Neglected tropical disease research and development

Neglected tropical diseases (NTDs) are a set of infectious diseases affecting an estimated 1.4 billion people worldwide. The classification of this group of neglected diseases is linked to their frequent neglect in public and private sector expenditure and attention at local, national, and international levels, and their concentration among the poor. Research and development yielding safe, effective drugs and vaccines for their treatment and prevention has been recognized as a global health priority.

Overview

The structure of ivermectin, an important drug in the control of Onchocerciasis.

Neglected tropical diseases are a set of infectious communicable diseases arising from a diverse group of parasitic worms, bacteria, and vector-borne protozoa.^[1] The NTDs result in an estimated 534,000 deaths annually^[2] and 57 million disability-adjusted life years (DALYs) lost.^[3] The social, economic, and health burden of these diseases falls primarily on low and middle income countries where the diseases are most prevalent.^[4] The NTDs represent the sixth greatest global health burden in terms of DALYs, equal to or potentially surpassing global malaria burden.^[3][5]

NTD interventions include both programs to address environmental and social determinants of health (e.g., vector control, water quality, sanitation), and programs offering mass drug administration for disease prevention and treatment. Drug treatments exist^[6] to confront many of the NTDs and represent some of the world's essential medicines.^[7][8] Despite significant health and economic improvements using available medicines,^{[4][9][10][11]} the low number of new compounds being researched and developed for NTDs is an ongoing and significant challenge.^[7][12][13] The dearth of candidates in pharmaceutical company drug pipelines is primarily attributed to the high costs of drug development and the fact that NTDs are concentrated among the worlds’ poor.^[12][14] Other disincentives to investment include weak existing infrastructure for distribution and sales, and concerns regarding intellectual property protection.^[11] However, the major stakeholders in NTD drug development—governments, foundations, pharmaceutical companies, academia, and NGOs—are involved in activities to help address the research and development shortfall and meet the many challenges presented by neglected tropical diseases.^[15] Initiatives include public private partnerships, global R&D capacity building, priority vouchers to speed drug approval processes, open source scientific collaborations, and harmonization of global governance structures concerning NTDs.

NTD list

The diseases considered neglected tropical diseases vary. Malaria, HIV, and tuberculosis have received an amount of public attention and increased funding to no longer be considered neglected by some researchers. Outside "The Big Three", the seven most prevalent neglected tropical diseases in order of their global prevalence are ascariasis, trichuriasis, hookworm infection, schistosomiasis, lymphatic filariasis, and trachoma.^[3] These seven are among a larger list of thirteen major NTDs: onchocerciasis, leishmaniasis, Chagas’ disease, leprosy, Human African trypanosomiasis (sleeping sickness), Dracunculiasis, and Buruli ulcer.^[3]

The World Health Organization's 2010 report dedicated to neglected tropical diseases offers an expanded list including dengue, rabies, yaws, cysticercosis, echinococcosis, and foodborne trematode infections.^[16]

Neglected Tropical Diseases Worldwide Burden

Disease	DALYs (million)	Deaths/Yr	Global Prevalence (million)	Population at Risk (billion)
Schistosomiasis	4.5	280,000	207	0.78
Hookworm	22.1	65,000	576	3.2
Ascariasis	10.5	60,000	807	4.2
Leishmaniasis	2.1	51,000	12	0.35
Trypanosomiasis	1.5	48,000	0.3	0.06
Chagas disease	0.7	14,000	8	0.025
Trichuriasis	6.4	10,000	604	3.2
Leprosy	0.2	6,000	0.4	ND
Lymphatic filariasis	5.8	0	120	1.3
Trachoma	2.3	0	84	0.59
Onchocerciasis	0.5	0	37	0.09

ND=Not Determined^[2][3]

