Commentary: Patents Pools and the AIDS Crisis
Essential Drugs and Health for All: Healthy Innovations from Bangladesh
An Epidemic of Neglect: Neglected Diseases and the Health Burden in Poor Countries
Cardiovascular disease and cancer, baldness and impotence -- in recent decades, innovative drug treatments have helped mitigate or cure everything from life-threatening disease to the unpleasant marks of aging. But this "health revolution," which has resulted in considerable gains in life expectancy and health improvements in some parts of the world, has left most of the world's population behind.
Drug research and development (R&D) for diseases that disproportionately affect poor people in developing countries diseases is at a virtual standstill. According to a study by Patrice Trouiller and colleagues, soon to be published in the Lancet, of the 1,393 new drugs approved between 1975 and 1999, only 16 (or just over 1 percent) were specifically developed for tropical diseases and tuberculosis, diseases that account for 11.4 percent of the global disease burden.
Doctors Without Borders/Médecins Sans Frontiéres (MSF), the international humanitarian organization that was awarded the 1999 Nobel Peace Prize, has called attention to the problem of "neglected diseases." These are seriously disabling or life-threatening diseases -- such as malaria, tuberculosis (TB), Human African trypanosomiasis (sleeping sickness), American trypanosomiasis (Chagas' disease), and visceral leishmaniasis (kala azar) -- which mainly affect people in developing countries, for which treatment options are inadequate or do not exist, and for which R&D is insufficient or non-existent.
Those stricken with neglected diseases do not constitute a valuable enough market to stimulate adequate R&D for new medicines by the multinational pharmaceutical industry.
With a global system that relies on private companies to bring drugs to market, this situation has left much of the world without prospect for treatment and cure of the diseases that take a dreadful toll on their populations.
However, there are now, for the first time, glimmers of hope on the horizon. With public health campaigners drawing some international attention to the problem of neglected diseases, a number of diverse initiatives have been launched to spur R&D into these illnesses. But these new efforts are unproven and poorly funded, and some are pursuing controversial partnerships with industry. Their ultimate, or even partial, success is far from assured.
The Burden of Neglected Diseases
According to the World Health Organization, 14 million people die each year from communicable diseases such as malaria, TB, sleeping sickness and kala azar. An estimated 97 percent of deaths from communicable diseases occur in developing countries, with the poorest people in those nations disproportionately affected. Infectious and parasitic diseases account for 25 percent of the disease burden in low- and middle-income countries, compared to only 3 percent in high-income countries. According to the World Bank, eliminating communicable diseases would dramatically close the mortality gap between the richest 20 percent of the world population and the poorest 20 percent.
In many instances, the ravages of communicable diseases are worsening. Old diseases are reappearing and drug resistance is spreading rapidly, rendering useless medicines that were once effective. Some of the medicines used today were invented decades ago and are highly toxic. For some diseases, there is no treatment to offer: no effective medicine has been found and nobody is looking for new possibilities.
Sleeping sickness is a primary example. A parasitic disease that affects 36 countries in sub-Saharan Africa, an estimated 300,000 to 500,000 people are currently infected with this disease, and the figure appears to be on the rise. Left untreated, sleeping sickness is 100 percent fatal. It kills more than 65,000 people each year.
In many places, melarsoprol has been the only treatment available for second stage sleeping sickness. Developed in 1949, melarsoprol is an arsenic derivative so toxic that it kills one in 20 patients. Production of eflornithine, a safer and far more effective medicine, was discontinued in 1995 because it was not considered profitable by its manufacturer (now Aventis).
Production of eflornithine resumed in 2001, after Bristol-Myers Squibb (BMS) discovered that a topical ointment containing eflornithine as the active ingredient was useful in removing unwanted facial hair in women. BMS received approval to market the ointment for cosmetic use in 2000.
Following a major behind-the-scenes advocacy effort by MSF and other health advocates, Aventis agreed to resume production of eflornithine, donating enough of the drug to meet global sleeping sickness need for the next five years. Aventis also committed to working with WHO to find a long-term solution for the manufacture of the drug, and to invest in R&D, for example, into an oral formulation of eflornithine that will be easier to administer in field conditions. Eflornithine has yet to reach all the hospitals and clinics in Africa that desperately need it in order to begin treating people, however.
