Drug Trial Industry Lacks Adequate Safeguards, Oversight

By DAVID EVANS, MICHAEL SMITH and LIZ WILLEN, Bloomberg News

Oscar Cabanerio has been waiting in an experimental drug testing center in Miami since 7:30 a.m.

The 41-year-old undocumented immigrant says he’s desperate for cash to send his wife and four children in Venezuela.

Cabanerio is one of many regulars who gather at SFBC International Inc.’s test center, which, with 675 beds, is the largest for-profit drug testing center in North America. Most of the people lining up at SFBC to rent their bodies to medical researchers are poor immigrants from Latin America, drawn to this five-story test center in a converted Holiday Inn motel. They are testing the compounds that the world’s largest pharmaceutical companies hope to develop into best-selling medicines.

Cabanerio, who has a mechanical drafting degree from a technical school, says he left Venezuela because he lost his job as a union administrator. For him, the visit to SFBC is a last resort.

"I’m in a bind," Cabanerio says in Spanish. "I need the money."

Every year, Big Pharma, as the world’s largest drug makers are called, spends $14 billion to test experimental drugs on humans. In the U.S., 3.7 million people have been human guinea pigs.

Few doctors dispute that testing drugs on people is necessary. No amount of experimentation on laboratory rats will reliably show how a chemical will affect people. Helped by human testing, drug makers have developed antibiotics capable of curing life-threatening infections as well as revolutionary treatments for cancer, AIDS and other diseases.

These medical success stories mask a clinical drug trial industry that is poorly regulated, riddled with conflicts of interest – and sometimes deadly. Every year, trial participants are injured or even die.

Pharmaceutical companies distance themselves from the experiments on humans by outsourcing most of their trials to private test centers across the United States and around the world, says Daniel Federman, a doctor who is a senior dean of Harvard Medical School in Boston.

The Food and Drug Administration, the principal federal agency charged with policing the safety of human drug testing, has farmed out much of that responsibility to a network of private companies and groups called institutional review boards, or IRBs.

The IRBs that oversee pharmaceutical company trials operate in such secrecy that the names of their members often aren’t disclosed to the public. These IRBs are paid by Big Pharma – just like the testing centers they’re supposed to be regulating.

Oversight questioned

The drug experiment companies and the private oversight firms have more incentive to satisfy pharmaceutical companies wanting speedy results than they have to ensure the safety of participants or integrity of research data, says Marcia Angell, editor in chief of the New England Journal of Medicine from 1999 to 2000.

"The fundamental problem is a system in which investor-owned businesses have control over the evaluation of their own products," she says. "Oversight of clinical trials is too important to leave in the hands of drug companies and their agents."

Rules requiring subjects to avoid alcohol and narcotics and to take part in only one study at a time are sometimes ignored by participants, putting themselves at risk and tainting the test data.

The consent forms that people in tests sign – some of which say participants may die during the trial – are written in complicated and obscure language. Many drug test participants interviewed say they barely read them.

Ken Goodman, director of the Bioethics Program at the University of Miami, says pharmaceutical companies are shirking their responsibility to safely develop medicines by using poor, desperate people to test experimental drugs.

"The setting is jarring," says Goodman, who has a doctorate in philosophy, after spending 90 minutes in the waiting rooms at SFBC’s Miami center, which is also the company’s headquarters. "It’s an eye- opener. Every one of these people should probably raise a red flag. If these human subject recruitment mills are the norm around the country, then our system is in deep trouble."

Who’s accountable

The chief executive officers of drug companies should be held accountable for any lack of ethics in these tests, says Harvard’s Federman, who chaired a national committee on clinical trial safety in 2003.

"The CEOs of the companies have to be publicly, explicitly and financially responsible for the ethical approach," says Federman, who still sees patients at age 77. "It’s not possible to insist on ethical standards unless the company providing the money does so."

Chief executives of 15 pharmaceutical companies that outsource drug testing to firms including SFBC – among them, Pfizer Inc., the world’s largest drug maker; Merck & Co.; and Johnson & Johnson – declined to comment for this story.

SFBC Chief Executive Arnold Hantman says his center diligently meets all regulations.

"We take very seriously our responsibilities to regulatory authorities, trial participants, clients, employees and shareholders," Hantman says. "We are committed to conducting research that fully complies with industry and regulatory standards."

Outsourcing oversight

The pressure that pharmaceutical houses face to develop new drugs has intensified in the past 15 years.

Faced with the expiration of patents on best-selling drugs such as AstraZeneca Plc’s Prilosec, which has helped tens of millions of people with heartburn and ulcers, Big Pharma has been in a frenzied race to find new sources of profit.

When the patent for a company’s blockbuster drug expires, a lucrative monopoly vanishes.

Such drugs typically lose 85 percent of their market share within a year of patent expiration, according to CenterWatch, a Boston- based compiler of clinical trial data.

The oldest and largest review company is Western IRB, founded in 1977 by Angela Bowen, an endocrinologist. WIRB, a for-profit company based in Olympia, Wash., is responsible for protecting people in 17,000 clinical trials in the U.S.

The company oversaw tests in California and Georgia in the 1990s for which doctors were criminally charged and jailed for lying to the FDA and endangering the lives of trial participants. No action was taken against WIRB. Bowen says she didn’t see human safety issues in those trials.

