Is GlaxoSmithKline Behaving Badly in Argentina?

SANTIAGO DEL ESTERO, Argentina, Sept. 23, 2008 — -- Maria Ester, 23, lives in a crumbling, one-room stucco cottage with her mother and daughter in Santiago del Estero, an Argentine province northwest of Buenos Aires.

Ester's 5-year-old daughter and assorted neighborhood children crowd the room, and a sagging mattress that smells like it belongs to a young bed wetter is the only place for a visitor to sit down.

An adult might find the room oppressive. But from a child's perspective, a benefit to living in a shanty is that no one really minds if you draw on the walls. Ester's walls are colorfully scribbled.

Sharp-featured, with glossy hair and warm, brown skin, Ester's small body is still plump with baby weight. She had another daughter, Michaela, but the 5-month-old died May 28.

Michaela had been one of more than 13,000 Argentine children to participate in a clinical study implemented a little more than a year ago by the London-based GlaxoSmithKline, the world's second-largest drug manufacturer.

Streptococcus pneumoniae is a major cause of meningitis and pneumonia in children in Latin America. More than 12 million pneumonia episodes occur each year in this region in children under five and it is estimated that at least 50,000 children die each year of pneumonia in the region according to 2006 data from UNICEF.

Ester says that if her infant hadn't participated in the study Michaela would still be alive.

Protocol Compas is the name of the study designed to test the efficacy of Synflorix, GSK's experimental pediatric pneumonia vaccine, which can also ward off the bacteria that causes meningitis and ear infections. Synflorix is still in the preapproval stage.

GSK compares Synflorix with Wyeth's hugely successful Prevnar vaccine, which has proved effective in the United States. Besides Argentina, trials are also being conducted in Panama, Chile and Colombia.

The Outsourcing of Clinical Studies

Americans are swallowing more prescription medications than ever, and the ever-increasing appetite for pharmaceuticals has fueled the drug industry's search for cheaper and faster ways to conduct clinical testing.

In 1997, the United States conducted 5 percent of its clinical studies outside of the United States and Western Europe, according to a study conducted by Tufts Center for Drug Development. By 2007, that number had climbed to 29 percent.

Because of the multinational business of major drug companies, and how Americans fit in as U.S.-based employees and stockholders of GSK, as well as consumers of drugs that will be available in the U.S. market, there are global ramifications of clinical testing being conducted around the world.

The lion's share of drug studies has gone to regions with "emerging markets": Eastern Europe and Central Europe, Latin America, and south and Southeast Asia. In order for a region to be of use to a legitimate drug company, the country has to maintain a minimal level of infrastructure, says Mary Jo Lamberti, director of market research at the Boston-based Center Watch, a consulting firm that bills itself as the "Global Destination for Clinical Trials Information."

According to Fortune magazine, it takes about $900 million to bring a new drug to market, and procuring and retaining human subjects typically accounts for about 40 percent of a drug company's budget. Conducting trials in regions considered "poor" by Western standards makes economic sense.

Yet money is not the only factor in the equation, Lamberti says, whose work includes helping pharmaceutical companies find suitable locations for clinical trials. It's easier and takes far less time to find suitable subjects in many developing countries, she says, because they have large "drug naive" populations.

In other words, a large percentage of Americans are already on various medications, so it's difficult to find subjects with unadulterated -- that is, completely unmedicated -- bodies in the United States.

Critics say there is an additional issue that has yet to be taken seriously.

Individual countries generally have their own boards of medical professionals charged with setting standards to ensure the safety of their citizens. And the United States, for example, has an arm of the Food and Drug Administration tasked with overseeing clinical studies performed abroad. The trouble, critics say, is that the standards that exist are sometimes not upheld.

Sonia Shah, author of the 2006 book "The Body Hunters: Testing Drugs on the World's Poorest Patients," tells ABCNews.com that there is a "whole steamrolling industry that needs more and more subjects."

She adds, "[The] political will is not there" to protect the interests of those who put their bodies at risk.

Clinical Study: 'Adverse Events Can Arise'

Pneumococcal diseases -- that is, diseases caused by bacteria that cause pneumonia, middle ear infections, meningitis and blood infections -- are a serious problem in Latin America. According to international health organizations, each year more than 50,000 children die from them.

