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Test Cases

December 18, 2002

Heather Heilman
Michael DeMocker

Virginia Garrison calls her workplace a little slice of heaven, and immediately you want to know more. Does she work at the Ben & Jerrys factory? As a massage school test subject? In fact, Garrison is the nurse manager at the Tulane-LSU-Charity Hospital General Clinical Research Center.

The GCRC, as its called, is one of about 80 National Institutes of Health-funded clinical research facilities in the country. Located on the fifth floor of Charity Hospital in downtown New Orleans, it provides medical researchers at Tulane and Louisiana State universities with the things they need to conduct clinical research on human subjects--including, sometimes, the funds.

Founded in 1990 by the late John Salvaggio of Tulane, the GCRC recently received a $15-million renewal of funds for another five years. Juan Lertora, a professor of medicine and pharmacology at Tulane, is the current director. At this writing, the GCRC has 194 active protocols (or study plans). Last year 73 investigators used the GCRC, 50 of them from Tulane. Its one of the few GCRCs that is shared by more than one school, and Lertora emphasizes that the center could not exist without research from both Tulane and LSU.

The research covers a broad range of topics--asthma, cancer, diabetes, growth hormones, heart diseases, HIV and AIDS, lupus, malaria, tuberculosis. The NIH wanted it to be that way. They wanted to support all the specialties, said Lertora, who is himself overseeing several drug protocols at the GCRC.

While not all of the research at the center is sponsored by the NIH, most of it is publicly funded. It would be hard to overstate how important the GCRC is to the medical research community in New Orleans. It plays a critical role in some of the most significant research done at Tulane.

For 10 years, it has been the site of both pediatric and adult HIV/AIDS clinical trials instrumental in developing the drug cocktails that have extended the life expectancy of people with HIV. Cyril Bowers, a professor of endocrinology, has done pioneering work in the area of growth hormones that may help prevent frailty in the elderly.

Albert Dreisbach, assistant professor of nephrology and clinical pharmacology, is doing the first work ever conducted at Tulane in pharmacogenetics, working to prevent adverse drug reactions and looking at how different ethnic groups may respond differently to drugs.

Joan Cheng, a professor of gynecology, is doing significant work on ovarian cancer. And Jiang He of epidemiology has received international attention for his work on the prevention and management of hypertension. Don Krogstad's anti-malarial drug is an interesting example of how the GCRC can help transform bench research into a clinical treatment that can save human lives. Malaria, eradicated in the United States but still a problem globally, kills thousands of African children every year. Chloroquine has historically been an effective treatment for malaria, but increasingly drug-resistant strains of the disease have developed and spread.

Krogstad, chair of tropical medicine, came to Tulane in 1992 with a basic science grant and the goal of making some analogs of chloroquine in order to figure out which part of the molecule makes it effective against malaria and which part is resisted. In the lab, he found that 20 percent of the analogs he had made were active against all known drug-resistant parasites.

Those were astonishing results in an enterprise where finding one biologically active compound in a thousand is considered a very good outcome. That was, to put it mildly, a shock, said Krogstad. 

Curious to see if the analogs did as well outside the test tube, he approached the Tulane National Primate Research Center about testing the compounds in monkeys. Two compounds were tested in monkey models, and both proved successful in eliminating even drug-resistant malaria. In order to test the analogs in humans, the FDA required further animal tests in order to acquire an Investigational New Drug patent. That took a couple of years but, finally, Krogstad had an IND and a plan for a phase I study comparing one of the new compounds, now dubbed AQ-13, to chloroquine. The problem was paying for it.

It can be tricky to write the grants and juggle the availability of funds so that you dont ever run dry and you dont have too much money early when you cant use it and no money later when you still need it, Krogstad said. The GCRC was able to cover some of the costs of the study, including inpatient stays and outpatient visits and some of the lab work. The rest was patched together with grants from the NIH, the Food and Drug Administration and the Centers for Disease Control.

The next challenge was finding people to participate in the study. The man or woman on the street in New Orleans is convinced that malaria has been eradicated, Krogstad said. Their interest in volunteering for a malaria study is about as close to zero as you can get. In the end, the majority of the 110 volunteers were students from the public health school, the medical schools and Xavier Universitys College of Pharmacy--people who had a greater-than-average awareness of malaria.

