Just think of the lives it could salvage or save. Here was a drug, praziquantel, that worked against all five species of schistosome worms. It showed higher efficacy, lower toxicity, and easier administration than existing drugs. And molluscicides to kill the snails that harbor and spread the disease-causing parasite can only be used in geographically limited areas due to cost and delivery problems. Meanwhile, schistosomiasis racks up the kind of grim statistics that put it second only to malaria as the most prevalent tropical disease in the world: 200 million infected, with 20 million made seriously sick by those infections, and 20,000 dead each year because of "schisto," according to World Health Organization (WHO) estimates. Clearly, in the right place, time, and hands, praziquantel could accomplish a lot of public health good.

And it has--to a point. Bayer A.G., the giant German pharmaceutical firm of aspirin-making fame, and E. Merck (now Merck KGaA), one of the oldest operating drug-chemical companies worldwide, discovered praziquantel’s antiworm properties over 25 years ago as part of routine screening of new compounds for veterinary purposes. By 1985 approximately one million people had been treated with praziquantel [pronounced pra-ZEE-quan-tel]--an impressive number, but just a start considering the millions more who might benefit from the powerful new medicine. Professor Michael Reich, Taro Takemi Professor of International Health Policy and chair of the School’s Department of Population and International Health, directed a research team that published a report from WHO last year on praziquantel. The report put the available supply of the drug in 1993 at about 89 million tablets, which represented only about one-fifth of the WHO estimate of the global need of 424 million that year. Even if WHO’s calculation of need is high, as some have suggested, that’s a huge gap. So the key question in the praziquantel case, says Reich, is "why is this great drug not available for poor people in poor countries?"

At some level, that question isn’t hard to answer. Great drugs are not available because poor countries can’t afford to buy them. The team’s report estimated that if Nigeria, a country with a very severe schistosomiasis problem, were to buy all the praziquantel it needs, the purchase would eat up almost 18 percent of the ministry of health’s budget for drugs and medical equipment--and that’s after a steep, UNICEF-negotiated price discount.

In the past, some pharmaceutical companies have sought to span the great drug—poor country gap by giving away small quantities of drugs, or by charging less for them in some circumstances, which is what Bayer did with praziquantel. The praziquantel case, however, highlights the limits of Bayer’s strategy in expanding access to drugs in developing regions.

In the late 1980s, another pharmaceutical company took a dramatically different approach to the same problem of getting good drugs to poor people. In October 1987, Merck & Co., Inc. in Whitehouse Station, N.J., announced it would donate, rather than sell, the human formulation of its big-selling veterinary antiworm medicine, ivermectin, "for as long as it might be needed" to as many people necessary to combat onchocerciasis, or river blindness. In the past 12 years, the MECTIZAN (the brand name for ivermectin) Donation Program has enabled more than 100 million treatments of onchocerciasis and, in 1998, nearly 25 million people--typically very poor--had been treated in 31 countries in Africa and Latin America and in Yemen in the Middle East.

In the late 1990s, the Merck program is generally considered a public health success, and the program has been emulated by a number of other drug companies. In 1996 the British drug company Glaxo Wellcome, perhaps best known as the maker of AZT, the AIDS drug, started a "controlled donation program" of its antimalaria drug, MALARONE. Two years later, SmithKline Beecham, another British drug company, launched its albendazole program, which is perhaps most ambitious yet: the 20-year goal of this collaboration with WHO is the elimination of lymphatic filariasis, a parasitic disease that can lead to disfiguring elephantiasis and serious male genital damage. Then in November 1998, New York—based Pfizer Inc. announced it would donate its best-selling anti-biotic, ZITHROMAX, as part of a large, integrated, five-country effort to control trachoma, which like onchocerciasis, is a disease that can lead to blindness and typically affects the poor in developing countries.

The Pfizer program has close ties to the School. Pfizer and the Edna McConnell Clark Foundation in New York have formed the International Trachoma Initiative to run the azithromycin (the generic name for ZITHROMAX) program. Joseph Cook, MPH’68, a longtime Clark Foundation official, is executive director, and Jeff Mecaskey, SM’90, is program director. Adetokunbo Lucas, SM’64, adjunct professor of population and international health and one of this year’s Alumni Award of Merit winners (see Three Roads Diverged), serves on the initiative’s expert committee as does Reich. The Clark Foundation also commissioned Reich to write a report that served as background for the trachoma initiative. "It was part of a facilitation effort to bring together a private foundation and a private corporation, which had different styles and organizational cultures," says Reich.

The drug donation programs have become popular for several reasons. These are good times in the drug industry, and healthy bottom lines do make it easier for corporations to be generous. Pfizer, for example, announced a three-for-one stock split in April 1999 as sales of VIAGRA and a new arthritis drug, CELEBREX (comarketed with G.D. Searle), have skyrocketed. Merck and the other donating companies are also reporting quarter after quarter of revenue and profit increases.

