In recent times after many decades of decreasing interest in R&D on neglected diseases particularly those affecting the tropical developing countries, there is a resurgence of interest in the area. The lull in activity in the recent past has been reportedly due to a number of factors including lack of commercial interest due to relatively small markets in value terms, lower innovative potential in these disease areas, low priority in view of low returns on investments, arguments that non-communicable diseases are a bigger problem even in developing countries and overall apathy to work in areas where rational drug discovery approaches are found wanting.
Neglected diseases
Apart from the well known communicable diseases of TB, Malaria and HIV/AIDS which are no longer neglected, there are over a dozen other diseases which need new drugs, if the healthcare needs of over a billion people world-wide who suffer from these diseases are to be addressed. They are vector, food, air and water borne with the causative agents being of bacterial, viral, fungal and parasitic in origin. Some of the major ones are Intestinal Heminthiasis, Visceral Leishmaniasis, Filariasis, Onchocerciasis Schistosomiasis, Japanese encephalitis, Dengue, Leptospirosis, Ebola, Trypanosomiasis, and some of the more recent ones such as Sars, Avian Flu, Swine Flu, Chikun gunea etc. Being vector borne, the strategies for their control or eradication go far beyond drugs into areas of vector control, providing potable water, cleaner air and better public health and sanitation facilities. All these diseases would fall under the category of neglected diseases since the industry, the prime discoverer of new drugs has paid very little attention during the last four decades for the discovery and development of drugs for these diseases. Out of the total expenditure on drug discovery and development only 0.001% is spent on research for neglected diseases which affect over a billion people world wide.
Problem areas
In terms of Disability Adjusted Life Years (DALYs) lost, diseases of the cardiovascular system, central nervous system disorders, cancer, pulmonary diseases and diabetes account for 25 per cent, while diarrhoea and other childhood diseases, TB, Malaria and HIV/AIDS account for 20 per cent.
Diarrhoeal and other childhood diseases result in close to 3 million deaths per year, malaria, 1.3 million and 500,000 new multi-drug resistant TB cases appear every year. Over 100 million children have vitamin A deficiency leading to several problems including night blindness. Over 100 million people are infected with Schistosoma mansoni infection. Number of cases with African Trypanosomiasis, Leprosy, Lymphatic Filariasis, Onchocerciasis and Trachoma are also substantial.
During the period 1975 to 2004 out of 1556 new drugs approved and marketed, only 21 were for neglected tropical diseases. The last new class of anti TB drug, Rifampicin was marketed 45 years back and the only anti-TB vaccine, BCG (none too effective) was discovered in 1923.
Tropical diseases account for 12 per cent of global disease burden, but account only for 1 per cent of the new drugs discovered.
Orphan diseases
The common factor between Neglected Tropical Diseases and Orphan Diseases is that in both cases there has been an inertia on the part of R&D based Pharmaceutical companies to include them in their R&D portfolios. The main reason for lack of interest in orphan diseases is the low level of customer (patient) base available. However, unlike neglected diseases, orphan diseases over time have attracted attention particularly by small and medium enterprises which license the candidate drugs to big pharma for development and commercialisation. Both US (1983) and Europe (2002) through appropriate legislations provide incentives including financial support and assured market exclusivity for prescribed periods to drugs developed for diseases which affect not more than 200,000 people world-wide. Some other countries including Switzerland, Japan and Australia have legislations which provide subsidies and other incentives. While the markets are small, the costs involved are also very low compared to drugs for major indications. Over 70 per cent of orphan drugs have originated from small companies many of which are licensed out to big pharma companies. During the last thirty years, the US FDA has approved over 350 orphan drugs for conditions such as glioma, multiple myeloma, cystic fibrosis, phenyl ketonurea, snake venom poisoning etc. Many of them qualify for fast track regulatory clearance resulting in relatively low development periods and costs.
Funding for R&D on neglected diseases
Realising the lethargy on the part of large pharma companies to invest in R&D for discovery of new drugs for Neglected Tropical Diseases (NTDs), a large number of organisations have been set up in recent times to support global efforts in the area. The major ones are Medicines for Malaria Venture (MMV), Global Alliance for TB drug development (GATB), Global Alliance for Vaccine Initiative (GAVI), Funds for Research in Neglected Diseases (FRIND), Drugs for Neglected Diseases Initiative (DNDi), Gates & Melinda Foundation, Clinton Foundation, WHO (TDR), Wellcome Trust etc. Among the category of neglected diseases, Malaria, TB and HIV/AIDS have recently attracted considerable funding even though returns on such investments are still to be realised.
It is interesting to look at the new attempts at networking by many institutions for development of drugs for neglected diseases pooling their resources for common goals in identified problem areas. The DNDi set up in 2003, for example is a programme sponsored by Indian Council Of Medical Research, Kenya Medical Research Institute, Malaysian Ministry of Health, Oswaldo Cruz Foundation, Brazil, Medicines Sans Frontieres, Institute of Pasteur, France and WHO.
Global Network for neglected disease is an advisory and research mobilisation initiative of the Sabin Vaccine Institute to control or eliminate some of the common neglected diseases Trachoma, Helminthic Infections, Schistosomiasis, Lymphatic Filariasis, Onchocerciaisis, and Trypanosomiasis.
The Global Alliance for TB drug development is a not-for-profit organisation set up through a partnership of public private, academic and philanthropic institutions to develop new drugs for underserved markets.
The Medicines for Malaria Venture (MMV), started in 1999 has as its objective bridging the gap between R&D and marketing through collaboration between academia and industry to provide new products for the control and/or eradication of malaria around the world with drugs which will be priced only on the basis of manufacturing costs.
Assessing outcomes
During the period 2000 to 2008, over 55 drugs were being developed for some of the neglected diseases. The investments have been of the order of $ 500 million. However, in order to take these to the final stages and successfully develop them around $ 8 billion would be required. That range of funding is not readily forthcoming even with all the various projects being pursued by the various agencies. Apart from funding, other aspects including dearth of additional incentives, lack of focus and direction, inadequate technical and management skills needed for effective drug development, poor intellectual property protection possibilities, difficulties in carrying out appropriate clinical trials are some of the issues which plague these efforts. Of the total number, 75% are from the projects under Public-Private Partnerships. The expertise needed to take them through the various phases of development including clinical evaluation require collaborative efforts with R&D based pharma companies . It is not clear as to how to incentivise the large pharma companies most suited to carry out such work to put these in their priority list for development is a question which is not easily answered.
(Author is consultant to Healthcare Industry, Chennai based)