A more well-known neglected disease in industrialized countries, because it affects travelers to, as well as residents in, tropical countries, is malaria. Every year, an estimated 300 million to 500 million cases of malaria occur in more than 90 countries worldwide. Ninety percent of cases occur in Africa. One child dies every 30 seconds from malaria. Chloroquine, a medicine developed in 1934, continues to be the only treatment available for many people with malaria, despite growing resistance to it. Unfortunately, high resistance in many parts of the world has rendered it virtually useless -- in some regions, the chloroquine resistance rate is up to 100 percent, and the parasite has now also developed resistance to some newer drugs, including sulfadoxine-pyrimethamine (SP) and mefloquine.
Unlike some other neglected diseases, effective treatments do exist for malaria, most notably combination therapies containing artemisinin, which is derived from a Chinese plant. But governments are hesitant to change national malaria protocols to include these new medicines because they are much more costly than traditional antimalarials like chloroquine and SP. In many places, doctors have no choice but to prescribe chloroquine or SP, often knowing these drugs will not work. Meanwhile, there is not enough in the research pipeline, particularly for drug-resistant malaria.
Leishmaniasis is another severe neglected disease. Around 2 million people become ill with leishmaniasis every year, and an estimated 12 million people are currently affected by leishmaniasis in its different forms. The most severe form, visceral leishmaniasis or kala azar, is a fatal disease that affects 500,000 and kills more than 65,000 annually.
Sodium stibogluconate (SSG), also known by its brand name Pentostam and marketed by GlaxoSmithKline, is the most common medicine available for kala azar. Developed in the 1930s, it is expensive, difficult to administer and requires hospitalization for one month. Many people affected live in conflict zones where it is hard for medical teams to reach patients, and the long course of treatment can be interrupted if the hospitals are caught in fighting. For them, a month's hospital stay is an impossibility. Resistance to SSG is on the rise and the few other drugs that can be used are highly toxic and very expensive.
Clinical tests in India are proving encouraging for miltefosine and paromomycin, but these results have yet to be finalized for registration.
Over the last few decades, major progress in molecular biology and biotechnology has enabled the development of increasingly sophisticated medicines to cure a wide variety of diseases.
Meanwhile, global expenditures on health R&D has increased dramatically. However, R&D funds are focused on diseases of the rich. Only 10 percent of global health research is devoted to conditions that account for 90 percent of the global disease burden -- an imbalance that has been referred to as the 10/90 disequilibrium.
"Heavy reliance on an increasingly consolidated and highly competitive multinational drug industry to generate new medicines has left the development of life-saving drugs subject to the forces of the market economy," says Els Torreele, co-chair of the Drugs for Neglected Diseases (DND) Working Group, an independent, international, interdisciplinary team formed by MSF.
"Pharmaceutical companies simply have no financial incentive to invest in the development of new treatments for diseases that effect people who can't afford the medicines," she says.
People in developing countries, who make up about 80 percent of the world population, only represent about 20 percent of worldwide medicine sales. All of sub-Saharan Africa totals less than 2 percent of the global pharmaceutical market.
Industry leaders acknowledge their narrow focus. "The United States has become the must-win market for every pharmaceutical company," Fred Hassan, CEO of Pharmacia Corporation, told the World Conference on Clinical Pharmacology and Therapeutics in July 2000. "In addition, there are just six or seven other critical markets, including Japan and key countries in Europe.
"This does not mean ignoring other markets," Hassan said. "But it does mean strategically concentrating resources and top management attention on success in the key market. Again, this is very different from our industry's approach in the past, which focused on therapeutic areas across geographical regions."
Following this model, the pharmaceutical industry has prospered, with companies often having sales of hundreds of millions or even billions of dollars a year on a single drug. Pharmaceutical companies top the U.S. industry performance list for return on investment, with a 39 percent return for shareholders, according to Fortune magazine.
This model has not worked to develop new drugs for diseases that affect the world's poor, however. A Harvard University survey of 11 top-grossing pharmaceutical companies found that none had brought a drug to market in the last five years for three of the most neglected diseases -- sleeping sickness, kala azar and Chagas' disease -- and that there is hardly anything currently in the research pipeline for these diseases. Overall R&D budgets for the responding companies ranged from $500 million to more than $1 billion per year.