Deficient market

In their 2002 review of the U.S. Food and Drug Administration (FDA) databases and the European Agency for the Evaluation of Medicinal Products, Troullier et al found that 16 out of 1393 new chemical entities were approved for NTDs between 1975 and 1999 (~1%).^[7] Cohen et al revisited the data and using the same methodology found 32 new chemical entities during the time period.^[8] In a second analysis using an expanded list of NTDs based on the G-FINDER survey,^[17] the number was slightly higher, with 46 new drugs and vaccines approved (~3% of the total including HIV drugs).^[8] Between 2000 and 2009, there has been some increase with an additional 26 newly approved drugs and vaccines for NTDs.^[8]

A number of factors are recognized as contributing to the low number. The barrier most reported is the high cost of drug development. Estimates are that pharmaceutical companies' development costs to approval fall between $500 million and $2 billion.^[18] DiMasi, Hansen, and Grabowski calculated an average of $802 million in year 2000 dollars.^[19] Furthermore, the time that drugs are approved for use averages seven years out of the twenty years on-patent, meaning a tendency for the market to focus on diseases of developed nations where high prices can be used to recoup research and development costs, and subsidize failed R&D efforts. In short, NTD research and development is considered a high investment risk given that NTDs predominantly affect the poor in low and middle income countries.^[12][14] Additional barriers include drug safety regulatory requirements, intellectual property protection problems, and poor infrastructure for distribution and sales.^[11][12]

Although drug companies have not invested heavily in the NTDs, in several cases, rather than focus on profits, some have decided to donate key drugs to address NTDs. For example, Merk has had a program since the mid-1980s to donate ivermectin (Mectizan) indefinitely to support the global fight of onchoceriasis. GlaxoSmithKline and several other large pharmaceutical companies have donation programs as well. Drug donation however, does not ameliorate the deficiency of new chemical entities being researched and developed. This is especially of concern with reports of emerging resistance among existing drugs.^[20][21]

Policy initiatives

Public private partnerships

Melinda and Bill Gates speak during press conference at the World Economic Forum in Davos, Switzerland, January 30, 2009.

Governments, foundations, the non-profit sector, and private sector have found new connections to help address market deficiencies by providing funding support and spreading both the costs and risks of NTD research and development. The proliferation of public private partnerships (PPPs) has been recognized as a key innovation in the past decade, helping to unlock existing and new resources.

Major PPPs for NTDs include: the Sabin Vaccine Institute, Norvartis Vaccines Institute for Global Health, MSD Wellcome Trust Hilleman Laboratories, Infectious Diseases Research Institute, Institut Pasteur and INSERM, and the International Vaccine Institute.^[14] Likewise, a number of new academic drug development centers have been created in recent years drawing in industry partners. Support for these centers is frequently traced to the Bill and Melinda Gates Foundation, the Sandler Foundation, and the Wellcome Trust.^[22]

R&D capacity building in middle income countries

Growing NTD research and development capacity in middle income countries is an area of policy interest. A 2009 study of biotechnology companies in India, China, Brazil, and South Africa revealed sixty-two NTD products in development and on the market out of approximately five hundred products offered (~14%). When products to fight HIV, malaria, and TB were included in the analysis, the number increased to one hundred twenty-three products, approximately 25% of the total products offered.

Researchers have argued that unlike most multinationals, small and mid-sized “Global South” companies see significant business opportunities in the development of NTD-related diagnostics, biologics, pharmaceuticals, and services.^[23] Potential actions to improve and expand this R&D capacity have been recommended including expansion of human capital, increased private investment, knowledge and patent sharing, infrastructure building for business incubation and innovation support.

Innovation prizes and grants

Competitive innovation prizes have been used to spur development in a range of fields such as aerospace engineering, clean technology, and genomics. The X-Prize Foundation is launching a competition for high speed, point-of-care diagnostics for tuberculosis. A more widely defined annual “Global Health EnterPrize” for neglected tropical diseases has been proposed to reward health innovators, particularly those based in countries where NTDs represent a serious health burden.

