NEWSLETTER 10: THE CONSTANT GARDENER: WHAT THE MOVIE MISSED

A lush, atmospheric drama, The Constant Gardener brings unprecedented exposure to crucial issues facing the Western pharmaceutical industry and all those who partake of it. Set mostly in a sun-dappled Kenya and based on a John le Carr้ thriller, the film is a fierce but flawed indictment of Big Pharma's complicity in African illness and poverty. The film revolves around the transformation of mild-mannered career diplomat Justin Quayle, played by Ralph Fiennes. Quayle's wife, Tessa, played by Rachel Weisz, has exposed a botched experimental trial conducted by a Western drug company (whose name, Three Bees, has a logo suspiciously close to Roche's logo) upon unsuspecting African villagers. After she is found mysteriously murdered, Justin is infected with his firebrand wife's righteous indignation.

The plot couldn't be timelier. According to a May 16 report in USA Today, giant drug outfits are outsourcing increasing numbers of drug trials outside the United States and Europe. Merck is now conducting 50 percent of its trials outside the United States. By 2006, 70 percent of Wyeth Pharmaceuticals trials are expected to occur offshore. Across Latin America, Eastern Europe, Asia and Africa, the sick are abundant, desperate and doc-trusting, and so recruitment into clinical trials is rapid. As one executive from an outfit specializing in running drug trials in Asia put it, patients in developing countries are "more willing to be guinea pigs."

As the film makes all too clear, Big Pharma's new experimental bodies in the developing world only rarely enjoy the benefits of the research they participate in. Sometimes the new drugs are unlicensed in their countries or priced out of reach, but more often the drugs are irrelevant to the medical needs of their communities. After all, 90 percent of the global medical research budget takes aim at illnesses that cause just 10 percent of the world's disease burden. And so, while 500 million cases of malaria rage across the developing world, the working poor of India, South Africa and elsewhere, desperate for the kind of high-tech care available to them almost solely through clinical research, line up for experimental doses of the latest arthritis, heart disease and obesity drugs.

Not surprisingly, ethical lapses are strikingly common in Drug Studies conducted outside of ICH regions. In one inquiry, out of thirty-three subjects enrolled in an experiment trial in Thailand, all of whom had signed forms stating their informed consent had been properly provided, thirty subjects were found to be dangerously misinformed. The experimental HIV vaccine they were about to receive had no known protective value, but, according to the subjects, it would, in fact, protect them from the deadly virus. "Informed consent is a joke," said one industry researcher in an anonymous survey sponsored by the National Bioethics Advisory Commission.
But challenging these practices is not nearly as black-and-white as this film would have it. Tessa Quayle, the martyred activist, stands up to yell "bullshit" at public lectures, shaking her lovely dark mane while she's at it. At cocktail parties, she loudly embarrasses the health minister, who marches off in a huff. Good stuff, but the reality is that uncompromising activists — even if they look like Rachel Weisz — rarely enjoy this kind of privileged access to power so effortlessly. Tessa has it too good and too bad, too. She ends up paying with her life for her exposure of the botched trial; in real life, bad drugs and unethical research practices often continue unhindered despite mountains of data and reports detailing their defects.

As I found while researching a book on the topic, experimental protocols that would be condemned as unethical in the West — including placebo trials among ailing AIDS patients as conducted by Roche — are frequently described in the medical press; when the subjects are poor Africans or Asians, nary an eye is batted. (Recall that papers describing this country's most egregious scientific study, the Tuskegee Syphilis Study, in which government doctors denied treatment to black syphilitics, regularly appeared in the medical press from the 1930s onward. That study wasn't terminated until 1972.)

In the film, the trial's results are so dangerous that they must be suppressed by an international conspiracy of corporate execs and state authorities. The trouble is that most of the time new drugs aren't uniformly deadly, rendering unequivocal data showcasing their killer properties. Rather, new drugs do work, just not very well, or not for everyone, or not without side effects or, most frequently, not any better than older, safer drugs. What that means is that challenging unethical trials requires more than wrenching a few critical reports from official dustbins.

Most disappointing, perhaps, is that the film tells us precious little about the explosive trial at its center, despite the fact that the entire plot hinges on its wickedness. Some of the African subjects died in the trial, the film tells us, but little else is revealed. There's a reason for this strange omission. Most Western audiences will easily jump to the conclusion that any experiment that rendered any deaths is irredeemable, no matter the condition of the patients, the purpose of the trial or the rates of deaths from traditional therapies or no therapy. And yet the business of testing experimental drugs in humans is a risky one, no matter what the condition or drug. Humane research practices may minimize the risks, which must be balanced against potential benefits, but the risks remain, regardless. As one HIV researcher put it, "I mean, shit, we learn by climbing over the bodies of humans."

