What has been done so far to address the R&D crisis?
Over the last few years, there has been increasing awareness of the lack of effective treatments for some diseases.
Some recent initiatives have sought to find novel approaches for stimulating research into neglected diseases. The following brief review describes some current approaches, policy tools, and initiatives.
Some examples of recent government response to the R&D crisis in neglected diseases include the European Commission's "Programme for Action: Accelerated Action on HIV/AIDS, Malaria and Tuberculosis in the Context of Poverty Reduction" and the report "Tackling the Diseases of Poverty," produced by the Prime Minister's office in the United Kingdom.1
Both institutions conducted a multi-sectoral analysis of the problem and their reports map out potential solutions. Although these efforts demonstrate some positive government engagement, recommendations focus primarily on market-oriented strategies. This is demonstrated by the European Commission's statement that it plans to offer "appropriate incentives to encourage private investment into Research and Development." The UK report also stresses incentives to private industry.
Moreover, both analyses focus exclusively on drugs for HIV/AIDS, tuberculosis (TB), and malaria, the UK plan going as far as recommending restricting "activities related to new products" to those for these three diseases, with this restriction up for periodic review. Strategies designed to focus on these three diseases are unlikely to stimulate the search for drugs to treat the most neglected diseases. The failure of both analyses to address the diseases that are most neglected - such as leishmaniasis and sleeping sickness - means that their proposed solutions will leave the people with these illnesses on the sidelines (see Figure 1B).
Traditionally, governments have played a positive role in developing drugs for communicable diseases. For example, with very few exceptions, today's malaria drugs were initially discovered outside the private sector in universities or government labs - institutions known for their competence in identifying promising prospective drugs. The Walter Reed Army Institute of Research, for instance, with a small budget from the US Department of Defense, invented four important anti-malarial drugs, which were then developed in collaboration with multinational drug companies.2
Despite the efforts of individual actors in the public sector, R&D into neglected diseases remains woefully inadequate. While the public sector is not powerless, it currently depends largely on the skills and expertise of the private sector to conduct final drug development. If the private sector is unwilling to take a drug through this final stage of development, it never leaves the laboratory. Recent proposals have sought to increase public sector involvement while increasing incentives for the private sector to move compounds beyond the laboratory and ultimately deliver them as drugs to patients.
"Push" and "Pull" In order to attract private sector R&D capacity back into needed areas, what are called "push" and "pull" mechanisms have begun to emerge as possible answers. "Push" mechanisms reduce costs and risks of R&D and can include tax credits, R&D grants, and support for clinical trials.
"Pull" measures help create a market for drugs or increase their profitability. Two examples are the creation of purchase funds and "patent exchange," whereby a company would invest in developing a drug for a neglected disease and
then, once the drug was approved, would have the right to extend the patent on one of its other, more profitable drugs. Both "push" and "pull" mechanisms are market-based measures that aim to increase the investment return for a drug to a level that will attract the private sector.
Orphan drug laws Orphan drugs laws are an example of a "push" mechanism. Orphan drug laws use tax credits and grants to promote research into drugs for diseases that affect a relatively small number of people (in the US this is set at 200,000 or fewer people).3 These rare diseases would otherwise represent a market return inadequate to motivate drug investment.
The Orphan Drug Act in the US (similar laws exist in Europe, Japan, Singapore and Australia) has successfully provided incentives for research into diseases such as cystic fibrosis.4 Some policymakers are recommending amending these kinds of laws to include neglected diseases in
developing countries. However, it is critical to note that orphan drug legislation has succeeded because, in addition to tax incentives and government grants, companies can recoup costs by charging high prices for the drugs. One extreme example is the drug Ceredase, used to treat Gaucher's disease, which was priced at hundreds of thousands of dollars per year of treatment.5 Since purchasing power is limited or non-existent among people with neglected diseases, the orphan drug mechanism alone is not likely to work. However, the concept may be useful if paired with other mechanisms, or modified to fit neglected diseases more specifically.
The history of this type of legislation also shows that it could be particularly effective in motivating small and medium-sized enterprises; in the US, over 50% of companies applying for orphan drug status are small and medium-sized.6 However, many of these companies depend on outside financing to support their R&D programs, and also need to maximize profits for their shareholders.
What about a "Pot of Gold"? One commonly suggested "pull" strategy is the creation in advance of purchase funds for drugs for neglected diseases. The idea is to secure purchase funds through donors - the "pot of gold" waiting at the end of the drug development rainbow - in order to supplement an existing market, and thus "pull" companies into drug development. However, to prompt a major pharmaceutical company to invest, the existing market plus the "pot of gold" would need to compete with the average return on commercial sales, put at about US$265 million annually in 1998.8 This would be a great expense, and in a sense is "buying into" the existing drug development system by subsidizing shareholders' needs for profits and other costs associated with private industry drug development.
This strategy could potentially work for some neglected diseases that affect large numbers of people, such as TB or malaria, because an existing market in wealthy countries would supplement the pot of gold (eg, TB in Europe or the malaria traveller market). For the most neglected diseases, a purchase fund by itself would likely be too costly for governments and other funders. Drugs for the most neglected diseases - again, those for whom a potential market does not exist - are still likely to be overlooked. Still, the concept may be useful if paired with other mechanisms or modified to fit the most neglected diseases specifically.
