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 two of the ivermectins, an important class of 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 world's 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
DiseaseDALYs (million)Deaths/YrGlobal Prevalence (million)Population at Risk (million)
Schistosomiasis4.5280,000207780
Hookworm22.165,0005763200
Ascariasis10.560,0008074200
Leishmaniasis2.151,00012350
Trypanosomiasis1.548,0000.360
Chagas disease0.714,000825
Trichuriasis6.410,0006043200
Leprosy0.26,0000.4ND
Lymphatic filariasis5.801201300
Trachoma2.3084590
Onchocerciasis0.503790
Cryptococcosis12400,00018

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, WIPO Re:Search, 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 & 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. Three drugs have earned NTD PRVs to date (December 2014): Coartem (by Novartis, for malaria); bedaquiline (by Janssen, for TB) and miltefosine (by Knight, for leishmaniasis). However, the success of the PRV system is now under much scrutiny, given that Knight benefitted by $125 million from the sale of a PRV earned from a drug (miltefosine) that was largely researched and developed by the WHO. Medicins San Frontiers are now pressuring Knight to guarantee supplying miltefosine at cost price, thus far without success.

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.

References

  1. ↑ Feasey N, Wansbrough-Jones M, Mabey DC, Solomon AW. Neglected tropical diseases. Br Med Bull. 2010;93:179-200. Epub 2009 Dec 10. Review.
  2. 1 2 Hotez PJ, Molyneux DH, Fenwick A, Ottesen E, Ehrlich Sachs S, Sachs JD. Incorporating a rapid-impact package for neglected tropical diseases with programs for HIV/AIDS, tuberculosis, and malaria. PLoS Med 2006 Jan;3(5):e102.
  3. 1 2 3 4 5 Hotez PJ, Molyneux DH, Fenwick A, Kumaresan J, Sachs SE, Sachs JD, et al. Control of neglected tropical diseases. N Engl J Med 2007 Sep 6;357(10):1018-1027.
  4. 1 2 Conteh L, Engels T, Molyneux DH. Socioeconomic aspects of neglected tropical diseases. Lancet 2010 Jan 16;375(9710):239-247.
  5. ↑ Hotez P, Ottesen E, Fenwick A, Molyneux D. The neglected tropical diseases: the ancient afflictions of stigma and poverty and the prospects for their control and elimination. Adv Exp Med Biol 2006;582:23-33.
  6. ↑ Reddy M, Gill SS, Kalkar SR, Wu W, Anderson PJ, Rochon PA. Oral drug therapy for multiple neglected tropical diseases: a systematic review. JAMA 2007 Oct 24;298(16):1911-1924.
  7. 1 2 3 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.
  8. 1 2 3 4 Cohen J, Dibner MS, Wilson A. Development of and access to products for neglected diseases. PLoS One 2010 May 12;5(5):e10610.
  9. ↑ 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.
  10. ↑ Merck Mectizan Drug Donation Program http://www.mectizan.org/
  11. 1 2 3 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.
  12. 1 2 3 4 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.
  13. ↑ Chirac P, Torreele E. Global framework on essential health R&D. Lancet. 2006 May 13;367(9522):1560-1.
  14. 1 2 3 Bethony JM, Cole RN, Guo X, Kamhawi S, Lightowlers MW, Loukas A, et al. Vaccines to combat the neglected tropical diseases. Immunol Rev 2011 Jan;239(1):237-270.
  15. ↑ Liese B, Rosenberg M, Schratz A. Programmes, partnerships, and governance for elimination and control of neglected tropical diseases. Lancet 2010 Jan 2;375(9708):67-76.
  16. ↑ World Health Organization. Working to overcome the global impact of neglected tropical diseases: first WHO report on neglected tropical diseases. 2010.
  17. ↑ G-FINDER Database http://www.georgeinstitute.org/about-us/media-centre/g-finder-database-open-public
  18. ↑ Adams CP, Brantner VV. Estimating the cost of new drug development: is it really 802 million dollars? Health Aff (Millwood). 2006 Mar-Apr;25(2):420-8.
  19. ↑ 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.
  20. ↑ Tchuem Tchuente LA. Control of soil-transmitted helminths in sub-Saharan Africa: Diagnosis, drug efficacy concerns and challenges. Acta Trop 2010 Jul 21.
  21. ↑ Smits HL. Prospects for the control of neglected tropical diseases by mass drug administration. Expert Rev Anti Infect Ther 2009 Feb;7(1):37-56.
  22. ↑ Renslo AR, McKerrow JH. Drug discovery and development for neglected parasitic diseases. Nat Chem Biol 2006 Dec;2(12):701-710.
  23. ↑ 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.
  24. ↑ Kesselheim AS. Drug development for neglected diseases - the trouble with FDA review vouchers. N Engl J Med 2008 Nov 6;359(19):1981-1983.
  25. ↑ Kar S. Opinion: Open innovation: an answer for neglected diseases. Future Med Chem 2010 Sep;2(9):1411-5.
  26. ↑ 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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