Non-profit diseases

There is a logic to the idea of neglected diseases. Historically the diseases poor people get--largely in the poorer parts of the world--haven't got enough attention from policy-makers in national governments and multilateral agencies precisely because they happen in 'invisible' areas to 'invisible' people.VIBHA VARSHNEY travelled through the impoverished district of East Champaran in Bihar.

May 21, 2007 The case of 16-year-old Dasai Manjhi of Madhubani block shows how easy it is for patients to get lost in the crowded district hospital at Motihari, East Champaran. Dasai had been suffering from fever for the past four months and local treatment hasn't helped. When he finally decided to go to hospital, the doctor on duty made a wrong diagnosis and prescribed antacids. But P N Pandey, in charge of the health programme of Samajik Shodh Evam Vikas Kendra an ngo based in East Champaran was sure that Dasai was suffering from kala-azar--the enlarged spleen was a dead give-away. He approached the additional chief medical officer, Panchanan Prasad, and complained about the doctor's negligence. Prasad sent the patient back to the doctor, who suggested Dasai be tested for kala-azar.

Meanwhile, the civil surgeon, G P Verma, arrived at the hospital with the deputy superintendent, A A Lari.Faced with Pandey's insistence, Lari checked Dasai's spleen and seconded Pandey's diagnosis. The rk-39 rapid diagnostic kit confirmed kala-azar. Verma called T P Singh, the doctor in charge of kala-azar patients in the hospital, and asked him to sort the matter out. Singh said he would not be able to do it since a family member was sick. People said he was probably busy with one of his three private practices.

An absent doctor adds to the problems of the district hospital, which is not equipped for the number of kala-azar patients it has to deal with in the first place. It does not have a specialised ward for these patients. Most patients don't get a bed in the wards. Of them, the lucky ones have recently started getting wooden cots in the corridors, the rest have to make do with the floor.

By 10 am that day, 61 of the 134 waiting patients had received sodium antimony gluconate (sag) shots. The rest, who were resistant to sag were preparing to get amphotericin b intravenously. Two nurses were running the show with two auxiliary nurse-and-midwives and a helper. The shortage of staff ensured that family members have to play nurse. Godavadi Devi was given the responsibility of taking care of her 45-year-old son-in-law Hiraman Mahto. She got a bottle of distilled water from the nurse and ties it to the ribbon hanging on the rope at the head of the bed. The nurses had already marked the bottle with the amount of medicine needed by Mahto according to his weight. As the attendant fixed the needle, Godavadi also had to ensure he put it in place with a band-aid she pulled off the side of the bed. She had to ensure the medicine didn't leak and flowed consistently for five hours.

Two prongs
The Regional Strategic Framework for Elimination of Kala-Azar from the South-East Asia Region (2005-2015), an agreement between India, Bangladesh and Nepal to eliminate the disease by 2015, had guidelines on both treatment and vector control. The Bihar government constituted a task force headed by former Union health minister C P Thakur in January 2007 to implement this agreement. The task force is yet to submit a report. Thakur says the focus will be on treatment, though he emphasises vector control using ddt is also vital. He says simultaneous treatment and vector control completely eliminated the disease in a village in Phulwari block of Patna district in 2003, where amphotericin b was used to treat the patients and supervised ddt spraying was done. A year on, the Rajendra Memorial Research Institute of Medical Sciences, Patna, surveyed the area and found no vectors. This model is needed for the whole state, Thakur says.

At the 60th World Health Assembly, 14-23 May, 2007, in Geneva member states approved a resolution on controlling kala-azar along the same lines as regional framework. The 2005 pact and the fresh resolution have had an impact a lot of activity has been generated, even if some of it is directionless.

Ineffective and costly
Treatment of kala-azar is dependent on a variety of drugs that are ineffective, expensive and difficult to administer. The drug policy for treating kala-azar recommends two drugs--sag and amphotericin b. Amphotericin b is given to people who do not respond to sag. For both, the treatment lasts at least a month. In Motihari, it's longer because medicines are administered only on alternate days. Bindu Kumari from Harsiddhi block says she had been in hospital for 40 days when doctors realised she was not responding to sag. Another month will now be needed for treatment with amphotericin b. In Bindu's case, the kala-azar pathogen was found to have become resistant to the first-line drug.

