When Does Assisting Fertility Clients Become Experimentation?

THE WASHINGTON POST

Stacie McBain was just 20 last fall when doctors told her the cancer treatment she needed would leave her infertile. But there was hope: an $11,000 experimental procedure in which researchers would remove pieces of her ovaries and freeze them for later use.

The novel approach was not guaranteed to work. But McBain jumped at the opportunity after the doctors running the experiment told her that animal studies had been successful.

"I love kids and I always wanted to have them," McBain said in a recent interview. "They said they'd tried it in sheep and it worked."

What she and her parents were not told, however, was that only one sheep has ever become pregnant by this method.

That kind of omission would be unusual in most medical research settings. Yet by fertility clinic standards, several experts agreed, McBain was relatively well-informed; she at least was told she was part of an experiment.

Fertility clinics receive no government funding, so the women who use them are not covered by federal laws that protect human subjects in research. And although doctors in all types of medicine have the prerogative to try novel techniques that may help their patients, reproductive technology is evolving so fast that the line between cutting-edge medicine and using women as guinea pigs is no longer clear, observers say.

"We have in many respects far better protections for hamsters than for human fertility patients," said R. Alta Charo, a professor of law at the University of Wisconsin and a member of the National Bioethics Advisory Commission, which is investigating abuses of human subjects in research.

"We can tell you how many swabs are used on animals in a year in this country, but we can't tell you how many people were involved in fertility research in this country or how many adverse events there were or anything," Charo said. "We require all of that for nonhuman animals, but not for people."

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Unlike the high-profile legal cases that have emerged recently in the reproductive technology arena--dramatic cases of embryos placed in the wrong women or of babies created from dead people's sperm or eggs--abuses of research subjects in the fertility field remain largely invisible. The scope of the problem remains unknown, since there is no system of oversight.

But more than 1,000 women undergo in vitro fertilization procedures every week in this country, and countless others receive other kinds of fertility treatments. And at least some of the recent exciting breakthroughs in reproductive medicine, critics say, have been the result of ethically questionable practices, in which women served as subjects in ill-defined research projects or their eggs or embryos were sidetracked to laboratories without the donors' knowledge, to be used in experiments and eventually tossed in the garbage.

Fertility doctors say they are just trying to give women the best odds of getting pregnant. Patients want nothing less than the latest technology, they say, even if it is still experimental. And, they argue, since the federal government has decided not to fund fertility research, it is up to the private sector to conduct that work.

"Many patients feel they have the right to the most innovative treatment around, especially since a lot of them are paying out of pocket," said Mark Sauer, chief of reproductive endocrinology at Columbia-Presbyterian Medical Center in New York.

Others, however, say the lack of regulations over fertility research makes it too easy to cross the line from assistance to experimentation--especially since these patients' urgent desire for a baby makes them susceptible to exploitation.

"It's an extremely vulnerable patient group," said Gary Ellis, director of the office for Protection From Research Risks at the National Institutes of Health. "Desperation reigns."

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McBain's ovarian preservation procedure is a case in point of how difficult it can be to tell the difference between modern reproductive medicine and unregulated human research. Like many of the country's larger fertility clinics, the Fairfax, Va.-based Genetics & IVF Institute, where the procedure was done, has voluntarily instituted many of the protective measures required of researchers at federally funded venues.

The clinic had McBain sign a consent form, for example, that says in part "we cannot guarantee that you will benefit" from the procedure. Yet accompanying materials refer to "extraordinary results" in sheep and call the experimental procedure "a revolutionary improvement" in fertility preservation for women with cancer.

Such mixed messages are at best confusing and at worst unethical, but are not uncommon in the fertility arena, says Lori Andrews, a professor of law and bioethics at Chicago-Kent College of Law. "Patients are being told they're getting the latest clinical evaluation and treatment, but they're rarely told that there have only been, say, three births before."

Michael S. Opsahl, a physician at Genetics & IVF, said human studies of frozen ovary transplants were justified because many sheep that have undergone the procedure have regained normal hormonal cycles, even if they have not become pregnant yet, suggesting that they could become pregnant. Equally important, he said, is the sense of empowerment a cancer patient can gain from trying something experimental. "It really does give them some hope," Opsahl said. "They are willing to take the chance because there are no alternatives."

McBain said she has no regrets about going ahead with the treatment. "It made me feel easier, knowing that I had some babies on ice," said the Macomb, Mich., woman, who calls the frozen tissue slices her parents' "grandcicles."

It's a classic bioethical dilemma, Andrews said: No one wants to undermine a cancer patient's hopes or place undue restrictions on new and reasonably promising techniques for infertile women. At the same time, people should not underestimate the harm that can come from raising false hopes.

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No one was paying attention two years ago when doctors at the Reproductive Biology Associates in Atlanta--a nationally renowned and respected fertility center--were figuring out how to make babies from frozen eggs.

The research required many eggs to practice on, said Joe B. Massey, the clinic's director, so RBA doctors turned to women who were donating eggs to infertile women and used some of the leftover eggs for research. "We call it sharing with the lab," he said.