Krogstad was pleased that a significant number of African students from the Tulane School of Public Health and Tropical Medicine participated in the study. Since we envision doing phase II in West Africa, we didnt want an entirely white and Asian study population, he said. The purpose of the phase I study, which is now winding down, was to test the safety of the drug in malaria-free subjects. Increasingly larger doses were given in a randomized trial where some subjects received AQ-13 and some chloroquine.

Investigators found no significant differences between AQ-13 and chloroquine in terms of safety and side effects, though it appears that AQ-13 is metabolized more quickly. By the end of this year, Krogstad plans to begin phase II studies in Mali. One of the remarkable things about this story is that Krogstad was able to find within Tulane the resources he needed to take the drug from bench science to human subjects --from the graduate chemistry courses that helped him catch up on the subject to the primate center and the GCRC.

It was important to Krogstad that the drug be tested first in the United States, both to please the FDA and for ethical reasons. I would only feel comfortable asking someone in Mali to volunteer if I could say that American subjects had taken the drug, he explained.

The GCRC offers researchers a state-of-the-art facility, core laboratory services, biostatistical support, the services of a research dietitian, and help with database management. But one of its most valuable resources is its staff of highly experienced research nurses, all of whom seem to love their jobs.

Many of them came from the emergency room or the intensive care unit at Charity, so part of the appeal of their work rests in its relative calm. Once they find their way to the GCRC, they tend to stay put. The turnover here is pretty low, Virginia Garrison noted. She used to enjoy the fix em up and turn em out aspect of working in the ER, but now she finds that she appreciates the chance to get to know her patients over time and follow them as their treatment progresses. She also likes the autonomy and the intellectual engagement of her work.

Nurses in the GCRC help investigators with the application process, write the orders (or instructions) for the protocols, and generally navigate the torrents of paperwork that go along with research on human subjects. Whats really nice is you can function as independently and autonomously as you would like to. You can work solely under the doctors supervision, or you can venture out a little bit more and coordinate studies, said Mary Schluter. She has been at the GCRC for more than 10 years and has specialized in chemotherapy studies.

Physicians start to trust your judgment and rely on you a lot, Garrison added. That helps to facilitate the autonomous thinking. Schluter recently became the first person to hold the new position of research safety advocate at the GCRC. Her job is to ensure patient safety by monitoring that investigators are really doing what theyve stated they will do in their protocol and patient-consent forms. Anything that goes wrong is reported and followed up on. We havent had any major problems. We just want to make sure the physicians are aware of the things theyre supposed to do, she said.

She also hopes to be able to connect Tulane and LSU researchers with each other. The GCRC could not exist without the participation of researchers from both schools, but there is undeniably some competition between the two as well. Individual investigators may simply have little opportunity to talk with their counterparts at the other school or be reluctant to venture into another researchers territory.

Sometimes that can be difficult, Schluter said. But we might have Tulane patients that would qualify for an LSU study, or vice versa. And were working for all the patients, not just the patients of one school or one investigator. Its worth noting, too, that in many cases the protocols offer a significant benefit for patients, who may receive cutting-edge treatments long before theyre available elsewhere.

Despite the satisfaction that the GCRC nurses find in their jobs, nursing positions there can remain unfilled for long periods. That can largely be attributed to an overall shortage of nurses, but its also true that many nurses just dont think to look for work in university research. From a nursing standpoint this is a great little niche. I think a lot of nurses just dont know about this area, Garrison said. They dont tell you about it in nursing school, Schluter added.

Shes trying to remedy that by going to talk to the senior nursing students at Delgado Community College in New Orleans every spring. And theyre working on getting students in to do a research rotation. But if theres a shortage of nurses in clinical research, there is also a shortage of doctors. There are many reasons for this, one of which is the fact that young doctors typically leave school with a heavy burden of debt, and an academic career means more work and more pressure at relatively lower pay.

Theres a shortage of clinical researchers across the board, said Bob Sullivan, the GCRCs administrator. People just arent going into clinical research. The standard is that an academician should be a good teacher, a good researcher and a good doctor, explained Ruth Berggren, a professor of infectious diseases whose protocol will soon get under way at the GCRC.