Recently, an oral drug, miltefosine, has been included in the treatment protocol. All these drugs have harmful side-effects. For example, miltefosine can harm a developing foetus and should not be given to pregnant women or women in reproductive age group.

The problem with the drugs available for kala-azar is that none of them has been developed specifically for the disease. Miltefosine is a cancer drug and amphotericin B is an anti-fungal drug. The Institute of OneWorld Health (iowh), a us-based non-profit pharmaceutical company, has shown that the existing oral anti-protozoal and anti-bacterial drug paromomycin can be used to treat the disease if administered intra-muscularly. Though the drug is cheap, the treatment protocol extends to 21 days and needs someone to supervise its injection. Phase-iv trials have been planned at seven sites in Bihar.

Medecin Sans Frontieres (msf) is carrying out a programme to provide liposomal amphotericin b treatment in Vaishali district, Bihar, through district hospitals and its two referral centres. Four doses of the drug will be provided to 300 patients over 10 days. Their will be follow-up observation for side-effects. The programme will continue for three years. A course typically costs us $5,000. msf gets the drug at a concession, but P L Joshi, director of the National Vector Borne Disease Control Programme (nvbdcp), says the government will be able to take over because control programmes will bring down the incidence of the disease drastically.

There might be some more choices soon, however, with GlaxoSmithKline working on an oral drug and Corixa on a vaccine. But as far as new research goes, this is all that exists.

The Regional Research Institute of Unani Medicine, Patna, a wing of the Central Council for Research in Unani Medicine (ccrum), has cured 69 patients in 2006-2007 using herbal medicines. "The results are encouraging and there are no side-effects," says deputy director Latafat Ali Khan. A memorandum of understanding (mou) has been signed between icmr and ccrum and drug trials are likely to start soon. The treatment takes around three months. Hospitalisation is needed only for a month.

The major consequence of the current lack of suitable drugs is that treatment gets most patients into debt. This is mainly because of delays in diagnosis and difficulty in getting drugs. Ashok Kumar Mishra of Muzaffarpur was sick for five months before he came to a clinic run by T K Jha, director, Kala-Azar Research Centre, Muzaffarpur. He had taken sag treatment from a local doctor but that did not help. He ended up with a loan of Rs 4,000 from relatives. "If one person in the family falls sick, the whole family is destroyed," says Arjun Kumar Das of the Musahar Vikas Manch, Jakhra village. "The disease is very undemocratic. It affects the poorest of the poor," says Jha. It doesn't help that in East Champaran, the dominant Musahar community don't want to go to hospital because of the bad treatment they receive at the hands of the staff. The centre has promised Rs 100 a day to patients and Rs 50 to attendants, but the money has not been disbursed yet.

The main problem with the national programme for eradicating kala-azar, which has been in existence since 1990, is that it has worked in fits and starts. For instance, as already mentioned, there is a whole lot of activity now because of the regional agreement and the World Health Assembly. Also, the programme is hamstrung because it depends on drugs that are being developed elsewhere and which are not sensitive to the specific needs of, say, East Champaran. If the centre invested public money on need-based research priorities it could probably get better results. For instance, the All India Institute of Medical Sciences had developed a diagnostic kit in 2003. But the national programme uses expensive imported kits because no one has bothered to carry out validation trials on this kit. This situation is similar to that of the unani treatment, in which the testing is progressing very slowly.

Inept and fund-starved
Vector control also faces basic problems. The sand fly, Phlebotomus argentipes, is the vector that transmits the pathogen Leishmania donovona. It stays inside cracks and crevices of huts. As sand flies can only hop around, vector control measures, mainly insecticide spraying, is needed only to the height of six feet. In India, ddt is used for vector control. Implementation is key. This year, though ddt treatment was supposed to have ended by March 31, lack of workers, pumps, buckets and money for paying daily wagers delayed the spraying of ddt in Motihari, though experts had identified February and March as peak transmission periods. The deadline was extended to May 30. The efficacy of vector control measures depends on how spraying is carried out. In Prem Nagar, Motihari, we observed a team at work. The process of making a suspension of ddt in water. The ddt is first mixed with a small amount of water to get the right consistency. One of the team members, Subba Lal, was given the responsibility to do this. Though he mixed the ddt with bare hands for half an hour, he failed to get the needed consistency. Ajaz Asgar, a health inspector with the team, lamented the lack of gloves--the skin starts to peel if the hands remain in the solution for too long. Though his department has been asking for gloves, none have been supplied.

