n the summer of 2002, after hearing news that researchers found a link between hormone replacement therapy—a common treatment to relieve symptoms of menopause—and an increased risk of heart disease and breast cancer, women across the globe anxiously contacted their physicians seeking advice on alternate treatments. While hormone therapy is still prescribed under some conditions, the discovery may have saved countless lives. Not all medical research findings are as dramatic, but reports of new therapies and treatments surface almost daily, altering both our lifestyles and the practice of medicine and changing our old assumptions about health and health care. Consider the following findings, all announced within recent months: moderate consumption of alcohol each day significantly reduces the risk of heart disease; people who are obese at age 40 are likely to die at least three years sooner than people of normal weight, even if they lose weight later in life; the common children’s stimulant drug Ritalin may reduce the risk of drug and alcohol abuse in adulthood; regularly riding a mountain bike reduces fertility rates in men. Many other findings never reach the mainstream media.

early all of these discoveries are the result of clinical research trials—carefully controlled studies of experimental drug therapies, diet, or lifestyle patterns using fully consenting human subjects. Some study participants are healthy individuals hoping to make a contribution to medical science; others are ill patients banking on a new treatment to relieve suffering or possibly cure their ailment.

At the University of Miami School of Medicine, clinical research has helped elevate many of the school’s departments and programs into the nation’s top tier. Ophthalmology, neurology, and neurological surgery enjoy national reputations. The school also is well-known for its work in otolaryngology, organ and cell transplantation, and HIV studies, among many other departments. Led by Mary Jo O’Sullivan, researchers in the Department of Obstetrics and Gynecology were among a few nationwide that participated in the study of hormone replacement therapy. In the most recent national rankings, the University of Miami School of Medicine ranked 42nd in the amount of research grant money received from the National Institutes of Health, the federal agency that funds most medical research. Last year the school received 214 grants totaling more than $75 million. The majority of those funds were used for clinical research trials.

“It is absolutely critical for a medical school to have a top-notch clinical research program,” says Camillo Ricordi, codirector of the School of Medicine’s Executive Office of Research Leadership and a world-renowned specialist in the field of cellular transplantation. “If you want to call yourself an academic institution, you must be continually working to define the standards, to find new cures, to develop treatments that go beyond our current ones.”

There were 1,750 ongoing studies involving human subjects in 2002 at the University of Miami—an increase of 43 percent since 1995. Such studies are carefully assessed and monitored by a multitiered panel of experts and community representatives known as the Institutional Review Board, or IRB. Before any research can begin, the IRB must approve a “protocol,” a kind of blueprint of a study. Protocols include a research hypothesis, a study design, a plan for recruiting patients to participate in the trials, and a patient consent form that outlines the risks to the participant. The protocol also must explain how those patients may benefit medically. Unlike some schools, the University of Miami does not permit clinical trials using healthy subjects.

“We’re not just producing knowledge for knowledge’s sake,” says Norman H. Altman, vice provost for research at the School of Medicine. “The most important thing about clinical research is that it brings cutting-edge technology to our patients. What we always ask is: ‘What’s in it for the patient? How will it help him in a tangible way?’” The IRB also receives regular updates from the researchers, and it may halt a study at any time if board members believe patients are at risk or procedures are not being followed.

The School of Medicine has always been blessed by geography, serving a large, ethnically and socioeconomically diverse community. Although recruitment of study participants is always a challenge, the sheer size of the UM/Jackson Memorial Medical Center’s patient population greatly increases the odds of locating enough medically similar individuals needed for a trial.

One such trial is the Diabetes Prevention Program at the Diabetes Research Institute. Researchers are working to develop therapies for reducing Type 2 diabetes, also known as adult-onset diabetes, among high-risk populations. The clinical trial began in 1996 with 165 patients identified with so-called “pre-diabetes.” The patients were randomly separated into four groups—two each receiving a different experimental drug, a third receiving a placebo (the control group), and the fourth receiving training in diet, exercise, and other lifestyle factors but no medications. The results were dramatic. Published last year in the New England Journal of Medicine, the three-year study showed that patients undergoing lifestyle training had a 60 percent lower rate of developing diabetes than the control group.

“This was very, very significant,” says Ronald B. Goldberg, associate director of medical affairs at the Diabetes Research Institute and one of the study’s principal investigators. “This illustrates the importance of a clinical research program to our patients: they’re receiving a direct benefit by being exposed to the latest, most advanced treatments.”

One such patient is Bennie Perdue. Six years ago at age 49, Perdue answered an ad calling for volunteers for the Diabetes Prevention Program study. Perdue was considered “at risk” for developing Type 2 diabetes because his mother suffered from the disease. Perdue also struggled with hypertension, often a precursor to its onset. After being placed in the group receiving lifestyle training, Perdue was instructed to consume no more than 1,500 calories per day (about half his normal intake) and virtually eliminate fat. He also was instructed to exercise daily. Although he was not overweight, he quickly reduced his body weight by about 10 percent. Within six months his hypertension was gone and he showed no signs of developing diabetes. “If this treatment could be packaged and marketed, somebody would make a fortune,” says Perdue, who is no longer participating in the study but maintains his strict diet and exercise regimen.

hile success stories like Perdue’s abound, clinical trials are not entirely without risks. Shortly after the Diabetes Prevention Program began, researchers determined that one of the experimental drugs, Rezulin, posed a risk of liver damage. Use of the drug within the trial ceased immediately, without any serious health consequence to study participants. Patients who received the drug had the option of joining the lifestyle-training group.

