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Stimulating pharmaceutical research and development for neglected diseases
Health Policy 64 (2003) 75 /88 www.elsevier.com/locate/healthpol
Stimulating pharmaceutical research and development for neglected diseases Monique F. Mrazek *, Elias Mossialos LSE Health and Social Care, London School of Economics and Political Science, Houghton Street, London WC2A 2AE, UK Received 19 November 2001; accepted 28 June 2002
Abstract New vaccines and drug treatments are needed for tackling the neglected diseases (NDs) of poor countries. These diseases are associated with high levels of mortality and/or morbidity, but lack appropriate vaccines and drug treatments because of bacterial resistance, toxicity, long-treatment protocols, problems with administration or because none are available. Current initiatives directed at research and development (R&D) of NDs are being led predominantly by the governmental, inter-governmental and private not-for-profit sectors implemented by way of public /private partnerships. Push and pull mechanisms targeted at the pharmaceutical industry have also been proposed as another way to stimulate R&D of NDs; however, these should be viewed with some caution. Stimulating R&D for NDs is important as part of a wider long-term public health strategy and must be addressed simultaneously with resolving more immediate problems of access to medicines and health system sustainability in less developed countries. # 2002 Published by Elsevier Science Ireland Ltd. Keywords: Neglected diseases; Pharmaceutical research and development; Public /private partnerships
1. Introduction Research and development (R&D) is needed for combating common diseases in poorer developing countries. There has been a proliferation of recommendations, proposals and debate on how to stimulate R&D to develop vaccines and drug treatments for diseases where these are either inappropriate or lacking [1 /5], including a special issue of the Bulletin of the World Health Organi-
* Corresponding author. Tel.: /44-207-9556470; fax: /44207-9556803 E-mail address: [email protected] (M.F. Mrazek).
sation (WHO) [6]. These mainly infectious diseases are referred to by many names: tropical or endemic diseases [7], diseases of the poor [8], widespread diseases [4], orphan diseases and neglected diseases (NDs) [9]. The term NDs is adopted as it is inclusive of all diseases for which there is a lack of investment in R&D to develop new vaccines and drug treatments. Proposals to stimulate R&D have mainly focused on the implementation of push and pull mechanisms as a way of introducing incentives for the pharmaceutical industry to invest more into R&D of NDs. There has also been an increase in the number of public /private partnerships (PPPs) devoted to R&D of NDs. This looks critically at the propo-
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sals to stimulate R&D of NDs and at the activities of PPPs, not in isolation but as part of a wider public health strategy for less developed countries (LDCs). Section 2 examines the size and scope of the problem of NDs followed by problems in preventing and treating them in Section 3. This is followed by an overview of current research strategies targeting NDs in Section 4 and a discussion about what else can be done to further stimulate R&D for NDs in Section 5.
2. The size and scope of the problem of NDs NDs are associated with high levels of mortality and/or morbidity in LDCs but appropriate vaccines and drug treatments are not available. The number of deaths and the burden of disease (estimated by disability-adjusted-life-years (DALYs)), associated with selected diseases that are predominant in LDCs, is shown in Table 1. Three infectious diseases */HIV/AIDS, tuberculosis (TB) and malaria */predominate globally both in terms of mortality and burden of disease. Other diseases less known outside LDCs such as Trypanosomiasis, Chagas disease, Dengue and Onchocerciasis also pose significant health and economic burdens in particular regions. Also included in the table are diarrhoeal diseases and acute lower respiratory infections which are also responsible for high levels mortality and disease burden in low and middle income countries despite the fact that treatments for these diseases do exist but fail to reach those in need. In fact, the data presented in Table 1 may underestimate the current burden caused by these selected infectious diseases because of poor epidemiological data. Nor are these data indicative of the future health and economic burdens these diseases may pose. The risk of Dengue, for example, has spread over a wider area of Asia and the Americas over the last 30 years, and the more severe form of the disease, dengue hemorrhagic fever, is the leading cause of childhood hospitalisation and death in many affected countries [13]. Rates of viseral leishmaniasis [14] and TB [15] are increasing in part because they are common co-infections of HIV/AIDS. The increas-
ing rates of drug resistance for diseases such as malaria [16] and TB [17] also raise cause for concern.
3. Problems in preventing and treating NDs An important and low cost way of tackling NDs is through preventative measures that reduce the transmission of infections. However, preventative measures are often poorly implemented, if implemented at all. A study by Goodman and Mills [18] on malaria control measures in Africa found low rates of implementation for many preventative strategies (e.g. mosquito nets, chemoprophylaxis for children and pregnant woman) and where implemented, poor rates of proper compliance (e.g. retreatment of mosquito nets). Low rates of compliance are associated with the possible negative health effects of insecticide use, but also with the cost of spraying in vast endemic areas [19]. Limited capacity and poor infrastructure in LDCs, impedes full implementation of preventative measures. Therefore, while preventive measures are important and should be the priority, they alone cannot overcome the problem of NDs. As part of the effort to tackle NDs, attempts must be made to overcome wider problems of access to health services and medicines. For some diseases safe and effective vaccines and drug treatments are not available in LDCs because of problems with access due to a lack of affordable drug prices, sustainable financing, rational selection and use, and a reliable systems of drug supply and health care [20]. These problems have prevented vaccines and drug treatments for diarrhoeal diseases, measles, acute lower respiratory infections and other diseases from reaching those in need in LDCs, and consequently, the number of deaths and/or burden of disease associated with these diseases has remained high [10]. Appropriate drug treatment has also been limited by a lack of diagnostic tools and appropriate follow-up. Increased resistance is associated in part with the over-prescribing, inappropriate prescribing or inadequate prescribing of antibiotics [21]. Therefore, simultaneous to other efforts to tackle NDs, the problems of access to drug treatments in LDCs
Table 1 Mortality and burden of disease world-wide, 1999 Africa
Americas
Eastern Mediterranean
Europe
Number of deaths (000)
Burden of disease (DALYs) (000)
Percentage (%) of total world-wide deaths
Percentage (%) of global burden of disease
Percentage (%) of total world-wide deaths
3963
96682
27
33
2673 2213
89819 72063
81 35
1669 1086 66 57 21 14 13 0
33287 44998 2048 1983 677 1932 465 4918
0
1085
South-East Asia
Western Pacific
Percentage (%) of global burden of disease
Percentage (%) of total world-wide deaths
Percentage (%) of global burden of disease
Percentage (%) of total world-wide deaths
Percentage (%) of global burden of disease
Percentage (%) of total world-wide deaths
Percentage (%) of global burden of disease
Percentage (%) of total world-wide deaths
Percentage (%) of global burden of disease
7
4
9
11
6
3
38
38
13
12
83 34
3 3
3 3
1 14
2 14
1 1
1 2
13 44
10 42
1 3
1 5
21 88 97 25 0 43 0 0
26 82 97 13 0 85 5 37
4 0 0 0 100 14 0 0
3 0 0 3 100 7 0 0
7 4 3 7 0 14 0 0
7 6 3 11 0 5 0 0
4 0 0 0 0 7 0 0
4 0 0 0 0 1 0 0
43 6 0 70 0 7 100 0
42 7 0 74 0 1 95 57
22 1 0 0 0 14 0 0
18 5 0 0 0 2 0 6
0
100
0
0
0
0
0
0
0
0
0
0
Note: Burden of disease is calculated as DALYs lost. This statistic combines death rates with information about disability to generate an estimate of overall population health [10]. However, these calculations should be treated with caution because of methodological issues involved in the calculation of DALYs [11,12]. Source: World Health Organization [10].