Also, the story tells us that Big Pharma with the aid of a CRO are studying an experimental TB drug and outlines forecasts that TB will be a huge epidemic in America in a few years. They bring the trial to an obvious vulnerable population in Africa without the proper safeguards of modern Western Medicine as promoted in ICH-GCP. They also let us know that the drug is not efficacious and is outright dangerous in at least a subpopulation of subjects who die as a SAE (Serious Adverse Event) from the experimental Study Drug and these subjects' data are removed and all of their data and their bodies are buried where no one will ever find them. Tessa points to one sick African girl in a local Hospital in one scene and proclaims that Big Pharma is killing her in front of our eyes. Albert Fiennes character later searches for the dead African girls source documents including her SAE forms and finds no record that she ever participated in the trial in the first place.

In another scene Albert, Fiennes' character, witnesses a research subject volunteer holding an ICF (Informed Consent Form) with the initials IC for Informed Consent. The subject withdraws consent and is then abandoned by the local healthcare system. She then has no access to healthcare. His character inquires of the local PI/Doctor running the study why this girl is being refused medical care. He is told that she was refusing medical care. He finds out, however, that the girl only refused to participate in the experimental TB drug study. She was begging to receive needed medical care. The African doctors were coercing their patients into becoming research subject volunteers by providing desperately needed healthcare only to those who agreed to do the study. This highlights the most extreme unethical research behavior a medical researcher could exhibit and of course does not exist in the ICH-GCP community.

What doesn't make sense, however, is that a TB study being done in Africa with a drug that is really not efficacious would ultimately be of no finincial value to the Drug Company. When the Drug Company would attempt to bring it to America, since the research was done outside of the ICH-GCP region, it would require repeat studies here in America. The Belmont Report in 1979 outlines the ethical principle of Distributive Justice whereby the group that bears the research risks should be the same group that bears the potential benefits of the research. Without the guarantees of modern research in ICH-GCP areas, the data would not support an NDA. What they could have written into the story line that would have made more sense would be the situation whereby a drug company had several experimental TB medications that they were contemplating applying for an IND to begin studying them here in America and they wanted to rapidly find out which one would be best to begin studying. Then, they would do the preliminary research in Africa using the relaxed research rules and rapidly find out the highlights of these experimental drugs. This would provide them with the information on which drug to begin studying here in America. This would have been a more real to world scenario that could actually occur and might actually be occurring and we in the medical research community need to protect the world from such research atrocities now.

Roche got in trouble a few years ago by studying their AIDS drug in Africa and including a placebo arm when it would be unethical here in America. They rationalized the research by stating that the community that they were using had absolutely no access to healthcare at all. They came in and supplied the neighborhood with a Hospital and a clinic and requested locals with HIV to volunteer in this study that was unethical in America. When results came out, they were harshly criticized.

That the film makes no allowance for this reality that the unethical TB research they were conducting in Africa would not be of any economic benefit at all is more than a problem of accuracy. Our reluctance to acknowledge the risks of drug development is the single biggest reason why drug companies have fled the empty test clinics of the United States and Western Europe to set up shop in Africa, Asia, Eastern Europe and Latin America in the first place. On average, every American buys more than ten prescription drugs every year, and yet most are loath to participate in the clinical trials that make new drugs possible. Less than one in twenty Americans take part in experimental trials, with half the American public maligning test subjects as "guinea pigs," according to a June 2004 Harris poll.

The logical outcome of this "all gain, no pain" attitude toward modern drugs is for drug companies to shift the burden of experimentation away from Western consumers and onto the world's poor — with all the moral quandaries, ethical lapses and egregious violations that inevitably follow. To paraphrase the rousing finale of The Constant Gardener, we enjoy the benefits of civilization so affordably because their lives are bought so cheaply. To end the cycle, we must own up to the risks of developing new drugs, and decide together how much we are willing to take on and who shall pay the price.

In conclusion, as we learned from Shakespeare's Julius Caesar, the ends do not justify the means. It is incumbent for us in the global drug development industry to maintain the high levels of ethical medical research no matter where the research is performed. Unethical research should be shunned and considered adulterated and unreliable.

Sincerely:

Joseph Saponaro, MD, DABIM, FACP, CPI, CCI, CCTI, CCRC, CCRP
Expert Medical Witness, ExpertMD
PI (Principal Investigator), DSI (Drug Study Institute)
Board Certified Internist, JPMC (Jupiter Preventive Medicine Center)
DABIM (Diplomat American Board of Internal Medicine)
FACP (Fellow American College of Physicians)
CPI (Certified Physician Investigator) by the AAPP (American Academy of Pharmaceutical Physicians)
CCTI (Certified Clinical Trial Investigator) by the ACRP (Association of Clinical Research Professionals)
CCI (Certified Clinical Investigator) by the DIA (Drug Information Association)
CCRC (Certified Clinical Research Coordinator) by the ACRP (Association of Clinical Research Professionals)
CCRP (Certified Clinical Research Professional) by SoCRA (Society of Clinical Research Associates)
Member, SIMPD (Society for Innovative Medical Practice Design)
Member, ACPM (American College Preventive Medicine)
Ethics Committee Member, Jupiter Medical Center
IRB Member, Jupiter Medical Center
Founder, CertifiedResearchers.com