The Bill and Melinda Gates Foundation offers the Grand Challenges Explorations Opportunities on a rolling basis. This grant program allows individuals from any organization or background to apply to address priority global health issues. Each project award is $100,000 dollars and is drawn from a Foundation funding pool of $100 million. Awardees have tended to offer research projects on topics that are highly speculative but offer potentially game-changing breakthroughs in global health.

FDA priority review vouchers (PRV)

In 2006, Ridley et al recommended the development of a priority review voucher (PRV) in the journal Health Affairs. It gained interest by Senator Sam Brownback of Kansas who championed its introduction in the FDA Amendments Act of 2007. Under the enacted law, FDA approval of a non-NTD drug can be accelerated through the drug review process if paired to a drug that addresses a NTD. The potential economic benefit to a pharmaceutical company is estimated to be potentially as high as $300 million per drug. One drug has come to market so far using this mechanism, Novartis’ Coartem, an anti-malarial medication.

The PRV isn't limited to the pairing of drugs within a single company, rather can be transferred between companies. Companies with NTD drug candidates in their pipelines but without a blockbuster drug, are able to sell their voucher producing financial returns. In the EU, similar priority review incentives are now under consideration to increase the speed of regulatory pricing and reimbursement decisions.

However, PRVs have been criticized as being open to manipulation and possibly encouraging errors through too rapid regulatory decision-making.^[24]

Open source collaboration initiatives

The Drugs for Neglected Diseases Initiative, a web focused not-for-profit drug R&D organization dedicated to creating new NTD treatments.

Several companies and scientific organizations are participating in open source initiatives to share drug data and patent information over the web, and facilitate virtual collaboration on NTD research.

One rich area to explore is in the wealth of genomic data resulting from the sequencing of parasite genomes. These data offer opportunities for the exploration of new therapeutic products using computational, and open source collaboration methods for drug discovery.^[25][26] The Tropical Disease Initiative, for example, has used large amounts of computing power to generate the protein structures for ten parasite genomes. An open source drug bank was matched algorithmically to determine compounds with protein interaction activity, and two candidates were identified. In general, such methods may hold important opportunities for off-label use of existing approved drugs.

Pool for Open Innovation against Neglected Tropical Diseases

The Pool for Open Innovation against Neglected Tropical Diseases, administered by BIO Ventures for Global Health, motivates innovative and efficient drug discovery and development by opening access to intellectual property or know-how in neglected tropical disease research. There are two ways to participate in the Pool for Open Innovation: as a contributor and a user. It is assumed that contributors are contributing to the Pool because they wish to make some of their assets available to improve the health of the poor around the world through the development of new therapeutics for diseases with little or no commercial market. At a minimum, contributors must agree to a core set of principles around the Pool. The Pool is accessible to anyone with a serious commitment to research and develop medicines for NTDs, including industry, academic researchers, funding agencies, and other third parties who can deliver real benefits for patients in least developed countries.

References

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Further reading

Progress and challenges in neglected tropical diseases. Lancet 2010 Oct 23;376(9750):1363.

Remembering the neglected tropical diseases. Lancet 2007 Dec 8;370(9603):1880.

WHO and Sanofi-Aventis expand programme to fight neglected tropical diseases. Indian J Med Sci 2006 Nov;60(11):487.

Research versus treatment for neglected diseases. Lancet 2006 Feb 11;367(9509):448.

Aksoy S. Solutions to neglected tropical diseases require vibrant local scientific communities. PLoS Negl Trop Dis 2010 Mar 30;4(3):e662.

Allotey P, Reidpath DD, Pokhrel S. Social sciences research in neglected tropical diseases: the ongoing neglect in the neglected tropical diseases. Health Res Policy Syst 2010 Oct 21;8:32.

Alvar J, Yactayo S, Bern C. Leishmaniasis and poverty. Trends Parasitol 2006 Dec;22(12):552-557.

Ameen M. Cutaneous leishmaniasis: therapeutic strategies and future directions. Expert Opin Pharmacother 2007 Nov;8(16):2689-2699.

Ault SK. Intersectoral approaches to neglected diseases. Ann N Y Acad Sci 2008;1136:64-69.

