by Sonia Shah
As wages fall, the price of goods increase, and social services shrink. Many indebted countries have fallen into violence and disarray, amid which the pernicious virus that causes AIDS has silently spread. By the turn of the century Africa would be home to more AIDS victims than anywhere else in the world. By at the very least failing to reduce poverty and at worst exacerbating it, some health economists say, World Bank and IMF loans had poured oil on HIV’s fire. As one AIDS policy adviser plaintively wondered, “given the increased needs in terms of health on the continent, largely due to the prevalence of AIDS, why didn’t the World Bank make increasing health budgets a condition for their loans?”55
Just as health care systems are being dismantled, multinational tobacco, soft drink, and fast-food companies have rushed into the emerging markets of the developing world, eased by international trade agreements forged throughout the 1990s. Sales of cigarettes in developing countries have skyrocketed, with many of the cigarettes sent to the developing world loaded with more addictive tar and nicotine than the ones allowed at home.56 Coca-Cola aimed to become the number one beverage on the planet, buying up water licenses in poor countries where they could sell their nutritionally valueless drink for less than the price of a glass of clean water.57 McDonald’s spread its inexpensive, fatty, high-calorie foods across the globe, with four of its five new restaurants opened daily outside the United States.58
When a torrent of fast-food, soda, and cigarettes splashes into stagnant waters of malnourishment and poverty, a whirlpool of disease starts to swirl. Malnourished mothers tend to bear babies predisposed to storing excess energy as fat. This is a useful adaptive advantage in communities where calories might be scarce, as it can better enable babies to survive nutritional deficits. But when such babies grow up to consume Western-style diets chock-full of fatty, sugary foods, that benefit turns into a deadly burden, leading them to gain disease-causing extra fat much more rapidly than they would have otherwise.59
And so, hot on the heels of the soda makers has followed an epidemic of diet and lifestyle–related heart disease, diabetes, lung disease, and asthma, jostling ominously with infectious diseases already tamed in the West. Today, four out of five people who die of these chronic, noncommunicable diseases perish in developing countries. More Indians and Chinese suffer cardiovascular disease than Americans, Japanese, and Europeans put together. “As for overweight and obesity, not only has the current prevalence already reached unprecedented levels, but the rate at which it is annually increasing in most developing regions is substantial,” a World Health Organization report noted in 2003. For developing countries barely treading water amid the flood of malnutrition, HIV infection, malaria, and tuberculosis, “the public health implications of this phenomenon are staggering,” the WHO noted, “and are already becoming apparent.”60
By 2000, tobacco-related diseases were felling ten thousand people every day—the vast majority of them, over two-thirds, in the developing world.61 Diabetes and coronary heart disease had become epidemic in India, home to the greatest concentration of sufferers of Type II diabetes in the world. Twelve percent of the population was suffering from the condition, four times more than had been in the 1970s, costing the Indian government somewhere around $2.2 billion a year.62 Worse, while diabetes in rich countries is primarily a condition of the elderly, in developing countries the disease strikes those in the prime of life, aged forty-five to sixty-five, slashing their average life expectancy by ten to fifteen years. In some areas of Africa as many as one in five people have diabetes, and nearly twenty million Africans suffer from hypertension.
In the middle-income countries of Latin America, the Middle East, and North Africa obesity has become as common as it is in the United States. By 1998, the World Health Organization deemed obesity, with all of its attendant health risks, to be a worldwide epidemic.63
Access to cheap medicines to address these ills is scarce. Multinational drug companies eager to access the growing markets of countries such as Brazil and India have pressured these governments to crack down on cheap local producers of medicines that undercut their sales. The problem was especially acute in India, where 1970s-era patent laws once protected only how products were made—not the products themselves. The rule had allowed local drugmakers who could reverse-engineer drugs to manufacture knockoffs of the latest brand-name drugs at a fraction of the cost. The biggest Indian drugmakers, such as Cipla and Ranbaxy, reverse engineered some of the most important medicines of modern times, slashing the cost of treating AIDS from $15,000 a year on patented, brand-name drugs to just a few hundred dollars. What’s more, bypassing the turf wars of brand-name companies, who would as readily add a competitor’s drug to their own as Coke would add some Pepsi to its six-pack, the Indian drugmakers had combined several different HIV medicines into combination pills that could be administered in simple, once-daily doses.
