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

Neglected Diseases

The neglected diseases are a group of tropical infections which are especially endemic in low-income populations in developing regions of Africa, Asia, and the Americas. Different organizations define the set of diseases differently...

 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

Research and development

The phrase research and development , according to the Organization for Economic Co-operation and Development, refers to "creative work undertaken on a systematic basis in order to increase the stock of knowledge, including knowledge of man, culture and society, and the use of this stock of...

 yielding safe, effective drugs and vaccines for their treatment and prevention has been recognized as a global health priority.

Overview

Neglected tropical diseases are a set of infectious communicable diseases

Infectious disease

Infectious diseases, also known as communicable diseases, contagious diseases or transmissible diseases comprise clinically evident illness resulting from the infection, presence and growth of pathogenic biological agents in an individual host organism...

 arising from a diverse group of parasitic worms, bacteria, and vector-borne protozoa. The NTDs result in an estimated 534,000 deaths annually and 57 million disability-adjusted life years

Disability-adjusted life years

The disability-adjusted life year is a measure of overall disease burden, expressed as the number of years lost due to ill-health, disability or early death. Originally developed by Harvard University for the World Bank in 1990, the World Health Organization subsequently adopted the method in 2000...

 (DALYs) lost. The social, economic, and health burden of these diseases falls primarily on low and middle income countries

Developing country

A developing country, also known as a less-developed country, is a nation with a low level of material well-being. Since no single definition of the term developing country is recognized internationally, the levels of development may vary widely within so-called developing countries...

 where the diseases are most prevalent. The NTDs represent the sixth greatest global health burden in terms of DALYs, equal to or potentially surpassing global malaria burden.

NTD interventions include both programs to address environmental and social determinants of health

Social determinants of health

Social determinants of health are the economic and social conditions under which people live which determine their health. They are "societal risk conditions", rather than individual risk factors that either increase or decrease the risk for a disease, for example for cardiovascular disease and...

 (e.g., vector control, water quality, sanitation), and programs offering mass drug administration

Mass drug administration

The administration of drugs to whole populations irrespective of disease status is referred to as mass drug administration . This article describes the administration of antimalarial drugs to whole populations an intervention which has been used as a malaria-control measure for more than 70 years...

 for disease prevention and treatment. Drug treatments exist to confront many of the NTDs and represent some of the world's essential medicines

Essential medicines

Essential medicines, as defined by the World Health Organization are "those drugs that satisfy the health care needs of the majority of the population; they should therefore be available at all times in adequate amounts and in appropriate dosage forms, at a price the community can afford."The WHO...

. Despite significant health and economic improvements using available medicines, the low number of new compounds being researched and developed for NTDs is an ongoing and significant challenge. The dearth of candidates in pharmaceutical company drug pipeline

Drug pipeline

A drug pipeline is the set of compounds that a pharmaceutical company has under development at any given point in time....

s is primarily attributed to the high costs of drug development and the fact that NTDs are concentrated among the worlds’ poor. Other disincentives to investment include weak existing infrastructure for distribution and sales, and concerns regarding intellectual property protection. However, the major stakeholders in NTD drug development—governments, foundations, pharmaceutical companies, academia, and NGOs

Non-governmental organization

A non-governmental organization is a legally constituted organization created by natural or legal persons that operates independently from any government. The term originated from the United Nations , and is normally used to refer to organizations that do not form part of the government and are...

—are involved in activities to help address the research and development shortfall and meet the many challenges presented by neglected tropical diseases. 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

Malaria

Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...

, HIV, and tuberculosis

Tuberculosis

Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...

 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

Ascariasis

Ascariasis is a human disease caused by the parasitic roundworm Ascaris lumbricoides. Perhaps as many as one quarter of the world's people are infected, with rates of 45% in Latin America and 95% in parts of Africa. Ascariasis is particularly prevalent in tropical regions and in areas of poor...

, trichuriasis

Trichuriasis

Trichuriasis is a parasitic infection primarily in the tissue of the cecum, appendix, colon and rectum that is caused by Trichuris trichiura , an intestinal parasitic nematode .-Agent :...

, hookworm infection, schistosomiasis

Schistosomiasis

Schistosomiasis is a parasitic disease caused by several species of trematodes , a parasitic worm of the genus Schistosoma. Snails often act as an intermediary agent for the infectious diseases until a new human host is found...

, lymphatic filariasis, and trachoma

Trachoma

Trachoma is an infectious disease causing a characteristic roughening of the inner surface of the eyelids. Also called granular conjunctivitis and Egyptian ophthalmia, it is the leading cause of infectious blindness in the world...

. These seven are among a larger list of thirteen major NTDs: onchocerciasis

Onchocerciasis

Onchocerciasis , also known as river blindness and Robles' disease, is a parasitic disease caused by infection by Onchocerca volvulus, a nematode . Onchocerciasis is the world's second-leading infectious cause of blindness. It is not the nematode, but its endosymbiont, Wolbachia pipientis, that...

, leishmaniasis

Leishmaniasis

Leishmaniasis is a disease caused by protozoan parasites that belong to the genus Leishmania and is transmitted by the bite of certain species of sand fly...

, Chagas’ disease, leprosy

Leprosy

Leprosy or Hansen's disease is a chronic disease caused by the bacteria Mycobacterium leprae and Mycobacterium lepromatosis. Named after physician Gerhard Armauer Hansen, leprosy is primarily a granulomatous disease of the peripheral nerves and mucosa of the upper respiratory tract; skin lesions...