Dr. Ricardo Ruttiman, the regional medical affairs and research and development director of GlaxoSmithKline responsible for Protocol Compas in Argentina, says the study is being conducted in three Argentine provinces -- Santiago, Mendoza and San Juan. Ruttiman says Compas clinical studies began a little more than a year ago.

Twelve Argentine children who participated in Protocol Compas have died, and of those 12, seven are being mourned in Santiago del Estero, one of Argentina's poorest provinces. Like Ester, many of the parents reportedly blame what they know as Protocol Compas, or simply, Compas.

"Within the COMPAS trial an Independent Data Monitoring Committee (IDMC) oversees safety aspects of the study and ensure that the highest ethical and compliance standards are followed," said Sarah Alspach, director of US Media Relations for GlaxoSmithKline. "The mortality rate of children participating in the COMPAS study is closely monitored by the IDMC and does not exceed the rate in the regions and countries participating in the study."

Some parents say they didn't know that their children were participating in a study at all. Others claim to have been coerced into participating -- a suggestion rebutted by Ruttiman, who told ABCNews.com that participation is always voluntary and that parents "are informed, clearly and in a language they can understand, by experienced medical investigators."

They are informed not only about the benefits, he says, such as round-the-clock access to medical care and vaccinations against diseases such as diphtheria, tetanus and hepatitis, but about potential risks.

Ruttiman says there are few risks. The safety of the drug has already been proved, he says, and the vaccine's efficacy against respiratory infections is only being tested.

He adds that "the vaccines used in this study may cause adverse reactions unknown up to now. … As with any vaccine, unexpected adverse events can arise, including allergic reactions."

Ester, who earns a living cleaning houses, says Michaela is among those who experienced an "adverse event."

Three weeks before Christmas, a nurse's aide came to the Esters' home. The nurse's aide, says Ester, who spoke to ABCNews.com through a translator, told her that doctors at the Eva Peron Children's Hospital, Santiago Del Estero's primary children's hospital, wanted to give Michaela a vaccine.

Ester -- who told her story to ABCNews.com and a small audience that included five neighborhood children sitting as quietly as possible on the pungent bed -- says that a friend had warned her to stay away from Protocol Compas. The friend told Ester that she knew of another new mother whose baby reportedly suffered health problems after participating in the study, according to Ester.

Ester only gave in, she says, when the nurse's aide threatened to go to the police and have her baby taken away from her. "I didn't know if the doctors, the police, the system would take her away, but I was afraid," she added.

Ester soon signed a 12-page consent form she says she couldn't really understand. Then she allowed Michaela to receive her first injection.

Many health-care professionals assert that holding clinical trials in regions with poor health-care systems has the potential to benefit everyone. GSK's Ruttiman points out that because of the high quality of care the children in the study receive, the infant mortality rate is significantly lower in those who participate in Protocol Compas than in those who do not. Ruttiman would not comment on individual cases citing patient privacy.

Benjamin Wilfond, head of Seattle's Treuman Katz Center for Pediatric Bioethics, says that although he is unfamiliar with Protocol Compas, it's difficult to know what really happened between Ester and the nurse's aide.

"I have no doubt that that was how [Ester] experienced the process. And you will not find anyone who will defend coercion," he said. "But I was in Argentina a few years ago, and the internal regulations seemed quite robust. It could very well be true, because even if the process is being appropriately reviewed, it's difficult to monitor what goes on [on] the ground, what individuals take it upon themselves to do. But I would be wary [of such accounts]. The death of a child could be processed in all sorts of ways. It could very well be true. But I am skeptical."

Trading participation in a medical trial for health care has become the standard operating procedure for drug companies and/or their medical contractors, according to Shah. Some see it as win-win, but Shah views the trade as nearly as coercive as the dramatic threat Ester alleges she received.

"The argument I make is that the drug companies are going [abroad] because people have less access to health care," said Shah. "So they offer incentives and the choice is, 'participate in the trial or your children won't get health care.' That's not a choice. Being in an experiment is not the same as standard care. In an experiment [the drug] might work, you might get a placebo or it might be worse than nothing. They might suffer some terrible unforeseen consequence."

Tricked Into Participation?