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Acute lower respiratory infections HIV/AIDS Diarrhoeal diseases Tuberculosis Malaria Trypanposomiasis Leishmaniasis Chagas disease Schistosomiasis Dengue Lymphatic filariasis Onchocerciasis
World-wide
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vaccine development is important in poorer countries where a lack of appropriate diagnostic and follow-up care may compromise effective drug treatment even if the latter is available. Increasing drug resistance is a serious threat to a number of current drug treatments for NDs. For example, a WHO study of 50 000 TB cases in 35 developing countries between 1994 and 1997 found that 14% of cases were drug resistant [30]. Resistance to chloroquine treatment for malaria has increased to the extent that it is no longer an effective treatment in over 80 of 92 countries where malaria is a major public health problem [31]. In some parts of India over 60% of cases of visceral leischmaniasis no longer respond to the first-line drug treatment [31]. Alternative treatments for drug resistant strains may be available, but these drugs may be more toxic and less effective requir-
need to be addressed at the macro level through increased funding, improving health system capacity and the pricing of medicines according to ability to pay [22,23], and at the micro level by improving the quality of drugs supplied distributional systems and rational prescribing in LDCs [24]. To fully tackle NDs, adequate vaccines and drug treatments are also needed. Some of the problems with current treatments for NDs are summarised in Table 2. Problems with current treatments include growing bacterial resistance to therapies (e.g. malaria, TB), toxicity (e.g. Chagas), long-treatment protocols (e.g. TB, Chagas), and administration (e.g. African trypanosomiasis). For other diseases such as HIV/AIDS, malaria and TB, as well as viral diseases such as Dengue, new preventative vaccines are needed. Preventative Table 2 Examples of problems associated with current treatments for NDs Disease
Treatment(s)
Tuberculosis
/BCG vaccine
Problem
The protectiveness in older age groups in different countries varies and therefore the impact of BCG on the epidemiology of TB in adults has not been great Tuberculosis /Single-drug and multi-drug treatments Long-treatment protocols and increasing resistance Malaria /Cholroquine, sufadoxine/pyrimethaWidespread resistance of P. falciparum but resistance of mine, mefloquine, halofantrine, quinine non-P. falciparum malaria species has also been reported African typanoso- /Eflornithine for early and late-stage Expensive. Injectible form only. Manufacturing of bulk miasis Gambian typanosomiasis material ceased in 1995 but Aventis (then Hoeschst Marion Roussel) donated rights and remaining stocks to WHO. Several companies have agreed to make and donate 60 000 doses estimated to last 3 years African typanoso- /Suramin against bloodstream stages Bayer planned to stop production but for the intervention miasis of WHO African typanoso- /Pentamidine against bloodstream Price increase since its potential to treat pneumocystis miasis stages carinii pneumoniae in AIDS patients was established Visceral leishma- /Antimonials Expensive. Comprising of daily injections in a hospital niasis setting for 1 month and is associated with side-effects. Drugs resistance also a problem Dengue /No specific treatment Treatment is based on treating symptoms. Vaccines in development Chagas /No specific treatment Experimental treatment may include nifurtimox and benznidazole but these are associated with long treatment courses, severe side-effects, poor tolerance and low compliance Schistosomiasis /Praziquantel and Oxamniquine Resistance Lympatic filriasis /Diethylcarbamazine and Ivermectin Neither fully kills adult worms Onchocerciasis /Ivermectin Does not kill adult worms Onchocerciasis /Suramin Must be administered by IV over several weeks
Reference [25]
[17] [16] [26]
[9] [9] [27]
[28] [29]
[29] [29] [29] [29]
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ing prolonged periods of treatment, as is the case for treating multi-resistant strains of TB [30]. Often these alternative treatment strategies for resistant strains are not available in LDCs because they are too expensive and too difficult to treat in already strained health care systems [32]. Problems also arise in administering some current drug treatments for NDs because they are not adapted to field conditions. As Table 2 shows, treatments such as Eflornithine for African trypanosomiasis or Suramin for Onchocerciasis have to be administered by injection or IV; oral formulations that would be more easily administered and affordable are not available. Also, longtreatment protocols as with TB or Chagas disease are impractical in length and administration. Consequently, as is the case for TB, compliance is poor and many patients do not complete the regime so that a resistant strain often emerges [33]. Shorter treatment courses that are adapted to administration in the field are needed. Although more appropriate forms of treatment to tackle NDs may seem obvious, until recently, there has been little investment in R&D for these diseases. For example, between 1980 and June 1999, tropical diseases accounted for approximately 1.5% of all biomedical citations on PubMed and of only 0.5% of all pharmaceutical patents world-wide between 1975 and 1995 [34]. Not surprisingly, of 1223 drugs licensed worldwide between 1975 and 1996, less than 1% of all new therapeutic innovations (11 new molecules and two reformulations of known molecules) were for tropical diseases [35]. Although NDs are particular problems for LDCs, many poor countries lack the resources and the capacity to conduct pharmaceutical R&D, although there are some exceptions (e.g. India, Thailand, Brazil) [36]. This lack of product development for NDs reflects what is commonly known as the 10/90 gap in health research because it was estimated only 10% of health research funds were targeted to diseases with 90% of the global disease burden. The recognition of this gap led to the establishment of the Global Forum for Health Research in 1998 to help correct this imbalance by facilitating collaboration between partners in both the public and private sectors through networks and the
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development of priority setting methodologies to focus research efforts. Although it is difficult to determine the extent to which this gap in funding is closing as few agencies are reported to collect data on research by disease and condition [37], nevertheless funding for health research in and relevant to low and middle income countries has been reported to be increasing due to the greater involvement of organizations such as the Bill and Melinda Gates Foundations, national research institutions, the pharmaceutical industry and most recently the Global Fund to Fight AIDS, Tuberculosis and Malaria [38].
4. Current R&D initiatives targeting NDs Much of the current R&D effort to tackle NDs has been initiated through the governmental, intergovernmental and private not-for-profit sectors. A number of these R&D initiatives to tackle NDs are being implemented as PPPs. However, both funding and focus is scattered. Often, efforts targeting similar outcomes are being run in parallel without an effective exchange of information. This has called into question both the governance and priorities of many of these initiatives. Some examples of major PPP initiatives to develop new vaccines or drug treatments for NDs are highlighted in Table 3. For most of these PPPs, R&D is their primary objective, while some, like the international Aids vaccine initiative (IAVI), target R&D along-side efforts to assure world-wide access to a vaccine once developed. The size and scope of the R&D efforts range from one targeted disease to multiple diseases. One of the few initiatives to engage in projects operated as PPPs covering multiple diseases is the Special Programme for Research and Training in Tropical Diseases (TDR). The TDR was initiated in 1974, co-funded by the United Nations Development Programme, World Bank and WHO. Between 1974 and 1995, the TDR, in collaboration with the private for-profit sector, developed ten products for the treatment of tropical diseases that were or are in clinical use [39]. Some of these collaborative efforts have involved only not-forprofit sector partners (e.g. the partnership to
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Table 3 Examples of PPPs targeting research and development of NDs Mission
Diseases covered
Governance
Budget
Sources of funding
Outcomes
For more information (websites accessed 12 June 2002)
Special Programme For TDR
R&D and training and strengthening capacity for implementation
Co-sponsored by UNDP, World Bank and WHO. Collaborations with a number of governments, agencies and industry
Total contributions in 2000 were US$30 297 702
Three co-sponsors, 22 governments (including some LDCs), 8 public and private foundations, agencies and companies
E.g. 8800 projects in 129 countries between 1975 and 1999
http://www.who.int/tdr/
International Aids Vaccine Initiative
Development of safe, effective and accessible HIV vaccines particularly for developing countries
Trypanosomiasis, Chagas, Dengue, Leishmaniasis, Leprosy, Lymphatic filariasis, Malaria, Onchocerciasis, Schistosomiasis, Tuberculosis HIV
