by Sonia Shah
But the NIH didn’t move fast enough. By the mid-1990s the notion of slamming HIV with multiple antiretroviral drugs had been born, miraculously beating back many of the opportunistic infections that debilitated and killed AIDS patients. Despite dramatic side effects, the difficulty of managing dozens of pills daily according to a strict schedule, and the $15,000 annual price tag for the drug cocktails, the mainstream press speculated that “this ordeal as a whole may be over,” as social critic Andrew Sullivan wrote in the New York Times Magazine. Was it “the End of AIDS?” as Newsweek magazine asked on its cover?14 Deep in the antipodes researchers wondered whether an onslaught of antiretrovirals might vanquish crypto, too. Between 1995 and 1996 nine HIV-infected men in Sydney, Australia, rushing to the toilet with explosive crypto diarrhea between three and ten times a day, were treated with multiple antiretroviral drugs. Every single one cleared the parasite. Most gained up to thirty pounds.15
And yet, despite the startling success of combination antiretroviral therapy, the NIH plodded onward with its placebo-controlled trial of nitazoxanide, trolling for Crypto-infected AIDS patients for the experiment in the spring of 1997. If the NIH trial had struck AIDS activists as unfriendly before, now it seemed downright repugnant. With the potent new therapy on offer, only the most altruistic or impoverished AIDS patients suffering with crypto would risk the chance of being given a placebo. By the spring of 1998, with only ten patients on board, the NIH was forced to abandon the trial.
Between Romark’s founding in 1993 and May 1998, when the FDA advisory committee finally met to review data on nitazoxanide, everything had changed. Romark presented its data on nitazoxanide without any data from the aborted NIH trial. The committee was less than impressed. The drug hadn’t cured any patients of cryptosporidiosis. The best that Romark had been able to prove was that the drug eased the diarrhea, lessening the number of trips to the toilet for a little over half of the patients who took it. Since the company had no data on how the patients who took the drug compared to others not given the drug, it was possible that even the weak salutary effect had nothing to do with the drug whatsoever, FDA advisers argued.
“We’re interested in controlled comparisons,” announced the FDA’s statistician, Nancy Silliman; that is, data showing how the drug works in contrast to how another drug—or placebo—works. “The interpretation of uncontrolled data,” such as Romark had presented, “is problematic at best,” she said. The only way to be able to tell for sure whether nitazoxanide worked, she and other FDA advisers maintained, was with a placebo-controlled trial such as the NIH had planned—and which was scuttled due to lack of interest.16
Silliman’s dismissive posture exasperated Rosemary Soave, MD, a cryptosporidiosis expert who had presented the data on nitazoxanide to the committee. Soave found the whole idea of a placebo-controlled trial for crypto in AIDS patients distasteful. “It was really very difficult to ask them to enroll in a trial where they would postpone getting a potentially effective agent for as long as perhaps three weeks,” she said. “This is three weeks of suffering that most patients who are in this condition and have numbered days ahead of them are really not willing to do. . . . And that is really understandable.” Placebo-controlled trials for such a dire condition, when evidence suggested that drug therapy could help, were “very difficult, if not impossible,” she told the committee. “Many physicians and patients feel it is totally unethical.”17
But the FDA committee wasn’t interested in such dilemmas, Soave said. They “didn’t pay one bit of attention when I was trying to explain how tough it was for the patients,” she remembered later.18 The committee rejected Romark’s application. Perhaps the drug could be tested against placebo elsewhere, one committee member suggested. “I think consideration has to be given to the international setting,” said Johns Hopkins gastroenterologist Cynthia Sears, “where HIV is rampant and additional therapies are obviously not available in many instances.”19
Disappointed, Soave soon moved on. There wasn’t much more work to be done on AIDS and cryptosporidiosis anymore anyway, she thought. With combination antiretroviral therapy the most effective way to cure opportunistic infection, she said, “a lot of these drugs went by the wayside.”20
Romark took the blow in stride. They could still capture $100 million in sales every year if they could get the drug approved, Rossignol told reporters. All they had to do was find a new market. Crypto may have stopped being a serious problem for AIDS patients, but it was still a nuisance for the handfuls of Americans, particularly children, who caught the bug from dirty swimming pools, farm animals, or unwashed fruits. If delivered in a three-day course of sweet, strawberry-flavored syrup, nitazoxanide prescriptions might be eagerly snatched up by frustrated parents caring for intestinally challenged toddlers.
