By David Evans, Michael Smith and Liz Willen
January 8, 2006
Oversight laxon clinical drugtrials, critics say
Big Pharma, as the world's largest drug makers are called, spends billions of dollars every year to test experimental drugs on humans.
In the U.S., 37 million people have been human guinea pigs.
Helped by human testing, drug makers have developed antibiotics capable of curing life-threatening infections as well as revolutionary treatments for diseases such as cancer and AIDS. 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.
These medical success stories mask a clinical drug trial industry that is poorly regulated, riddled with conflicts of interest -- and sometimes deadly.
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.
Pharmaceutical companies distance themselves from the experiments on humans by outsourcing most of their trial to private test centers across the U.S. and around the world, said Daniel Federman, a doctor who is a senior dean of Harvard Medical School in Boston.
By law, drug companies must conduct tests to determine whether potential drugs produce dangerous side effects, such as organ damage, impaired vision or difficulty breathing -- called Phase I tests.
In 1991, 80 percent of industry-sponsored drug trials were conducted by medical faculty at universities, with protection for participants provided by the schools' 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, a Boston compiler of clinical trial data.
Nobody has ever tracked how many people are injured or killed each year during clinical trials, said Dr. Federman, who headed a national committee on clinical trial safety in 2003.
"An intelligent person would assume we know this," he said. "We don't know the number of persons harmed in clinical trials each year and are missing a registry of all subjects that participate in trials."
The chief executive officers of drug companies should be held accountable for any lack of ethics in the tests, Dr. Federman said.
"The CEOs of the companies have to be publicly, explicitly and financially responsible for the ethical approach," said Dr. Federman, 77, who still sees patients. "It's not possible to insist on ethical standards unless the company providing the money does so."
CEOs of 15 pharmaceutical companies that outsource drug testing -- among them, Pfizer Inc., the world's largest drug maker; Merck & Co.; and Johnson & Johnson -- declined comment.
Arnold Hantman, then the chief executive of SFBC Inc. -- the largest of the testing-center companies -- said last year his center meets all regulations.
"We take very seriously our responsibilities to regulatory authorities, trial participants, clients, employees and shareholders," said Mr. Hantman, who retired last week. "We are committed to conducting research that fully complies with industry and regulatory standards."
Desperate for cash
Most of the people who recently lined up at the SFBC experimental drug-testing center in Miami to voluntarily participate in clinical trials were poor immigrants from Latin America, drawn to the five-story, converted Holiday Inn.
Oscar Cabanerio, 41, had been waiting at the center run by SFBC International Inc. since 7:30 a.m. The illegal alien said he is desperate for cash to send his wife and four children in Venezuela.
More than 70 people crowded into reception rooms furnished with rows of attached blue plastic seats. Mr. Cabanerio was one of many regulars who gathered at SFBC International Inc.'s test center, which, with 675 beds, is the largest for-profit drug-testing center in North America.
Mr. Cabanerio, who has a mechanical drafting degree from a technical school, said he left Venezuela because he lost his job as a union administrator. For him, the visit to SFBC was a last resort.
"I'm in a bind," he said in Spanish. "I need the money."
Ken Goodman, director of the Bioethics Program at the University of Miami, said pharmaceutical companies are shirking their responsibility to safely develop medicines by using poor, desperate people to test experimental drugs.
"The setting is jarring," said Mr. Goodman, who has a doctorate in philosophy, after spending 90 minutes in the waiting room 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."
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 are paid by Big Pharma -- just like the testing centers they are supposed to be regulating.
The oldest and largest review company is Western IRB, founded in 1977 by Dr. Angela Bowen, an endocrinologist. WIRB, an Olympia, Wash., a for-profit company, is responsible for protecting people in 17,000 clinical trials in the United States.
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. Dr. Bowen said she didn't see human safety issues in those trials. WIRB aims to visit test sites it monitors once every three years, she said.
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.
Review boards can have blatant conflicts of interest. The one policing the Fabre clinic was founded by Dr. Louis Fabre, the same doctor who ran the clinic.
Southern IRB of Miami has overseen some testing at SFBC and was owned by Alison Shamblen, wife of E. Cooper Shamblen, SFBC's vice president of clinical operations. Both Shamblens declined to comment, although Rosa Fraga, Southern IRB's chairwoman, said Mrs. Shamblen decided in October to shut Southern after 16 years.
Arthur Caplan, director of the Center for Bioethics at the University of Pennsylvania, said handing oversight of human drug experiments to private, for-profit companies is a mistake.
"This whole world gives me hives, this privatized review process," Mr. Caplan said. "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 trade and lobbying group, said 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," said PhRMA, as the group is known. "The U.S. regulatory system is the world's gold standard, and the Food and Drug Administration has the best product safety record."
No 'gold standard'
Dr. Joanne Rhoads, the physician who directs the FDA's Division of Scientific Investigations, said that view isn't realistic.
"What the FDA regulations require is not any gold standard for trials," she said. The agency doesn't have enough staff to aggressively monitor trials, she said, adding that FDA regulations are a bare minimum and much more oversight is needed.
"You cannot rely on the inspection process to get quality into the system," she said. "I know many people find this not OK, but that's just the truth."
Dr. Michael Hensley, a pediatrician who was an FDA investigator from 1977 to 1982, said the agency has become less active in clinical trial oversight in recent years.
"The FDA's backbone has been Jell-O," said Dr. Hensley, who is now president of Chapel Hill, N.C., company Hensley & Pilc Inc., which advises pharmaceutical companies on FDA compliance. "The folks at the FDA stopped enforcing the rules several years ago."
Some test centers, FDA records show, have used poorly trained and unlicensed clinicians to give participants experimental drugs. The centers -- 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," Dr. Rhoads said. "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."