Asgar talks about how the ddt-spraying process has proceeded in fits and starts over 15 years. In 1992, a paramedical staff would go with the spraying team to ensure spraying was done properly. The whole of East Champaran was covered and kala-azar incidence fell. This changed in 1995, when spraying became intermittent and the presence of paramedical staff was eliminated. In 1999, the whole of the district was covered again. But between 2001 and 2006, only some areas were sprayed. This year, the orders are to cover the whole district.

Housing solution
The state government has decided that the disease will be easier to control with better housing. In February 2007, it wrote to the centre for a package for kala-azar-affected areas. Rs 24.3 crore has been sanctioned to the affected districts, including East Champaran. In response, the East Champaran authorities held a meeting on May 19, 2007, and decided to choose the target recipients from among those who had contracted the disease. "Money for 12,840 families has been provided to the civil surgeon's office. It is now up to them to distribute the money," says Anup Mukerji, commissioner and secretary, rural development department, government of Bihar.

The problem is that the Indira Awaas Yojana, for people below the poverty line, does not work. A 2003 report by the comptroller and auditor general revealed that in Bihar 2,393 extra houses were reportedly built. The state did not keep an inventory, making it difficult to assess whether the intended persons had benefited. "In Rulahi village (East Champaran), nearly everyone got the money for Indira Awas but only seven houses are complete," says Ram Dev Ram, mukhiya of Rulahi.

The idea of improving housing is important given a survey conducted by the Bihar Voluntary Health Association that found most people in affected areas lived in inappropriate surroundings. It will run a programme to educate people about reducing risk by sleeping on beds and using mosquito nets.

Private-public partnerships (ppps) are trying to address the kind of problems highlighted in Bihar, with very mixed results.

Diseases that affect the poorest of people are usually neglected. Since the poor do not have the capacity to pay for treatment, the pharmaceutical industry and researchers do not invest on these diseases. The Commission on Health Research for Development categorises those diseases as neglected which affect 90 per cent of people but get only 10 per cent of research funding--the 10/90 gap. WHO's Special Programme for Research and Training in Tropical Diseases puts 10 diseases in the neglected disease category. We sample some of these.

Lymphatic filariasis
The goal is to eliminate the disease also known as elephantiasis by 2020. The Global Programme to Eliminate Filariasis was established in 1998 by WHO. Around one billion people in 83 tropical countries in Africa, Asia, the Pacific region and the Americas are vulnerable. Filariasis can be eliminated by administering five rounds of a combination of safe and available drugs five times a year. Two of them--albendazole and mectizan--are donated by GlaxoSmithkline and Merck, which have promised to donate as much of these drugs as necessary to eliminate the disease--valued at US $1 billion. Additional partners and funds are needed to deliver these drugs. With the existing drugs, the treatment has to be repeated every year. There is no research on better diagnosis and a drug that can cure the disease.

Chagas disease
Chagas disease is found only in Latin America, with the total number of cases estimated at 16-18 million. Approximately 120 million people, 25 per cent of the inhabitants of Latin America, are at risk of contracting the disease. People suffering from Chagas disease may suffer cardiac, gastrointestinal, or neurological damage. Vector control has been found very effective. Two drugs, nifurtimox and benznidazole, are cures, but both drugs have serious side-effects so their use has been limited. Due to lack of testing facilities, this disease is usually diagnosed too late for available drugs to be effective. Five drugs are being developed through public-private partnerships (PPPs).

Schistosomiasis
This disease is widespread in 74 countries. Eighty per cent of people suffering from it are in sub-Saharan Africa. The disease has a relatively low mortality rate, but causes a debilitating illness. It is associated with proximity to water resource development projects, such as dams and irrigation schemes, where snails, the intermediate hosts of the flatworm pathogen, breed. People are infected by contact with contaminated water. The flatworm lives in blood vessels and their eggs are passed out of the body. The disease occurs when some eggs are trapped in body tissues and trigger an immune reaction. The focus of research is on vaccines. Better tools for diagnosis are needed.