A vaccine fund that identifies partners supporting promising vaccine candidates
Government agencies, international organisations, and other foundations
E.g. Four pro- http://www.iavi.org/ mising vaccine candidates identified each targeting different strains
Medicines For Malaria Venture
Discover, develop Malaria and commercialise 1 new antimalarial every 5 years
International not-for- Not available profit organisations dedicated to working in partnership with scientists, vaccinologists and development projects to identify promising vaccines
Not available Government agencies, public foundations, private companies (drug discovery expertise and related technologies) Established in 1999 Not available as an initiative of the Programme for Appropriate Technology and Health with a US$50 million grant from the Bill and Melinda Gates Foundation
Malaria Vac- Development of a Malaria cine Initiative malaria vaccine
Invested almost US$20 million in four innovative Vaccine Development partnerships since 1996 Virtual not-for-profit Target funR&D company draising budget US$30 million
http://www.malariamedicines.org/
http://www.mmv.org/
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Organisation
Table 3 (Continued ) Organisation
Mission
Diseases covered
Global Alliance for TB Drug Development
Shorten and sim- Tuberculosis plify TB treatment; provide more effective treatment for latent TB infections and multi-drug resistant TB
Action TB
Aim is to develop Tuberculosis new anti-tuberculosis drugs in partnership with academic and public institutions
Budget
Sources of funding
Outcomes
For more information (websites accessed 12 June 2002)
Established by the European Commission and interested European Union Member States in 1998
Not available
European Commission and some European Union Member States
Not available
http://www.emvi.org/
Not available Established by USAID but works with both public and private partners
USAID
Not available Not-for-profit PPP that outsources R&D projects to the public and private sector. They provide funding, scientific and management support but retain some of the IP rights Funded and co-ordi- £10 million per nated by Glaxo year Wellcome (now GlaxoSmithKline)
Government agencies, public foundations, private companies
http://www.usaid.gov/poTested two inp_health/cs/csmvdp.htm vestigational vaccines against malaria in humans in 1996 / 1998; however not successful Not available http://www.tballiance.org/
GlaxoSmithKline
Not available
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Malaria European Provide a meMalaria Vac- chanism through cine Initiative which the development of experimental malaria vaccines can be accelerated within Europe and in developing countries Malaria USAID Ma- Focused on the laria Vaccine development of Development vaccines that will reduce malaria-asProgram sociated mortality and morbidity
Governance
http://corp.gsk.com/community/tbinitiative.htm
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develop a combination therapy for malaria between Me´desins Sans Frontie`res and the International Dispensary Association [40]), while others have added for-profit partners (e.g. the partnership with GlaxoSmithKline, the University of Liverpool, the Wellcome Trust and UK Department for International Development (DFID) developed LAPDAP, a new first-line antimalarial drug in late-stage clinical development [41]). All these PPP initiatives bring together funds and/or expertise from governmental, inter-governmental and not-for-profit organizations along-side funds and/or expertise from the for-profit sector. The public/private mix and the type of lead partners differ from international organisations and governments, to the pharmaceutical industry. Public institutions (e.g. US National Institutes for Health), government organisations (e.g. DFID), international organisations (e.g. WHO) and private foundations (e.g. Rockerfeller Foundation, Wellcome Trust) often directly support basic research on NDs, as well as provide funding for R&D through PPPs. The administrative and governance structures of these partnerships vary. Some of these PPP initiatives are led by established governmental, inter-governmental and private not-for-profit organisations working with other similar and/or forprofit sector partners. Other PPPs have been established as independent legal entities outside existing organisations that are sometimes referred to as ‘social venture capital funds’ [42] or ‘virtual companies’ (e.g. medicines for malaria venture (MMV), global alliance for TB drug development). These PPPs control funds and take key decisions centrally, but conduct R&D via external partners in academia, public institutions, and companies. There are a number of issues such as research objectives, product selection, intellectual property (IP) rights and product pricing where partners in a PPP venture may find themselves at odds. For this reason, it is important that PPPs set out clear criteria up-front for selecting and rejecting projects, so that their objectives do not get redirected by other agendas. MMV, for example, has targeted priorities to produce medicines for malaria that would be affordable in LDCs [42]. To ensure that the public interest is protected in these
ventures, as well as the integrity and the legitimacy of the PPPs, clear guidelines should be used to govern the interactions between governmental, not-for-profit sectors and the for-profit sector [43]. The distribution of IP rights is another area that should be treated up-front. It is important to monitor how both costs and IP rights are shared between public and private partners. Current distribution of IP rights differs between PPPs. IAVI, for example, has negotiated agreements where although the private partner retains the IP rights, IAVI has the right to obtain licenses to contract with other manufacturers if the original company should decline to produce the vaccine for developing countries in reasonable quantities at a reasonable price. In the case of MMV, the IP rights in LDCs belong to MMV while private partners retain IP rights outside LDCs. In some collaboration the TDR has been able to arrange for both raw materials and formulated products arising from the partnership to be treated as a public good belonging to the public sector [40]. Further co-ordination and collaboration between PPPs would help to ensure information exchange and to avoid duplication. To some extent this is already occurring. The Global Forum for Health Research currently supports information exchange through the development of networks and partnerships between those involved in research for NDs including the Global Alliance for TB Drug Development, Multilateral Initiative on Malaria, and MMV [38]. Elsewhere three initiatives aimed at vaccine development */European Malaria Vaccine Initiative, USAID Malaria Vaccine Development Program and the Malaria Vaccine Initiative*/have agreed to work together to facilitate malaria vaccine development [44]. Some co-ordination of research activities also occurs through the TDR. A more systematic information exchange and collaboration process could also be part of the mandate of the Global Fund to Fight AIDS, Tuberculosis and Malaria [45] for its three target diseases as the G8 articulated in establishing the fund that it should promote improved co-ordination among donors and provide further incentives for private sector R&D [46].
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The role of WHO, the World Bank and other international organisations coordinating activities to set global priorities for R&D of NDs and in addressing issues of transparency of PPPs should also be considered. This is important particularly given that public funding is going into PPPs. PPPs should be transparent, accountable to the public interest, and have a clear governance structure [47]. The highest priority for R&D of NDs should be assigned to those diseases with a large unmet need and a high economic burden but where there is low for-profit sector R&D investment. Research attention should not only be focused on new drug development, but also on finding new regimes, combinations or formulations of existing treatments to facilitate administration in the field. Vaccine development is also essential particularly for widespread diseases in LDCs where diagnosis and follow-up care essential for appropriate drug utilisation may not be secured.
5. What else can and should be done to stimulate R&D for NDs? Recent governmental and academic proposals have supported the introduction of push and pull mechanisms to stimulate R&D of NDs. Push mechanisms attempt to reduce the cost of R&D through incentives for the pharmaceutical industry such as either direct public funding for R&D (i.e. research grants), tax credits for R&D, investment in clinical trial infrastructure and fast tracking. Pull mechanisms on the other hand are used to enhance the attractiveness of the market to firm entry through enhanced IP rights (longer patents on certain products or roaming exclusivity), tax credits on sales, and advance purchase funds. Common proposals have included push mechanisms such as R&D tax credits [4,48] and public funding for R&D [5], as well as pull mechanisms such as tax credits on sales [1,5,49], enhanced IP protection (i.e. extended patents and roaming exclusivity) [2,5] and an advanced purchase fund [5,22,50]. These incentives are meant to correct for the lack of investment in product development for NDs by the for-profit sector.
