Neglected Tropical Disease Research and Development
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Neglected tropical diseases (NTDs) are a set of communicable diseases arising from a diverse group of parasitic worms, bacteria, and vector-borne protozoa.[1] The NTDs result in a 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,[9][10][4][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 myriad challenges presented by neglected tropical diseases.[15] Initiatives include public private partnerships, global R&D capacity building, priority vouchers to speed approval processes, and open source scientific collaborations.
Neglected Tropical Disease List
editThe 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 NTDs with high prevalence: onchocerciasis, leishmaniasis, Chagas’ disease, leprosy, Human African trypanosomiasis (sleeping sickness), Dracunculiasis, and Buruli ulcer.[3]
The WHO's 2010 report dedicated to neglected tropical diseases offers an expanded list including dengue, rabies, yaws, cysticercosis, echinococcosis, and foodborne trematode infections.[16]
Deficient Market
editIn their 2002 review of the 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] The associated risk is considered high given that NTDs predominantly affect the poor in low and middle income countries.[12][14] Regulatory barriers over drug safety requirements, issues regarding intellectual property protection, and poor infrastructure for distribution and sales have been considered additional barriers to development as well.[12][11]
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 developed, and concerns regarding emerging drug resistance.[20][21]
Public Private Partnerships
editGovernments, 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) in the past decade has been recognized as a key innovation in the past decade, that has helped 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. Likewise, a number of new academic drug development centers have been created in recent years drawing in industry partners. Support across such groups is often from the Bill and Melinda Gates Foundation, the Sandler Foundation, and the Wellcome Trust.[22]
R&D Capacity Building in Middle Income Countries
editGrowing 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, and business incubators and innovation support.
Development Prizes and Innovation Grant Support
editCompetitive 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 accurate, high speed, easy-to-use, 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.
Currently, the Bill and Melinda Gates Foundation offers on a rolling basis the chance to apply to the Grand Challenges Explorations Opportunities. 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 Vouchers
editIn 2006, Ridley et al recommended the development of a priority review voucher in the journal Health Affairs. It gained interest by Senator 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 dollars per drug. One drug has come to market so far using this mechanism, Novartis’ Coartem, an anti-malarial medication.
The priority voucher isn't limited to the pairing of drugs within a single company, rather permits vouchers to be transferred between companies. This permits companies with NTD drug candidates in their pipelines but without a blockbuster drug, 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, priority vouchers been criticized as by being potentially open to manipulation and possibly encouraging errors through rapid regulatory decision-making.[24]
Open Source Collaboration Initiatives
editOver a dozen parasite genomes related to neglected tropical diseases have been sequenced, producing a wealth of genomic data. This offers 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 then matched algorithmically to determine candidate compounds with activity against these organisms. Such methods may hold opportunities for off-label use of existing approved drugs.
A number of companies and scientific organizations are participating in and promoting open source initiatives that share databases of drug data, create open patent pools, and facilitate virtual collaboration on NTD research.
Harmonization of Governance Structures
editRelated Links
editUnited Nations World Health Organization
edithttp://www.who.int/neglected_diseases/en/
FDA
edithttp://www.fda.gov/NewsEvents/Testimony/ucm216991.htm
Bill and Melinda Gates Foundation
edithttp://www.gatesfoundation.org/topics/Pages/neglected-diseases.aspx
Global Network for Neglected Tropical Diseases
edit
References
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- ^ a b c Trouiller P, Olliaro P, Torreele E, Orbinski J, Laing R, Ford N. Drug development for neglected diseases: a deficient market and a public-health policy failure. Lancet 2002 Jun 22;359(9324):2188-2194.
- ^ a b c d Cohen J, Dibner MS, Wilson A. Development of and access to products for neglected diseases. PLoS One 2010 May 12;5(5):e10610.
- ^ Chu BK, Hooper PJ, Bradley MH, McFarland DA, Ottesen EA. The economic benefits resulting from the first 8 years of the Global Programme to Eliminate Lymphatic Filariasis (2000-2007). PLoS Negl Trop Dis. 2010 Jun 1;4(6):e708.
- ^ Merck Mectizan Drug Donation Program http://www.mectizan.org/
- ^ a b c Villa S, Compagni A, Reich MR. Orphan drug legislation: lessons for neglected tropical diseases. Int J Health Plann Manage 2009 Jan-Mar;24(1):27-42.
- ^ a b c d Trouiller P, Torreele E, Olliaro P, White N, Foster S, Wirth D, et al. Drugs for neglected diseases: a failure of the market and a public health failure? Trop Med Int Health 2001 Nov;6(11):945-951.
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- ^ G-Finder Database http://www.georgeinstitute.org/about-us/media-centre/g-finder-database-open-public
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- ^ DiMasi JA, Hansen RW, Grabowski HG. The price of innovation: new estimates of drug development costs. J Health Econ. 2003 Mar;22(2):151-85.
- ^ Tchuem Tchuente LA. Control of soil-transmitted helminths in sub-Saharan Africa: Diagnosis, drug efficacy concerns and challenges. Acta Trop 2010 Jul 21.
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- ^ Frew SE, Liu VY, Singer PA. A business plan to help the 'global South' in its fight against neglected diseases. Health Aff (Millwood) 2009 Nov-Dec;28(6):1760-1773.
- ^ Kesselheim AS. Drug development for neglected diseases - the trouble with FDA review vouchers. N Engl J Med 2008 Nov 6;359(19):1981-1983.
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- ^ Ortí L, Carbajo RJ, Pieper U, Eswar N, Maurer SM, Rai AK, Taylor G, Todd MH, Pineda-Lucena A, Sali A, Marti-Renom MA. A kernel for open source drug discovery in tropical diseases. PLoS Negl Trop Dis 2009;3(4):e418.
Further Reading
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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.
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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.
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