Building capacity in developing countries Building capacity in developing countries is another important strategy for stimulating R&D. Public health institutes in some developing countries are playing an increasingly important role in drug development. For example, the Thai government's support for malaria research has led to the development of an effective modern pharmaceutical version of artemisinin, a traditional Chinese medicine. In clinical trials, drugs using Thai artemisinin cured 90% of malaria cases,9 and elsewhere cut infection among children by 90% in camps for displaced people on the Thai/Burmese border.10 However, while this new formulation is saving lives in Thailand, it is not recognized as a legitimate treatment by international regulatory agencies because the research reporting methods used in Thailand do not match international agencies' reporting requirements. In this case, "harmonization" regulations on drug R&D, which were created to meet the needs of wealthy markets, are hampering access to new treatments created in developing countries (see box page 25).
Drug research, development and production is increasing in, among other countries, Brazil, India, South Korea, Thailand, Malaysia and Argentina, countries that had not been considered in the past to have innovative R&D capacity. Some initiatives to build capacity in developing countries involve stimulating collaboration between the public and private sectors in those countries. For example, the International AIDS Vaccine Initiative (IAVI) is working directly with university scientists, governments and companies in South Africa, Kenya, Uganda, India and China. The IAVI has in particular identified India as an ideal location for "fast-tracking" vaccine development, given the country's thriving pharmaceutical industry, experience in clinical trials and government commitment to research.11
Regional ventures also attempt to maximize developing country capacity through inter-country collaboration. The International Vaccine Institute in South Korea is a non-
profit organization that was created to develop vaccines for diseases prevalent in developing countries. The Institute has pooled the skills and knowledge of scientists in various developing countries, and has been identified as a possible model for drug development and production.12
Public-private partnerships
Another type of policy initiative that is often discussed as a potential solution to the R&D crisis is the public-private partnership (PPP). PPPs attempt to foster R&D for neglected diseases by mobilizing expertise, capacity, and funding from both the public and private sectors. Typically, the PPP plays a coordinating and management role around a disease-specific R&D agenda, tries to take advantage of appropriate push and pull mechanisms, and seeks a combination of public funding, philanthropic donations and in-kind donations from industry. Major examples of this kind of approach are the Medicines for Malaria Venture (MMV), the Global Alliance for TB Drug Development (GATB), and International AIDS Vaccine Initiative (IAVI). So far, no
public-private partnerships have been designed specifically for developing drugs for the most neglected diseases.
Current government initiatives, "push" and "pull" mechanisms, building capacity for R&D in developing countries, and public-private partnerships are all only partial solutions to the continuing R&D crisis for neglected diseases. Many are new initiatives whose effectiveness will need to be evaluated over time. And all depend to a greater or lesser extent on market forces. None of them provides an adequate strategy for developing drugs for the most neglected diseases.
Footnotes:
1) European Commission, Programme for Action: Accelerated Action on HIV/AIDS, Malaria and Tuberculosis in the Context of Poverty Reduction, COM(2001)96, (Brussels: European Commission, 2001).
Performance and Innovation Unit, Tackling Diseases of Poverty: Meeting the Okinawa Millenium targets for HIV/AIDS, tuberculosis and malaria. (London: Cabinet Office,
8 May 2001).
2) Amir Attaran, "Malaria Drug Treatment: Prescription for Curing Policy," working paper of the Drugs for Neglected Diseases Group, Geneva, October 23-24, 2000.
3) U.S. Orphan Drug Act of 1983 [Online]. Available: www.fda.gov/orphan/regs.htm.
4) James Love, "Paying for health care R&D: Carrots and Sticks," working paper of the Drugs for Neglected Diseases Working Group, Geneva, October 18, 2000.
5) James Love, affidavit at the High Court of South Africa in the matter between Pharmaceutical Manufacturers' Association of South Africa and Others and The President of South Africa and Others, and Treatment Action Campaign (Amicus Curaie), Case: 4183/98, 9 April 2001 (South Africa, 2001).
6) Institute for Global Health, "Creating Global Markets for Neglected Drugs and Vaccines: A Challenge for Public-Private Partnership," (consensus statement of Creating Global Markets for Neglected Drugs Vaccines: A Challenge for Public-Private Partnership conference, Carmel Valley, California, February 18-21, 2000).
7) Patrice Trouiller, Peter Folb, and Kris Weersuriya, "Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use," working paper of the Drugs for Neglected Diseases Working Group, Geneva, October 23-34, 2000.
8) This $265 million refers to the 1998 average revenue of new launched drugs as calculated by Dr. Steve Arlington. Dr. Steve Arlington, "Pharma 2005: The Challenges" (paper presented at the American Society for Clinical Pharmacology and Therapeutics meeting, Orlando, Florida, March 7, 2001).
9) Dr. Krisana Kraisintu and Dr. Chada Phisalaphong, et al, "Domestic Production of Dihydroartemisinin in Thailand," paper, Research and Development Institute, Government Pharmaceutical Organization, Thailand (June 2001).
10) "One Perfect Combination: Malaria Therapies Double up to Beat Resistance," Wellcome News. Wellcome Trust.
[Online]. Available: www.wellcome.ac.uk/en/1/biosfginttrpinfcom.html [2001, September 4].
11) International AIDS Vaccine Initiative. [Online]. Available: www.iavi.org [2001, August 13].
12) International Vaccine Institute. [Online]. Available: www.ivi.org [2001, August 13].
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