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It is argued that the private pharmaceutical industry does not find markets for NDs economically attractive. Although for a number of NDs there is a high level of unmet need, the size of the actual market in LDCs able to purchase new medicines at global prices is very small. Despite developing countries representing 85% of the global population in 1999 [10], they account for only approximately 16% of global pharmaceutical sales with African countries accounting for less than 5% [51]. R&D decisions in the private sector are based on expected returns to maintain profits and income flows to marketing and administration, as well as R&D. Strategic R&D decisions are also driven by how stock market investors will perceive a drug company’s product pipeline and the size of the market for potential returns. Consequently, pharmaceutical companies seek markets for new product developments where they are assured to see a profit on their investment */traditionally North America, Europe and Japan. Furthermore, even if a potential discovery was made in a governmental or notfor-profit research laboratory, it is unlikely that a for-profit company would pursue it for commercial reasons [38]. It has also been argued that weak or nonexistent patents in many LDCs also deter R&D investment in NDs. With a number of LDCs soon to become TRIPS compliant (by 2016 for least developed countries), pharmaceutical companies will be able to access the same patent privileges afforded them in industrialised countries. However, it is unlikely that ensuring patent rights will do much, at least in the short-term, for ensuring access to medicines or stimulating R&D for NDs because of the potentially higher drug prices that may follow. While the suggested push and pull mechanisms seem to be attractive, careful consideration must be given to whether such incentives would actually be effective, and more importantly, whether they could create any undesirable or perverse incentives. For example, extended market exclusivity may not be an appropriate incentive to develop new vaccines or treatments for NDs. Market exclusivity provisions are a common part of orphan drug legislations. These exclusivity periods
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prevent the approval of marketing applications for the same drug, for the same indication, for a maximum of 7 years in the US and 10 years in the EU. In the late 1980s these exclusivity periods raised concerns in the US about companies charging high prices and making large profits on sponsored orphan products [52]. If similar exclusivity periods were to be granted as incentives on product discoveries for NDs, it could serve to enhance problems of access associated with high prices. Roaming market exclusivity would allow a company to transfer a patent granted on a product for a ND to any other product they preferred in developed countries [53]. However, the application of such a concept would be fraught with complications. Questions would arise as to which products should be selected, for how long should they gain additional exclusivity and in which countries would this extended exclusivity apply. Extended exclusivity on some products and not on others in a given therapeutic market, for example, could seriously undermine competition. Roaming exclusivity could also contravene current patent systems, and arguments may be raised from other industrial sectors as to why pharmaceuticals should be entitled to these enhanced IP rights. Tax credits on R&D expenditures have been used across industries to stimulate R&D, as well as in the pharmaceutical sector specifically to stimulate R&D for orphan diseases. According to a report by the UK Treasury [54], firms are permitted to write off all current expenditure on R&D against their taxable profits in the year the expenditure was made across industry sectors in Canada, France, Germany, Italy, Japan, United Kingdom and United States. Some of these countries go further allowing firms to write off most or all of their R&D capital expenditure (e.g. UK, Canada, France, Germany, US) and/or have a tax credit for small and medium sized enterprises (e.g. UK, Canada, Italy). The US orphan drug legislation, for example, provides tax credits of up to 50% on qualified clinical research expenses incurred in developing the product. There is some evidence that tax credits on R&D expenditures does have a positive but somewhat limited impact on the levels of R&D across industry
sectors [55]. However, the question is if other R&D tax credits are already in place to stimulate pharmaceutical R&D then how high would a tax credit aimed at R&D of NDs have to be in order to compete against other tax credits? Would an R&D tax credit for NDs be separate or combined with other tax breaks? It may well be the case that the marginal benefit of tax credits versus direct financing of PPPs may tip the balance in favour of the latter. This needs to be further examined through consultations with both public and private stakeholders before actions are taken. Proposals for tax credits on sales should also be viewed with some caution. It is questionable whether tax credits on sales would directly stimulate R&D on NDs as there is a considerable delay between investment and outcome. The success of any tax credit would seem more dependent on securing a market through an advanced purchase fund. Without a guaranteed purchase arrangement, a tax credit on sales is unlikely to have any impact on R&D. A tax credit on sales, however, may have an impact on a firm’s decision to manufacture and distribute a product after development as a way of offsetting production costs. However, this is decidedly apart from an R&D incentive. If a tax credit on product sales were to be introduced, it is imperative that it be tied to sales in LDCs at affordable prices [38]. Even an advanced purchase fund may not be a secure enough or sustainable proposition to stimulate R&D. Such a fund would rely on the continued goodwill of individual countries and may not provide enough security for firms to invest heavily in long-term projects. One estimate that the size of the annual purchase pre-commitment needed to motivate pharmaceutical firms would have to be approximately US$250 million [56]. This is a sizeable commitment, particularly given the lengthy period required for product development. The problems of the Global Fund to Fight AIDS, Tuberculosis and Malaria to raise funds to achieve targets highlights how difficult it would be to give certain pre-purchase commitments to stimulate R&D for NDs. Again, the concept of an advanced purchase fund does raise the issues of co-ordination and sustainable financing.
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Despite these caveats it is important that any legislation enacted to stimulate R&D for NDs apply a clear and appropriate definition of what is a ND, as well as fair and appropriate criteria of burden of disease in order to determine designation for a subsidy. The proposed US legislation on vaccines for the New Millennium Act of 20011 excluded R&D for those diseases where the level of annual mortality was less than 1 000 000, where there is a high burden of disease and not necessarily a high rate of mortality, as well as those diseases that pose a high burden of disease in particular regions [4]. Similarly, it is also important to define what types of product development would receive a subsidy. Here again the proposed vaccines for the New Millennium Act of 2001 limited product development to vaccines and microbicides. Guidance to assist individual countries and international agencies in defining priority diseases for R&D, priority areas for product development, as well as providing guidance on appropriate and effective incentives to stimulate R&D needs to be more systematically co-ordinated along with reporting mechanisms and periodic evaluations of PPPs conducting R&D of NDs.
6. Conclusions Stimulating R&D of new, safe, effective and appropriate vaccines and drug treatments for NDs is an important part of furthering health improvements and economic development in LDCs. For a number of infectious diseases that are more common in poor countries, appropriate vaccines and drug treatments are lacking. The spread of these infections and the associated health and economic costs, are certain to grow without continued support and expansion of current PPP initiatives focused on R&D of NDs among other 1
Was referred to the following committees on 4 April 2001 for consideration: Committee on Ways and Means, Committee on Energy and Commerce (subsequently referred to the Subcommittee on Health for a period to be determined by the Chairman on 25 April 2001) and the International Relations Committee [57].
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public health initiatives. These R&D initiatives should not only focus their attention on new product developments, but they should also ensure that current and new products are appropriate for administration in the field. The involvement of the governmental, intergovernmental and private not-for-profit sectors in stimulating R&D for NDs will continue to be essential. Sustained support of basic research, as well as subsidy at later stages of product development, particularly through PPPs, should be a key part of any future initiatives. Push/pull incentives to stimulate R&D of NDs directed at the private pharmaceutical industry should be reviewed carefully. It may be more cost-effective to directly subsidise PPPs provided issues of co-ordination, priority-setting, governance, accountability and transparency are also addressed. PPPs in the development of treatments for NDs are a sort of social experiment that have reached the point in their evolution where it is important to determine what structures and approaches work best, while ensuring that duplication is avoided as much as possible through information exchange and appropriate practices. Governmental, inter-governmental and private not-for-profit sector support of R&D for NDs should not only be a way of risk sharing in the process, but also of ensuring priorities, collaboration, and diffusion of new product developments. A global co-ordinated effort is required to facilitate the public and for-profit sectors working together in current and new product development initiatives for NDs. The sustainability of the individual and collective actions of industrialised countries, LDCs and international agencies is important. The collaboration of the for-profit sector in LDCs in R&D and clinical trials will be essential to ensure technology transfer. It is important to keep both short-term and longer-term objectives in mind as NDs are tackled. In the short-term solutions need to be found to secure access in LDCs to available vaccines and treatments. LDCs need to continue to work toward sustained budget commitments to better the reliability of drug supply, distribution and use, and the quality of their health care systems. Efforts to ensure access to basic immunisations (i.e.
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diphtheria, tetanus, pertussis [58], measles, meningitis), prevention through chemoprophylaxis (i.e. for malaria) and drug treatments (i.e. for acute respiratory infections and diarrhoeal diseases) should be pursued. Current and future treatments for NDs must be made available to LDCs at prices they can afford. Proposed mechanisms to reduce drug prices such as differential pricing combined with advanced purchasing, for example, would require support from both LDCs (i.e. export controls, review of drug taxes and tariffs) and industrialised countries (i.e. import controls), as well as the pharmaceutical industry. A long-term strategy for health care, urban planning, housing, employment and environmental controls is imperative in LDCs in advance of disease eradication so that these countries will be prepared to cope with longer life expectancies. The clinical fight against disease must be fought sideby-side environmental initiatives such as the draining of marshlands or stagnant water supplies to reduce the concentration of mosquitoes in the habitat. In terms of health care, while new vaccines and drug treatments are certainly important, the need for trained personnel, facilities, equipment and a sustained political and financial commitment to health care improvement in LDCs cannot be understated. R&D of NDs therefore must be seen to be a part of a wider public health strategy and not viewed in isolation. But as we work towards improvements in the short-term, it is equally cost-effective and important to keep in mind the long-term and the need for research priorities that include NDs. As product development can take 20 years or more it is important to seriously begin to address the problem of stimulating R&D for NDs.
Acknowledgements The authors of this paper benefited extensively from the points raised and issues discussed during a conference on ‘Stimulating research and development of neglected diseases’ organised by the London School of Economics and Political Science and Me´decins Sans Frontie`res in June 2001. We would also like to thank Professor Walter Holland
and the journal’s anonymous referees for their helpful comments.