Onchocerciasis
Onchocerciasis is the world's second leading infectious cause of blindness. The blackflies that transmit the disease abound near rivers, giving the disease the name river blindness. It has been found in 35 countries--28 in tropical Africa, six in South America and Yemen. It is caused by a parasitic worm, Onchocerca volvulus. Blackflies carry the immature larval forms of the parasitic worms from human to human. These worms cause visual impairment and blindness, rashes, lesions, itching and depigmentation. Ivermectin, developed in the 1980s, is a safe and effective antidote and is provided free by Merck through WHO. Insecticide spraying has succeeded in controlling the vector. The Onchocerciasis Control Programme launched in 1974 in seven countries in west Africa focused on controlling the vector, but now the focus is on treatment. But eradication is not possible with the existing drug. Moreover, a drug is needed to kill the adult worm. Delivery systems must also be improved.

African trypanosomiasis
Commonly called sleeping sickness, this disease is fatal if left untreated. It affects 36 countries in sub-Saharan Africa. Sixty million people are at risk but less than 4 million are under surveillance; only 40,000 are being treated. The disease is caused by a protozoa of the genus Trypanosoma, which is transmitted by tsetse flies. The parasites invade the central nervous system. Treatment is difficult, especially when the disease has reached an advanced stage, since few effective drugs are available. Diagnosing this disease requires a lumbar puncture which is beyond the capacity of regular health facilities in affected countries. Treatment is based on a very toxic arsenic derivate in use since the 1940s and a former cancer drug from the 1980s. A new drug, eflornithine, originally developed as an anti-cancer agent, has shown promising results. Aventis supplies drugs to WHO to treat this disease. Four more drugs are in pre-clinical development stage and three are in clinical trial stage.

Tuberculosis
With one-third of the world's population at threat, TB is an attractive area for research for pharmaceutical companies. It is estimated that by 2020, 1 billion more people are likely to be affected by the disease, which is not restricted to the poorest of people. About 18 per cent of people in the US and 15 per cent in Europe provide rich markets for research products. TB is a contagious, airborne infection. Though most infected people can carry TB bacilli without becoming sick, a weakening of the immune system increases the chance of the TB bacilli becoming active. The bacterium has been found to be getting resistant to the available multi-drug treatment. The Global Alliance for TB Drug Development is a non-profit venture that aims to accelerate the discovery and development of new drugs. It was established in October 2000. Treatment takes six months and is difficult to implement, depending on increasingly ineffective drugs dating from the 1950s and 1960s. The only test simple enough to be widely implemented is sputum microscopy developed in 1882, but it detects the disease in only 45-60 per cent of cases. There are 32 drugs in early development stages and seven in various stages of clinical trials.

Malaria
Every year, more than 500 million people contract malaria. It has been estimated that around 40 per cent of the world's population are at risk. Though the disease mainly affects poor people in developing countries, travellers from malaria-free regions going to affected areas are also vulnerable. The pathogen is resistant to most drugs. Artemisinin is the only effective drug against resistant strains. Since artemisinin is derived from a plant, there is a shortage of raw material, which makes the drug expensive. Two drugs have been developed through PPPs: Lapdap for uncomplicated malaria by GSK and CoartemR, an artemisinin-based combination drug by Novartis for drug-resistant malaria. Eighteen drugs are now in development and pre-clinical trial stages and 15 in various stages of clinical trials.

The preferred paradigm to address the obvious shortage of drugs for neglected diseases has been ppps between governments or international agencies on one side and the pharmaceutical industry on the other. Though the success of this paradigm has been loudly trumpeted, it has fundamental problems that make it unworkable in existing formats.

To begin with, it must be stressed, there is a mismatch between what is needed and what is being done. In a 30-year period between 1975 and 2004, only 21 drugs have been developed for tropical diseases and tb. Research on drugs for neglected diseases did gain some momentum after 2000 when 60 drug development projects for neglected disease were initiated, mainly as ppps. By 2005, 18 of these drugs were in clinical trials and two drugs were registered.