And as changes have come about in health care with respect to the regulations that are increasingly imposed on us, doctors have more and more paperwork to do just related to their clinical practice. That diminishes the amount of time were able to effectively spend conducting research or teaching.

Berggren, who is also the mother of two young children, says she usually feels like she has too many balls in the air. Shes on call 24 hours a day, conducts business from her car and works on grant applications after she has put her kids to bed. But despite the nonstop work, she has never really considered any other career path. The questions are compelling, she said. In clinical research, the link between the questions being asked and the potential impact on patient lives is obvious and rather immediate. Theres something very satisfying about that.

No one at the GCRC can take away the many difficulties faced by clinical researchers. But they do try to introduce medical students, interns and residents to the satisfactions of clinical research, and to support young investigators as they build their careers. Twice a year, a course in clinical research is offered to students of both medical schools, as well as to nurses, residents and fellows. Researchers talk to students about study design, biostatistics, epidemiology, ethical issues, grant writing, and how to find a mentor.

Grant money is available through the GCRC for new researchers who want to explore an avenue of research through a pilot study. And many big research projects include sub-studies that can represent opportunities for young doctors. One of their goals is to help a young investigator get a competitive K23 Research Career Development Award from the NIH.

Two Tulane investigators, Karen Friday and Mark Beilke, have had similar awards in the past. And Ruth Berggren, who recently joined the Tulane faculty, brought a K23 award with her from the University of Texas Southwestern Medical Center. She could not have come to Tulane if the GCRC didnt exist, because the award requires such a facility.

Berggren's research is focused on patients who are infected with both hepatitis C and HIV. About a third of HIV patients in the United States fall into this category. Those large numbers can be explained by the fact that both viruses are spread the same way, through sex and injection drug use, although hepatitis C is more easily spread through drug use and HIV through sexual activity.

If you separate HIV patients according to how they acquired the virus, up to 90 percent of those who got it through injection drug use are also infected with hepatitis C, while 10 to 14 percent of those infected through sex are co-infected with hepatitis C. In the early days of the AIDS epidemic, no one really paid attention to co-infection because patients didnt live long enough for it to matter. Hepatitis C takes 20 or 30 years to progress to cirrhosis, end-stage liver disease or liver cancer.

These days, HIV patients are living much longer. At the same time, researchers have discovered that hepatitis C progresses faster in co-infected patients. Only very recently have patients and physicians begun to examine the possibility or the need to treat hepatitis C along with HIV, Berggren said.

At Parkland Hospital in Texas, Berggren conducted a study of causes of death in people with HIV. She found that, both before and after the advent of the highly active antiretroviral therapies that have extended the prognosis for these patients, liver disease was one of the main causes of death.

In fact, it was the No. 1 cause of death in those with the strongest immune systems. Its ironic, but in people with chronic hepatitis C, enhancing the immune system also enhances the bodys ability to damage itself as it attempts to fight off the virus, she said. Complicating the picture even further is evidence that one of the drugs used to treat hepatitis C can weaken the immune system in a way that could be dangerous to HIV patients.

It is possible to treat both infections concurrently, but it has to be done with some expertise, Berggren said. She is getting ready to begin a study, conducted at the GCRC, in which half of the subjects will receive the standard therapy for hepatitis C and half will receive a modified, lower dose. The hypothesis is that the lower dose will be as efficient as the standard dose but better tolerated by patients with HIV, Berggren said. Shes identified 50 co-infected patients and is in the process of enrolling them in the study. New Orleans is only one site in the study, which will enroll 400 patients nationwide.

As Berggren begins her study, the GCRC continues to grow. It has expanded the database management and the laboratory services offered. Its researchers are venturing into gene therapy protocols, supporting more outpatient studies and involving more residents in research. The recent renewal of funding is evidence that the center has been successful in its mission of supporting research in many different specialties. It has helped carry forward a strong tradition of clinical research at Charity Hospital and allowed the medical schools to attract high-caliber faculty. Its really worked, said Lertora.

Heather Heilman is an editor in university publications and a regular contributor to Tulanian. She can be reached at hheilman


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