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Stimulating pharmaceutical research and development for neglected diseases Monique F. Mrazek *, Elias Mossialos LSE Health and Social Care, London School of Economics and Political Science, Houghton Street, London WC2A 2AE, UK Received 19 November 2001; accepted 28 June 2002
Abstract New vaccines and drug treatments are needed for tackling the neglected diseases (NDs) of poor countries. These diseases are associated with high levels of mortality and/or morbidity, but lack appropriate vaccines and drug treatments because of bacterial resistance, toxicity, long-treatment protocols, problems with administration or because none are available. Current initiatives directed at research and development (R&D) of NDs are being led predominantly by the governmental, inter-governmental and private not-for-profit sectors implemented by way of public /private partnerships. Push and pull mechanisms targeted at the pharmaceutical industry have also been proposed as another way to stimulate R&D of NDs; however, these should be viewed with some caution. Stimulating R&D for NDs is important as part of a wider long-term public health strategy and must be addressed simultaneously with resolving more immediate problems of access to medicines and health system sustainability in less developed countries. # 2002 Published by Elsevier Science Ireland Ltd. Keywords: Neglected diseases; Pharmaceutical research and development; Public /private partnerships
1. Introduction Research and development (R&D) is needed for combating common diseases in poorer developing countries. There has been a proliferation of recommendations, proposals and debate on how to stimulate R&D to develop vaccines and drug treatments for diseases where these are either inappropriate or lacking [1 /5], including a special issue of the Bulletin of the World Health Organi-
* Corresponding author. Tel.: /44-207-9556470; fax: /44207-9556803 E-mail address: [email protected] (M.F. Mrazek).
sation (WHO) [6]. These mainly infectious diseases are referred to by many names: tropical or endemic diseases [7], diseases of the poor [8], widespread diseases [4], orphan diseases and neglected diseases (NDs) [9]. The term NDs is adopted as it is inclusive of all diseases for which there is a lack of investment in R&D to develop new vaccines and drug treatments. Proposals to stimulate R&D have mainly focused on the implementation of push and pull mechanisms as a way of introducing incentives for the pharmaceutical industry to invest more into R&D of NDs. There has also been an increase in the number of public /private partnerships (PPPs) devoted to R&D of NDs. This looks critically at the propo-
0168-8510/02/$ - see front matter # 2002 Published by Elsevier Science Ireland Ltd. PII: S 0 1 6 8 - 8 5 1 0 ( 0 2 ) 0 0 1 3 8 - 0
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M.F. Mrazek, E. Mossialos / Health Policy 64 (2003) 75 /88
sals to stimulate R&D of NDs and at the activities of PPPs, not in isolation but as part of a wider public health strategy for less developed countries (LDCs). Section 2 examines the size and scope of the problem of NDs followed by problems in preventing and treating them in Section 3. This is followed by an overview of current research strategies targeting NDs in Section 4 and a discussion about what else can be done to further stimulate R&D for NDs in Section 5.
2. The size and scope of the problem of NDs NDs are associated with high levels of mortality and/or morbidity in LDCs but appropriate vaccines and drug treatments are not available. The number of deaths and the burden of disease (estimated by disability-adjusted-life-years (DALYs)), associated with selected diseases that are predominant in LDCs, is shown in Table 1. Three infectious diseases */HIV/AIDS, tuberculosis (TB) and malaria */predominate globally both in terms of mortality and burden of disease. Other diseases less known outside LDCs such as Trypanosomiasis, Chagas disease, Dengue and Onchocerciasis also pose significant health and economic burdens in particular regions. Also included in the table are diarrhoeal diseases and acute lower respiratory infections which are also responsible for high levels mortality and disease burden in low and middle income countries despite the fact that treatments for these diseases do exist but fail to reach those in need. In fact, the data presented in Table 1 may underestimate the current burden caused by these selected infectious diseases because of poor epidemiological data. Nor are these data indicative of the future health and economic burdens these diseases may pose. The risk of Dengue, for example, has spread over a wider area of Asia and the Americas over the last 30 years, and the more severe form of the disease, dengue hemorrhagic fever, is the leading cause of childhood hospitalisation and death in many affected countries [13]. Rates of viseral leishmaniasis [14] and TB [15] are increasing in part because they are common co-infections of HIV/AIDS. The increas-
ing rates of drug resistance for diseases such as malaria [16] and TB [17] also raise cause for concern.
3. Problems in preventing and treating NDs An important and low cost way of tackling NDs is through preventative measures that reduce the transmission of infections. However, preventative measures are often poorly implemented, if implemented at all. A study by Goodman and Mills [18] on malaria control measures in Africa found low rates of implementation for many preventative strategies (e.g. mosquito nets, chemoprophylaxis for children and pregnant woman) and where implemented, poor rates of proper compliance (e.g. retreatment of mosquito nets). Low rates of compliance are associated with the possible negative health effects of insecticide use, but also with the cost of spraying in vast endemic areas [19]. Limited capacity and poor infrastructure in LDCs, impedes full implementation of preventative measures. Therefore, while preventive measures are important and should be the priority, they alone cannot overcome the problem of NDs. As part of the effort to tackle NDs, attempts must be made to overcome wider problems of access to health services and medicines. For some diseases safe and effective vaccines and drug treatments are not available in LDCs because of problems with access due to a lack of affordable drug prices, sustainable financing, rational selection and use, and a reliable systems of drug supply and health care [20]. These problems have prevented vaccines and drug treatments for diarrhoeal diseases, measles, acute lower respiratory infections and other diseases from reaching those in need in LDCs, and consequently, the number of deaths and/or burden of disease associated with these diseases has remained high [10]. Appropriate drug treatment has also been limited by a lack of diagnostic tools and appropriate follow-up. Increased resistance is associated in part with the over-prescribing, inappropriate prescribing or inadequate prescribing of antibiotics [21]. Therefore, simultaneous to other efforts to tackle NDs, the problems of access to drug treatments in LDCs
Table 1 Mortality and burden of disease world-wide, 1999 Africa
Americas
Eastern Mediterranean
Europe
Number of deaths (000)
Burden of disease (DALYs) (000)
Percentage (%) of total world-wide deaths
Percentage (%) of global burden of disease
Percentage (%) of total world-wide deaths
3963
96682
27
33
2673 2213
89819 72063
81 35
1669 1086 66 57 21 14 13 0
33287 44998 2048 1983 677 1932 465 4918
0
1085
South-East Asia
Western Pacific
Percentage (%) of global burden of disease
Percentage (%) of total world-wide deaths
Percentage (%) of global burden of disease
Percentage (%) of total world-wide deaths
Percentage (%) of global burden of disease
Percentage (%) of total world-wide deaths
Percentage (%) of global burden of disease
Percentage (%) of total world-wide deaths
Percentage (%) of global burden of disease
7
4
9
11
6
3
38
38
13
12
83 34
3 3
3 3
1 14
2 14
1 1
1 2
13 44
10 42
1 3
1 5
21 88 97 25 0 43 0 0
26 82 97 13 0 85 5 37
4 0 0 0 100 14 0 0
3 0 0 3 100 7 0 0
7 4 3 7 0 14 0 0
7 6 3 11 0 5 0 0
4 0 0 0 0 7 0 0
4 0 0 0 0 1 0 0
43 6 0 70 0 7 100 0
42 7 0 74 0 1 95 57
22 1 0 0 0 14 0 0
18 5 0 0 0 2 0 6
0
100
0
0
0
0
0
0
0
0
0
0
Note: Burden of disease is calculated as DALYs lost. This statistic combines death rates with information about disability to generate an estimate of overall population health [10]. However, these calculations should be treated with caution because of methodological issues involved in the calculation of DALYs [11,12]. Source: World Health Organization [10].
