively with both public and private sectors, MMV has already made a significant start towards producing much needed new antimalarial drugs. The vision that one day these will become public goods with a significant impact on this disease seems attainable within the time-frame.
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1. Size of the problem
T h roughout the 20th century, mental health was the “poor relation” of health and medicine. Mental disorders were mystified and stigmatized, and mental health services were centralized, institutionalized, pro f e s s i o n a l i z e d and de-personalized. It was widely believed that mental disorders were culture - b o u n d s y n d romes of the West and the North, that the incidence and prevalence in low- and middle-income countries were low, that most cases w e re not amenable to effective treatment and that existing treatment regimes would be
u n a ff o rdable in low- and middle-income c o u n t r i e s .
The concept of burden of disease introduced and estimated for a wide range of diseases in the 1993 World Bank Report dramatically changed this picture. It was shown that mental and neurological disorders cause a higher burden than all forms of cancer. And that in both high- and low- to middle-income countries they account for over 10% of the total disease burden. At least one in four