In some cases, ppps have managed to get a few 'low-hanging fruits'--drugs on which work has been taken past the preliminary stage mainly by public agencies. Some diseases have been known for centuries and scientists have done extensive work on them. More is known about and published on the biology of kala-azar and the trypanosomes parasites than any other. Many useful leads have been abandoned midway due to lack of funds, however. In some cases, successes of ppps are based on taking this work forward. Paromomycin is a good example. The anti-kala-azar activity of the drug was known since the 1980s and who even carried out some clinical trials. The work of the ppps started only with phase-iii clinical trials. Similarly, some of the successful anti-malarial drugs introduced by ppps are also low-hanging fruits.

The field of neglected diseases gives drug companies tangible and intangible incentives. They range from image-building through the corporate social responsibility route to gaining market access. Developing countries with thousands of trained researchers also help reduce cost of research. AstraZeneca's first Asian r&d centre, its neglected disease institute in Bangalore, provided it with low-cost, high-skilled researchers. But these do not necessarily translate into benefits for people on the ground.

A study by Mary Moran and her team at the London School of Economics in 2005 showed the pitfalls of ppps in developing drugs for neglected diseases. The research was on miltefosine, the first oral drug for kala-azar. Miltefosine is a big asset in terms of profile for Zentaris, which has just one other drug in the market. The drug was initially taken up by Wellcome for kala-azar in the mid-1980s but the project was abandoned and the biotech company Zentaris GmbH, Frankfurt, started working on it as an oral anti-cancer agent but found it unsuccessful. When who and the Indian government decided to eliminate kala-azar by 2010, Zentaris had the opportunity to develop it for the disease. Public assistance was provided all the way. who/tdr set up a joint public-private steering committee for the project, provided specialist leishmaniasis and developing country inputs, helped develop trial protocols and sponsored clinical trial monitoring. Indian public research groups helped the company conduct clinical trials within five years (1997-2002). The drug was quickly registered in India due to involvement of who and the Indian government.Despite all this, the drug did not become available to kala-azar patients in government hospitals until recently, though the company had been selling it in the open market at us $145 for a 28-day course. The reasons for the delay were that who declined to include the drug in its Essential Drugs List because of toxicity and teratogenecity (the capacity to cause foetal malformation). Zentaris also did not agree with who on the price though initially it was agreed that the drug would be provided at us $60-85 for a 28-day course.

Moran's team also showed that the tb Alliance could not pursue the development of derivatives of the anti- tb drug ethambutol because Sequella, a small pharmaceutical firm that had the patent to the drug, refused to sign a deal on the grounds that the ppp's pricing, production and distribution terms were incompatible with the company's business model. Meaning, that the company was not willing to sacrifice a large potential market its drug had for a public cause.

Some drugs developed for neglected diseases become successful because they have other more lucrative markets. The anti-malarial developed by the Medicines for Malaria Venture (mmv) in collaboration with Ranbaxy will be available at a lower cost in developed countries but Ranbaxy can sell it a higher price in the travellers' market--people from the developed world travelling to malaria-affected countries. Similarly, paromomycin will be available at a lower price to the Indian government but the manufacturer has a vast secondary market in developed countries because kala-azar has become an important co-infection associated with hiv/aids.

This is also the reason why ppps for malaria and tb have been more successful than others. In 2004 nearly 60 per cent of ppp projects in pre-clinical stages and 82 per cent in clinical stages were working on malaria. Moreover, 75 per cent of total ppp budgets were used for malaria projects. More funding is available for these drugs than for other neglected diseases. According to statistics from usaid, the Department for International Development, uk, the Global Fund to fight aids, Tuberculosis and Malaria, and the President's Malaria Initiative websites, the funding for research on hiv/aids, malaria and tb is to the tune of us $10 billion compared to just us $35 million available for other neglected diseases (see table Skewed; graph Some are not so neglected).

Bad models
The problem with ppps is not restricted to drug development, delivery models are sometimes also a problem. "Our phase-iv trials will include a replicable and affordable access model for delivery of the medicine. We hope to be able to scale this up for government use," says Mireille Cronin Mather, director, communications and outreach, iowh, which is providing paramomycin to kala-azar patients in East Champaran. But the fact is that instead of using the government health machine already working in the area, iowh is giving private players a free run in operationalising the drug. Janani, an ngo affiliated to the Washington-based charitable organisation dkt-International, will be instrumental in taking the drug to rural areas.The pilot access programme is being funded by a us $30-million grant from the Bill and Melinda Gates Foundation.

