Marcia Angell: The Body Hunters & The Constant Gardner

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[sSRI-Research] Marcia Angell: The Body Hunters & The

Constant Gardner

 

 

 

 

Marcia Angell: The Body Hunters & The Constant Gardner

 

ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)

 

Promoting Openness, Full Disclosure, and Accountability

www.ahrp.org

 

FYI

 

Marcia Angell's insightful and informative review of the film and John

le Carre's book, The Constant Gardner, needs no additional commentary:

" On the basis of the research I did for my book I believe that most of

the background facts about drug company behavior in The Constant

Gardener, however hard to believe, are correct. "

 

Contact: Vera Hassner Sharav

212-595-8974

veracare

 

http://www.nybooks.com/articles/18301

The New York Review of Books: Volume 52, Number 15 ·October 6, 2005

Review: The Body Hunters

By Marcia Angell

 

The Constant Gardener

a film directed by Fernando Meirelles, based on the novel by John le Carré

 

Shortly before I started work on my book The Truth About the Drug

Companies:

How They Deceive Us and What to Do About It,[1] a friend gave me John

le Carré's newly published novel, The Constant Gardener, and urged me

to read it right away. I did as I was told, and found the tale

apposite, to put it mildly.

 

The villain is a global pharmaceutical company called Karel Vita

Hudson (KVH). The heroine, Tessa Quayle, is the wife of a low-level

British diplomat stationed in Nairobi, Kenya. She stumbles across

evidence that KVH is testing a dangerous tuberculosis drug, called

Dypraxa, on powerless and unsuspecting poor Africans, and not

reporting the resulting deaths. When she threatens to expose the

company, she is brutally murdered, and the British government colludes

in the cover-up. Her husband, Justin Quayle, a seemingly docile civil

servant at first, becomes obsessed with finding out why his wife was

murdered and by whom. He finally does, and at the end of the book, he

too is murdered. In between the deaths, we follow Justin's gradual

awakening to the ruthless activities of a corporation too powerful to

be accountable to anyone.

 

Now The Constant Gardener has been released as a film, starring Ralph

Fiennes and Rachel Weisz and directed by Fernando Meirelles. It is

both better and worse than the book. Visually, it is stunning. The

many aerial shots of Kenya show the stark beauty and sweep of the

African countryside, and the film also conveys in its urban scenes the

miserable overcrowd-ing and hopeless poverty in Nairobi, something the

book only suggests.

 

Where the film most improves on the book is in its treatment of the

main characters. Fiennes and Weisz portray the relationship between

Tessa and Justin as touching and believable, something the book fails

to do. Le Carré presents Justin as self-contained to the point of

inertness and seemingly with no serious interests beyond his garden.

It hardly seems plausible that such a man would throw over his career,

and risk his life, to investigate the death of his wife. In this film,

Justin is revealed as not so much passive and narrow as controlled and

quietly determined. And Weisz portrays Tessa, a passionately

uninhibited champion of the poor and downtrodden, as a shrewder and

more perceptive woman than the one we find in le Carré's book; she

does not share her discoveries about the drug companies with her

husband for fear of compromising him. As in the book, Tessa's murder

takes place at the beginning, and we come to know her through

flashbacks. But Fiennes's face at hearing of her death, controlled and

virtually immobile, somehow manages to convey the enormity of his loss

as well as his determination to find out the truth about her death.

 

The film falls far short of the book, however, in telling us what KVH

(for some reason renamed KDH in the film) was up to; it never explains

why every institution that might have interfered with the company,

including the British government, was colluding with it. We only get

hints. We are told in passing that KDH and the people it controlled

coerced poor Africans into acting as guinea pigs by denying them

medical care unless they took part in company experiments; but we

learn little about the rules which prevent that sort of coercion in

prosperous countries but not in poor ones. We're told that deaths were

covered up-literally; bodies were thrown into a lime pit and their

existence denied. But we learn little about why that was done, or why

companies conduct clinical trials (that is, tests on human beings) in

the first place, and why they find it advantageous to do so in Africa.