But running trials that might satisfy the FDA would be daunting in the United States. Cases of cryptosporidiosis had become rare, sporadic, and dispersed. Enrolling sufficient numbers of sickened patients would require the help of thousands of physicians across the country, each of whom might pass months if not years before seeing a single case. Romark didn’t have hundreds of millions of dollars to spend on developing the drug, unlike the big pharmaceutical companies. They had $40 million.21
And so Romark’s hunt for bodies began. It began in Romark’s home state of Florida and ended in a small, impoverished country in sub-Saharan Africa.
When the British left Zambia in 1964, the country was “little more than a hole in the ground” where copper veins had been mined, a government official remembered. Infrastructure, save whatever was required to claw out the copper, was minimal.22 The new government set about bringing the copper mines and farms back under Zambian control, building bridges and roads, and providing water services, free education, and free health care to a populace that would grow to ten million strong. Soon the country was one of the richest in all of sub-Saharan Africa,23 boasting two universities, as well as a medical school and university teaching hospital located in the dusty capital city, Lusaka.24
But the country was dangerously dependent on income from selling copper, and when copper prices collapsed while the price of the petroleum products needed to run the mines spiked in the early 1970s, the country rapidly descended into debt. By 1980, Zambia’s external debt had skyrocketed from $800 million in 1970 to over $3 billion, and desperate government officials turned to the IMF and World Bank for relief.25 Over the following decades Zambia’s nascent welfare state was methodically dismantled. More than 250 formerly government-run programs were sold to private investors. Farmers were cut off from government-supplied fertilizers and other subsidies. Formerly free public clinics and hospitals started to charge hefty fees, whittling the flow of patients into health care facilities by 60 percent. Tens of thousands of government workers were retrenched, as the country waited for foreign investors to sense their opportunity and invest in rebuilding Zambia.
The investors came, but squeezing a profit out of Zambia’s aging copper mines and embryonic infrastructure proved trying. The new mine owners promptly closed the clinics and hospitals the government used to run for the mine workers and their families. Some, such as mining giant Anglo-American, simply cut their losses and fled. Inflation ran at 100 percent by the early 1990s. Abruptly put out of work and suddenly bereft of government support, whole towns and cities collapsed.26 By 1998, 73 percent of all Zambians were living in poverty, and half of the populace was unable to scrabble enough food to meet their minimum requirements.27 According to UNICEF, over a fifth of all Zambians risked death by starvation.28 The flow of water and electricity to the capital city slowed to a sporadic trickle, creating conditions for paroxysms of cholera.
HIV began to spread as well. By 2003, 15 percent of the population harbored the deadly bug, including 150,000 children. The number of years Zambians could expect to live plummeted from over five decades in 1990 to less than thirty-five years by 2001, leaving the country with one of the shortest life expectancies of any co
untry in the world.29 The combination antiretroviral therapy that had effectively stanched the AIDS epidemic in the West had yet to arrive. In 2003, at least two hundred thousand Zambians were sick enough with AIDS to require immediate therapy with antiretrovirals, but the government was able to treat only six hundred patients.30 A 2002 survey showed that 66 percent of Zambians had never even heard of antiretroviral drugs, let alone had the means to pay for them.31
The country’s main hospital, the University Teaching Hospital in Lusaka, was at the forefront of dealing with the AIDS crisis, tracking the epidemic, offering testing and counseling when few in southern Africa were.32 But its facilities were near collapse. Water and telephone services were sporadic. Shortages of medicines and equipment were so severe the hospital was deemed “nonfunctional,” as Canadian journalist and Africa correspondent Jonathan Manthorpe put it.33
Thirty children perished every day in the hospital’s pediatric wards, where as many as five infants might be found sharing a single oxygen tank.34 The UN’s special envoy for AIDS in Africa, Stephen Lewis, who visited the wards, described what he saw to a group of activists in late 2004.