Several of the drugs are significantly better than prior therapies--more effective, safer, and easier to administer. People can fight off onchocerciasis-induced blindness by taking a single, annual dose of ivermectin. Research in the early 1980s showed that the previous therapy for the disease, a drug called diethyl- carbamazine citrate (DEC), caused severe damage to the eye and increased the risk of blindness. Ivermectin safely kills the micro-filariae of the disease-causing Onchocerca volvulus worm; the drug developed to kill the adult worms, suramin sodium, turned out to have toxic side effects and could only be given intravenously at weekly intervals. Trachoma can be treated with another antibiotic, tetracycline. But it comes in ointment form and must be applied to the eyes twice a day for about six weeks to be effective. Like ivermectin, Pfizer’s azithromycin is a one-dose, once-a-year proposition. SmithKline Beecham says the goal of eliminating lymphatic filariasis is realistic because the traditional antifilarial treatments of ivermectin and DEC are highly effective in breaking disease transmission when co-administered with albendazole, the antiparasitic drug it is donating. The company also cites rapid, easy-to-use, and less expensive screening tests for the disease. Glaxo Wellcome’s MALARONE isn’t easier to administer than other antimalaria therapies because it must be given over a three-day period, but the drug can be a lifesaver for people infected with a strain of the disease resistant to standard remedies, such as chloroquine and fansidar.

As celebrated as Merck’s MECTIZAN program is now, executives at other drug companies were initially opposed to it, according to Power and Responsibility, a 1997 book written by Lee A. Tavis, a University of Notre Dame business professor. Reich says Merck officials were originally concerned that giving ivermectin away for free would set a bad example: "I think the record shows that instead of it being a bad precedent, it has been seen as a pathbreaking precedent--that other companies have looked at the Merck ivermectin experience and see the way it has enhanced corporate values and corporate image in ways that Merck had not originally anticipated. It has become in some sense a touchstone for Merck." To illustrate the point, Reich notes that Merck has a sculpture of a child leading a blind man (a common scene in areas afflicted by onchocerciasis and other blindness-inducing diseases) prominently on display at its corporate headquarters. The World Bank--which has agreed to raise funds to finance onchocerciasis control efforts, including distribution of the drug, to the tune of about $132 million over an 8 to 12 year period--has a replica of the same statue in its new headquarters in Washington. The statue also stands at The Carter Center in Atlanta, reflecting that organization’s commitment to the river blindness cause, and this fall a fourth will be installed at WHO headquarters in Geneva, to represent the role it has played in this partnership.

These drug donation programs do not come without problems and controversy. Richard Laing, a professor of international health at the Boston University School of Public Health, says the ivermectin program is on balance a positive effort that is meeting a real need. "But it is not easy to administer," he continues, "and these are incredibly poor countries so there are always opportunity costs." Money spent on ivermectin distribution and oncho- cerciasis control might go, argues Laing, to other programs like meningitis and yellow fever control, both of which have suffered badly from the collapse of vaccine programs. Besides, Laing says the generosity of the drug donation programs needs to be put in some perspective. In exchange for good publicity and a tax write-off if the drugs are donated to a charitable organization, he notes, all a company needs to do is make a little more of what is often a very popular, and profitable, drug--and frequently in drug manufacturing, the actual production costs of making a drug are quite low.

Philippa Saunders, at the Essential Drugs Project in London, a non-profit group that supports NGO pharmaceutical services in developing countries, is generally supportive of drug company donation programs and says that the ivermectin program has "proven itself" over the past 11 years. Saunders notes, however, that every donation scheme is unique and must be assessed for its potential problems as well as benefits: "There are clearly much greater challenges in administering combinations of drugs, as is proposed for lymphatic filariasis, than single ones," she says. Saunders also comments that the misgivings of some NGOs and consumer groups may be justified as other drugs of great potential public health value are coming on the market at prices higher than poor countries can afford. "There is a suspicion," she says, "that the donation schemes of individual companies are, in reality, public relations exercises designed to undermine the case for fair trade in drugs."

On the other hand, these donation programs meet important public health goals that most likely wouldn’t have been achieved in any other way, argue Tavis and Reich. "The victims of onchocerciasis were in desperate physical as well as economic need," wrote Tavis. "Their only assistance was through the WHO spraying program, a preventive but not curative alternative. Merck was in a very real sense their last resort, as the only institution in the world, public or private, with a potential cure." Tavis adds that even though Merck was not in proximity to the disease sufferers, the company created the "capability of making a difference." Reich notes that Merck might have tried to exploit its monopoly position as having the only effective drug against onchocerciasis. "Instead," he says, "Merck made the decision to donate ivermectin, which has spared millions of people from blindness."