RBA researchers used such eggs, in some cases without the donor's knowledge, to try various freezing and thawing techniques until they found a way that seemed not to damage the eggs, Massey said. Some eggs that looked good after thawing were mixed with sperm to see if a normal embryo would develop.

"When we started getting some embryos that lived, we approached a patient," Massey said. "We told her, 'We don't know if this will work. We won't charge you, but if we make an embryo with one of these thawed eggs and your husband's sperm, would you take it?' "

The woman, who like many fertility patients could barely afford her treatments, said yes. Last year, she became the first in this country to give birth to a baby from a frozen egg.

The experience with frozen eggs at RBA demonstrates the ease with which women's eggs may be diverted for research and the ease with which new fertility techniques can be tried on women. And although that story had a happy ending, some question whether she would have agreed to the procedure had she and the researchers been fully aware of the uncertainties associated with it.

Very little is known about whether freezing might damage the genetic material inside eggs and boost a woman's odds of giving birth to a deformed baby. A few months after the Atlanta woman gave birth to her apparently healthy baby, researchers in South Korea published a report suggesting that the freezing process often does damage the DNA inside human eggs--a finding that Massey said has made him rethink the wisdom of making babies from frozen eggs.

"It raises a real caution flag," he said.

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The main way that research subjects are protected in this country is through something called an institutional review board, or IRB. Any federally regulated research lab wanting to conduct human research needs approval from an IRB, consisting of independent scientists and ethicists. But fertility clinics don't have that restriction.

Massey said his clinic used to show its research protocols to the review board at a nearby hospital, but the hospital dropped out of that role. "They didn't want to look at this strange stuff," Massey said. "Why would they take the potential medical legal risk on embryo freezing, for crying out loud, when no one knew if it would work?"

Instead, Massey said, the clinic simply worked without any outside review for a while, and lately has been using an agency that reviews research proposals for $1,500 apiece--a system that some have criticized as being potentially problematic, since for-profit ethics review companies may be disinclined to be tough on their paying customers.

"There is a real concern that these companies are going to be under pressure to make sure they are not financially a burden to their clients," said the University of Wisconsin's Charo. "There's very little accountability."

At the Genetics & IVF Institute, McBain was assured that the frozen embryo procedure had passed muster with an IRB. But the five-person review board that gave that green light consisted of three of the clinic's own doctors and the director's administrative secretary and a lawyer who is a close friend of one of the clinic's doctors. Opsahl, the overseeing physician, said the experiments were also approved by an IRB at the nearby hospital where McBain's surgery was performed.

In addition, because of a federal regulatory quirk, many fertility center laboratories are not subject to the inspections and proficiency testing imposed upon other medical laboratories in the United States.

"A fertility doctor can literally set up a lab in his garage and hire his son or daughter who might have a bachelor's degree to run it, and it would be perfectly legal," said Brooks A. Keel, professor of obstetrics and gynecology and associate dean for research at the University of Kansas School of Medicine in Wichita. "A woman gets more regulatory oversight when she gets a tattoo than when she gets IVF."

Medical laboratory rules in the United States break down along gender lines, Keel said. Labs that conduct sperm counts or other kinds of semen analysis are subject to the Clinical Laboratory Improvement Amendments of 1988, an act of Congress that sets strict quality control standards for medical laboratories and requires lab directors to have a minimum level of training.

But labs that deal with women's eggs are exempt from those standards--or at least claim they are, by arguing that egg manipulations are not "diagnostic tests." Keel, president-elect of the American Assn. of Bioanalysts, which represents laboratory professionals, is spearheading an effort to persuade the Department of Health and Human Services to bring fertility labs under the 1988 law's federal regulatory umbrella.

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Fertility clinic doctors argue that much of the criticism of human fertility research is misplaced. In fact, they say, there is a powerful camaraderie among fertility patients, and many ask to participate in reproductive research.

"These patients understand that no one in society supports their problem, so many seek an opportunity to participate in a protocol," said Richard T. Scott Jr. of the Institute for Reproductive Science at St. Barnabas Hospital in Livingston, N.J. "Personally, I think there is a lot of good work being done."

Moreover, some doctors said, it is paternalistic to presume that fertility patients--many of whom are well educated and informed--need to be protected from their doctors or themselves. "It can be a slippery slope kind of question, where at some point people are going too far, but mostly these women know what they are doing," said Richard Paulson, director of reproductive endocrinology and infertility at USC.

Things may be getting better. Many clinics now use IRBs, and consent forms are becoming more complete and routine--especially at the larger of the nation's 300 or so fertility clinics.

Sauer, of Columbia-Presbyterian, said he thinks a split is occurring in the fertility field, with larger centers adhering more closely to standards that would apply in the federal sector, while some smaller clinics are cutting corners to break into the field.

"There is an increasing amount of cavalier behavior out there, even though the stuff we've done is with strict protocols and [IRB] approval," Sauer said. "We don't really have a public policy for fertility patients in this country. I wish we did."

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