Saturday, December 23, 2006

A Woman's Fight to Save the Poor From Black Fever

By Uwe Buse
Der Spiegel

Thursday 21 December 2006

Black fever kills about 60,000 people a year, most of them poor. There is a cure, but the global pharmaceutical industry wasn't interested in producing the drug, at least not until an American woman began her crusade.

It is 10 a.m. as Victoria Hale walks into her office in a glass-fronted high-rise in San Francisco's financial district, the city's conservative heart. She takes a seat and nods curtly, almost in military fashion, to her press agent. The press agent once worked for Bill Clinton when he was still president of the United States. Hale sits down in front of a glass of water, places her hands on the table, palms down, and says: "Yes?" She seems a bit stressed.

Hale returned from London a few days ago. She travels to Seattle tomorrow, to the East Coast at the end of the week and then on to India. With so much travel through so many different time zones, it isn't surprising that Hale might be just a bit disoriented and not exactly sure what she is doing here in this office.

In Seattle, Hale plans to meet with representatives of Bill Gates, who wants to make sure that the $47 million he has given her so far are being spent wisely. The purpose of her trip to the East Coast is to meet with representatives of the Rockefeller family.

Hale, 45, a mother of two and a pharmaceutical executive, is the current darling of America's major philanthropists. Bill Gates's wife Melinda has praised her publicly, and Hale is being showered with international awards. Her name appears on a list of America's 50 most important scientists, Switzerland's renowned Schwab Foundation has called her one of the "most extraordinarily socially minded businesswomen," and US magazine Esquire named her its businesswoman of the year.

Hale is being celebrated because she is a woman who offers hope, and because she is living proof that it is possible for an individual to fight glaring injustice, even in a globalized world in which everything is supposedly interconnected and in which all too often events are shaped by the power of reality rather than by politicians.

Her financial backers support her for these reasons, and because what Hale offers them is unusual and exceedingly rare in the global charity business: the opportunity to go down in history as someone who helped liberate an entire continent from a killer plague. It's an opportunity that only comes around once every few decades, if at all.

Aid organizations and their backers spend most of their time fighting recurring calamities - earthquakes, floods, famine. In the tough battle against poverty, disease and war, getting the chance to eliminate an epidemic is like winning the lottery. The last time a prize was awarded for wiping out disease was in the mid-1970s, when the World Health Organization eradicated smallpox.

Killer Disease

This time the enemy is called "Kala Azar," or black fever. A disease of the poor, black fever currently infects an estimated 1.5 million people worldwide. It kills about 60,000 people a year, primarily in India, Nepal and Bangladesh. Hale has made it her mission to save these people - and herself.

Victoria Hale's story began nine years ago in San Francisco, at DNA Drive Number One at the headquarters of a company called Genentech. Genentech, a legend in the industry and in the United States, develops drugs using genetic manipulation, and when it was founded in 1976 it was the first company whose researchers played God, essentially giving evolution a kick start. The company attracted and continues to attract the best and the brightest, the ambitious and the devout, from all over the world.

Hale began her career as a manager at Genentech in 1995, working as an expert in the complex licensing process of the government health bureaucracy. She was partly responsible for making decisions over whether years of work and an investment of well over a $100 million would lead to a marketable drug or a ruinous loss.

Hale, who had worked for the Food and Drug Administration (FDA) - the enemy, in a manner of speaking - before coming to Genentech, understood the workings of these licensing procedures. At the FDA she quickly developed a reputation for working not as a bureaucrat but as an investigator who was skilled at pin-pointing weaknesses in her opponents' arguments. She had studied pharmacology, and she routinely inundated companies with questions whenever she had any doubts about the safety of a drug, how data were derived or the results of clinical trials. Her future bosses at Genentech liked her approach and were convinced that they had a place for someone as tough as Hale. So they poached her.

She spent the next three years working diligently, was promoted and offered stock options. She had no reason to leave the company.