Brian Bagnall, the U.S.-based project director for SmithKline Beecham, quips that "it is much harder to give a drug away than it is to sell it." The donation is just the first step, after all, and a fraction of the total cost of a drug donation program once distribution and the training of health workers are factored in. Moreover, pick almost any disease anywhere, and there is a tangle of existing, and sometimes competing, interests with which to deal, ranging from ministries of health to WHO to NGOs to local hospitals and health clinics. "One of the key lessons of the successful donation program is to get very different organizations to work together across a complicated distribution chain," comments Reich. "It is bringing together private companies, private foundations, nongovernmental organizations, governmental organizations, health facilities, and patients--people--and making sure that everyone has a reasonably good understanding of what the others are doing and what their own particular roles and responsibilities are." But while this cooperative, joint—problem solving approach may be complicated, it may also be just the thing that makes a donation program work. Says Bagnall, "The reality is that we are all finding it essential to be highly involved in the entire program and to help coalitions of partners solve unique and complex problems through clinical research, community attention, training, distribution logistics, political will, funding, and more." He notes that his company regards the albendazole program as a chain of partnerships: "Neither SmithKline Beecham nor WHO can do this alone. It’s all about coalition building."

Each of the drug donation programs has followed a different path in working with WHO. Merck’s relationship with WHO goes back to the late 1970s when a Merck scientist participated in a working group of WHO’s Special Program for Research and Training on Tropical Diseases, which gave high priority to the search for a new drug against onchocerciasis. Researchers identified ivermectin in the process of screening drug compounds for anti-onchocercal activity. This result contributed to Merck’s critical decision to pursue development of ivermectin for human use. Ivermectin attacks the worm’s microfilariae; according to Tavis, WHO onchocerciasis experts had favored drugs that kill adult worms. WHO and Merck cooperated in running the clinical trials that showed that ivermectin was highly efficacious and had limited side effects. But according to Tavis, from 1985 to 1987, when Merck was searching for a donor to buy the drug (unsuccessfully, as it turned out, and thus the decision to give it away), the relationship between the two organizations was tense. Tavis writes that WHO pushed Merck on pricing the drug, and Merck thought WHO should be working harder on promoting its distribution.

Merck decided to establish the donation program in collaboration with the Task Force for Child Survival and Development in Atlanta. The company also set up the MECTIZAN Expert Committee as an independent entity to review and approve applications from NGOs, ministries of health, and other parties that wanted a role in distributing the drug. WHO representatives have participated in this committee, which is chaired by William Foege, MPH’65, the charismatic former director of the Centers for Disease Control and Prevention, and a global leader in public health. Merck pays for production of the drug and shipping it overseas; once the shipment reaches the consignee, the NGO is in charge of getting the drug to people who need it.

One of the larger participating NGOs in the ivermectin program is The Carter Center, which in 1996 incorporated the operations of the River Blindness Foundation as a major component of its public health programs. Frank Richards is technical director of the Center’s Global 2000 River Blindness Program under the leadership of Associate Executive Director Donald Hopkins, MPH’70. In Richards’s opinion, well-intentioned health projects have foundered in the past as money and resources were squandered: "People find all sorts of ways to say it in newspeak, but money was given, and it just disappeared down a black hole." He says the ivermectin program, with its independent expert committee, NGO involvement at ground level, and open process of review, is a healthy rejoinder to that waste: "The key word is transparency--transparency and accountability are very real strengths of this program." Brenda Colatrella, the Merck executive who manages the company’s ivermectin program, admires the NGOs: "They have shown an amazing effort in the most difficult situations."

In trachoma, the Clark Foundation has worked closely with WHO for the past ten years on several projects and continues to do so. The foundation funded the work that resulted in a simplified grading scheme for the disease as well as three WHO trachoma technical manuals. Pfizer and the Clark Foundation are also major financial supporters of the WHO Alliance on Global Elimination of Trachoma by 2020. In the early 1990s, the Clark Foundation contacted Pfizer about ZITHROMAX. The foundation, along with the company and the National Institute of Allergy and Infectious Disease, supported a three-country trial of the drug that helped lay the scientific foundation for the trachoma initiative. WHO officials are members of the trachoma initiative’s expert committee. The five countries targeted by the trachoma initiative were selected from the 16 that WHO’s antitrachoma effort has given the highest priority.

SmithKline Beecham has directly engaged WHO in a public-private collaboration. The British company established a joint WHO/SmithKline Beecham committee to plan the albendazole program, including the establishment of the Lymphatic Filariasis Elimination Program Review Committee to oversee applications from ngos and health ministries. Bagnall, the SmithKline Beecham spokesman, says WHO now sees the "absolute necessity of working with the private sector" under the new leadership of Gro Harlem Brundtland, MPH’65: "You have to distinguish between the new WHO and the old WHO. You have to be careful about labeling WHO with stereotype opinions."