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; and Marlon Matos, 27, an immigrant from Venezuela, say they have 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.
"We maintain many safeguards to help us ensure that the participants of our clinical trials are not participating simultaneously in multiple clinical trials," Mr. Hantman said. "Unfortunately, there is no clearinghouse that we're aware of that would allow us to find if they were participating in another trial at the same time."
An independent counsel recommended last month that the company create a centralized database of clinical study participants.
In April, Mr. Alvarez signed up for a 36-day clinical trial at Miami testing company Elite Research Institute for a new sustained-release form of donepezil, an Alzheimer's drug that Tokyo company Eisai Co. sells in the U.S. with Pfizer.
At the time, Mr. Alvarez was in the middle of a 212-day test sponsored by Wyeth at SFBC for an experimental muscular dystrophy drug, according to consent forms he signed.
'Asking for trouble'
"I hop around to get around that," said Mr. Alvarez, a part-time construction worker. "They ask, but I just don't tell them. Everybody does that."
Steve Simon, a research biostatistician at Children's Mercy Hospital in Kansas City, Mo., said that when people participate in more than one clinical trial at a time, it can be harmful to people and research.
"When neither researcher knows about the potential interactions with the other trial, that raises concerns about scientific validity," said Mr. Simon, who has a doctorate in statistical research. "You don't know how these things might interact. It's asking for trouble."
The top two officials at SFBC International Inc. quit last week after U.S. Senate investigators sought to interview them about their business practices.
Lisa Krinsky resigned as president and chairman, and Mr. Hantman retired as chief executive, the company said.
Ms. Krinsky, whom the company refers to as a medical doctor, is a graduate of Spartan Medical School on the Caribbean island of St. Lucia and is not a licensed doctor. Mr. Hantman, referred to in company Securities and Exchange Commission filings as a CPA, is not licensed as a certified public accountant.
Mr. Hantman and Ms. Krinsky were among SFBC's founders.
Pharmaceutical companies sponsored 26,839 clinical trials from 2001 to 2004, six times more than from 1981 to 1985.
The search for the next money-spinning drug is fueling the surge in human testing. Pharmaceutical companies that make 28 top-selling drugs will lose a total of $50 billion in revenue as their patents expire from 2003 to 2008, according to Norwalk, Conn., research firm BCC Inc.
As drug companies try to get new drugs to market, time is literally money. They lose as much as $5 million a day waiting to get approval of new medications, according to CenterWatch. Eighty percent of all experimental drugs tested in humans are never approved by the FDA.
Big Pharma has an insatiable demand for people to be in clinical trials, said Dr. Marcia Angell, who was editor in chief of the New England Journal of Medicine from 1999 to 2000.
"Human subjects are in very short supply, so it's not surprising that under the growing pressure to find them, there are sometimes terrible ethical violations," said Dr. Angell, a Harvard Medical School senior lecturer. "Drug companies may claim innocence, but they need to take responsibility."
In 1978, the National Commission for the Protection of Human Research Subjects, an advisory committee appointed by President Nixon four years earlier, recommended that clinical-trial participants be fully informed of risks and sign a consent form. Informed consent wasn't required by the FDA until 1981.
Interviews with people in clinical trials and relatives of participants who died in medical experiments across the U.S. suggest that researchers often don't fully explain risks and potential side effects.
Dr. Bowen, whose Western IRB has overseen trials at SFBC sites, said Phase I centers often don't conduct the informed-consent process properly.
"I'd say it's fairly widespread," she said. "It's a genuine social problem that needs to be dealt with."
Mr. Alvarez said he skimmed over the 12-page consent form for a test SFBC managed for KW-6002, an experimental Parkinson's disease drug made by Tokyo firm Kyowa Hakko Kogyo Co. before signing the form.
"The thing I pay more attention to when filling this thing out is this," said Mr. Alvarez, flipping through the form, written in Spanish, to a page that describes payment terms. "How much it pays and how long it takes. I don't read them too carefully."
Page 8 of the consent form explains that the 57-day test pays $4,300, spread out in payments tied to completion of three eight-night "confinements" in an SFBC building.
The consent form said KW-6002 can produce side effects that include heart palpitations, sleep disorders and breathing difficulties. An SFBC employee asked if Mr. Alvarez had read the consent form and understood what the test entailed when he signed up, Mr. Alvarez said. He told the clinician he had read the form, and the clinician didn't say anything more about risks.
SFBC Executive Medical Director Kenneth Lasseter said the center always explains risks to participants. "We have a whole team of people," he said. "They go over the risks and discomforts and explain them to the subject.
"Everyone who is screened has a one-on-one interview with one of the screening team that goes over the informed consent," he said. "If they are denying that, that's simply a fabrication. They are not being truthful."
Dr. Laura Dunn, a professor of psychiatry at the University of California at San Diego, wrote an article on informed consent that appeared in 2004 in the Journal of the American Medical Association.
"Informed-consent documents routinely fail to explain risks to potential participants," she said. "Decades of research show that poor understanding of informed-consent documents is widespread."
It is inevitable that tests that often make people sick rely on the poor, said Dr. Greg Koski, who from 2000 to 2002 was head of the federal Office for Human Research Protection. A division of the Department of Health and Human Services, the office oversees all federally funded clinical trials, but doesn't review pharmaceutical company-sponsored tests in private centers.
"I have little doubt that there is a disproportionate burden of risk that falls on the disadvantaged members of our society," said Dr. Koski, who is a radiologist in Boston.
SFBC Executive Vice President Greg Holmes said money is the main reason people sign up for Phase I tests.
"Look at the benefits," he said. "There is little benefit other than getting paid. There's no secret there."