 

Since the film tells us very little about the motives of the drug

company, we are left with a story that has plenty of passion and

intrigue but is played out in something of a historical vacuum. In

fact, most viewers would probably conclude that insofar as we do learn

anything about KDH, its deadly practices are wildly implausible, in no

way representative of real drug company behavior. After all, in the

real world, we don't hear of pharmaceutical whistle-blowers being

murdered, and there have been several whistle-blowers recently.

 

But le Carré himself cautions us against drawing any such conclusions.

In an author's note at the end of the book he makes a grudging

disclaimer to the effect that no person or organization in the book is

based on an actual person or organization. He also makes it clear,

however, that he is obliged to say this " in these dog days when

lawyers rule the universe. " He adds, " But I can tell you this. As my

journey through the pharmaceutical jungle progressed, I came to

realize that, by comparison with reality, my story was as tame as a

holiday postcard. "

 

Quite so. Le Carré obviously did careful research, and the book is

rich in details about ordinary drug company practices. Without being

pedantic, he has his characters explain how drug companies distort

research to make their drugs look safer and more effective than they

are; how they can get away with this more easily in poor regions of

the world; and how they use their vast wealth to influence governments

and the medical profession and any other institutions that might

interfere with their single-minded pursuit of profits. On the basis of

the research I did for my book I believe that most of the background

facts about drug company behavior in The Constant Gardener, however

hard to believe, are correct.

 

Yet the story is based on the premise that a pharmaceutical company

would be so threatened by disclosures of its activities that it would

have someone killed. That is what is fantasy. In fact, many of the

practices that so horrified le Carré's heroine are fairly standard and

generally well known and accepted. They seldom provoke outrage, let

alone murder. A company like KDH would not kill someone like Tessa

even if it were willing to do so; it wouldn't have to. Her concerns

would have seemed isolated and futile, and the companies would hardly

have taken notice of them.

 

There is no question that the US and other rich countries have been

conducting more and more clinical research in Africa and other parts

of the third world. Although exact figures are hard to come by, it is

likely that tens of thousands of studies sponsored by first-world drug

companies and governments are now underway in Africa, parts of Latin

America and Asia, and the former Soviet Union. Most of this research

is intended to find new treatments for use in well-to-do countries.

After all, that is where the paying cus-tomers are. In this sense,

third-world countries are being used as laboratories for first-world

needs. Relatively few studies are devoted to finding treatments for

the diseases that plague poor countries, such as malaria, sleeping

sickness, and schistosomiasis. The big companies are more interested

in the usual first-world conditions, like high cholesterol, obesity,

and arthritis.

 

The rapid movement of drug studies to third-world countries began in

1980, when the US Food and Drug Administration (FDA), in considering

applications to approve new drugs, first agreed to accept foreign

trials as evidence of safety and effectiveness. Before a company can

sell a drug in the US (or market an old drug for a new use), it must

get approval from the FDA, which means it must demonstrate in clinical

trials that the drug is reasonably safe and effective. Nearly every

large drug company, wherever it is located, wants to get into the US

market, because that is the major source of profit for

pharmaceuticals. Probably close to half of all clinical trials are now

conducted in the third world, although there is no way to know for sure.

 

The reasons are clear. It is cheaper and in many respects easier and

faster to do them there. A huge new industry has arisen that conducts

third-world research for drug companies (like le Carré's fictional

research firm, ThreeBees). These companies, called contract research

organizations, or CROs, hire local doctors to find people who will

take part in clinical trials, and while the payments to the doctors

per patient are lower than in first-world studies, by local standards

they are munificent. Doctors can multiply their income tenfold or

more. Patients, too, are readily enticed by small amounts of money and

promises of free care. In fact, as in le Carré's story, enrolling in a

trial may be the only way they can get any care at all.

 

This system makes a mockery of the notion of informed consent-the

requirement that subjects be given full information about the nature

of the research and have the right to refuse to participate, without

penalty or consequences for their usual health care. That requirement

is enforced in the US and other well-to-do countries, and partly for

that reason, drug companies are having a hard time getting enough

volunteers for the growing number of clinical trials. Not so in the

third world, where authoritarian regimes and corrupt local government

officials and health authorities are eager to be paid off by

first-world organizations and to have good relations with them. They

" encourage " entire villages or provinces to enroll in research

programs, while local doctors enrich themselves by providing human

subjects.

