Globalizing Clinical Research
Big Pharma tries out first world drugs
on unsuspecting third world patients
by Sonia Shah
The Nation magazine, July 1, 2002
By the end of July a US district court will decide whether
drug giant Pfizer should stand trial in the United States for
presiding over a coercive, botched 1996 experiment on Nigerian
children with meningitis. In a class-action suit filed last August,
thirty Nigerian families say the company violated the Nuremberg
_ Code by forcing an unapproved, risky experiment on unwitting
subjects who suffered brain damage, loss of hearing, paralysis
and death as a result.
If allowed, the case will open a rare window on a business
generally shrouded in FDA and Big Pharma secrecy: the global commerce
in human experimentation. Over the past decade, the drug industry
has quietly exported its clinical testing overseas, where oversight
is slim and patients plentiful. According to a largely unnoticed
Health and Human Services (HHS) report, the number of foreign
investigators seeking FDA approvals increased sixteen-fold between
1990 and 1999. The actual numbers are probably much higher-companies
aren't required to alert the FDA before taking their research
overseas, nor does the FDA track research by location after approving
Globalizing clinical research solves the pharmaceutical paradox
that while the average American brings home more than ten prescriptions
a year, just one in 350 is willing to play guinea pig for new
drug testing. An abundance of poor, undertreated and doctor-trusting
patients in Eastern Europe, Latin America and Southeast Asia renders
the quick, positive results corporate sponsors need to get new
drugs approved fast. According to one review, a whopping 99 percent
of controlled trials published in China bestowed positive results
upon the treatment under investigation.
Although the HHS report found that the "FDA cannot assure
the same level of human subject protections in foreign trials
as domestic ones," industry officials say that companies
have little interest in bending the rules. "Occasionally
things go wrong," allows Pharmaceutical Research and Manufacturers
of America official Caroline Loew. But generally speaking, she
says, "companies that are investing $800 million in every
single drug are not going to waste money on trials that don't
meet . [the FDA's] exacting standards." Loew says that companies
test new drugs abroad so they can sell them to needy foreign patients.
Analysts disagree. "There may be a market" in some
developing countries, says Tufts University's drug-development
expert Kenneth Kaitin, "but they are really interested in
the United States, Europe and Japan," which dominate more
than 80 percent of the global drug market. Indeed, all this foreign
experimentation can hardly be counted on to develop malaria vaccines
or cure multi-drug-resistant TB. "The diseases that are of
most interest are mainly the degenerative diseases-arthritis,
obesity, heart disease-the diseases of people in the developed
world," says South African bioethicist Dr. Solomon Benatar.
Just 0.3 percent of the drug industry's much-touted R&D
resulted in the handful of drugs approved for tropical diseases
between 1975 and 1997, despite tens of thousands of industry-sponsored
clinical trials conducted around the world every year. Currently,
US companies are investigating treatments for oral cancer in China,
lupus in Mexico and severe short stature in Eastern Europe, among
other studies-not exactly a list of the world's most pressing
public health problems.
Even if Americans were willing to participate in trials, they
take so many medications that they make poor lab rats anyway,
clinical researchers say. To prove a new drug safe and effective,
"you want patients with no other disease states and no other
treatments. Then you can say relatively clearly that whatever
happens to those patients is from the drug," says MDS Pharma's
Simon Yaxley, whose company sells what industry PR folks call'
patient recruitment solutions" in Eastern Europe, South Africa,
Latin America and China. In developing countries, many people,
because they are poor and don't have access to clinicians and
hospitals, aren't taking any medicines for their illnesses.
Not only do experiments on such patients yield clearer results,
but recruitment is rapid. "Say you need 1,000 patients in
your trial. If you tried Western Europe, it would take you a long
time to find untreated patients," Yaxley says. In a developing
country, "you might find those patients in half the time."
After all, "the healthcare systems aren't as sophisticated,"
he adds, and "because of that, there is an increased interest
in accessing drugs via clinical research, and therefore we can
leverage that interest." Indeed' consumer health advocates
say that clinical trials are the only way some poor patients can
get any formal healthcare at all.
Government bureaucracy overwhelms clinical research in the
United States, scientists complain, but in developing countries
"there is tremendous government cooperation," says Kaitin.