Ault SK, Nicholls RS. Integrated approach to neglected tropical diseases in Latin America and the Caribbean: an ethical imperative to reach justice and social equity. Biomedica 2010 Jun;30(2):159-163.

Baker MC, Mathieu E, Fleming FM, Deming M, King JD, Garba A, et al. Mapping, monitoring, and surveillance of neglected tropical diseases: towards a policy framework. Lancet 2010 Jan 16;375(9710):231-238.

Bethony JM, Diemert DJ, Oliveira SC, Loukas A. Can schistosomiasis really be consigned to history without a vaccine? Vaccine 2008 Jun 25;26(27-28):3373-3376.

Bitran R, Martorell B, Escobar L, Munoz R, Glassman A. Controlling and eliminating neglected diseases in Latin America and the Caribbean. Health Aff (Millwood) 2009 Nov-Dec;28(6):1707-1719.

Bockarie MJ, Deb RM. Elimination of lymphatic filariasis: do we have the drugs to complete the job? Curr Opin Infect Dis 2010 Dec;23(6):617-620.

Bockarie MJ, Pedersen EM, White GB, Michael E. Role of vector control in the global program to eliminate lymphatic filariasis. Annu Rev Entomol 2009;54:469-487.

Boelaert M, Meheus F, Robays J, Lutumba P. Socio-economic aspects of neglected diseases: sleeping sickness and visceral leishmaniasis. Ann Trop Med Parasitol 2010 Oct;104(7):535-542.

Bottazzi ME, Brown AS. Model for product development of vaccines against neglected tropical diseases: a vaccine against human hookworm. Expert Rev Vaccines 2008 Dec;7(10):1481-1492.

Bottazzi ME, Miles AP, Diemert D, Hotez PJ. An ounce of prevention on a budget: a nonprofit approach to developing vaccines against neglected diseases. Expert Rev Vaccines 2006 Apr;5(2):189-198.

Brady MA, Hooper PJ, Ottesen EA. Projected benefits from integrating NTD programs in sub-Saharan Africa. Trends Parasitol 2006 Jul;22(7):285-291.

Brownback S. Eliminating neglected diseases: impact of published paper. Health Aff (Millwood) 2007 Sep-Oct;26(5):1509.

Butler D. Neglected disease boost. Nature 2009 Feb 12;457(7231):772-773.

Canning D. Priority setting and the 'neglected' tropical diseases. Trans R Soc Trop Med Hyg 2006 Jun;100(6):499-504.

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Chaves LF, Pascual M. Comparing models for early warning systems of neglected tropical diseases. PLoS Negl Trop Dis 2007 Oct 22;1(1):e33.

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Dantas-Torres F, Marcondes CB. Fighting neglected tropical diseases in the postgenomic era. Trends Parasitol 2008 Apr;24(4):156-7; author reply 157-8.

Denery JR, Nunes AA, Hixon MS, Dickerson TJ, Janda KD. Metabolomics-based discovery of diagnostic biomarkers for onchocerciasis. PLoS Negl Trop Dis 2010 Oct 5;4(10):e834.

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Ebrahim GJ. Neglected tropical diseases. J Trop Pediatr 2009 Jun;55(3):141-144.

Engels D, Savioli L. Reconsidering the underestimated burden caused by neglected tropical diseases. Trends Parasitol 2006 Aug;22(8):363-366.

Fenwick A, Webster JP, Bosque-Oliva E, Blair L, Fleming FM, Zhang Y, et al. The Schistosomiasis Control Initiative (SCI): rationale, development and implementation from 2002-2008. Parasitology 2009 Nov;136(13):1719-1730.

Frearson J, Wyatt P. Drug Discovery in Academia- the third way? Expert Opin Drug Discov 2010 Oct 1;5(10):909-919.

Frezard F, Demicheli C. New delivery strategies for the old pentavalent antimonial drugs. Expert Opin Drug Deliv 2010 Dec;7(12):1343-1358.

