The Body Hunters (6 page)

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.

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

It is possible to conduct RCTs successfully by providing an alternative treatment for subjects in control groups, but according to Temple and Kelly, using placebos as a control renders the most unequivocal data. And yet, deciding what to use as a control has not always been driven primarily by scientific considerations. Politics often grabs front seat.

Take, for example, the 1954 trials of Jonas Salk's experimental polio vaccine, the RCT's big national debut. Polio wasn't a huge killer at the time, but as a crippler of the young, particularly those of the upper and middle classes, it was a terror-inducing scourge, forcing communities to shut down their swimming pools and movie theaters at the height of the summer's polio season. Salk's sponsor, the March of Dimes, aware that leading virologists were skeptical of the experimental vaccine—it consisted of the entire, virulent polio virus itself rather than a similar virus that could train the body to fend off more dangerous foes—was eager to produce the most convincing data possible.
⁵¹
A double-blind RCT would be ideal, a “beautiful . . . experiment over which the epidemiologist could become quite ecstatic,” as Salk put it.
⁵²
The plan was to give the control group placebos. Nobody really knew if Salk's vaccine worked anyway, so it wasn't as if they'd be depriving anyone of some known effective medicine. For all they knew the vaccine might even hurt the children: those randomized to placebo might have better outcomes than those in the vaccine group.

But just as Romark and the NIH discovered years later when they attempted to run a placebo trial for nitazoxanide among U.S. AIDS patients, the majority of the state health departments approached about running the trial in their public school systems
objected to the placebo control. So great was their faith in Salk and the March of Dimes that they wanted
all
of their enrolled children to get the vaccine, experimental or not.
⁵³

Salk, publicly at least, agreed with the underlying sentiment: denying the experimental vaccine to any child would be a travesty, indeed. The placebo-controlled design, he said, “would make the humanitarian shudder,” he opined.
⁵⁴
The compromise the foundation settled on was less rigorous but more politically palatable, involving an awkward mix of two concurrent trials: a large-scale trial in which all participants would be vaccinated, and a smaller one that compared vaccinated children to those injected with placebos.
⁵⁵

The same year, Louis Lasagna, MD, called by some the father of modern pharmacology, discovered the “placebo effect,” the phenomenon by which patients are healed by inert compounds, and became a forceful advocate for more rigorous standards for drug approvals. For Lasagna, as for Temple later, trials that pitted an experimental drug against an alternative treatment too often told scientists nothing. “In the absence of placebo controls, one does not know if the ‘inferior' new medicine has any efficacy at all,” Lasagna wrote in a 1979 editorial. “‘Equivalent' performance may reflect simply a patient population that cannot distinguish between two active treatments that differ considerably from each other, or between active drug and placebo.” In his myriad appearances at congressional hearings, Lasagna urged the FDA to require placebo-controlled trials for all new drugs.
⁵⁶

Today, the FDA's position is that it prefers placebo-controlled trials, if they are ethical and feasible.
⁵⁷
Temple took the baton as placebo-control advocate from Lasagna, who died in 2003. And now, the placebo-control orthodoxy is firmly entrenched, with a number of novel arguments forwarded in its favor. Kelly, for example, was certain that using placebos in Lusaka was the right thing to do. “There is no other way of being absolutely sure that the stuff actually works,” he says. “It is very very important to do this in third world countries, for two reasons. One, because if
you misguide people into thinking that your drug works when it doesn't, you'll be responsible for diverting precious resources away from something else which may also be important. Two, we cannot assume that something which works in other countries will work here. . . . There are geographical differences and we have to be sure that it works where we're planning to use it.”
⁵⁸

There are other rationales that are somewhat less lofty. Most new drugs are not miraculous cures like penicillin, or a shot of insulin to a comatose diabetic. For most, the margin of effectiveness is narrow, colored in shades of gray. “I'm not used to finding black and white,” agrees Rosemary Soave. “You usually have to struggle to find the difference” between patients who got the drug and those who didn't.
⁵⁹
Anecdotal evidence might be sufficient in the case of a wonder drug, but discerning how a weakly acting drug works requires the precision, and relatively low expectations, of a placebo-controlled trial.