Some private agencies try to complement the government and factor in local circumstances in working out their delivery model. "We have not come here to replace the government but support the government in what we have identified as a health problem in the area," says Javier Roldn Salado, project coordinator, msf, Spain which has taken up anti-kala-azar work in Vaishali district. To ensure the programme maximises benefits, the organisation also plans to provide nutritional support to patients, a novel feature. Additional support of 2,500 kilocalories will be given to the severely undernourished and 1,200 kilocalories to those who are moderately malnourished. The government also gives nutritional support in its programmes, but the diet it provides is not very nutritious.

Fund crunch
The success of a ppp depends on whether it can raise sufficient funds to carry its projects through to fruition. Currently, ppps have not even secured funding for their existing projects; as they fill their pipelines funding, needs will increase. It is unclear at this moment where the resources to finance the very expensive later stages of development and clinical trials will come from. A 2004 estimate by the Initiative for Public-Private Partnerships for Health, Geneva, compared needs with pledged funding for a sample of ppps and suggested a shortfall of us $1.2-2.2 billion up to 2007. There is a need to increase public funding to ensure that progress in basic science and biomedicine results in new, affordable drugs for neglected diseases (see pie chart Donor stack-up).

With funding gaps increasing, researchers around the world are trying to find ways of promoting research on neglected diseases that break both the existing ppp model and the established intellectual property rights system.

who set up the Inter-governmental Working Group on Public Health, Innovation and Intellectual Property (igwg) in 2003. Tasked to create mechanisms to develop products to fight diseases in the developing world, igwg authored a report in April 2006 suggesting patent pools, advance purchase commitments, prize funds and no-profit, no-loss models for pharmaceutical companies as suitable mechanisms. igwg will now have to come up with a global plan by 2008.

Proposed solutions
A patent pool is an arrangement between several patent holders for the collective management of their patents, which could make access to research tools easier, in turn facilitating research in both the public and private sector. Patent pools can be voluntary or imposed by governments.

Similarly, advance purchase commitments can create a market by guaranteeing the purchase of a drug or vaccine that does not yet exist. It is believed that if the demand and price are high enough, and the commitment originates from credible organisations with sufficient financial backing, this can provide an incentive for the development of necessary drugs.

A prize fund is a variation on the idea of an advance purchasing commitment. Instead of rewarding innovators indirectly, via profits on the sale of the final product, a prize fund can directly pay a significant sum as a reward or 'prize' to any entity invents a new drug or vaccine. The prize will have to be substantial in order to be effective.

Some firms like GlaxoSmithKline, Novartis, AstraZeneca and Sanofi Aventis have been involved in r&d for neglected diseases on a no-profit, no-loss basis.They have said products will be affordable and accessible in developing countries.

In 2005, a group of ngos, professional organisations and scientists, including Nobel laureates, submitted a draft medical r&d policy to who. Among other things, it advocated a credit system. For example, research on neglected diseases could earn countries credits that protected them from other trade agreements on patents or drug prices. Other things that would bring in credits would include transfer of technology and capacities to developing countries and help in preserving traditional knowledge. It also proposed that under the treaty, governments could commit to spending a certain percentage of their gdp on medical r&d to help increase research on neglected diseases and get certain benefits. If a government, for example, opted to fund research (for example, by giving grants to research institutions or via a prize fund), it would not have to respect patents on pharmaceuticals, having already have paid its share of the r&d.

The problem with these solutions is getting industry on board, across the board. At a meet in Brussels on April 2, 2007, to help eu prepare for discussions at igwg, industry did not agree that the system wasn't working. Members of the International Federation of Pharmaceutical Manufacturers Associations said the existing property rights model was fine and industry was active in r&d into many neglected diseases. They said ppps should be strengthened and the intellectual property rights system complemented, such as through advanced purchase schemes, not replaced.

As many point out, the problems in working with private industry and private or international donors to serve the public interest means that ultimately an injection of public money at the national level is crucial in making further headway on research into and control of neglected diseases. This was demonstrated spectacularly by China with its public research on artemisinin, the anti-malarial drug.