And yet, in the summer of 1998, Victoria Hale went to her boss and told him that, as much as she appreciated everything Genentech had done for her, she was resigning. Her boss was surprised, and so were her colleagues, and her family was speechless. Why was she throwing away her career?

"There were a few numbers that I couldn't get out of my head," Hale says in her San Francisco office.

Drug Industry Ignores the Poor

The global pharmaceutical industry spends about €90 billion a year on research, and 90 percent of this enormous sum is used to treat the illnesses and minor discomforts, cosmetic and erectile problems of less than 10 percent of the world's population. Of the 1,556 drugs that were invented and marketed worldwide between 1975 and 2004, only 21, a paltry 1.3 percent, have been used to treat diseases that primarily affect the poorest people in the world.

In Africa, Asia and South America - the world's poverty zones - almost three million people die every year of tuberculosis and malaria, and about 170,000 are ravaged by diseases that are virtually unknown in the more affluent regions of the world. Chagas disease, for example, claims 13,000 lives each year. Sleeping sickness kills 50,000, dengue fever 21,000, bilharziosis 15,000 and black fever 60,000 annually. Next to malaria, black fever is the second-most severe parasitic disease.

These were the numbers and facts that prompted Hale to quit her job at Genentech. She felt that by continuing to work at the company she would have made herself complicit in developing drugs almost exclusively for the world's more affluent citizens. To this day, she can only conjecture why she was the one who was so affected by this sense of injustice. Perhaps it had something to do with her childhood. Hale was a sickly child, often bedridden, who spent an inordinate amount of time in doctors' waiting rooms. Perhaps it was precisely because she had suffered so much herself that she could no longer ignore the suffering of others.

No one - neither her colleagues nor her friends - truly understood why she left Genentech. She kept hearing the same sentence over and over again: "You're destroying your career." But Hale didn't care. She believed in the mission she had chosen. It began with many unanswered questions.

Which disease did she plan to fight? With which drug would she succeed? Did this drug already exist, or would she have to invent it herself? And how would she pay for it all? Where would she get the millions her mission would cost?

Hale spent the next year traveling to conferences in Europe, North America and Asia. She spoke with experts, with epidemiologists, searching for the right infectious disease, searching for the solution to her problem. She wrote lists to keep track of her thoughts. Malaria was too big, and the financing would be impossible. The same applied to tuberculosis. Sleeping sickness was already being addressed by the aid organization Doctors Without Borders.

Finding the right killer wasn't an easy task.

After about a year, Hale's savings and those of her husband, about $100,000, had been spent. She took out a loan for $315,000. Her husband agreed, even though he had doubts about his wife's prospects for success.

In the fall of 1999, at a conference in Antwerp on drug resistances in tropical diseases, Hale found her infectious disease - and the corresponding cure.

Black Fever

A man from India was standing at the podium. He was restless, not matter-of-fact like everyone else at the conference. In fact, the man was furious and bitter, and he spoke about a crime the world is committing. The crime, he said, was a crime of omission, the crime of failing to provide the kind of assistance that could prevent the deaths of thousands of people in a remote corner of the world, in India, Nepal and Bangladesh.

The speaker, a physician named Shyam Sundar, knew more about Black Fever than anyone else. He had been fighting it for more than 20 years. Hale approached Sundar after his presentation. She was impressed by his outrage over an injustice that leaves most people cold. She saw something of herself in this Indian doctor.

Sundar invited Hale to visit the region in northern India where the disease was rampant - the hot, wet plains of the Indian state of Bihar - for a first-hand look at its consequences.

Black fever, or visceral leishmaniasis, always begins with a bite from a tiny insect, the sandfly, a bite victims rarely even feel. Jokhran Bhagat, a farmer and father of two sons, was one of these victims.

A female sandfly pierced Bhagat's skin and drank his blood to feed its eggs. It left behind a small, dot-shaped bite mark and a few inconspicuous single-celled organisms that entered Bhagat's body through the puncture site. The sandfly's bite marked the beginning of an invasion.