M.F. Mrazek, E. Mossialos / Health Policy 64 (2003) 75 /88
Acute lower respiratory infections HIV/AIDS Diarrhoeal diseases Tuberculosis Malaria Trypanposomiasis Leishmaniasis Chagas disease Schistosomiasis Dengue Lymphatic filariasis Onchocerciasis
World-wide
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M.F. Mrazek, E. Mossialos / Health Policy 64 (2003) 75 /88
78
vaccine development is important in poorer countries where a lack of appropriate diagnostic and follow-up care may compromise effective drug treatment even if the latter is available. Increasing drug resistance is a serious threat to a number of current drug treatments for NDs. For example, a WHO study of 50 000 TB cases in 35 developing countries between 1994 and 1997 found that 14% of cases were drug resistant [30]. Resistance to chloroquine treatment for malaria has increased to the extent that it is no longer an effective treatment in over 80 of 92 countries where malaria is a major public health problem [31]. In some parts of India over 60% of cases of visceral leischmaniasis no longer respond to the first-line drug treatment [31]. Alternative treatments for drug resistant strains may be available, but these drugs may be more toxic and less effective requir-
need to be addressed at the macro level through increased funding, improving health system capacity and the pricing of medicines according to ability to pay [22,23], and at the micro level by improving the quality of drugs supplied distributional systems and rational prescribing in LDCs [24]. To fully tackle NDs, adequate vaccines and drug treatments are also needed. Some of the problems with current treatments for NDs are summarised in Table 2. Problems with current treatments include growing bacterial resistance to therapies (e.g. malaria, TB), toxicity (e.g. Chagas), long-treatment protocols (e.g. TB, Chagas), and administration (e.g. African trypanosomiasis). For other diseases such as HIV/AIDS, malaria and TB, as well as viral diseases such as Dengue, new preventative vaccines are needed. Preventative Table 2 Examples of problems associated with current treatments for NDs Disease
Treatment(s)
Tuberculosis
/BCG vaccine
Problem
The protectiveness in older age groups in different countries varies and therefore the impact of BCG on the epidemiology of TB in adults has not been great Tuberculosis /Single-drug and multi-drug treatments Long-treatment protocols and increasing resistance Malaria /Cholroquine, sufadoxine/pyrimethaWidespread resistance of P. falciparum but resistance of mine, mefloquine, halofantrine, quinine non-P. falciparum malaria species has also been reported African typanoso- /Eflornithine for early and late-stage Expensive. Injectible form only. Manufacturing of bulk miasis Gambian typanosomiasis material ceased in 1995 but Aventis (then Hoeschst Marion Roussel) donated rights and remaining stocks to WHO. Several companies have agreed to make and donate 60 000 doses estimated to last 3 years African typanoso- /Suramin against bloodstream stages Bayer planned to stop production but for the intervention miasis of WHO African typanoso- /Pentamidine against bloodstream Price increase since its potential to treat pneumocystis miasis stages carinii pneumoniae in AIDS patients was established Visceral leishma- /Antimonials Expensive. Comprising of daily injections in a hospital niasis setting for 1 month and is associated with side-effects. Drugs resistance also a problem Dengue /No specific treatment Treatment is based on treating symptoms. Vaccines in development Chagas /No specific treatment Experimental treatment may include nifurtimox and benznidazole but these are associated with long treatment courses, severe side-effects, poor tolerance and low compliance Schistosomiasis /Praziquantel and Oxamniquine Resistance Lympatic filriasis /Diethylcarbamazine and Ivermectin Neither fully kills adult worms Onchocerciasis /Ivermectin Does not kill adult worms Onchocerciasis /Suramin Must be administered by IV over several weeks
Reference [25]
[17] [16] [26]
[9] [9] [27]
[28] [29]
[29] [29] [29] [29]
M.F. Mrazek, E. Mossialos / Health Policy 64 (2003) 75 /88
ing prolonged periods of treatment, as is the case for treating multi-resistant strains of TB [30]. Often these alternative treatment strategies for resistant strains are not available in LDCs because they are too expensive and too difficult to treat in already strained health care systems [32]. Problems also arise in administering some current drug treatments for NDs because they are not adapted to field conditions. As Table 2 shows, treatments such as Eflornithine for African trypanosomiasis or Suramin for Onchocerciasis have to be administered by injection or IV; oral formulations that would be more easily administered and affordable are not available. Also, longtreatment protocols as with TB or Chagas disease are impractical in length and administration. Consequently, as is the case for TB, compliance is poor and many patients do not complete the regime so that a resistant strain often emerges [33]. Shorter treatment courses that are adapted to administration in the field are needed. Although more appropriate forms of treatment to tackle NDs may seem obvious, until recently, there has been little investment in R&D for these diseases. For example, between 1980 and June 1999, tropical diseases accounted for approximately 1.5% of all biomedical citations on PubMed and of only 0.5% of all pharmaceutical patents world-wide between 1975 and 1995 [34]. Not surprisingly, of 1223 drugs licensed worldwide between 1975 and 1996, less than 1% of all new therapeutic innovations (11 new molecules and two reformulations of known molecules) were for tropical diseases [35]. Although NDs are particular problems for LDCs, many poor countries lack the resources and the capacity to conduct pharmaceutical R&D, although there are some exceptions (e.g. India, Thailand, Brazil) [36]. This lack of product development for NDs reflects what is commonly known as the 10/90 gap in health research because it was estimated only 10% of health research funds were targeted to diseases with 90% of the global disease burden. The recognition of this gap led to the establishment of the Global Forum for Health Research in 1998 to help correct this imbalance by facilitating collaboration between partners in both the public and private sectors through networks and the
79
development of priority setting methodologies to focus research efforts. Although it is difficult to determine the extent to which this gap in funding is closing as few agencies are reported to collect data on research by disease and condition [37], nevertheless funding for health research in and relevant to low and middle income countries has been reported to be increasing due to the greater involvement of organizations such as the Bill and Melinda Gates Foundations, national research institutions, the pharmaceutical industry and most recently the Global Fund to Fight AIDS, Tuberculosis and Malaria [38].
4. Current R&D initiatives targeting NDs Much of the current R&D effort to tackle NDs has been initiated through the governmental, intergovernmental and private not-for-profit sectors. A number of these R&D initiatives to tackle NDs are being implemented as PPPs. However, both funding and focus is scattered. Often, efforts targeting similar outcomes are being run in parallel without an effective exchange of information. This has called into question both the governance and priorities of many of these initiatives. Some examples of major PPP initiatives to develop new vaccines or drug treatments for NDs are highlighted in Table 3. For most of these PPPs, R&D is their primary objective, while some, like the international Aids vaccine initiative (IAVI), target R&D along-side efforts to assure world-wide access to a vaccine once developed. The size and scope of the R&D efforts range from one targeted disease to multiple diseases. One of the few initiatives to engage in projects operated as PPPs covering multiple diseases is the Special Programme for Research and Training in Tropical Diseases (TDR). The TDR was initiated in 1974, co-funded by the United Nations Development Programme, World Bank and WHO. Between 1974 and 1995, the TDR, in collaboration with the private for-profit sector, developed ten products for the treatment of tropical diseases that were or are in clinical use [39]. Some of these collaborative efforts have involved only not-forprofit sector partners (e.g. the partnership to
80
Table 3 Examples of PPPs targeting research and development of NDs Mission
Diseases covered
Governance
Budget
Sources of funding
Outcomes
For more information (websites accessed 12 June 2002)
Special Programme For TDR
R&D and training and strengthening capacity for implementation
Co-sponsored by UNDP, World Bank and WHO. Collaborations with a number of governments, agencies and industry
Total contributions in 2000 were US$30 297 702
Three co-sponsors, 22 governments (including some LDCs), 8 public and private foundations, agencies and companies
E.g. 8800 projects in 129 countries between 1975 and 1999
http://www.who.int/tdr/
International Aids Vaccine Initiative
Development of safe, effective and accessible HIV vaccines particularly for developing countries
Trypanosomiasis, Chagas, Dengue, Leishmaniasis, Leprosy, Lymphatic filariasis, Malaria, Onchocerciasis, Schistosomiasis, Tuberculosis HIV
A vaccine fund that identifies partners supporting promising vaccine candidates