When nonprofit health organizations and activist groups across the developing world started importing the cheap, Indian-made generic drugs the Western drug giants who had patented the compounds unleashed a firestorm of protest. In 1998, thirty-nine multinational drug companies sued the South African government for allowing the cheap drugs into the country.64 By 2005, India, along with other developing countries roped into World Trade Organization (WTO) agreements, would be forced to strike down its relaxed patent laws, instituting instead twenty-year patent protection for drugs and other products. The vibrant generic drug industry is now crippled.65
In the end, each of these encounters with the West, from colonization to globalization, played a part in producing the ideal human tabula rasa for drug-industry trials: bodies that were sick, untreated, suffering the same diseases as those in the major drug markets, and more likely to die of them to boot.
In South Africa, Boehringer Ingelheim taps into such patients at its Lung Institute, a modern, airy building surrounded by an expansive parking lot in downtown Cape Town. Inside, two-story-high glass windows throw shafts of sunlight onto a stylish seating area that is replete with the latest fashion magazines. In the well-appointed examining rooms, labs, and surgeries discreetly tucked down sparkling hallways, a well-paid staff conducts hundreds of clinical trials on new drugs for drug companies, from the latest anti-aging creams to allergy drugs and respiratory medicines.
The subjects for the institute’s trials do not, on the whole, reside in the city of Cape Town itself, with its impeccable roads and dramatic skylines. Instead, most live in the gigantic, isolated shantytowns that ring the city, places where untreated disease runs rampant. One such shanty sits just yards from the edge of the national highway that speeds professionals from the tony white suburbs to the city of Cape Town. Handmade shacks patched together from found pieces of tin and cardboard jauntily sport the logos of the fancy appliances they had once encased. Tiny dirt alleyways wind between the dark one-room shacks. The people live cheek by jowl, until recently part of the 80 percent of black South Africans who don’t have running water, the 50 percent who don’t have electricity, and the 16 percent who have no toilet. (Nearly every residence housing a white or Asian in the country has access to all three amenities.)66
In some townships like this one more than one in five residents are infected with HIV, in aggregate forming the largest army of HIV sufferers on the planet. Spanish pharmacist Marta Darder works at an AIDS clinic a few miles away from the Lung Institute. Toiling out of a battered office in the sprawling township of Khayelitsha, she might as well be on another planet. “That is the schizophrenia of this country. It is completely divided,” she said. The sounds of traffic and blaring pop music waft in through the open windows. The floors under Darder’s feet are sagging and covered with threadbare carpeting.67
South Africans would need every ounce of resources from their public health facilities to rise to the challenge of the exploding AIDS crisis, Darder said. But many decimated public health facilities are increasingly turning to lucrative offers from the omnipresent, deep-pocketed drug i
ndustry instead. The case of the University of Cape Town’s Groote Schur Hospital is typical. Back in 1967, the world’s first heart transplant was conducted in the hospital’s Brazil-like warren of padlocked buildings.68 The apartheid government showered the institution with largesse. Over the years the mighty hospital grew to enjoy a budget of 450 million rand (around $70 million in today’s dollars), an expanse of 3,600 beds, and the labor of 10,400 staff.
All that changed after apartheid fell. In the rush to privatize the economy and open it up to multinational companies, the hospital was devastated, along with much of the country’s public health system. The facilities were splintered. Academic doctors fled for private practice. The staff shrank by 60 percent.69
Robin M. Pelteret, MD, a bushy-eyebrowed white South African physician, was hired in the early 2000s to help save the fallen facility—and in particular its ability to continue cutting-edge medical research—from ruin. Grants for vaccination programs or AIDS hospice care might provide a stream of funds, but Pelteret and the people who hired him had other ideas. “We need entrepreneurial opportunities,” he said firmly.