"The governments of China, India and Taiwan are bending over
backward to get these companies to conduct research and manufacture
there. They are giving tax breaks, building facilities. In Taiwan,
many hospitals have switched overall record-keeping to English,
so if Western companies want to do a clinical trial there, they
will have no problem."
Conveniently, many of the FDA's ponderous regulations stop
at the border. For example, the FDA's requirement that companies
prove that their experimental drugs are safe on animals before
starting tests on humans doesn't apply for tests conducted outside
the United States. And experiments on Americans must undergo painstaking,
lengthy reviews by government-regulated "institutional review
boards" (IRBs). But "if you go to some countries and
say you want the IRB to review this, they say, 'What is an IRB?"'
comments Dennis DeRosia, chair of the Association of Clinical
Research Professionals. The FDA simply requires that foreign trials
conform to the World Medical Association's Declaration of Helsinki,
a series of ethical recommendations that critics call rudimentary,
nonbinding and ambiguous. Scientists routinely ignore Helsinki
directives to publish negative results and make study designs
public, and they liken Helsinki-required ethics committees in
developing countries to rubber stamps. "No ethical questions
are raised at all," one investigator admitted to the National
Bioethics Advisory Commission (NBAC).
What results is one set of acceptable risks for patients at
home and quite another for patients abroad, a double standard
that has left hundreds of preventable deaths in its wake. Most
notoriously, in the mid- and late l990s, the National Institutes
of Health and the Centers for Disease Control funded and defended
studies in which Western scientists withheld treatment from HIV-infected
pregnant women in developing countries, even though they knew
antiretroviral drugs would reduce the rate of HIV infection in
their infants by two-thirds. Hundreds of infants "needlessly
contracted HIV infection" while Western doctors presided
over their care, according to an incendiary New England Journal
of Medicine paper by Public Citizen's Dr. Peter Lurie and Dr.
It wasn't that the lifesaving antiretroviral drugs weren't
available to the scientists-the manufacturer offered them free
to clinical researchers. Rather, the demands of scientific rigor
required that some sick patients go untreated' as NIH and CDC
officials explained in a later NEJM issue. Only by observing how
these untreated patients fared and comparing the* outcomes with
those of experimental treatments could scientists quickly and
decisively determine whether the experimental treatments worked,
they wrote. Comparing experimental treatments to antiretroviral
therapy-standard in the West but deemed too expensive, risky and
difficult to administer in poor countries-could only prove whether
new treatments equaled or improved upon antiretroviral therapy.
But in some cases, "the really relevant question is whether
this quick, cheap, easy thing works. You don't really care if
the thing works better," explains international-health ethicist
Nancy Kass. "What you care about is, does it work, period."
Plus, since none of the study subjects could have afforded antiretroviral
drugs at the time, NIH's Dr. Harold Varrnus and CDC's Dr. David
Satcher argued' "the assignment to a placebo group does not
carry a risk beyond that associated with standard practice."
Such justifications, retorted former New England Journal of
Medicine editor Marcia Angell, "are reminiscent of those
for the Tuskegee study"-a kind of ethical relativism that
results in "widespread exploitation of vulnerable Third World
populations for research programs that could not be carried out
in the sponsoring country."
Government-funded scientists' willingness to sacrifice a few
African lives in search of a cheap, effective way to save many
more backfired nastily when South African parliamentarian Peter
Mokaba recently charged South Africa's new AIDS treatment programs
with foisting dangerous and unnecessary Western drugs upon an
unsuspecting African public. According to the New York Times,
recent revelations of improper conduct in an NIH-funded HIV-transmission
trial in Uganda intensified South Africans' receptivity to Mokaba's
dangerous accusations. "You set yourself up for these kinds
of problems if you don't conduct your study properly," says
Lurie. "The researchers have to take responsibility for this."
