Untried but True

Clinical trials at research institutions adhere to the highest standards of patient care, which means that human subjects today are far better protected than they have ever been.

by Jon Nalick

 

Patients facing serious illness and little prospect of relief can often find hope in experimental treatments-ones that are, by definition, promising but untried.


Individuals nationwide volunteer for those trials, knowing that even if treatment fails, the effort will help physicians better understand illness and use that knowledge to help others. Patients also do so because they trust that medical researchers will not submit them to undue risk, or place the goals of research above their well-being.


To ensure that this trust is never broken, the Keck School of Medicine of USC and other research institutions nationwide that perform testing on human subjects maintain powerful internal oversight committees known as Institutional Review Boards (IRBs). These federally mandated boards wield veto power over every clinical trial and can call for any changes they deem necessary to ensure patient safety.


Darcy Spicer, M.D., associate professor of medicine, associate dean for clinical studies and chair of the IRB on the USC Health Sciences Campus, says that the oversight function of the board is crucial.

"We review the proposed research activities and protections for the research participants to ensure that the research protocol is sound and that all of the pieces are in place to protect the participants," Spicer says. "This review takes place both before and during the conduct of the research activities."


Deirdre Anglin, M.D., M.P.H., associate professor of clinical emergency medicine and vice chair of the IRB, says that the IRB reviews about 600 new protocols each year, in addition to monitoring the progress of roughly 2,500 previously approved studies.


In addition, the 33-member board, made up of a diverse group of researchers, physicians, administrators and community representatives unaffiliated with the university, nurtures a campus-wide culture of concern for the protection of patients, she says.


Far from being a rubberstamp process, the IRB rarely approves studies without requiring modifications to ensure that they are consistent with all requirements necessary to protect patients, Anglin adds. The most common concerns raised by the board stem from issues regarding informed consent.

"Sometime the consent form is not in lay language, so the average person may not understand it," she says. "We really want clearly spelled out why the patient was asked to join the study, what the procedures involved will be, what the risks and benefits are and what [happens] if the patient wants to leave the study or has unanswered questions."

Melinda Hurst, a retired teacher and Los Angeles resident, joined the IRB in 1973 as a community representative and has served for all but six years since.


"As a community representative, I try to bring a different voice, a different perspective. I try to be in the skin of the patient to do everything I can to support them," she says. "And even though it can be hard to be assertive in a room full of doctors, I'm not timid at all about questioning a study."


Despite the crucial work performed by the IRB, Hurst laments that most people have no idea of its importance-or even of its existence.

"I don't think the public knows very much about us, and I think this is an area that needs improvement. We need better outreach and we need more members of the community who are willing to serve on review boards," she says.

Although most medical institutions feel they have an exemplary historical record in protecting patients, truly shocking historical lapses have, at times, shaken the faith Americans have in the medical research community.

Infamous experiments from the past that have been exposed include: A syphilis study performed by the U.S. Public Health Service from 1932 to 1972 that misled African-American subjects about their disease and deliberately withheld treatment when it became available; MIT-led studies in the 1940s and 1950s in which mentally retarded children were fed radioactive food supplements in the absence of proper informed consent from their parents; A 1963 study by the U.S. Public Health Service and the American Cancer Society in which chronically ill non-cancer patients were injected with cancer cells without their consent.

"These researchers weren't setting out to do something nefarious or trying to be malevolent. They were just trying to do their research, and if you were in the way, too bad," Hurst says.


But, she adds, these scandals had a positive effect, too-they mobilized the government and the medical community to codify the rights of research subjects and the ethical responsibilities of researchers.


"Things are different today. We're more focused on the protection of the subject. The federal government and the various institutions sponsor conferences that our members attend. And we require an in-house education course for all investigators and IRB members," she says.


In the early 1970s, the Food and Drug Administration issued regulations that bolstered consumer protection, including the first rules to require that investigators obtain fully informed consent from potential subjects.


In 1973, the U.S. Congress established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Made up of 11 members, including experts in law, ethics, philosophy and theology, the commission issued a highly influential
document known as the Belmont Report in 1979.