Every 10 minutes there is an anguished howl that sears the psyche and you turn around and there’s a woman kneeling by a cot, four and five infant kids in the cot, a combination of AIDS and famine in that particular situation. And she’s weeping, and the nurse comes in with a white sheet and covers up the infant babe and takes the child away.35
It was, according to Lewis, “a scene from hell.”36
The AIDS and infectious diarrhea that were killing the children stemmed from three interlocked aspects of their poverty: the lack of adequate food, the lack of clean water, and the lack of access to antiretroviral medicines. Untreated water teeming with a host of pathogens, from Shigella and cholera to E. coli, easily overcame the immune systems of weakened, hungry children, the resulting diarrhea draining them of nutrients and predisposing them to yet more intestinal infections and more diarrhea. The rampage of untreated HIV further weakened children’s ability to fight off the parasites. Worldwide the deadly diarrhea-malnutrition-diarrhea cycle took the lives of two million children every year.37
But where foreign investors saw financial risks, Western medical researchers, including those that Romark would later employ, saw opportunity. Epidemiologists, virologists, and gastroenterologists all flocked to the University Teaching Hospital to set up studies in the new disease hotbed. “If you are going to study the problem, you go where the problem is the worst, and Africa was it,” explained University of Texas infectious disease specialist Herbert DuPont, MD, who first jetted down to Zambia in 1992.38
“I like to travel. I like foreign things. I like exotic things,” DuPont told a Houston Chronicle reporter in 1993. As an epidemic intelligence officer for the Centers for Disease Control, DuPont had been involved in the global malaria eradication program. “I’d much rather go to a developing country than Europe. I think there’s a little bit of a missionary zeal too. I would really like to help people,” he said. And Zambia was special, DuPont explained. Unlike elsewhere in southern Africa in the early 1990s, Zambian officials were relatively “open to any suggestions to save their nation” from AIDS. DuPont had tried to set up some research in Zimbabwe, he recalled, but “we were not allowed to discuss seroprevalence [the proportion of the population infected with HIV] or use the word vaccine.” In Zambia, by way of contrast, DuPont said, “Anything is fair game. This is a special thing about Zambians—and the fact that they can only say yes.”39
DuPont was not the only Western specialist excited by the research opportunities in Zambia. Like DuPont, University of London gastroenterologist Paul S. Kelly had set up research collaborations with clinicians at University Teaching Hospital in Lusaka. It was Kelly whom Romark employed to run its trial on how nitazoxanide worked against crypto in children.40 At Lusaka’s University Teaching Hospital Romark found something special. The sad tide of sick children washing over the hospital, the company announced in a press release, comprised a “consistent and controlled study group” for their drug.41
Between November 2000 and July 2001 thousands of parents straggled into Lusaka’s clinics and hospital, clutching tiny bundles: their shrunken, malnourished babies and toddlers whose innards, it seemed, were seeping out. Kelly and his Zambian colleagues screened them all, hoping to find a sufficient number who were infected with Crypto. Outside, the rutted roads overflowing with water had turned into orange swamps.42 Of the over fifteen hundred children suffering from diarrhea who had staggered into the hospital and clinics, Kelly found one hundred who were willing to be part of his study.
The toddlers whose parents agreed to enroll them in the trial in Lusaka were extremely ill. They’d been plagued with diarrhea for days. Most were severely underweight. Half were infected with HIV. The children were dying.