By all accounts, the quest for rapid results sent Pfizer scientists
jetting to Nigeria in late March 1996. Pfizer scientists had been
industriously collecting data on its experimental broad-spectrum
antibiotic Trovan when one of the worst epidemics of meningococcal
meningitis broke out in Nigeria. The scourge presented a golden
opportunity to test their hot new drug, which they suspected could
effectively treat meningitis in oral form, bypassing the painful
injections their competitors' drugs required. "We had to
move quickly," a Pfizer spokesperson told the Washington
Post. In Nigeria, where the contagion infected more than 100,000,
the company could test Trovan on hundreds of patients in a matter
The Nigerian government was happy to cooperate, arranging
for the company's accommodation and silencing criticism from local
physicians, according to court documents. The FDA granted permission
to export the experimental medicine the very same day it was requested'
Pfizer says. And a Nigerian hospital ethics committee sanctioned
the study design, as required by Helsinki, the company claims.
Not so, confessed two Nigerian doctors to the Post in January
2001. "There was no ethical committee at the time of the
trial, none met, and no approval was properly given for the trial,"
said one. The "approval" document was cobbled together
long after the experiment concluded and was then backdated, the
other doctor said. And Pfizer's study design was dangerously risky,
critics say. One of Pfizer's own scientists, Dr. Juan Walterspiel,
warned management that the study methods were "improper and
unsafe" before and after the study was conducted, acts of
integrity that led to his swift dismissal.
The company, in a heady mix of haste and arrogance, planned
to give 100 deathly ill Nigerian children experimental Trovan
either orally or by injection, and compare their outcomes to 100
others given shots of competitor Roche's FDA-approved Rocephin.
But an oral form of Trovan, though convenient, was too risky to
test on dangerously sick poor kids, Walterspiel complained. "Some
of the children were in critical condition and most of them malnourished,
which made oral absorption even more unpredictable," Walterspiel
wrote to Pfizer officials in a December 18, 1997, letter. According
to Nigerian families' class-action suit against the company, Pfizer
then forced sick children into its study, failing to inform them
either of the experimental nature of the drug they'd be subjected
to or the availability of WHO-approved meningitis treatment from
a nearby Doctors Without Borders team. Not a single Helsinki-required
informed-consent form was signed, the company admits. No witnesses
signed statements attesting to the "verbal consent"
Pfizer claims to have obtained either, the company admits on its
website. "These people had no idea they were part of any
clinical trial," says Elaine Kusel, an attorney representing
the Nigerian families suing Pfizer.
It wasn't the first Third World trial involving lack of consent.
One analysis of South African patients who had participated in
a study of HIV transmission found that almost 90 percent felt
forced into the trial. Thirteen percent of researchers interviewed
by NBAC said they weren't sure if their study participants were
aware that they were in a research project. "Informed consent
is a joke," a clinical investigator who worked in developing
countries commented to NBAC. Pfizer scientists took other liberties
as well. When some children resisted the painful Rocephin shots,
Pfizer scientists slashed the dose to one-third the FDA-approved
levels. This unapproved, reckless deviation from the study protocol
endangered lives, Kusel charges. Pfizer disputes the claim.
The extent of the damage from Trovan and the low dose of Rocephin
remains unclear. Pfizer claims it lost just 6 percent of its patients
in both the Trovan and Rocephin groups, proving that oral and
injected Trovan worked as well as Rocephin. But the company didn't
adequately track the long-term recovery of its patients, Kusel
says. Initial fatality rates may have been relatively low, but
with only one follow-up visit (the FDA recommended two in 1998),
nobody knows how many children ended up deaf, brain-damaged or
dead-whether from meningitis, experimental Trovan or a low dose
of Rocephin, she says.
Pfizer defends the study by stressing that the FDA itself
found little seriously amiss when it reviewed the data in 1997,
a fact maybe more suggestive of the FDA's selective oblivion than
Pfizer's propriety. While the agency did decline to consider Pfizer's
application, noting "discrepancies," it didn't object
to the lack of signed consent forms or note problems with the
ethics-approval letter, the company says. The agency's approval
of Trovan for no less than fourteen adult indications netted Pfizer
more than $160 million until reports of liver damage led the FDA
to pull the plug in 1999.