Government agencies, international organisations, and other foundations
E.g. Four pro- http://www.iavi.org/ mising vaccine candidates identified each targeting different strains
Medicines For Malaria Venture
Discover, develop Malaria and commercialise 1 new antimalarial every 5 years
International not-for- Not available profit organisations dedicated to working in partnership with scientists, vaccinologists and development projects to identify promising vaccines
Not available Government agencies, public foundations, private companies (drug discovery expertise and related technologies) Established in 1999 Not available as an initiative of the Programme for Appropriate Technology and Health with a US$50 million grant from the Bill and Melinda Gates Foundation
Malaria Vac- Development of a Malaria cine Initiative malaria vaccine
Invested almost US$20 million in four innovative Vaccine Development partnerships since 1996 Virtual not-for-profit Target funR&D company draising budget US$30 million
http://www.malariamedicines.org/
http://www.mmv.org/
M.F. Mrazek, E. Mossialos / Health Policy 64 (2003) 75 /88
Organisation
Table 3 (Continued ) Organisation
Mission
Diseases covered
Global Alliance for TB Drug Development
Shorten and sim- Tuberculosis plify TB treatment; provide more effective treatment for latent TB infections and multi-drug resistant TB
Action TB
Aim is to develop Tuberculosis new anti-tuberculosis drugs in partnership with academic and public institutions
Budget
Sources of funding
Outcomes
For more information (websites accessed 12 June 2002)
Established by the European Commission and interested European Union Member States in 1998
Not available
European Commission and some European Union Member States
Not available
http://www.emvi.org/
Not available Established by USAID but works with both public and private partners
USAID
Not available Not-for-profit PPP that outsources R&D projects to the public and private sector. They provide funding, scientific and management support but retain some of the IP rights Funded and co-ordi- £10 million per nated by Glaxo year Wellcome (now GlaxoSmithKline)
Government agencies, public foundations, private companies
http://www.usaid.gov/poTested two inp_health/cs/csmvdp.htm vestigational vaccines against malaria in humans in 1996 / 1998; however not successful Not available http://www.tballiance.org/
GlaxoSmithKline
Not available
M.F. Mrazek, E. Mossialos / Health Policy 64 (2003) 75 /88
Malaria European Provide a meMalaria Vac- chanism through cine Initiative which the development of experimental malaria vaccines can be accelerated within Europe and in developing countries Malaria USAID Ma- Focused on the laria Vaccine development of Development vaccines that will reduce malaria-asProgram sociated mortality and morbidity
Governance
http://corp.gsk.com/community/tbinitiative.htm
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develop a combination therapy for malaria between Me´desins Sans Frontie`res and the International Dispensary Association [40]), while others have added for-profit partners (e.g. the partnership with GlaxoSmithKline, the University of Liverpool, the Wellcome Trust and UK Department for International Development (DFID) developed LAPDAP, a new first-line antimalarial drug in late-stage clinical development [41]). All these PPP initiatives bring together funds and/or expertise from governmental, inter-governmental and not-for-profit organizations along-side funds and/or expertise from the for-profit sector. The public/private mix and the type of lead partners differ from international organisations and governments, to the pharmaceutical industry. Public institutions (e.g. US National Institutes for Health), government organisations (e.g. DFID), international organisations (e.g. WHO) and private foundations (e.g. Rockerfeller Foundation, Wellcome Trust) often directly support basic research on NDs, as well as provide funding for R&D through PPPs. The administrative and governance structures of these partnerships vary. Some of these PPP initiatives are led by established governmental, inter-governmental and private not-for-profit organisations working with other similar and/or forprofit sector partners. Other PPPs have been established as independent legal entities outside existing organisations that are sometimes referred to as ‘social venture capital funds’ [42] or ‘virtual companies’ (e.g. medicines for malaria venture (MMV), global alliance for TB drug development). These PPPs control funds and take key decisions centrally, but conduct R&D via external partners in academia, public institutions, and companies. There are a number of issues such as research objectives, product selection, intellectual property (IP) rights and product pricing where partners in a PPP venture may find themselves at odds. For this reason, it is important that PPPs set out clear criteria up-front for selecting and rejecting projects, so that their objectives do not get redirected by other agendas. MMV, for example, has targeted priorities to produce medicines for malaria that would be affordable in LDCs [42]. To ensure that the public interest is protected in these
ventures, as well as the integrity and the legitimacy of the PPPs, clear guidelines should be used to govern the interactions between governmental, not-for-profit sectors and the for-profit sector [43]. The distribution of IP rights is another area that should be treated up-front. It is important to monitor how both costs and IP rights are shared between public and private partners. Current distribution of IP rights differs between PPPs. IAVI, for example, has negotiated agreements where although the private partner retains the IP rights, IAVI has the right to obtain licenses to contract with other manufacturers if the original company should decline to produce the vaccine for developing countries in reasonable quantities at a reasonable price. In the case of MMV, the IP rights in LDCs belong to MMV while private partners retain IP rights outside LDCs. In some collaboration the TDR has been able to arrange for both raw materials and formulated products arising from the partnership to be treated as a public good belonging to the public sector [40]. Further co-ordination and collaboration between PPPs would help to ensure information exchange and to avoid duplication. To some extent this is already occurring. The Global Forum for Health Research currently supports information exchange through the development of networks and partnerships between those involved in research for NDs including the Global Alliance for TB Drug Development, Multilateral Initiative on Malaria, and MMV [38]. Elsewhere three initiatives aimed at vaccine development */European Malaria Vaccine Initiative, USAID Malaria Vaccine Development Program and the Malaria Vaccine Initiative*/have agreed to work together to facilitate malaria vaccine development [44]. Some co-ordination of research activities also occurs through the TDR. A more systematic information exchange and collaboration process could also be part of the mandate of the Global Fund to Fight AIDS, Tuberculosis and Malaria [45] for its three target diseases as the G8 articulated in establishing the fund that it should promote improved co-ordination among donors and provide further incentives for private sector R&D [46].
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The role of WHO, the World Bank and other international organisations coordinating activities to set global priorities for R&D of NDs and in addressing issues of transparency of PPPs should also be considered. This is important particularly given that public funding is going into PPPs. PPPs should be transparent, accountable to the public interest, and have a clear governance structure [47]. The highest priority for R&D of NDs should be assigned to those diseases with a large unmet need and a high economic burden but where there is low for-profit sector R&D investment. Research attention should not only be focused on new drug development, but also on finding new regimes, combinations or formulations of existing treatments to facilitate administration in the field. Vaccine development is also essential particularly for widespread diseases in LDCs where diagnosis and follow-up care essential for appropriate drug utilisation may not be secured.
5. What else can and should be done to stimulate R&D for NDs? Recent governmental and academic proposals have supported the introduction of push and pull mechanisms to stimulate R&D of NDs. Push mechanisms attempt to reduce the cost of R&D through incentives for the pharmaceutical industry such as either direct public funding for R&D (i.e. research grants), tax credits for R&D, investment in clinical trial infrastructure and fast tracking. Pull mechanisms on the other hand are used to enhance the attractiveness of the market to firm entry through enhanced IP rights (longer patents on certain products or roaming exclusivity), tax credits on sales, and advance purchase funds. Common proposals have included push mechanisms such as R&D tax credits [4,48] and public funding for R&D [5], as well as pull mechanisms such as tax credits on sales [1,5,49], enhanced IP protection (i.e. extended patents and roaming exclusivity) [2,5] and an advanced purchase fund [5,22,50]. These incentives are meant to correct for the lack of investment in product development for NDs by the for-profit sector.