The Belmont Report spelled out basic ethical principles for the conduct of clinical trials, specifically requiring that: individuals are regarded as autonomous agents, and their opinions and choices respected. Some people, such as children or individuals with mental incapacities, are not fully capable of self-determination, and they should receive special protection; patients are protected from harm and every effort is made to secure their well-being; and the risks of research as well as the benefits derived from it are distributed fairly among members of society.


The Belmont Report also spelled out the requirements pertaining to adequate informed consent and stated that no clinical trial could be conducted whose risks exceeded its potential benefits.
Lastly, it insisted on fairness in the selection of research subjects, prohibiting favoritism or discrimination.

Anglin says failure to adhere rigorously to the standards promulgated in the Belmont Report hurts everyone. The patients suffer, people lose faith in researchers and become less inclined to participate in studies, and society loses out on medical advances that could help future patients.


"That's really a problem because you want trials to succeed so that we can continue to improve patient care. And the only way to do that is to do good studies that are well-designed scientifically and take care of the patient," she says.


When patients feel appreciated and well cared for, they are frequently willing to volunteer-often out of sheer altruism, she says.


"A lot of times in clinical trials, especially in HIV and cancer trials, patients participate in studies that they know will probably not prolong their lives, but may eventually help someone else," Anglin says.


Fortunately, most research institutions have adhered to the highest standards of patient care, which means "human subjects today are far better protected than they have ever been-and rightly so," she adds.


Even so, the rare failures in the protection of human subjects are often portrayed in the media as the norm, instead of the exception.


For example, in 2001, the death of a healthy young Maryland woman involved in an asthma study at Johns Hopkins University, as well as serious lapses at other research institutions received wide coverage in the media, which seized on the event to suggest that researchers nationally have questionable ethics. Time magazine, for example, ran a cover depicting a woman in a cage with the label "Human Guinea Pigs"-hinting that medical researchers conducting clinical trials view their human subjects as little more than lab animals.

Keck School Dean Stephen J. Ryan, M.D., says that the real story the media missed is how rare such aberrations are, but he also agrees that the exceptions "underscore to the rest of us how serious an issue this is.

"We must remain vigilant in monitoring our own research activities and make sure that we honor our ethical obligations to the people who participate in our research."


Ryan emphasizes that the only way to truly keep human research volunteers safe is to make sure that each and every clinical researcher understands the importance of such protections and plays an active role in ensuring that they are strictly followed.


Spicer agrees: "The commitment of the individual investigators to protect human subjects is among the most important elements of making the entire process work. We are fortunate that we have a group of investigators that has demonstrated that personal commitment."


He cites several recent changes enacted at USC to enhance the efficiency and operation of its IRB.
"The recruitment of additional staff and plans for an additional vice chair are giving us more opportunities to serve both the investigators and those who participate in our trials. We also plan to create a second IRB to help in the review of research protocols," he says.


Another added layer of protection for patients, created by the National Center for Research Resources in 2001, is the Research Subject Advocate Program (RSA). The program's sole purpose is to ensure that research protocols plan for and enact to the letter all procedures designed to enhance patient safety.


At USC, Robert Larsen, M.D., associate professor of infectious diseases and vice chair of the IRB, heads a three-person RSA team. He says, "We make sure the protocols are followed as written and we actively monitor the safety of every participant in every study."


"There has always been a trusting relationship between the National Institutes of Health and researchers, with the understanding that if you do research, you do it safely. By and large that has always been done, but there have been instances where it was not done. So the NIH said, 'We need to have someone looking over shoulders to guarantee that everyone is held to the highest standard,'" he says.


"As a result, clinical trials are now receiving more oversight than ever before, which just reinforces the understanding everyone already had: Your patients are volunteers, and you have to treat your volunteers right," Larsen says.


He adds that patients are also encouraged to look out for themselves by paying attention to disclosures about what procedures will be performed, what kinds of risks are inherent in the study and whom they should call if they have any concerns or questions.


Larsen says that volunteers are the unsung heroes in the advancement of medicine to whom every person owes a personal debt.


"We can learn a lot from studies of cells, or animals like mice, but we're not trying to treat mice or cells. We're trying to treat people, so, ultimately, we have to test on people.


"Advances in medicine are difficult to make, and they require a lot of commitment from a lot of people. It does not always come with a personal benefit, but it's necessary to move forward and find better treatments for disease," Larsen says.


He adds: "Fortunately, we have people who are willing to say, 'I will be part of the process.'"