Germani Y, Sansonetti P. "Neglected diseases": it is better to respond to future challenges—the model of a pilot North-South program on enteric infections integrating many research components. C R Biol 2008 Dec;331(12):973-981.

Gloeckner C, Garner AL, Mersha F, Oksov Y, Tricoche N, Eubanks LM, et al. Repositioning of an existing drug for the neglected tropical disease Onchocerciasis. Proc Natl Acad Sci USA 2010 Feb 23;107(8):3424-3429.

Gray DJ, Forsyth SJ, Li RS, McManus DP, Li Y, Chen H, et al. An innovative database for epidemiological field studies of neglected tropical diseases. PLoS Negl Trop Dis 2009 May 26;3(5):e413.

Gray DJ, McManus DP, Li Y, Williams GM, Bergquist R, Ross AG. Schistosomiasis elimination: lessons from the past guide the future. Lancet Infect Dis 2010 Oct;10(10):733-736.

Grepin KA, Reich MR. Conceptualizing integration: a framework for analysis applied to neglected tropical disease control partnerships. PLoS Negl Trop Dis 2008 Apr 30;2(4):e174.

Gustavsen K, Hanson C. Progress in public-private partnerships to fight neglected diseases. Health Aff (Millwood) 2009 Nov-Dec;28(6):1745-1749.

Gyapong JO, Gyapong M, Yellu N, Anakwah K, Amofah G, Bockarie M, et al. Integration of control of neglected tropical diseases into health-care systems: challenges and opportunities. Lancet 2010 Jan 9;375(9709):160-165.

Hanvoravongchai P, Warakamin B, Coker R. Critical interactions between Global Fund-supported programmes and health systems: a case study in Thailand. Health Policy Plan 2010 Nov;25 Suppl 1:i53-57.

Hopkins AD. Challenges for the integration of mass drug administrations against multiple 'neglected tropical diseases'. Ann Trop Med Parasitol 2009 Oct;103 Suppl 1:S23-31.

Hotez P. A national school of tropical medicine and neglected infections of poverty for North America. PLoS Negl Trop Dis 2010 Jun 29;4(6):e735.

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Hotez PJ. Neglected tropical disease control in the "post-American world". PLoS Negl Trop Dis 2010 Aug 31;4(8):e812.

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Hotez PJ. Mass drug administration and integrated control for the world's high-prevalence neglected tropical diseases. Clin Pharmacol Ther 2009 Jun;85(6):659-664.

Hotez PJ. Neglected infections of poverty in the United States of America. PLoS Negl Trop Dis 2008 Jun 25;2(6):e256.

Hotez PJ. The giant anteater in the room: Brazil's neglected tropical diseases problem. PLoS Negl Trop Dis 2008 Jan 30;2(1):e177.

Hotez PJ. Reinventing Guantanamo: from detainee facility to Center for Research on Neglected Diseases of Poverty in the Americas. PLoS Negl Trop Dis 2008 Feb 27;2(2):e201.

Hotez PJ, Bethony J, Bottazzi ME, Brooker S, Diemert D, Loukas A. New technologies for the control of human hookworm infection. Trends Parasitol 2006 Jul;22(7):327-331.

Hotez PJ, Brindley PJ, Bethony JM, King CH, Pearce EJ, Jacobson J. Helminth infections: the great neglected tropical diseases. J Clin Invest 2008 Apr;118(4):1311-1321.

Hotez PJ, Brown AS. Neglected tropical disease vaccines. Biologicals 2009 Jun;37(3):160-164.

Hotez PJ, Ehrenberg JP. Escalating the global fight against neglected tropical diseases through interventions in the Asia Pacific region. Adv Parasitol 2010;72:31-53.

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External links

• United Nations World Health Organization
• U.S. Food and Drug Administration
• Bill and Melinda Gates Foundation
• Global Network for Neglected Tropical Diseases
• Pool for Open Innovation against Neglected Tropical Diseases
• BIO Ventures for Global Health