Federal Rules for Research on People Often Fail
By Edward T. Pound, USA TODAY 2/26/01
TAMPA - In 1994, eye surgeon James Rowsey invented a medical device that he thought would revolutionize corneal transplant surgery and make millions of dollars. It did neither. Instead, it cost him a high-paying university job and led to federal findings that he performed unapproved research on more than 60 people, including children. The device and the case against Rowsey exposed severe flaws in the nation's system for protecting humans in medical experiments.
Rowsey began using his new corneal transplant technique on cats. Then, without telling the university, he started doing the procedure on humans. "He was using all of us as guinea pigs," says Joanne Cassidy, 14, a straight-A high school student from St. Petersburg, Fla. Rowsey used his new technique when he operated on Joanne's left eye in 1996. The transplant didn't take. Her parents say he did not tell them he was using an experimental technique. They recently sued him in Florida and accused him of "wanton and willful disregard of human rights and safety."
Her father, Hugh Cassidy, a cable television installer, says she will undergo another transplant this year. He expresses frustration: "Who in the hell is he to be experimenting on my kid?"
No one died at Rowsey's hands, and he denies experimenting on anyone. But his story is about more than one man's fall from grace. Stripped to its essentials, it shows how federal rules for human research often fail to protect a vulnerable public.
Despite issuing critical findings, regulators did not play a role in stopping him. His university, which could have profited from his invention, did not monitor his work. It was his staff members, worried that he might harm patients, who finally blew the whistle.
Across the nation, clinical studies on human subjects - designed to test the safety and efficacy of drugs and medical devices - are multiplying rapidly. Studies are underway in universities, other research centers and doctors' offices. Great medical advances have been made, but there also has been a cost: increasing scientific misconduct and patient deaths. Shocked into action, officials in the Department of Health and Human Services vow to improve protections. Patient advocates say changes are overdue.
Research is big business. The drug industry spends about $9 billion a year, and the federal government, primarily through the National Institutes of Health, pours in $5 billion more. As doctors and drug companies rush to find the next big discovery, patient advocates say they worry that the most important protection - fully informing human volunteers of health risks - is being eroded in a mad dash for money and fame.
"I call it Nasdaq medicine," says Alan Milstein, a plaintiffs' lawyer in New Jersey. "It is not scientists racing for a cure. It is scientists racing against each other for the money that a cure would bring."
Milstein represented the family of Jesse Gelsinger, 18, who died in a gene therapy trial at the University of Pennsylvania in 1999. His death pointed to flaws in the protections system and prompted a national debate on clinical studies. Jesse's father, Paul Gelsinger, who recently settled a lawsuit with the university for an undisclosed amount, says he worries that many volunteers "are not being protected."
Patient advocates say the government has a long way to go to improve protections. So much research is going on that officials don't even know how many studies are underway in the USA and overseas, although the number reaches into the tens of thousands. Also, there are no reliable statistics on how many people volunteer for studies. Though regulators acknowledge that people die in research, they don't know how many.
"We know more about cats, pigs and frogs in research than we do about people," says Arthur Caplan, a bioethicist at the University of Pennsylvania. "How many people are involved in experiments? How many old people are involved? How many children? Try and find out how many people died in human experiments last year in the United States.
"There is no place to get that answer. My hunch is dozens of people die from adverse events," he says.The Problems Are Many:
- Local boards, set up at research sites under federal regulations adopted in the 1970s, review and approve experiments. These Institutional Review Boards, numbering about 6,000 in the USA, serve as the foundation for patient protection. But the federal health department's inspector general office says many are "overwhelmed" with work and have too little expertise. The boards generally consist of physicians, scientists and community members.
- Many researchers have financial ties with private companies that pay for clinical trials. In the case of teenager Jesse Gelsinger, the principal researcher had a financial stake in a company that funded the gene therapy research and stood to profit from it.
- Federal regulators are undermanned. The Office for Human Research Protections, a principal oversight agency in the health department, has only six people on its compliance staff yet has about 150 open investigations. One inquiry can take a year or more to complete. Officials promise more staff.
Some regulators see no crisis. "We do not have massive problems in clinical trials. We do have isolated problems, clearly," says David Lepay, the senior adviser for clinical science at the Food and Drug Administration.
But prodded by the health department's inspector general, regulators are doing more inspections of review boards and research centers. In their boldest move, they shut down briefly all 2,000 medical experiments at Duke University in North Carolina in May 1999 because of safety issues.
Even so, the government's chief regulator, Greg Koski, says he hopes that voluntary standards for Institutional Review Boards will help cure the problem. The standards are to be issued this spring.
Koski, director of the Office for Human Research Protections, says boards and researchers must be more accountable. He won't get an argument from the University of South Florida, the institution that employed Rowsey. Largely as a result of the Rowsey case, the school says it has implemented reforms, which include keeping a closer watch on its 1,400 clinical trials.
When Rowsey served as the $380,000-a-year chairman of its Department of Ophthalmology, the university had only one Institutional Review Board. That board didn't supervise his work, despite evidence that he was doing research on humans. In a report, regulators found its lax oversight "objectionable." The university now has two more review panels.
University officials say the lack of oversight wasn't influenced by money. Both Rowsey and the university stood to profit if his transplant device, which he called the Tampa Trephine, had been marketed successfully. He projected $112 million in sales over five years.
Former patients interviewed by USA TODAY say Rowsey never told them of the risks they might face from the technique. Two sued him in a state court in Tampa. They allege that he experimented on them without their consent.