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It is argued that the private pharmaceutical industry does not find markets for NDs economically attractive. Although for a number of NDs there is a high level of unmet need, the size of the actual market in LDCs able to purchase new medicines at global prices is very small. Despite developing countries representing 85% of the global population in 1999 [10], they account for only approximately 16% of global pharmaceutical sales with African countries accounting for less than 5% [51]. R&D decisions in the private sector are based on expected returns to maintain profits and income flows to marketing and administration, as well as R&D. Strategic R&D decisions are also driven by how stock market investors will perceive a drug company’s product pipeline and the size of the market for potential returns. Consequently, pharmaceutical companies seek markets for new product developments where they are assured to see a profit on their investment */traditionally North America, Europe and Japan. Furthermore, even if a potential discovery was made in a governmental or notfor-profit research laboratory, it is unlikely that a for-profit company would pursue it for commercial reasons [38]. It has also been argued that weak or nonexistent patents in many LDCs also deter R&D investment in NDs. With a number of LDCs soon to become TRIPS compliant (by 2016 for least developed countries), pharmaceutical companies will be able to access the same patent privileges afforded them in industrialised countries. However, it is unlikely that ensuring patent rights will do much, at least in the short-term, for ensuring access to medicines or stimulating R&D for NDs because of the potentially higher drug prices that may follow. While the suggested push and pull mechanisms seem to be attractive, careful consideration must be given to whether such incentives would actually be effective, and more importantly, whether they could create any undesirable or perverse incentives. For example, extended market exclusivity may not be an appropriate incentive to develop new vaccines or treatments for NDs. Market exclusivity provisions are a common part of orphan drug legislations. These exclusivity periods
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prevent the approval of marketing applications for the same drug, for the same indication, for a maximum of 7 years in the US and 10 years in the EU. In the late 1980s these exclusivity periods raised concerns in the US about companies charging high prices and making large profits on sponsored orphan products [52]. If similar exclusivity periods were to be granted as incentives on product discoveries for NDs, it could serve to enhance problems of access associated with high prices. Roaming market exclusivity would allow a company to transfer a patent granted on a product for a ND to any other product they preferred in developed countries [53]. However, the application of such a concept would be fraught with complications. Questions would arise as to which products should be selected, for how long should they gain additional exclusivity and in which countries would this extended exclusivity apply. Extended exclusivity on some products and not on others in a given therapeutic market, for example, could seriously undermine competition. Roaming exclusivity could also contravene current patent systems, and arguments may be raised from other industrial sectors as to why pharmaceuticals should be entitled to these enhanced IP rights. Tax credits on R&D expenditures have been used across industries to stimulate R&D, as well as in the pharmaceutical sector specifically to stimulate R&D for orphan diseases. According to a report by the UK Treasury [54], firms are permitted to write off all current expenditure on R&D against their taxable profits in the year the expenditure was made across industry sectors in Canada, France, Germany, Italy, Japan, United Kingdom and United States. Some of these countries go further allowing firms to write off most or all of their R&D capital expenditure (e.g. UK, Canada, France, Germany, US) and/or have a tax credit for small and medium sized enterprises (e.g. UK, Canada, Italy). The US orphan drug legislation, for example, provides tax credits of up to 50% on qualified clinical research expenses incurred in developing the product. There is some evidence that tax credits on R&D expenditures does have a positive but somewhat limited impact on the levels of R&D across industry
sectors [55]. However, the question is if other R&D tax credits are already in place to stimulate pharmaceutical R&D then how high would a tax credit aimed at R&D of NDs have to be in order to compete against other tax credits? Would an R&D tax credit for NDs be separate or combined with other tax breaks? It may well be the case that the marginal benefit of tax credits versus direct financing of PPPs may tip the balance in favour of the latter. This needs to be further examined through consultations with both public and private stakeholders before actions are taken. Proposals for tax credits on sales should also be viewed with some caution. It is questionable whether tax credits on sales would directly stimulate R&D on NDs as there is a considerable delay between investment and outcome. The success of any tax credit would seem more dependent on securing a market through an advanced purchase fund. Without a guaranteed purchase arrangement, a tax credit on sales is unlikely to have any impact on R&D. A tax credit on sales, however, may have an impact on a firm’s decision to manufacture and distribute a product after development as a way of offsetting production costs. However, this is decidedly apart from an R&D incentive. If a tax credit on product sales were to be introduced, it is imperative that it be tied to sales in LDCs at affordable prices [38]. Even an advanced purchase fund may not be a secure enough or sustainable proposition to stimulate R&D. Such a fund would rely on the continued goodwill of individual countries and may not provide enough security for firms to invest heavily in long-term projects. One estimate that the size of the annual purchase pre-commitment needed to motivate pharmaceutical firms would have to be approximately US$250 million [56]. This is a sizeable commitment, particularly given the lengthy period required for product development. The problems of the Global Fund to Fight AIDS, Tuberculosis and Malaria to raise funds to achieve targets highlights how difficult it would be to give certain pre-purchase commitments to stimulate R&D for NDs. Again, the concept of an advanced purchase fund does raise the issues of co-ordination and sustainable financing.
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Despite these caveats it is important that any legislation enacted to stimulate R&D for NDs apply a clear and appropriate definition of what is a ND, as well as fair and appropriate criteria of burden of disease in order to determine designation for a subsidy. The proposed US legislation on vaccines for the New Millennium Act of 20011 excluded R&D for those diseases where the level of annual mortality was less than 1 000 000, where there is a high burden of disease and not necessarily a high rate of mortality, as well as those diseases that pose a high burden of disease in particular regions [4]. Similarly, it is also important to define what types of product development would receive a subsidy. Here again the proposed vaccines for the New Millennium Act of 2001 limited product development to vaccines and microbicides. Guidance to assist individual countries and international agencies in defining priority diseases for R&D, priority areas for product development, as well as providing guidance on appropriate and effective incentives to stimulate R&D needs to be more systematically co-ordinated along with reporting mechanisms and periodic evaluations of PPPs conducting R&D of NDs.
6. Conclusions Stimulating R&D of new, safe, effective and appropriate vaccines and drug treatments for NDs is an important part of furthering health improvements and economic development in LDCs. For a number of infectious diseases that are more common in poor countries, appropriate vaccines and drug treatments are lacking. The spread of these infections and the associated health and economic costs, are certain to grow without continued support and expansion of current PPP initiatives focused on R&D of NDs among other 1
Was referred to the following committees on 4 April 2001 for consideration: Committee on Ways and Means, Committee on Energy and Commerce (subsequently referred to the Subcommittee on Health for a period to be determined by the Chairman on 25 April 2001) and the International Relations Committee [57].
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public health initiatives. These R&D initiatives should not only focus their attention on new product developments, but they should also ensure that current and new products are appropriate for administration in the field. The involvement of the governmental, intergovernmental and private not-for-profit sectors in stimulating R&D for NDs will continue to be essential. Sustained support of basic research, as well as subsidy at later stages of product development, particularly through PPPs, should be a key part of any future initiatives. Push/pull incentives to stimulate R&D of NDs directed at the private pharmaceutical industry should be reviewed carefully. It may be more cost-effective to directly subsidise PPPs provided issues of co-ordination, priority-setting, governance, accountability and transparency are also addressed. PPPs in the development of treatments for NDs are a sort of social experiment that have reached the point in their evolution where it is important to determine what structures and approaches work best, while ensuring that duplication is avoided as much as possible through information exchange and appropriate practices. Governmental, inter-governmental and private not-for-profit sector support of R&D for NDs should not only be a way of risk sharing in the process, but also of ensuring priorities, collaboration, and diffusion of new product developments. A global co-ordinated effort is required to facilitate the public and for-profit sectors working together in current and new product development initiatives for NDs. The sustainability of the individual and collective actions of industrialised countries, LDCs and international agencies is important. The collaboration of the for-profit sector in LDCs in R&D and clinical trials will be essential to ensure technology transfer. It is important to keep both short-term and longer-term objectives in mind as NDs are tackled. In the short-term solutions need to be found to secure access in LDCs to available vaccines and treatments. LDCs need to continue to work toward sustained budget commitments to better the reliability of drug supply, distribution and use, and the quality of their health care systems. Efforts to ensure access to basic immunisations (i.e.
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diphtheria, tetanus, pertussis [58], measles, meningitis), prevention through chemoprophylaxis (i.e. for malaria) and drug treatments (i.e. for acute respiratory infections and diarrhoeal diseases) should be pursued. Current and future treatments for NDs must be made available to LDCs at prices they can afford. Proposed mechanisms to reduce drug prices such as differential pricing combined with advanced purchasing, for example, would require support from both LDCs (i.e. export controls, review of drug taxes and tariffs) and industrialised countries (i.e. import controls), as well as the pharmaceutical industry. A long-term strategy for health care, urban planning, housing, employment and environmental controls is imperative in LDCs in advance of disease eradication so that these countries will be prepared to cope with longer life expectancies. The clinical fight against disease must be fought sideby-side environmental initiatives such as the draining of marshlands or stagnant water supplies to reduce the concentration of mosquitoes in the habitat. In terms of health care, while new vaccines and drug treatments are certainly important, the need for trained personnel, facilities, equipment and a sustained political and financial commitment to health care improvement in LDCs cannot be understated. R&D of NDs therefore must be seen to be a part of a wider public health strategy and not viewed in isolation. But as we work towards improvements in the short-term, it is equally cost-effective and important to keep in mind the long-term and the need for research priorities that include NDs. As product development can take 20 years or more it is important to seriously begin to address the problem of stimulating R&D for NDs.
Acknowledgements The authors of this paper benefited extensively from the points raised and issues discussed during a conference on ‘Stimulating research and development of neglected diseases’ organised by the London School of Economics and Political Science and Me´decins Sans Frontie`res in June 2001. We would also like to thank Professor Walter Holland
and the journal’s anonymous referees for their helpful comments.
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