 

Perhaps the most important reason for conducting human research in

Africa and other poor regions outside the US is that it is a way of

circumventing FDA regulations. In the US, drug companies are required

to file " investigational new drug applications " (INDs) with the FDA

before they begin human testing of a drug they hope to get approved.

The applications give detailed descriptions of the proposed research,

including plans for obtaining informed consent and for monitoring the

progress of the study.

 

Companies must also provide evidence that ethics committees (called

institutional review boards, or IRBs) have been set up to review each

clinical trial. These committees are supposed to ensure that risks to

human subjects are, in the words of the applicable federal

regulations, " reasonable in relation to anticipated benefits, if any,

to subjects, and the importance of the knowledge that may reasonably

be expected to result, "

 

and further, that all risks are " minimized. " The FDA can deny approval

of the IND or request changes in the proposed research. It may also

conduct on-site inspections of the trials.

 

The requirements for foreign research are much looser. In fact, the

FDA may not even know about such trials until after they are

completed, when the company applies for final approval of a new drug.

Only then-when there is no longer an opportunity to verify the

information-does the company have to describe the way in which the

research was conducted, or say whether there was ethics committee

approval and informed consent. Furthermore, the FDA rarely conducts

on-site inspections abroad. While it conducts very few in the US,

there is always the possibility that it will decide to do so. For

research done in the third world, the agency simply takes the word of

the sponsors of the research. When research does not require FDA

approval, there may be no oversight at all. Companies can conduct

preliminary studies of drugs in poor countries before formal testing

even begins. Quite literally, the participants in their studies are

used as guinea pigs, subjects of research that really should be done

on experimental animals. That was the case in le Carré's fictional

account. Although some research in the US and other wealthy countries

also escapes formal oversight, there are generally more restrictions

on what researchers can get away with.

 

 

 

Several real third-world clinical trials were described in detail in a

six-part Washington Post series in 2000, called " The Body Hunters. "

One of them has parallels to le Carré's story. In 1996, Nigeria was in

the grip of a widespread epidemic of bacterial meningitis, which

eventually claimed over 15,000 lives. Pfizer, the world's biggest drug

company, was at that time conducting the largest research program it

had ever undertaken to get FDA approval for a new antibiotic called

Trovan. Eventually the drug was tested on 13,000 people in

twenty-seven countries. When one of Pfizer's doctors heard about the

epidemic in Nigeria, he immediately got approval from Nigerian

authorities to bring a team to Kano, a city of two million people in

northern Nigeria, to test Trovan in children with meningitis. The aim

was to demonstrate that oral Trovan would work as well in these

children as an established fast-acting intravenous antibiotic.

 

Within six weeks, the Pfizer team had set up its program in the

squalid Kano Infectious Diseases Hospital at the center of the

epidemic. A local doctor was named as principal investigator, and the

team rapidly enrolled two hundred children for the study. Half were

given Trovan, many of them in pill or drink form. The other half were

given injections of ceftriaxone, an antibiotic known to be effective

against epidemic meningitis. Two weeks later, at the end of the trial,

an equal number of children had died in both groups. The new drug was

apparently just as effective as the old one, and it could be given in

oral form. On that basis, Pfizer applied to the FDA for approval to

market oral Trovan for use in children with meningitis.

 

Those are the bare outlines of what happened. But critics such as

Médecins Sans Frontières, the Nobel Prize- winning international

medical relief organization, charge that this was exactly the sort of

study that would not have been permitted in the United States. To

these critics, it was unethical to test an experimental drug orally in

the midst of an epidemic. The usual treatment for meningitis in such

urgent conditions would be intravenous antibiotics. In fact, the

Pfizer doctor who organized the study told The Washington Post that

antibiotics " would never be used like that in the United States. The

standard is IV therapy. " It was also charged that there had not been

adequate preliminary research into how Trovan is absorbed and

metabolized by children or how effective it is against meningitis.