, Human African trypanosomiasis (sleeping sickness), Dracunculiasis

Dracunculiasis

Dracunculiasis , also called guinea worm disease , is a parasitic infection caused by Dracunculus medinensis, a long and very thin nematode . The infection begins when a person drinks stagnant water contaminated with copepods infested by the larvae of the guinea worm...

, and Buruli ulcer

Buruli ulcer

The Buruli ulcer is an infectious disease caused by Mycobacterium ulcerans. The genus also includes the causative agents of tuberculosis and leprosy...

.

The World Health Organization

World Health Organization

The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...

's 2010 report dedicated to neglected tropical diseases offers an expanded list including dengue

Dengue fever

Dengue fever , also known as breakbone fever, is an infectious tropical disease caused by the dengue virus. Symptoms include fever, headache, muscle and joint pains, and a characteristic skin rash that is similar to measles...

, rabies

Rabies

Rabies is a viral disease that causes acute encephalitis in warm-blooded animals. It is zoonotic , most commonly by a bite from an infected animal. For a human, rabies is almost invariably fatal if post-exposure prophylaxis is not administered prior to the onset of severe symptoms...

, yaws

Yaws

Yaws is a tropical infection of the skin, bones and joints caused by the spirochete bacterium Treponema pallidum pertenue...

, cysticercosis

Cysticercosis

Cysticercosis refers to tissue infection after exposure to eggs of Taenia solium, the pork tapeworm. The disease is spread via the fecal-oral route through contaminated food and water, and is primarily a food borne disease. After ingestion the eggs pass through the lumen of the intestine into the...

, echinococcosis

Echinococcosis

Echinococcosis, which is often referred to as hydatid disease or echinococcal disease, is a parasitic disease that affects both humans and other mammals, such as sheep, dogs, rodents and horses. There are three different forms of echinococcosis found in humans, each of which is caused by the larval...

, and foodborne trematode infections.
ND=Not Determined

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

European Medicines Agency

The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...

, Troullier et al found that 16 out of 1393 new chemical entities were approved for NTDs between 1975 and 1999 (~1%). Cohen et al revisited the data and using the same methodology found 32 new chemical entities during the time period. In a second analysis using an expanded list of NTDs based on the G-FINDER survey, the number was slightly higher, with 46 new drugs and vaccines approved (~3% of the total including HIV drugs). Between 2000 and 2009, there has been some increase with an additional 26 newly approved drugs and vaccines for NTDs.

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. DiMasi, Hansen, and Grabowski calculated an average of $802 million in year 2000 dollars. 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. Additional barriers include drug safety regulatory requirements, intellectual property protection problems, and poor infrastructure for distribution and sales.

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.

Public private partnerships

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

Sabin Vaccine Institute

The Sabin Vaccine Institute is a non-profit, 501 organization dedicated to reducing needless humansuffering from vaccine preventable and neglected tropical diseases through prevention and treatment...

, Norvartis Vaccines Institute for Global Health, MSD Wellcome Trust Hilleman Laboratories, Infectious Diseases Research Institute, Institut Pasteur and INSERM, and the International Vaccine Institute

International Vaccine Institute

The International Vaccine Institute is an international organization exclusively devoted to vaccine research and development for people in developing countries, especially children...

. 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

Sandler Foundation

Sandler Foundation is a charitable foundation formed in 1991 with support from Herb Sandler and Marion Sandler. The foundation's website is '. In 2006, the Sandlers made a contribution of $1.3 billion to the foundation, which was the second largest American charitable contribution of 2006...

, and the Wellcome Trust

Wellcome Trust

The Wellcome Trust was established in 1936 as an independent charity funding research to improve human and animal health. With an endowment of around £13.9 billion, it is the United Kingdom's largest non-governmental source of funds for biomedical research...

.

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. 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

Priority Review Voucher

The priority review voucher is a prize awarded in the United States to the developer of a treatment for neglected diseases. The prize was proposed by Duke University faculty David Ridley, Henry Grabowski, and Jeffrey Moe in their 2006 Health Affairs paper: "Developing Drugs for Developing...

 (PRV) in the journal Health Affairs

Health Affairs

Health Affairs is a peer-reviewed healthcare journal established in 1981 by John K. Iglehart. It was described by The Washington Post as "the bible of health policy". Health Affairs is indexed and/or abstracted in PubMed, MEDLINE, EBSCO databases, ProQuest, LexisNexis, Current Contents/Health...

. It gained interest by Senator Sam Brownback

Sam Brownback

Samuel Dale "Sam" Brownback is the 46th and current Governor of Kansas. A member of the Republican Party, he served as a U.S. Senator from Kansas from 1996 to 2011, and as a U.S. Representative for Kansas's 2nd congressional district from 1995 to 1996...

 of Kansas who championed its introduction in the FDA Amendments Act of 2007

Food and Drug Administration Amendments Act of 2007

On September 27, 2007, President of the United States George W. Bush signed the Food and Drug Administration Amendments Act of 2007 into law. This new law is an important step for the Food and Drug Administration . It reviewed, expanded, and reaffirmed several existing pieces of legislation...

. 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

Coartem

The combination artemether/lumefantrine is an artemisinin-based combination therapy indicated for the treatment of acute uncomplicated plasmodium falciparum malaria. Coartem is produced by the Swiss pharmaceutical company, Novartis.Artemether is a derivative of artemisinin, and lumefantrine is...

, 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.

Open source collaboration initiatives

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

Open source

The term open source describes practices in production and development that promote access to the end product's source materials. Some consider open source a philosophy, others consider it a pragmatic methodology...

collaboration methods for drug discovery. 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.

Further reading

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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