For now, Merck’s ivermectin program has the most solid track record with just over a decade of experience. The International Trachoma Initiative is just getting into gear, approving the national plans for Tanzania and Morocco, with Mali and Vietnam to follow in the fall. The lymphatic filariasis program is just getting started too, but Bagnall says "many people tell us we are moving faster than they could imagine." Still, this program, which depends on the co-administration of SmithKline Beecham’s albendazole with either ivermectin or DEC, is only at the point of reviewing national disease elimination plans.

These other programs are also tackling bigger health problems. Onchocerciasis is a major cause of blindness in the world. WHO estimates that 100 million people are at risk of getting the disease, 17—18 million have it, and 270,000 have been blinded by it. Yet compare those numbers to trachoma: 540 million (about one out of every ten people in the world) at risk and six million blinded. Lymphatic filariasis is a health threat for 900 million (one out of every six people in the world) and affects 120 million. Some have questioned whether SmithKline Beecham, in particular, has bitten off more than it can chew. But David Addiss, a medical epidemiologist at the CDC and an expert on lymphatic filariasis, says the technical tools are there for stamping out the disease. And he credits the SmithKline Beecham donation with "energizing the whole field" of lymphatic filariasis research and efforts to eliminate it as a major health problem. Pfizer and the Clark Foundation have taken a more cautious route, limiting their trachoma initiative to five countries for two years, and longer if the program is successful.

With the rise in donation programs, there is some apprehension among both drug companies and NGOs that the programs will start competing with each other and stretch the NGOs that do the ground-level work too thin. Colatrella says the drug companies proactively established the Donor Coordination Group to address these concerns. By July, she says they plan to spell out some common objectives.

But in Laing’s opinion these donation programs are a "magic bullet" approach to public health that wins headlines but ends up taking away from a community development approach that emphasizes sanitation, among other things. In public health circles, this argument would be familiar: it is the well-known vertical v. horizontal health program debate. "Azithromycin for trachoma is not necessary in the U.S. because people have clean water," says Laing. "Providing azithromycin is a Band-Aid on the underlying problem." But Reich says "the problem is that when you get to marginalized, disadvantaged populations on the periphery of poor societies, the existing horizontal health services don’t tend to be particularly good. These donation programs have the potential to provide lasting benefits for people." More-over, he continues, for onchocerciasis, local hygienic measures cannot protect the population at risk because of the habits of the flies that spread the disease. Reich says it is doubtful that general development would cause the disease to disappear without spraying the breeding sites of the flies or treating infected people. And as for trachoma, supplies of clean water might reduce the risk of future infections, says Reich, but they wouldn’t help people who are currently infected. Most often those people are women and children, who also have the highest risk of going blind from an untreated trachoma infection.

Many also believe that the vertical/horizontal choice is a false dichotomy and that so-called vertical programs wind up strengthening and even seeding broader health services at the local level. Cook says in those areas where poverty and poor sanitation exist, an anti-infective agent can be used to reduce transmission of disease but may also actually change human behavior and get to the underlying causes of the disease’s continued spread. "This is not simply an antibiotics program," he says and goes on to explain that the trachoma initiative promotes implementation of the WHO-endorsed SAFE program against trachoma (the S stands for surgery that rotates eyelashes away from cornea, which prevents blindness; the A for antibiotic treatment; the F for face washing; and the E for environmental change). Virginia Turner, MPH’80, a field researcher and eye disease expert working for Helen Keller International in Tanzania, says she fought tooth and nail to make sure that the surgery was first in the formulation for an effective strategy against trachoma because it is the best, most immediate way to prevent blindness. She applauds the Pfizer donation for energizing people working on eye disease in the developing world, but is concerned that the antibiotic part of the SAFE program could overwhelm the other components. "I am," says Turner, "going to be watching the direction of the program carefully."

HOPE FOR MORE

In the report on praziquantel and schistosomiasis, Reich and his colleagues wrote: "For tropical disease products, companies confront a basic dilemma: the ultimate consumers are usually very poor people in the world’s poorest countries." As difficult as the organizational issues and logistics might be, these disease-specific drug donation programs are perhaps one way out of that dilemma, at least for a few select diseases. Tavis says the programs reflect the changing, and more powerful, role of the multinational corporation in world affairs. "The nation-state no longer plays the role it did," he said during a recent interview. "The multinational corporation is playing a greater role and with this added power comes responsibility. Their own employees are demanding it."

Reich is hopeful. He hopes there will be more, not fewer, drug donation programs: "I think other companies are beginning to see that this is something they should do to improve the welfare of poor people in poor countries and to enhance corporate morale and image."