“Research grants are not the most reliable,” he said. “This faculty doesn’t focus on the pure science but on clinical medicine . . . and we have huge numbers of people which have a unique profile for third world countries.” The fluorescent tubes lighting the halls outside his office flicker on waiting black patients. Asian and white clinicians stride purposefully by. Pelteret said that the industry funding will subsidize public health research and services at the hospital, although clinicians such as Darder toiling in the townships profess skepticism.
Pelteret ensures that patients who show up at Groote Schur’s public hospital looking for treatment are channeled into industry trials, at the hospital and at places like the Lung Institute. In return for referring patients and conducting industry experiments on them, the Groote Schur Hospital earns over 150 million rand—over US$20 million—every year.70
2
The Placebo Control
There’s nobody more influential in determining how drug companies conduct clinical trials than legendary clinical trials expert Robert Temple, MD, a grizzled, mustached man in his midsixties with a vaguely groovy 1970s hairstyle. Now director of medical policy at the FDA, Temple’s thinking has held sway at the FDA—and the international medical research establishment that looks to the FDA as a model—for over thirty years. He’s judged countless new drugs, designed trial protocols, and written federal rules about them. Savvy investigators pay careful heed to the kinds of experimental data that Temple blesses, and design their trials accordingly. As a regulator and an analyst he has “made his mark,” writes Philip Hilts in his history of the FDA, Protecting America’s Health, “not just in American medicine but worldwide.”1
Temple reserves his most unwavering support for the placebo-controlled trial design; that is, experiments in which one drug is pitted against an inert substance. Most investigators seek to shield subjects from the hazards of their experimental inquiries, but developing new drugs has never been a risk-free endeavor. Clinical research often puts investigators, who are also physicians, between a rock and a hard place. As physicians, they’re obligated to provide their patients with the best care they can; but, as scientists, they must randomly assign one experimental method or some alternative not to help the patient per se but just to see what will happen.
That’s why the only ethically acceptable circumstances under which a clinical researcher can assign a sick person to a placebo (or some other possibly inferior treatment) is when they really don’t know whether an active intervention will work any better, a state of confusion described as “equipoise.” If researchers know that one option is better than the other, they are ethically obligated to simply administer it: failing to do so puts subjects—who are also their patients—in harm’s way.
Nevertheless, in the wake of even the most wondrous new drug lies a trail of failed ones, their dangers revealed only through the bodies of living beings. Overall, 40 percent of new drugs that have already passed several rounds of testing in the laboratory nevertheless afflict human subjects with toxic reactions in Phase 1 trials.2 Nearly half of Phase 3 trials of new drugs fail, exposing subjects to drugs that turn out to be ineffective or dangerous.3
The placebo-control orthodoxy promulgated by Temple and others boosts the peril. For in placebo-controlled trials, even if the experimental drug is safe and effective, some ailing subjects will have had to tolerate no treatment whatsoever, and the consequences for them can be dire indeed. For this reason, it is a trial design that has been attacked as unethical time and time again.4
Throughout the periodic skirmishes with activists and ethicists, though, Temple’s support has been steadfast. As he’s expounded in interviews, published papers, and conferences, for Temple placebo-controlled trials render the clearest data on whether a drug works or not in less time than any other kind of experiment. “We have very strong feelings on placebo,” Temple said, “when people [in the trial] won’t be harmed.”5
But as the example of the drug nitazoxanide suggests, the harm considered tolerable for experimental subjects varies, depending in part on where in the world the subjects live.
Most new drugs, despite the aspirations of drugmakers, are neither wonder drugs nor blockbusters, but compounds that fall into the cavernous gray area in between: drugs with mostly subtle, fairly nonspecific effects on human physiology. Nitazoxanide is one such drug.
