Keith Epstein

Overseers Operate in the Dark

Ethics Panels Only Manage Cursory Reviews of Research

Plain Dealer – December 18, 1996

SERIES: DRUG TRIALS – Do People Know the Truth About Experiments?

Last of four articles

Twice each month, the University of Rochester summoned them: Four scientists, three doctors, a nurse, a priest, and a mother whose daughter died of cancer.

They convened around a long table in a conference room on the third floor of the Department of Medicine.

The door was always closed.

While obligated to preserve the proprietary secrets of companies developing new drugs, the Research Subjects Review Board was there to fulfill a single, vital mission: Protecting human test subjects.

On the frontiers of medicine, such committees are the front line.

“Actually the only line, like the thin blue line, all there is out there for protecting people against the risks of research,” said Charles R. MacKay, an official at the National Institutes of Health.

Each time somebody wanted to conduct a new experiment, the Rochester committee was expected to pore over stacks of technical documents. It had to decide: Was the consent form clear? Did patients really volunteer? Did they understand the risks? Did they even realize it was research? Had alternative treatments been offered?

Not only that. The ethics committee was supposed to keep tabs on ongoing research, which meant still more volumes of paperwork.

Agendas were always full. Rochester’s medical school – known well beyond New York state for retinal cell transplants, treatments for Parkinson’s disease and potential AIDS vaccines – is a research center typical of large universities. It invests more than $90 million each year on medical research, most in grants from the National Institutes of Health.

During any given year, scientists at Rochester are conducting about 1,700 studies on people.

Rochester’s ethics committee seldom meets for more than two hours, said its chairman, Dr. John Baum, a retired rheumatologist.

Average time for reviewing each experiment: two minutes.

At such a clip, members were sometimes “unfamiliar with studies” up for approval, a Food and Drug Administration investigator reported last year. In April 1994, the committee adopted a list of new experiments “with no discussion on the individual studies themselves,” the investigator noted.

The committee, the FDA concluded six months ago, was functioning in a way that “may not adequately protect the rights and welfare of human subjects of research.”

The research reviewed by Baum’s committee included a National Institutes of Health study of how smoking and air pollution can affect the human body.

Test subjects, paid up to $150 for volunteering, received lidocaine during a lung exam. The anesthetic is usually used for people with bronchial ailments.

For Nicole Wan, a healthy 19-year-old University of Rochester sophomore from Queens who loved children, enjoyed Mozart and wanted to be a teacher, it proved fatal.

Within two days of an overdose of lidocaine in April, she died of a heart attack.

She had more than double the usual safe blood level of the anesthetic, dosages of which should have been limited by the ethics committee, New York’s Health Department determined in September.

Baum’s committee, it concluded, failed to “minimize the risks to volunteers.”

“Research involving human subjects at the University of Rochester was being carried out with insufficient safeguards to adequately minimize risks and protect individuals,” New York health Commissioner Barbara A. DeBuono said after a state investigation.

Baum’s committee continues its work.

He wants to do better, but with only one assistant, two secretaries, a $100,000 budget – and 10 “very busy” professionals who receive no pay for their services – he admits the committee has limitations.

“To do what we should do, go out every so often and say to the researcher, ‘Let me look at your records, your consent forms, are you informing the patients?’ – I’d like to do that, but we don’t have the time or the staffing,’ Baum said. “This is not work that is perceived as making a contribution to research.”

Baum’s plaint is heard often among medical researchers.

“These committees are overwhelmed by the work they have to do,” said Princeton University President Harold T. Shapiro, chairman of a new federal commission created to study how people are protected in medical research. The National Bioethics Advisory Commission was appointed last summer after disclosures of Cold War-era radiation experiments on unwitting Americans.

Mackay, now coordinating for NIH the first in-depth attempt to figure out whether ethics committees are doing their jobs, shares Shapiro’s concerns.

“If a committee is reviewing 1,000 clinical trials a year, one has to ask: How thorough are some of those reviews?”

The size of the workload also troubled the General Accounting Office, the investigative arm of Congress. It reported last March that “in some cases the sheer number of studies necessitates that IRBs spend only one or two minutes of review per study.”

The lack of aggressive oversight “may permit human subject protection violations to go undetected,” the GAO said.

Shapiro said that very issue was at the top of his agenda.

“My major concern is that [the ethics committees] do not always understand the weight of the responsibility on their shoulders,” he said.

When it all began in earnest – in the aftermath of the notorious experiment in Tuskegee, Ala., in which the federal Public Health Service withheld treatment and diagnosis from 412 black men with syphilis – “institutional review boards,” or IRBs, were widely regarded as an ingenious innovation.

It was “the best protection” for people used in research, a national commission was convinced in 1978.

IRBs were supposed to wrest the monopoly on decision-making from the scientific establishment, placing it in the hands of a group that could balance the best interests of medicine, human beings and the community.

There would be at least five members, including a nonscientist. One member was not to be affiliated with the research institution. They were supposed to represent the racial and cultural spectrum of American society.

Paul W. Goebel Jr., head of the FDA’s Human Subject Protection Team, regards the committees as nothing less than the “cornerstone of the whole process” for making sure what happened at Tuskegee never happens again.

Evidence shows the cornerstone is cracking, at least partly due to the burden of an explosive growth in medical research.