The intruders slowly drifted along Bhagat's bloodstream waiting to be noticed. In its chosen host, the human body, this parasite's survival strategy is to be attacked and encased by phagocytes, or "devouring cells." But the parasites, instead of being digested by the human immune system's killer commandos, establish a foothold inside those devouring cells and use them as a site to breed and transform themselves. Once the phagocytes have served their purpose, the parasites burst out to conquer new cells.

A few days after the sandfly bite, Bhagat complained that he felt unwell and developed a fever. By this time the parasites had developed a flagellum, or means of propulsion, and were heading for his bone marrow, liver and spleen. They continued to replicate relentlessly, attacking healthy cells and intact organs and transforming them into production sites for armies of microorganisms.

Bhagat's fever began to rise. He became weak and lost his appetite. After nine months his body capitulated and became grotesquely swollen, and Bhagat died in pain.

The man telling this story is Bhagat's son, Jawahar Bhagat. He is a thin, silent man who sits on a bed frame without a mattress, sheets or blankets. Bhagat is surrounded by his wife and his children, who observe the world with big, astonished-looking eyes.

Epidemic Among India's Poor

The village of Rajwara Purvi lies just beyond the wall of his house. It is the rainy season and water has been pouring from the sky in long streams for days. There are no paved roads, and the dirt paths have been turned to mud. There is no sewage system, only a few useless power lines winding through the village on crooked poles.

Many cows walk around the village chewing their cuds. Their dung falls on the paths and in the courtyards. It sticks to walls and shoes, and children play with it. It also serves as a breeding ground for the sandflies that carry the parasites that cause leishmaniasis. Bhagat knows that this is the case, but is unwilling to do anything about it. Cows are considered holy in predominantly Hindu India, and dried cow dung is an important source of fuel.

Bhagat grew up here. He attended school for a few years, and then he began working in the fields, following in his father's and his grandfather's footsteps. The soil in the region is depleted of nutrients, working the fields with a hoe and plow is laborious and the harvest is meager - enough to pay for the bare essentials and an old bicycle. Bhagat only left his village once, when he took a bus to Delhi, a trip of more than 1,000 kilometers (about 620 miles), to look for work. He returned after a month, unsuccessful, and never left again.

There is nothing in his house to suggest a world beyond the horizon. Globalization, the flow of goods, makes a wide berth around Bhagat and his village. No one makes any money here. If Bhagat falls ill he will go to a relative who sells tablets. If the tablets don't help, all he is left with is prayer.

The people of Rajwara Purvi pray a lot. In this village of 150 houses and huts, the fever has struck one in every two families. One in two. The numbers have been rising for the past four years as a new epidemic develops. Like its predecessors, the epidemic kills whole families and wipes out entire villages. And like its predecessors, Black Fever will kill the weak and the undernourished, because the only ones who survive the disease are those whose immune systems are still intact.

Seven years ago Hale traveled through northern India's fever zone, speaking with the sick, their caregivers and Shyam Sundar, the doctor who had invited her to visit the death zone. Sundar's hospital is in Patna, the capital of the state of Bihar, a city overcrowded with people, garbage and rats. Goats doze in the mud outside the hospital, which boasts all of 50 beds - iron frames with thin, worn-out mattresses. Sundar's hospital, together with two other smaller clinics, represents the first and last line of defense against the epidemic.

Doctors at these hospitals have two drugs at their disposal to combat the disease. Both are equally unsuitable, but for different reasons. The first is a drug called AmBisome, which is used to treat fungal infections, both internally and externally. AmBisome is effective, even against Black Fever, but too costly for the people in this region. A full course of treatment costs about $500.

Search for Drug

The second weapon in the Indian physicians' pathetic arsenal is antimony therapy. Although it was successful decades ago, antimony, a toxic heavy metal, is practically worthless today, because the parasite has become largely resistant to the substance.