Study participants often suffer from terminal diseases such as cancer or AIDS, and they enter trials as a last resort. To them, the benefits nearly always outweigh the risks. But in rare, often publicized cases, even healthy study participants have suffered ill side effects or death after volunteering for experimental treatments. In 1999 a teenager died from drugs administered as a part of a gene therapy study at the University of Pennsylvania. In early 2001, reports surfaced suggesting that as many as 20 cancer patients, some of them terminal, may have died prematurely as a result of flawed experiments conducted at the Fred Hutchinson Cancer Research Center in Seattle, Washington. In what may be the most publicized case of a clinical trial mishap, a healthy 24-year-old woman volunteered for an asthma study at Johns Hopkins University School of Medicine and became ill after inhaling a toxic chemical. Researchers had hoped the experiment would allow them to better understand the reaction of the human airway when exposed to irritants. Her illness grew progressively worse, and she died after weeks of hospitalization. Within days of her death, the U.S. Office for Human Research Protections (OHRP), which oversees all human clinical trials, briefly suspended all federally funded research at Johns Hopkins that involved human subjects.

The fallout of that incident is still being felt. The OHRP threatened to withhold federal funding from institutions that did not revamp their system of approving and overseeing protocols. In response, virtually every U.S. institution conducting research using human subjects reevaluated its IRB system, in many cases strengthening the process investigators must follow before and during clinical trials.

The University of Miami School of Medicine took that challenge a step farther, inviting the National Institutes of Health to evaluate its human subjects protection systems and to recommend changes. Today, everyone engaged in human subject research at the University—from the principal investigators to part-time lab technicians—must complete a training course and an annual review course on patient protection. While acknowledging that no system is perfect, University officials believe they have developed a national model for review and oversight of clinical research.
 

“UM has become a leader in human subject protection,” says Leo B. Twiggs, assistant provost for human subjects protection and associate dean of Women’s Health at the School of Medicine. “Unfortunately, from time to time, researchers make errors, and so systems must be in place to identify problems in advance. The most important thing always is to protect the patient, and at UM we have made that commitment our top priority.”

s evidence of that commitment, Twiggs points to the Collaborative IRB Training Initiative or CITI, a Web-based training tool created here and offered to research institutions around the nation. CITI is a 13-part program focusing on different aspects of bioethics and human-subject research protections. Goldberg, who recently completed the course, says CITI standardizes a set of guidelines that, in the past, may have been taken for granted. “Everyone involved in this kind of research needs to be reminded about the importance of rules and documentation,” he says. “The ethical standards must underlie everything we do.”

Perhaps ironically those standards are rooted in one of history’s most unspeakable medical atrocities. Following the 1947 Nuremberg War Crimes Trial, in which nearly two dozen Nazi physicians were charged with torture, mutilation, and murder while allegedly conducting medical experiments during World War II, the court released a ten-point statement outlining ethical conduct for human subject research. Among other things, this “Nuremberg Code” requires voluntary consent by all patients and stipulates that risks be fully explained. The code also states that the potential benefits to the patient must outweigh any risks. The code was largely replaced in 1964 by the World Medical Association’s Declaration of Helsinki, a more comprehensive document that adds guidelines for protocol review and oversight by independent committees.

Since then, clinical research has become a cornerstone of most major medical institutions, allowing physicians to advance science while offering hope and comfort to patients who only a few years earlier may have had neither. “Years ago many forms of cancer were fatal. A diagnosis was like a death sentence,” Altman says. “But today, thanks to ongoing research with human subjects, we have countless new therapies—many of them noninvasive. The same is true with HIV and other diseases that we now view as chronic rather than acute. For that we owe much to the advances of clinical research.”

etting a drug to market is a long, arduous process and largely impossible without human volunteers, both healthy and sick. Clinical research trials investigate the safety and effectiveness of new drugs not yet approved for public use. Before beginning a trial, investigators must demonstrate three fundamental standards: the study must address a legitimate medical need; it must include only fully informed and consenting participants; and it must allow for a participant’s withdrawal at any stage of the study.

Trials typically include three phases, and often a fourth, which may take years to complete. Phase 1 clinical studies are designed to determine how the drug reacts with the human body. Although some evidence of effectiveness may be observed, researchers primarily are looking at the drug’s pharmacologic properties and the side effects of various dosages. Trials are generally small, with 20 to 80 participants. Healthy volunteers normally are used, but patients with illnesses that are progressing despite currently available treatments also may participate.

Phase 2 clinical studies typically will involve no more than a few hundred participants, all of whom suffer from the disease or condition targeted by the new drug. Investigators hope to measure the drug’s effectiveness as well as identify adverse reactions associated with differing dosages. These trials usually include control groups, requiring randomization of participants. In so-called randomized controlled trials, participants with similar medical or demographic characteristics are allocated to two or more groups. Each group receives different interventions—the new drug, an existing drug, or a placebo. Differences observed are inferred to be a reaction to the drug being evaluated.

Drugs found to have some degree of effectiveness may advance to Phase 3 clinical research. Investigators often compare the drug’s efficacy to that of existing treatments with the goal of evaluating the overall benefit-to-risk relationship of the new treatment. Phase 3 clinical trials generally will include hundreds or thousands of study participants and often involve multiple research institutions working independently.

Drugs found to be safe and effective as well as therapeutically useful in light of existing treatments may receive FDA approval. Such drugs are often put through Phase 4 clinical studies, also known as “post-marketing surveillance.” These studies are designed to gather additional information about the drug’s wide-scale use. Investigators also may look at the long-term effectiveness and side effects of the drug.