Joanne Cassidy was 9 years old when Rowsey operated on her in August 1996 at Tampa General Hospital. Her lawsuit says he did not reveal he had departed from "the standard method for performing a corneal transplant." It says he attached an "adult-size" and "misshapen" cornea to her left eye.
Her vision in that eye was blurred before her operation, and she says her eyesight never improved, despite repeated promises from Rowsey that it would.
Sitting in the kitchen of her pink-shingled house in St. Petersburg, Joanne says she has 20-20 vision in her right eye. But because of poor sight in her left eye, she says, she broke her ankle in a basketball game. She expresses no bitterness, only disappointment: "Maybe my eyesight would be better if he had done the normal procedure."
Harry Rogers, 85, of Homosassa, Fla., who filed the other lawsuit, says he had lost the sight in his left eye before he went to see Rowsey. In June 1995, Rowsey implanted a new cornea in his right eye. Rogers says his vision in that eye worsened. Now, he says, he is legally blind and can't stand sunlight.
"Everything's a blur," says Rogers, once a gifted athlete who ran against the fabled Jesse Owens. "Rowsey did not tell me my eyesight could get worse. He just decided that this new procedure was safe without telling me of the risks. I don't know whether it was or wasn't. All I know is I can't see."
Rowsey won't comment on the lawsuits. He has disputed such assertions and maintained that he told patients of the possibility of transplant rejection, bleeding, infection and glaucoma - the same risks in conventional surgery.
In written answers to USA TODAY's questions, he says he did not tell patients of his financial interest in the Tampa Trephine because any chance he might profit from its sale was purely "speculative."
He also denies allegations in a government report last year that he experimented on patients. Regulators wrote that in operating on patients, he had collected data on "the safety and effectiveness of the Tampa Trephine," had "introduced unknown risks and uncertain efficacy" and had "unequivocally" engaged improperly in human research. Rowsey, describing research as a "systematic investigation" designed to broaden general knowledge of a medical issue, says his technique "was never used on my patients as part of any systematic investigation."
He was forced to resign as chairman of the ophthalmology department in October 1997. He left the university two years later to become a surgeon at St. Luke's Cataract & Laser Institute in Tarpon Springs, Fla.Research or clinical care?
Rowsey, now 57, has been a leading eye surgeon for three decades. He has helped design important modifications on surgical tools used in corneal transplants, an operation that has a 90% per cent success rate. His development of the Tampa Trephine in 1994 seemed to cap a prestigious career.
That October, the university gave him the go-ahead to test his technique on cats. But while those studies were underway, he began using the technique on humans.
Traditional trephines, which are blades, cut round sections of tissue from the donor eye of a cadaver. The donated cornea is sewed into the patient's eye. Though successful in restoring vision to about 40,000 people annually, the healing time often takes a year or more. Rowsey was certain his trephine would reduce healing time and complications from surgery. It cut a piece of tissue from the donated cadaver eye with petal-like tabs that were attached to the patient's eye. This allowed for fewer sutures. The trephine never touched the patient.
Rowsey's questionable conduct might never have surfaced had it not been for his born-again religious beliefs. Some staff doctors, feeling that he was forcing them to pray at faculty meetings, began looking into his new technique.
What developed was an internal debate over whether Rowsey was doing unapproved research on humans or just caring for patients. That debate underscores how the line between research and clinical practice can be blurred.
In May 1995, two months after first using the technique on a human, Rowsey asked the university's Institutional Review Board to approve a clinical trial. The 18-member panel, mostly university affiliated personnel, gave its approval. The informed consent document for volunteers described the Tampa Trephine as an "investigational device" and said the trial would evaluate its safety and effectiveness.
Rowsey never conducted the trial, but he continued operating on humans. When questions arose, he convinced the review board that he was providing "standard therapy" not requiring its oversight, according to minutes of a meeting on Oct. 2, 1995. The board rejected the views of a university lawyer, Camille McWhirter, who quoted the advice a regulator had given her staff: "When in doubt, give the project full review."
However, doctors in Rowsey's department moved to stop him. The most persistent were Robert Urban and Curtis Margo, who no longer work at the university. Urban later filed a federal lawsuit for religious discrimination against Rowsey. Documents released by Urban's attorney, John MacKay, helped shed light on his and Margo's actions.Rowsey Confronted
In sworn testimony, Margo, who as director of eye pathology reviewed Rowsey's cat studies, testified that he uncovered design flaws in the Tampa Trephine. He said he confronted Rowsey to no avail: "I told him that I thought it was inappropriate to be using this device when you don't know how safe it's going to be." Margo went to the Tampa health care center where Rowsey performed operations; the center directed Rowsey to stop using his technique. But Rowsey continued using it at Tampa General Hospital.
That, too, would end, this time because of Urban.
After leaving Rowsey's staff in March 1997, Urban went to work at Tampa General, a university teaching hospital. He lodged complaints about Rowsey with hospital officials and with the American Academy of Ophthalmology, an organization of eye doctors. Urban got results. In the summer of 1998, Tampa General told Rowsey to stop using the trephine. The academy later concluded he had violated its ethics rules for informed consent and conflict-of-interest.
To this day, Rowsey says he did his best for patients and never harmed them. Meanwhile, regulators closed their inquiry in January after the university notified patients they were unwitting participants in experimental surgery.
Nevertheless, bitterness lingers. In his testimony, Margo described Rowsey as a great manipulator, "a Jimmy Swaggart" type: "You have a person telling you how religious he is and how pure he is and how he respects humans and then (he) practices experiments on humans without even giving them informed consent."