The only drug that was effective, inexpensive and devoid of serious side effects was paromomycine, but it was unavailable. That was the reason for Sundar's outraged speech at the Antwerp conference.

Paromomycine was developed in the mid-1950s by an Italian company, Pharma Italia, not as a treatment for Black Fever but as a general purpose antibiotic. Its life cycle followed that of many drugs. It was sold successfully for a number of years but was eventually displaced by newer, more effective drugs.

In the mid-1980s, researchers discovered that paromomycine could be a suitable cure for Black Fever. But no one was interested in paying for the expensive tests and studies needed to ensure that paromomycine could be used safely and reliably to treat Black Fever. The dying continued in Bihar.

Hale spent a week in India before returning to San Francisco, where she set up an office in her house to begin her fight against the rest of the world. She had found her epidemic and her drug.

Her original plan was to go up against the pharmaceutical industry and fight its indifference head-on, but she also realized that she would need the industry. Expensive experts, equipment and laboratories are needed to fight diseases that infect hundreds of thousands and even millions of people. And funding is needed, millions of dollars in funding. Hale's plan was to get it.

In the global humanitarian aid business, roles are clearly defined. The job of aid organizations is to submit requests and distribute aid. The pharmaceutical industry produces and supplies the necessary drugs and equipment - when it can and when it is willing to do so.

But the industry is rarely willing, because in most cases it is the companies that bear the costs. Most of them prefer to shun the expense. So do aid organizations, who tend to confine themselves to distributing the drugs the companies hand them.

Hale's plan was to expand the system by adding a third factor - herself.

She wanted to establish an aid organization that operates like a pharmaceutical company or, to be more precise, like a non-profit pharmaceutical company. The desire to help, and not to earn profits, would be the company's driving force. Hale wanted to build a company that would do what she believed the industry ought to be doing.

As her first project she envisioned pushing paromomycine through the complicated approval process. She would plan, conduct and analyze the tests and clinical trials, produce the drug and find a company willing to manufacture it at cost. Hale's company would be funded by charitable contributions.

Her friends called it an "interesting idea," implying that there were easier ways to throw away one's money.

Hale sat in her living room, thinking about the men and women in their executive offices, high up in the palaces of globalization, people who she was convinced would be willing to spend a lot of money on building monuments to themselves - not as corporate executives but as friends of humanity.

She offered her future backers a unique project - the rare opportunity to save hundreds of thousands of people. It would also be a chance to prove that the system can work, and that the globalized economy is capable of producing the tools to correct its own deficiencies. There were few arguments against her idea.

Hale called her non-profit organization the Institute for OneWorld Health, dubbing it the "first non-profit pharmaceutical company in the United States." She developed a business plan and sent it to potential donors. One of her letters ended up on the desk of Bill Gates, the co-founder of Microsoft, a multi-billionaire and the world's biggest philanthropist. Gates liked the idea and sent Hale a check for $4.7 million as a first installment. That was the beginning. Once the man who spends almost as much of his own money on fighting poverty as the World Health Organization had expressed his confidence in Victoria Hale, others followed, including the Chiron Foundation, the investment bank Lehman Brothers, the Skoll Foundation and many others.

Hale established her company, began searching for office space and hiring employees, first 10, then 20 and finally 50. She needed them to ensure that the approval procedure for paromomycine satisfied international standards. It was a bureaucratic nightmare, and to tackle the task Hale enlisted the help of the World Health Organization (WHO).

Red Tape

She flew to WHO headquarters in Geneva and walked into a four-story concrete, glass and metal building, to a corner office on the top floor to meet the man instructed by the world community to rescue the poor from diseases and epidemics. Robert Ridley is the director of the Special Program for Research and Training in Tropical Diseases (TDR) at WHO. His desk is littered with files and documents to be read and signed. His job often consists of little more than delegating responsibility.

TDR was established in 1975, just as biotechnology and genetic manipulation were beginning to revolutionize the pharmaceutical industry. It was set up to find ways in which the new technologies could be used to help the poor. But there was one problem: the program was to be operated on a shoestring budget.