When it comes to Protocol Compas specifically, Dr. Ana Maria Marchesse of Eva Peron Children's Hospital is one of several Argentine doctors who is highly critical of the study's methodology.

She heads up the Health Professionals' Labor Association, a group of local doctors who alerted La Federacion de Profesionals de la Salud de la Republica Argentina (the Argentinean FDA) of their concerns about possible wrongdoing.

"It's impossible to say whether the 12 babies' deaths are due to the vaccine or not, because half of the [total number of] children were given a placebo," the pediatrician told ABCNews.com through a translator. "But the way the study has been conducted is reprehensible."

A large part of the problem lies in the consent form, says Marchese. The language in the 12-page document is so convoluted, she charges, that even she had to read it more than once to fully grasp its meaning. Another problem is how subjects say they were recruited, Marchese says.

Claudia Nazarena Hoyos, 31, and Alvaro Martin Ovejero, 32, spoke to ABCNews.com in Ovejero's father's kitchen.

Hoyos and Ovejero allege that a Protocol Compas nurse's aide told them that 4-month-old Gabriel, who suffered from bronchial trouble, would probably get better if they allowed him to be a part of the study. Instead, Gabriel died two months after receiving his first injection.

Ovejero, who works as a part-time disc jockey, alleges the couple was misled by the "agente saniterio," a kind of nurse's aide, who told them about the study. "She did not say it was a test. She said it was a vaccine for his lungs that would keep him from getting worse."

One week after the baby received his first injection, says Hoyos, her son began to produce a lot of mucus. His eyes were perpetually runny, and his breathing grew slow and labored.

GlaxoSmithKline denies allegations of ethical misconduct. Ruttiman says the deaths have been analyzed, and says all of them were clearly unrelated to the vaccine. One child died in a choking incident, he says.

"GSK is saddened to hear of any mortality in clinical trials. Safety of patients is always our primary concern in the development of any new treatment or vaccine," Alspach said. "It is, however, important to review such cases in the context of the rates of post-neonatal infant mortality for the country in which the trial is being conducted."

Nevertheless, Ovejero insists that "something in the process was bad," and that his family and the other affected families "want to find out who or what is responsible."

Unintended Consequences

Global health advocates say bad press is making it difficult for doctors working with children in the developing world, even when the doctors have no connection to clinical studies.

The Nigerian state of Kano is one well-publicized example. In 2004, Kano's government refused to take part in the Global Polio Eradication Initiative sponsored by the World Health Organization out of fears that the immunizations constituted a plot to reduce the country's Muslim population.

According to The Associated Press, the boycott was initiated after Pfizer faced accusations made by families and human rights groups of putting about 200 children at risk during what they claimed was a poorly managed meningitis study 11 years ago.

Eleven children died, while others suffered brain damage, according to the Nigerian government, which this summer filed suit against the London- and Connecticut-based pharmaceutical company. The case is still pending.

Although the immunization boycott lasted 10 months, international health experts reportedly noted a rapid polio expansion, in a pattern that radiated from the west African state.

Shah says that the Kano example points to the public health issues at stake when countries lose trust in the pharmaceutical industry. "It's not that drug companies are trying to go out and harm people," she said. "They really hope and believe that their drugs will work."

Back in Argentina

Franklin Moyano, Santiago del Estero's health minister, told state news media that the province is conducting an independent investigation into the children's deaths. But the families of the children are taking matters into their own hands.

Ovejero, who wears a T-shirt bearing his late-son's photo, says that the family is planning to take legal action. The family also told Inter Press Service that their lawyer had been offered money to halt any legal action, but they rejected the offer.

A GlaxoSmithKline representative told ABCNews.com that the company was aware of reports in the Argentine press that Ovejero and his wife were offered money through their lawyer, but GSK said in an e-mail response, "The company has acknowledged this information through the articles that have been published in the media. Therefore, we do not have acquaintance of this fact."

In the meantime, Ovejero participates in weekly protest marches on the Plaza Liberdad, the town square. For the last month, every Monday around 7 p.m., close to 20 to 50 parents, extended family members and friends carry signs bearing the blown-up likenesses of their dead babies.

"Gabriel was born with a purpose," said Hoyos, Gabriel's mother. "His purpose was to bring justice."