Jean-François Rossignol, MD, PhD, a drug developer for Smith-Kline Beecham, synthesized nitazoxanide in 1993. The molecule appeared to have some effect against parasitic infections, and a hopeful Rossignol jumped ship to start his own drug company, Romark Laboratories.
The new company’s mission was to somehow commercialize nitazoxanide, turning it into “the foundation for a profitable pharmaceutical company,” as newspapers based in the company’s home state of Florida noted. First, Rossignol and his partner, investment banker Marc Ayers, coaxed $3 million from investors upon founding the company. Then, on the basis of early studies showing the drug’s activity against intestinal parasites, they quickly got the drug approved in Mexico, netting another $10 million to further develop the drug.6
To turn the drug into a true success, though, the vast American market would have to be breached. The most likely pest that nitazoxanide might take on was a parasite called Cryptosporidium. Small even by parasite standards, Crypto wasn’t even spotted by scientists until the early 1900s. The parasite burrows into cells in the intestines, reproduces rapidly, and then sheds tiny, dormant cysts that depart through the intestines, floating in sewage and pipes until taken up by another creature. In the mid-1970s scientists recognized with alarm that Crypto could perform this feat in human intestines as well as in animals. While parasitic infections on the whole are rare in the United States, when there are outbreaks, either Crypto or Giardia is the culprit.
In most people Crypto’s residency in the gut provoked diarrhea for a week or two, after which it would rapidly depart, leaving the host otherwise unscathed, and functional water filtration systems generally screened out the cysts anyway.7 But every now and again, when water systems failed, the parasite could wreak havoc. In 1993, severe flooding in Milwaukee triggered an outbreak that sickened over half the population, killing 100 of the weakest and most vulnerable. One of the most daunting attributes of the parasite was its defiant resistance to disinfectants: in fact, scientists prepared pure samples of the parasite by mixing Crypto-infected stool with undiluted bleach.8
But Romark wouldn’t have to wait for periodic water department meltdowns to sell nitazoxanide for cryptosporidiosis. In immune-compromised AIDS patients crypto could be devastating. The parasite could settle in for months, even years. And the diarrhea it caused was explosive and uncontrollable. A bite of an unwashed fruit or an innocent nuzzle from a contaminated farm animal, and HIV-infected people would find themselves rushing to the toilet day and night, the great v
olumes of water exploding from their intestines leaving them withered and dehydrated nearly to death. So uncontrollable was the crypto-induced diarrhea that while Rossignol and Ayers scrambled for funds, wasted AIDS patients with crypto were turning up at clinics wearing diapers. If nitazoxanide might work for these patients, it could be a lifesaver.9
By the mid-1990s Rossignol’s company had started to test the drug in AIDS patients with crypto. They administered the drug to eighteen AIDS patients with diarrhea in Mali; four cleared the parasite.10 When word got out to American AIDS doctors struggling with their suffering patients, they started to clamor for supplies of the drug. The FDA allowed nitazoxanide’s distribution under a “compassionate use” program, whereby experimental drugs can be administered legally to patients with life-threatening illnesses if no alternatives are available. The minuscule Mali study with its four-out-of-eighteen odds hardly anointed nitazoxanide a miracle cure, but at the time the tug of HIV into the dark abyss of AIDS appeared as relentless as the tide. Patients and clinicians seized anything that might help.
Now Romark had scores of patients around the country taking its experimental compound. By carefully tracking how they fared, they might be able to use the data to garner FDA approval, especially in conjunction with data from a study of the drug about to be launched by researchers at the esteemed National Institutes of Health.11 The government docs planned to enroll sixty AIDS patients with cryptosporidiosis, randomly assign them to receive either nitazoxanide or a placebo, wait a few weeks, and then compare their outcomes.12 With its requirement that some patients crippled with crypto accept sugar pills from their doctors for weeks on end, the trial protocol was “not too friendly to people with AIDS, unfortunately,” remarked Bill Bahlman, a founding member of ACT UP New York who served on a community advisory board for AIDS trials,13 but would be a surefire way of proving to the agency that the drug was effective and worthy of approval.