Romark’s studies of nitazoxanide in Egypt and Peru had shown the drug to be remarkably effective against Crypto, at least in non-HIV-infected patients. In Egypt, the drug had cured around 80 percent of the subjects;43 all they seemed to need was a three-day course of the drug.
Treating the HIV-infected children with crypto in Lusaka would prove more challenging. Rosemary Soave’s studies had shown some limited effectiveness when the drug was administered for weeks and even months at a time. Kelly’s own investigations, one of which he’d published in 1996, had found that a two-week course of another drug, albendazole, helped alleviate the diarrhea in such patients, too.44
As per the study protocol, Kelly gave nitazoxanide to twenty-five of the children—those who were HIV free—for three days. Fourteen improved within a week. The other eleven children, given a second three-day course, likewise improved. The drug had, arguably, saved their lives.
Twenty-two other children, their bodies wasted with crypto, were not as lucky. These children had fallen into the placebo group. Besides the fluids and vitamins that all diarrhea patients got, these children were given nothing. A week later, four were dead.
The fate of the HIV-infected children in the trial was worse. Twenty-five were given a short, three-day course of the drug, despite evidence that suggested such a short course wouldn’t work. Five perished. Another twenty-four of the HIV-infected children didn’t even get the three-day course. They got placebos. Four died.45
It would be useful to know how the surviving children and the relatives of the dead felt about the experiment after it was all over. Did they know, as their doctors must have, about the evidence that better cures for their children could have been had with antiretroviral therapy, lengthy treatment with nitazoxanide, or alternative drugs such as albendazole? Was the history of the drug and the experiment—the facts that patients in the United States had refused to be involved in an experiment such as this, and that it was designed to launch a drug aimed at societies far distant from their own—made clear to them? These are unknowns. Their experiences, save perhaps for a few lines of technical data, went unrecorded. Like so many experimental subjects in poor countries, they melted back into a social sphere that science rarely penetrates.
* * *
Two central tenets of medical research sealed the fates of the children enrolled in the nitazoxanide trial in Zambia. The first is that clinical trials should be randomized and controlled, a standard that doomed Romark’s early, uncontrolled trials, and forced it to revamp its drug for a new market. The second, articulated most forcefully in recent years by Robert Temple among others, is what compelled the drugmaker and the investigators to leave U.S. shores in search of patients who wouldn’t balk at being given inert compounds. It’s a corollary of the first tenet: within randomized, controlled clinical trials, the very best thing to give to the control group, from a scientific point of view, is a placebo.
In a randomized controlled trial (RCT) subjects are randomly assigned to receive either the experimental drug or some other intervention. Both groups are treated exactly the same in all other respects save for this one difference.
Then, whatever difference emerges in how the two groups fare can fairly be attributed to the experimental intervention.46 To cancel out any bias researchers might have in assigning subjects to one or the other group, or might inadvertently impart to subjects while in the study, RCTs are often “double-blind,” meaning that neither subjects nor clinicians know which subjects are receiving the experimental drug and which aren’t. After the trial period lapses investigators “unblind” the study and see which group did better.47
Patients around the world can thank the RCT for convincing Western physicians to abandon the medicine by anecdote and received wisdom that reigned for millennia, during which blood letting, earthworms rolled in honey, owl brain, deer heart, fox lung, goat liver, powdered human skulls, rabbit testicles, cow dung, and the fresh blood of a dying Christian gladiator passed for medical treatment.48 Only a precious handful of these enthusiastically prescribed regimens—salicin from willow bark, digitalis from foxgloves, quinine from cinchona bark—would later be proven to treat pain and disease effectively.49
That allopathic medicine works at all owes much to the RCT. The experimental design, which first emerged in London in 1946, is “nothing less than the single most important development in the revolution of modern therapeutics,” wrote Harvard pharmacologist Jerry Avorn—“the most powerful intellectual medicine we have.”50