WIRB tries to visit test sites it monitors once every three years, Bowen says.

The FDA’s own enforcement records portray a system of regulation so porous that it has allowed rogue clinicians, some of whom have phony credentials, to continue conducting human drug tests for years, sometimes for decades.

The Fabre Research Clinic in Houston, for example, conducted experimental drug tests for two decades even as FDA inspectors documented the clinic had used unlicensed employees and endangered people repeatedly since 1980. In 2002, the FDA linked the clinic’s wrongdoing to the death of a test participant.

Conflicts of interest

Review boards can have blatant conflicts of interest. The one policing the Fabre clinic was founded by Louis Fabre, the same doctor who ran the clinic. Miami-based Southern IRB has overseen testing at SFBC and is owned by Alison Shamblen, wife of E. Cooper Shamblen, SFBC’s vice president of clinical operations. Both Shamblens declined to comment.

SFBC’s 2005 shareholder proxy, filed with the Securities and Exchange Commission, lists Lisa Krinsky as its chairman and a director of medical trials and refers to her 26 times as a doctor. Krinsky has a degree from Sparta Medical College in St. Lucia in the Caribbean; she is not licensed to practice medicine.

Arthur Caplan, director of the Center for Bioethics at the University of Pennsylvania in Philadelphia, says handing oversight of human drug experiments to private, companies is a mistake.

‘Gives me hives’

"This whole world gives me hives, this privatized review process," Caplan says. "I’ve never seen an IRB advertise by saying, ‘Hire us. We’re the most zealous enforcer of regulations you could have.’ People say, ‘We’ll turn it around faster. We’re efficient. We know how to get you to your deadlines.’-"

The Pharmaceutical Research and Manufacturers of America, a Washington-based trade association and lobbying group, says human drug tests in the U.S. are safe and well-monitored.

"The vast majority of clinical trials conducted in the United States meet high ethical standards," PhRMA, as the group is known, said in a written response to questions. "The U.S. regulatory system is the world’s gold standard, and the Food and Drug Administration has the best product safety record."

Joanne Rhoads, the physician who directs the FDA’s Division of Scientific Investigations, says that view isn’t realistic.

"What the FDA regulations require is not any gold standard for trials," Rhoads says.

The agency doesn’t have enough staff to aggressively monitor trials, she says, adding that FDA regulations are a bare minimum and much more oversight is needed.

‘That’s just the truth’

"You cannot rely on the inspection process to get quality into the system," Rhoads says. "I know many people find this not OK, but that’s just the truth."

Michael Hensley, a pediatrician who was an FDA investigator from 1977 to 1982, says the agency has become less active in clinical trial oversight in recent years. Families of injured or dead trial participants seeking accountability for mistakes have to file lawsuits.

"The FDA’s backbone has been Jell-O," says Hensley, who’s president of Hensley & Pilc Inc. of Chapel Hill, N.C., which advises pharmaceutical companies on FDA compliance. "The folks at the FDA stopped enforcing the rules several years ago."

In 1991, 80 percent of industry-sponsored drug trials were conducted by medical faculty at universities, with protection for participants provided by the school’s own oversight boards, according to the New England Journal of Medicine.

Now, more than 75 percent of all clinical trials paid for by pharmaceutical companies are done in private test centers or doctors’ offices, according to CenterWatch.

Some test centers, FDA records show, have used poorly trained and unlicensed clinicians to give participants experimental drugs. The centers – there are about 15,000 in the U.S. – sometimes have incomplete or illegible records. In California and Texas, clinicians have used themselves, staff or family members as drug trial participants.

"Unfortunately, I don’t think it’s been recognized how important it is that people who actually conduct the trial be trained," Rhoads says. "We oftentimes see people with no qualifications whatsoever, but they’ll go to a one-day training course and they call themselves a certified study coordinator."

These people often run 90 percent of the study with little involvement by physicians, she says.

Breaking the rules

Participants in Miami clinical trials talk openly about how they violate SFBC rules intended to protect the integrity of research findings. SFBC prohibits people from taking part in two clinical trials at the same time.

Roberto Alvarez, 36, an Argentine in the U.S. on a visa. Efrain Sosa, 35, a Cuban native. Marlon Matos, a 27-year-old immigrant from Venezuela. All say they’ve participated in more than one clinical trial in Miami at the same time or gone from one test to another, ignoring required waiting periods.

They say they do it for the money, without telling the test centers, and that no one has ever caught them violating the rule.

Steve Simon, a research biostatistician at Children’s Mercy Hospital in Kansas City, Missouri, says that when people participate in more than one clinical trial at a time, it can be harmful to people and research.

There are better ways to do research, says Koski, the physician who headed the federal agency for human protection for two years. Koski says a single U.S. panel should oversee all experimental tests.

The National Bioethics Advisory Commission suggested that informed consent discussions between researchers and participants be audiotaped or videotaped to ensure they’re done right.

Mark Yessian, who oversaw investigative reports on IRBs over the past decade as Boston’s regional inspector general for the Department of Health and Human Services, says changes are needed.

"The drug industry is trying to bring products to market," says Yessian, who retired in October. "We don’t want to suffocate that, but we need to do it in a more balanced way to give subjects confidence that there are people looking out for their interests."

Koski says the mission won’t be easy. "It’s not really a ‘few bad apples’ problem," he says. "We need to create a system that grows better apples."

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