Furthermore, to lessen the pain of injections, the dose of intravenous

ceftriaxone given for comparison was much smaller than originally

planned. But if the dose of the comparison drug were inadequate, that

would make Trovan look better than if it were compared with a full

dose of ceftriaxone. Pfizer maintained that the smaller dose was still

more than sufficient, but the medical director of Hoffmann-La Roche,

the manufacturer of ceftriaxone, was quoted as saying, " A high dose is

essential. "

 

Questions were also raised about whether the subjects had given

informed consent and whether an ethics committee had approved the

trial. The families did not sign informed consent documents, but the

company maintained they had consented orally. However, some doctors

and family members disputed this. A laboratory technician in Kano

said, " The patients did not know if it was research or not. They just

knew they were sick. "

 

Even more troubling was the issue of ethics committee approval. A

Pfizer spokeswoman told The Washington Post that the research had been

approved by a Nigerian ethics board. But a month later, the Post found

that the lead Nigerian researcher admitted to creating and backdating

the approval document. According to the Post, the document was typed

on the letterhead of the Aminu Kano Teaching Hospital and dated March

28, 1996 (six days before the trial began), but the researcher said

that he actually wrote it about a year later. Pfizer reportedly gave

the document to the FDA in 1997 during an audit of records supporting

its application for approval of Trovan. The hospital's medical

director told the Post the document was " a lie. " In fact, he said, the

hospital didn't even have an ethics board at the time the trial was done.

 

In 1997, Trovan was approved by the FDA to treat certain infections,

but not for children and not for epidemic meningitis. The FDA found

dozens of discrepancies in the documents from Nigeria. Trovan quickly

became a highly profitable antibiotic widely used against a variety of

infections. However, after less than two years on the market, there

were over a hundred reports that the drug produced liver toxicity,

causing several deaths, and it is no longer sold. In 2001, the

families of thirty Nigerian children who either died or suffered

serious injury in the Kano trial filed suit against Pfizer in a New

York federal district court. They alleged that the company increased

the risk of death and injury by failing to provide a treatment of

proven efficacy for children who did not respond to Trovan and by

giving the patients used for comparison a weakened version of

ceftriaxone. They also complained that they had not given informed

consent. According to the complaint, Pfizer took the opportunity

presented by the chaos caused by the civil and medical crises in Kano

to accomplish what the company could not do elsewhere-to quickly

conduct on young children a test of a potentially dangerous antibiotic.

 

During the following four years, Pfizer argued that the case should

not be heard in a US court at all. In August of this year, Southern

District of New York Judge William H. Pauley III agreed, ruling that

Nigeria, not the US, was the proper place to try a lawsuit over

Pfizer's conduct of the Trovan trial. The families plan to appeal.

 

Drug companies are not the only sponsors of research in the third

world that wouldn't be allowed at home. In the 1990s, two government

agencies, the National Institutes of Health (NIH) and the Centers for

Disease Control (CDC), sponsored some nine clinical trials in the

third world in which thousands of HIV-infected pregnant women under

study were given a placebo (or sugar pill) instead of the drug AZT,

even though the latter had been shown to cut by 70 percent the risk of

transmission of HIV/AIDS from mother to infant. The aim of the studies

was to see whether a shorter, simpler course of treatment might be as

effective. The standard course required taking oral AZT for the last

trimester of pregnancy, an intravenous infusion of the drug during

labor and delivery, and oral treatment of the newborn for six weeks.

There was preliminary evidence that oral treatment limited to the last

few weeks of pregnancy and the first few days of the newborn's life

might also be effective.

 

But instead of comparing the transmission rate in women who received

an experimental short course of treatment with that in women receiving

the standard course, the researchers compared it with the transmission

rate in women who received only a placebo-thus consigning many babies

in their care to be born with HIV/AIDS that could have been prevented.