The trial would have remained Pfizer's dirty little secret
had the Washington Post not unearthed it in a late 2000 investigative
series. The sensational, John le Carre-like story of coercive
experimentation brought thousands of Nigerians into the streets,
launching belated Nigerian and FDA inquiries. In a flurry of outrage,
US Representatives Tom Lantos and Henry Hyde sponsored a patient-protection
amendment to the Export Administration Act, which would make it
more difficult for companies to export experimental medicines
But Pfizer stands by its study. On its website the company
argues that given the impoverished, squalid conditions Pfizer
found in Nigeria, patients ought to have deemed themselves lucky
to get the cutting-edge medical care and upgraded local facilities
that Pfizer's trial offered. "Overall medical care substantially
improved due to the presence of this clinical trial," Pfizer
This specious argument, that "whatever we do is better
than nothing," as Nigerian physician Alphonsus Obayuwana
put it, underpins ongoing attempts to rationalize shoddy treatment
of poor patients in developing countries. In January 2001, for
instance, as part of a trial of a new drug, Discovery Laboratories
planned to administer saltwater or air placebos to 325 deathly
ill premature infants-arguing that in the poorly equipped Latin
American hospitals where the trial would be conducted, patients
couldn't afford effective drugs anyway. Discovery admitted to
the FDA that its new surfactant drug, called Surfaxin, probably
wouldn't improve upon any of the four surfactants the agency had
approved since 1990, according to internal FDA documents procured
by Public Citizen. But however marginal Surfaxin's contribution
to patient care, the drug would be easier to manufacture, the
company says. Since the FDA only requires that new drugs prove
effective-not more effective than already approved drugs-Discovery
planned to seek FDA approval by showing that Surfaxin was better
than nothing. The problem of finding parents of dying infants
desperate enough to risk being assigned to a placebo group could
be overcome by exporting the trial to impoverished Latin American
hospitals, "where other drugs in its class are approved,
but not standard of care because of financial limitations or government
rationing," FDA officials explained in an agency review of
After Public Citizen stepped up pressure, the company redesigned
the study without placebos in April 2001, but FDA medical policy
associate director Dr. Robert Temple, who participated in an agency
review of the study, defends the original study design. "At
present nobody in the places where the study would have been done
is getting surfactant," he told me. "If they did, the
trial half of the people would get surfactant and better perinatal
care, and the other half would get better perinatal care. It seems
to me all the people in the trial would have been better off."
Indeed, Public Citizen's Lurie says, Discovery intended to upgrade
research sites to the standards of a Western intensive-care unit-"they
just wouldn't squirt active drug down the tube."
The international health advocates one would expect to mount
a noisy campaign against shoddy corporate trials have been surprisingly
muted. There's a certain wariness about imposing impossible demands
and idealistic ethical standards on companies that can easily
take their business elsewhere. Doctors Without Borders, the WHO
and other international health organizations have made increasing
corporate research interest in the Third World a primary goal,
making critiques of such trials secondary, at least for now. "It
takes half a second to look at how much more burdened the developing
world is with ill health and disability. What we need, if anything,
is more health research in the developing world, not less,"
says Johns Hopkins bioethicist Ruth Faden.
Plus, even when companies aim for rich Western consumers,
testing new drugs on poor patients "brings benefits to the
They get special attention and potential therapy," adds
HIV re- I searcher Arthur Ammann, who has tried to convince drug
companies to run more trials in developing countries.
Watchdogs like Public Citizen's Health Research Group vociferously
decry unethical study designs but can do little to police study
conduct, which both the FDA and the drug industry view as secret,
"proprietary" information. Ethics documents issued by
international associations such as the World Medical Association
and the WHO/UNESCO's Council for International Organizations of
Medical Sciences, as important as they are, are alarmingly toothless.
Pharma companies themselves have attempted a voluntary "harmonization"
of clinical research standards abroad to meet FDA standards but,
not surprisingly, such efforts are frighteningly nascent in many
In the end, such voluntary endeavors, while crucial, are hardly
sufficient to protect the would-be guinea pigs of the world sacrificed
on the altar of Big Pharma profit. The IRB reviews, FDA approvals
and the like that protect patients at home need to be not only
universal but mandatory. With any luck, the class-action suit
against Pfizer will strengthen the argument for such protections-
at least until the gap between Western elites glutted on the latest
medicines and a world majority lacking access to simple antibiotics
somehow begins to close.
Sonia Shah is a freelance writer currently based in Queensland,