The number of research sites has more than tripled in the last six years, from 6,000 to 18,500. Nobody knows for sure how many ethics committees there are, though the number is estimated to be 4,000 to 6,000.

They operate at universities, hospitals, private research firms. The Army has them. NASA has them. The National Institutes of Health has 14 of them.

There are even corporate ethics committees-for-hire.

None must register or be accredited by the government.

And when the FDA does conduct an inspection – there have been fewer than 1,000 this decade – records are frequently in a shambles.

Forty percent of the ethics committees could not produce evidence they had met, held discussions and voted. Research had been approved by committees that had not even kept accurate lists of their members.

For 188 committees, the FDA discovered more serious shortcomings. Consent forms, injury reports and research proposals were missing from their files. There was no convincing proof that these committees had fulfilled their safety-monitoring mission.

Arthur Horowitz, a consultant who helps drug companies prepare for FDA audits, recognizes the problem. “All too frequently,” he said, “I’ve seen the wrong informed consent document in the hands of the IRB – or the wrong draft of the consent form in the hands of the patient. It’s not the same version submitted to the FDA.”

Pharmaceutical companies “assume the IRBs know what they’re doing. This is sadly not always the case.”

Not that ethics committees are at much risk of punishment. For failures the FDA identified at the University of Rochester, neither the ethics committee nor the institution faced penalties. They got a warning letter, the FDA’s standard practice, and, from the federal Office for Protection from Research Risks, a list of recommended improvements.

“We are one of the least confrontational compliance operations within FDA,” said Goebel, head of the FDA’s Human Subject Protection Team. “We spend most of our time writing letters. … But if we need it, we have the authority to disqualify them.”

It is, for the FDA, the ultimate sanction: Seriously deficient ethics committees can be prohibited from approving any more research.

The FDA has put ethics committees out of business only once or twice.

Of course, by the time the FDA figured out what was going on, the Ethical Board of Review Inc., had already stopped meeting.

Last year in Austin, Texas, FDA investigator Maira Brading found the privately operated committee, among a growing number of ethics panels for hire, had not met for 13 months.

But drug companies and researchers were still getting correspondence from the Ethical Board of Review Inc. showing it continued to oversee their research.

Two years earlier, the FDA had cited the Ethical Board of Review Inc. for allowing medical research that had not been reviewed by a physician.

Gail Findlay, the majority owner, agreed to shut down the business last April. In a “consent agreement” with the FDA, she acknowledged “falsely representing the Ethical Board of Review Inc. as a properly constituted and currently functioning IRB.”

By signing, she also agreed with the FDA’s criticism of the committee’s “failure to adequately protect the rights and welfare of human subjects involved in research.”

Not that any of them knew anything about the IRB that failed to protect their rights and welfare.

The FDA doesn’t tell.

Findlay did not respond to a message seeking comment.

Paul J. Godley, Ethical Board of Review Inc.’s chairman and minority owner, said he disagreed with the FDA’s finding.

Godley, a hospital executive in Temple, Texas, said the committee was a serious operation that had proper “concern for patients and subjects” while in business, and that the committee got in trouble after his partner, a doctor named Steven Findlay, died of cancer in 1992.

Even if a committee is diligent and halts a medical experiment on sound ethical grounds, the study can be resurrected elsewhere. If a drug company or researcher doesn’t like what one ethics committee says about its clinical trial, it can simply find another committee.

It is a practice known in the pharmaceutical industry as “IRB-shopping.”

When the ethics committee at Bowman Gray School of Medicine in Winston-Salem, N.C., stopped a human test of experimental urinary catheters a few years ago because it found significant risk, the sponsoring drug company withdrew its big research grant, said Robert J. Sheretz, the physician who planned to conduct the study.

“Wishing to press on,” the company said in its letter of cancellation, “we are forced to invite participation from another investigator.”

The medical school stuck to its guns, Sheretz said.

So did the drug company, which took its experiment elsewhere.

Ezekiel J. Emanuel, a researcher at the Dana-Farber Cancer Institute in Boston, considers the system “just too haphazard.” When he sought approval for the same experiment at 40 different sites, he got almost 40 different answers. Some committees approved; others rejected.

The system is so haphazard the government can’t even find every ethics committee to tell it what rules to follow.

At a recent FDA-sponsored conference for hundreds of people who run ethics committees at hospitals, universities and for private consultants, fewer than one-third of the audience knew about a change in the regulations – even though the government had sent more than 3,500 letters to university presidents and committee chairmen.

“We still don’t know if we’ve sent that to every IRB in the nation,” said Gary Ellis, the University Heights-reared director of the Office for the Protection of Research Risks.

He explained: The government doesn’t know where to find them.

Some argue the current system is badly in need of repair. Jay Katz, the Yale University professor who helped write reforms after Tuskegee, says protections for people in research should no longer be left solely to “low-visibility decision-making of IRBs with regulations that are porous and invite abuse.”

Ellis has poignant black-and-white photos of the Tuskegee victims he shows to scientists “as a reminder of the cost of missteps in our work. I hope our successors will never be able to show slides like these again.”

Tucked away in the federal budget each year, 65 years after the first blood samples were collected from farm hands in the cottonfields of Alabama, is an enduring testament to the consequences of unfettered medical research: $2.8 million in payments to 23 wives, 18 children and the 12 men who survived.

“These are real people, our fellow citizens,” Ellis said. “The government can never really repay that debt.”

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