This was justified as being the fastest way to show whether a short

course was reasonably effective, but designing the trials in that way

certainly wasn't scientifically necessary, and, in any case, it would

never have been permitted in the US. In 1997, in an article in The New

England Journal of Medicine, Peter Lurie and Sidney M. Wolfe of Public

Citizen's Health Research Group protested that the trials should have

compared short courses of treatment with the standard long one, not a

placebo.[2] As executive editor of the Journal, I wrote an

accompanying editorial in support of their view ( " The Ethics of

Clinical Research in the Third World " ). The public reaction was

intense. Many in the US research establishment, including the

directors of the NIH and CDC, vigorously defended the trials, pointing

out that the women denied AZT probably wouldn't have been able to

obtain it where they lived anyway. But that argument, which was meant

to mitigate criticism of the trials, simply underscored the fact that

the NIH and CDC were willing to take advantage of the women's poverty

and vulnerability. The researchers could easily have supplied the drug

to all the women they enrolled (and for whom they thereby assumed

responsibility), even if it wasn't widely available in the region.[3]

 

Some writers who comment on medical ethics are not so much concerned

with the design and conduct of particular trials in the third world as

with the legitimacy of carrying on research there in the first place.

They believe it is virtually impossible to conduct medical research

ethically in poor countries, because it is inherently exploitative.

Although this seems to me too broad a judgment, I believe the amount

of research sponsored by the first world in the third world should be

sharply curtailed. It is driven too much by the search for profits. It

offers quick answers precisely because it is so easy to cut corners.

 

Before a study is exported to the third world, two important questions

should be asked. First, would it be possible to do the research in the

first world? And second, why is it being diverted to poor countries?

It is sometimes claimed that research should be done where health

needs are greatest-and that is certainly the case in the third world.

But this view confuses research with treatment. There is a great need

to apply the results of research, wherever it is conducted, to the

treatment of people in the third world. Unfortunately, that is not

what happens. Research findings are applied predominantly in

well-to-do countries even when the research is done in poor ones. The

only clinical research that clearly needs to be conducted in the third

world is research on third-world diseases. Such work is amply

justified, and far more of it is needed. Unfortunately, it is not a

high priority either for the pharmaceutical industry or the National

Institutes of Health. In my view, research should not be done in the

third world unless it concerns diseases that are virtually confined to

those regions. And regulations governing research in poor countries

should be every bit as stringent-and enforced just as vigilantly -as

in well-to-do countries. There is no justification for the present

situation in which the standards are looser precisely where human

subjects are most vulnerable.

 

Before research on human subjects is undertaken anywhere in the world,

there should be adequate animal studies and preliminary tests on

normal subjects to eliminate all unnecessary risks. Consent should be

truly informed, and there should be no penalties for refusing to

participate or undue inducements to do so. It is not enough to claim

that informed consent was oral. It should be documented. If there is

any doubt about whether the information given to subjects was

understood, subjects should be asked to repeat their understanding of

the research. To be on the safe side, that conversation and their

consent could be videotaped. Companies should no longer be allowed to

conduct research in the third world that they would not be permitted

to do at home.

 

Le Carré seems bleak about the chances of any such reform. At the end

of the novel, both Quayles are dead, no one is called to account, and

KVH and all the people who serve its interests in and out of

government presumably continue undeterred. The film, however, adds a

Hollywood-style hint of justice to come. At Justin's funeral in

London, Tessa's cousin, in whom she had confided, reveals in a eulogy

for the couple just why they were killed. Reporters scribble in their

notebooks and race for phones, while Sir Bernard Pellegrin, the

unctuous and complicit director of affairs for Africa of the British

Foreign Office, looks increasingly uneasy and finally flees in

consternation. In adding this unlikely scene, the film writers did a

disservice to le Carré's book, but that is a small fault. The larger

one is in not making it clear, as le Carré did so well, exactly what

Tessa Quayle was unhappy about.

 

Notes: [1] Random House, 2004; see also my essay " The Truth About the

Drug Companies, " The New York Review, July 15, 2004.

 

[2] " Unethical Trials of Interventions to Reduce Perinatal

Transmission of the Human Immunodeficiency Virus in Developing

Countries, " The New England Journal of Medicine, September 18, 1997.

 

[3] This controversy was discussed in detail in David Rothman's " The

Shame of Medical Research, " The New York Review, November 30, 2000.

 

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