A recent survey on new medicines in development conducted by the U.S. drug industry lobby group PhRMA reports that of the 137 medicines for infectious diseases in the pipeline during 2000, only one mentioned sleeping sickness as an indication, and only one mentioned malaria. There were no new medicines in the pipeline for tuberculosis or leishmaniasis. PhRMA's 2000 "New Medicines in Development" list shows eight drugs in development for impotence and erectile dysfunction, seven for obesity and four for sleep disorders.
From Markets to Public Health
With purchasing power defining the industry research agenda and priorities, there is little prospect for the pharmaceutical industry addressing neglected diseases.
But public health activists say doing nothing is unacceptable. Governments, which should have a broader outlook than corporations, they say, have also failed.
"Having left drug development to the most profitable industry in the world, governments have shirked their responsibility to meet the health needs that the market does not care about," says Dr. Bernard Pecoul, director of MSF's Campaign for Access to Essential Medicines.
"Patents are granted with the aim of stimulating innovation," says Pecoul, "but a market monopoly is irrelevant when the market is non-existent. No amount of market tinkering will stimulate drug companies to invest in drug development for patients with kala azar and sleeping sickness in Sudan, Congo or India, who are too poor to ever represent a ëviable market.'"
In this vacuum, advocates for neglected diseases are searching for solutions.
Some recent initiatives have sought to find novel approaches for stimulating research into neglected diseases. Public-private partnerships, such as the Global Alliance for TB Drug Development (GATB) and the Medicines for Malaria Venture (MMV), are emerging, seeking to induce public and private sector research.
The single biggest change in funding for neglected diseases over the past few years has come not from private industry or the public sector, but from the increased commitment of foundations. The Bill and Melinda Gates Foundation has become a major force in neglected disease drug development. The Gates Foundation has given $25 million (over five years) to both GATB and MMV.
It is too early to say how successful these efforts will be. Dr. James Orbinksi, co-chair of the DND Working Group, worries that many of the public-private partnership initiatives still largely depend on the fact that there are "overlap" markets in wealthy countries -- as for malaria and TB -- that can be leveraged.
"Ensuring the development of life-saving medicine," says Orbinski, "should not be based on philanthropic donations or a coincidence of government and industry interests. These strategies, while extremely important, still rely partially on market forces -- tourists get malaria, and TB affects the western world. This does not work for the most neglected diseases like sleeping sickness and kala azar. The only way to solve this chronic health crisis is to change the way we think about medicines for neglected diseases. They must be considered public goods, not simply consumer products."
(The Gates Foundation, to its credit, has in at least one instance broken away from the overlap market model, and is providing funding for kala azar vaccine research.)
The DND Working Group is looking to a new model for stimulating R&D for the most neglected diseases. With MSF's preliminary support, the DND Working Group is carrying out a feasibility study for a not-for-profit Drugs for Neglected Diseases Initiative (DNDI), which Orbinski describes as a "partnership for public response." The DNDI would aim to develop new, effective, field-relevant medicines for the most neglected diseases, and would be firmly committed to ensuring that these drugs are affordable for those who need them.
"Ensuring the development and availability of treatments for these diseases will require a paradigm shift from market-driven to needs-driven drug development, with public responsibility and leadership in both developing and developed countries," says Dr. Yves Champey, the chair of the Drugs for Neglected Diseases Initiative Task Force, which is heading up the feasibility study.
According to the DND Working Group, the DNDI, should it be created, will differ from market-driven drug development in two critical respects: it will be guided by a clear focus on the most neglected diseases and it will be driven by need rather than return on investment.
In addition to identifying and developing new chemical entities, the DNDI will place special attention on developing and registering novel combinations of existing drugs, and reformulating existing products to improve use. These relatively simple and low-cost efforts, it is hoped, may yield major advances to address neglected diseases.
A complementary focus of DNDI will be to invest in sustainable capacity and leadership in developing countries at all stages of R&D. Public leadership from developed countries will also be vital to the DNDI.
"National self-interest and profit prospects can no longer be the single motor of medical research and development," says Dr. Pecoul. "Without serious political commitment and a clear realization that there is a public duty to commit to health issues at a global level, advances in science and medicine will contribute nothing to alleviating the suffering and meeting the critical medical needs of the millions who die of neglected diseases in the developing world."