To this day, Ridley's department has no fixed budget and is almost completely dependent on charitable spending. As a result, Ridley must make do on about $30 million a year, $30 million to coordinate the global fight against the 10 biggest killers of the modern age. It isn't much, and it certainly isn't enough to achieve progress. Indeed, much of Ridley's job consists in finding ways to economize.

Hale's reason for visiting TDR was that the organization's researchers had attempted to introduce paromomycine into the Indian market themselves in the early 1990s. But the process dragged on, the budget shrank, cuts had to be made and, in the end, the approval process for paromomycine was suspended. Hale had come to Geneva because she needed the results of the TDR's first two clinical trials, results that could save her years of work.

Today Ridley says that there was a "resource bottleneck" at the time, a phrase he uses to explain why Hale had to wait so long for the data.

At the time, as Hale was requesting the data on paromomycine, TDR was interested in another drug that seemed promising in the fight against black fever. Ridley believed that the drug would offer a better cost-benefit ratio than paromomycine. The drug, known as impavido, is manufactured by a German company whose CEO, Jürgen Engel, has the luxury of producing a drug that doesn't make economic sense.

Rival Drug

"We had actually developed impavido as an oral cancer drug, but it couldn't be used for that purpose," says Engel. The side effects were intolerable. But, according to the professional literature, the drug's active ingredient, miltefosine, could be used to treat black fever. Although it has serious side effects that can weaken an already weak patient even further, including nausea and vomiting, impavido is effective.

Like Hale, Engel turned to TDR for assistance, but the man in charge of the research department at the time lacked the funding to support paromomycine and impavido at the same time. He chose impavido, mainly because of its cost-benefit ratio. Impavido comes in tablet form, whereas paromomycine is administered by intramuscular injection. This complicates distribution, and complications cost money. Besides, Engel's company, Zentaris, was a conventional business, and TDR is accustomed to working with conventional companies. Hale, on the other hand, was the head of an oddball, hard-to-comprehend entity that threatened to change the system.

Hale was kept waiting for two years before she got her data. To make matters worse, she had a competitor. It was the last thing she had expected.

When she finally received the data from the TDR, Hale went straight to work. She sent employees to villages in Bihar to document the numbers of the sick. Five hundred patients received paromomycine injections. They were monitored for a year, during which they received regular checkups and potential side effects were addressed.

Samples were sent to laboratories and Hale's employees traveled back and forth between San Francisco and Bihar. Her company's annual expenditures climbed to $30 million. In the end, it was clear that paromomycine is effective in 95 percent of cases, without causing serious side effects. Hale celebrated and continued her work.

She found a company that was willing to produce paromomycine and sell it at a price of $10 for a full course of treatment. The company, Gland Pharma, is based in the Indian city of Hyderabad. Its price calculations were partly influenced by a sense of patriotism and PR considerations.

Ten dollars, which Gland Pharma says is the cost of producing the drug, is affordable for the poor in Bihar. A treatment with Engel's drug, impavido, costs $100 in Bihar.

The approval process ended a few weeks ago when the Indian government approved paromomycine. Impavido was also approved. Hale and Engel are now competing on a level playing field. Both are at equal distances from the finish line, and they will likely cross it together.

A large-scale program to attack black fever is scheduled to begin next year. The Indian government, which is coordinating the attack, has publicly announced its goal of eradicating the disease in India by 2010. The target date for eradication in neighboring Bangladesh and Nepal is 2015.

In a multi-pronged approach, an insecticide will be used to control the sandflies, local doctors will distribute the medication and the three countries' governments will subsidize prices. The treatment will likely consist in a combination therapy that will include both paromomycine and impavido.

This time it seems as though there will be no losers, only winners who will be forced to share the spotlight. For once, here's a story that looks set to have a happy ending.

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Translated from the German by Christopher Sultan.

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