In the ensuing investigations of the Johns Hopkins study, it became clear that the researchers involved made errors: they used a drug no longer approved by the Food and Drug Administration for human use; they missed important research papers on the drug; their consent forms were incomplete; they changed the protocol for mixing the drug without consulting the Institutional Review Board (IRB), which has oversight for human research; and they delayed reporting other adverse responses to the IRB.
In both the Johns Hopkins and NIH cases, the researchers were experienced clinical researchers. But clinical research requires specific training--not just how to test hypotheses, but how to deal with the complicated jumble of federal requirements for human research. "While there is great satisfaction that comes from being on the front edge [of research] and actually being able to bring patients into a trial and see a new therapy work, the compliance issues, the informed consent issues, the tracking and data collection issues, are part and parcel of the trial itself; but it's sometimes pretty easy to see how those could be seen as stumbling blocks," explains Joanne Baughman, executive vice president of the American Society of Human Genetics in Bethesda, Md. "The investigator-initiated clinical trials require a clinical scientist who has been both broadly and deeply trained," Baughman notes.
An article in the April 2001 issue of CenterWatch, the newsletter of CenterWatch (Boston), an information company dealing with clinical trials, notes that although there are more principal investigators (PIs) than ever before carrying out industry clinical trials (33,000 in 2000), by 2005, clinical research, which includes pharmaceutical research, will need 56,000 PIs for industry-sponsored drug development alone.2 This does not include federally sponsored clinical research or clinical research sponsored by not-for-profits or other groups. "When some folks say we need more people to do clinical trials, it's the early clinical trials or the translational research that they're talking about," says Baughman, who, until last summer, was vice president for academic affairs at the University of Maryland, Baltimore.
|Courtesy of Judith Vaitukaitis|
Although CenterWatch reports that 96 percent of PIs engaged in clinical research for the industry are "physician MDs," Judith Vaitukaitis, director of the NIH's National Center for Research Resources (NCRR), notes that the percentage of MDs who were PIs on NIH- sponsored research dropped from 40.6 percent in 1970, to 22.5 percent in 1992, and to 19 percent in 1998. John Gallin, director of the NIH Clinical Center, notes that his center, the largest clinical program in the world, had "about 90 fewer clinical investigators a year ago than we had in 1975." This comes at a time when the NIH budget is at an all-time high.
Last April, acting director of the NIH Ruth Kirschstein said in a speech, "a career in basic research may subtract from the pool of new physicians and scientists who might, at other times, have pursued clinical research." She noted that 20 years ago, former NIH director James Wyngaarden called clinical investigators "an endangered species."3 "It's not a lack of resources at the NIH," remarks Andrew Marks of the department of molecular cardiology, Columbia-Presbyterian Medical Center in New York, and incoming editor of the Journal of Clinical Research.
Why the Shortage
|Courtesy of John Gallin|
Vaitukaitis, who was a clinician in academia before moving to NIH, expands on the problems related to managed care. When in academia, Vaitukaitis notes that she didn't get paid for seeing patients. She was on salary and the insurance payments for her clinical services went back to fund research in one of the institution's medical departments. Managed care reimbursement rates, however, do not "quite recover full costs" of treating patients. Now, "there's much less money for institutions to use those funds to supplement salaries for both clinical and basic researchers," she says.
"There've been dramatic reductions in the levels of support, particularly in clinical departments for trainees," notes Marks. "All of this is a function of the reorganization of health care. [In] the golden era of biomedical research in this country, physician-scientists were supported by clinical dollars; and most of this disappeared in the past decade."
Baughman comments that clinical researchers are in a tough position: "These are the people who want to be on the very front edge, yet they're competing [for funding] with the research scientists who are on the front edge of research and clinicians who are on the front edge of science, and they're expected to be both."
Is There a Solution?
NCRR is beginning a program that will allow medical or dental students to take a year off from their classroom studies to work "in a mentored setting to learn how to do clinical research in a Clinical Research Center," says Vaitukaitis. This program will provide support for up to five candidates per year at each of the 80 GCRCs. Vaitukaitis also notes that there are five separate loan repayment programs sponsored by NIH for young clinical researchers who can work on renewable, two-year contracts. Gallin says that these programs will give young researchers up to $35,000 a year to pay off their debts and that taxes on that money will also be paid.
The GCRCs, which Gallin describes as small, 10- to 20-bed centers that do outside patient work for all types of clinical research, have broad functions. These centers "have between 325,000 and 350,000 outpatient research visits per year," says Vaitukaitis. The centers have research nurses, dietary consultants, support staff, and educational programs. Although researchers are not required to use the GCRCs--which do not cost the investigator anything to use--researchers are encouraged to use them. A researcher need not be located at the institution that houses the GCRC to use the services, but must have an IRB-approved protocol. Vaitukaitis notes that had the Johns Hopkins asthma researchers whose volunteer died used the GCRC--Johns Hopkins has three GCRCs, including one at the site where the protocol was carried out--the weakness in the study more than likely would have been noticed.
The NIH itself runs a clinical investigator curriculum to train researchers. And in light of a number of high-profile deaths of clinical research subjects, the Association for the Accreditation of Human Research Protection Programs (AAHRPP), will begin a voluntary accreditation process of clinical research centers--beginning with the NIH in December. The AAHRPP is modeled after the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC), Bethesda, Md., the accrediting organization for institutions that do research on laboratory animals.
|Courtesy of Andrew Marks|
To increase the number of clinical researchers Columbia-Presbyterian's Marks notes there must be "support at all levels of the system, starting from medical school residency, fellowship, and so on; and from the hospital side, there has to be a greater recognition of the importance of clinical research." Baughman sees improvements in the way researchers work: "I think that the public and private sectors, the academic and industry sectors ... in fact, are working in a much more integrative fashion than we were five or 10 years ago, certainly." Vaitukaitis admits that optimal size of the clinical researcher pool has not been determined. But, she remarks, that if research results do not make their way to the consumer, then there aren't enough researchers.
1. S. Levine, "The story of patient #10," The Washington Post, July 31, 2001:F1.
2. S. Zisson, "Anticipating a clinical investigator shortfall," CenterWatch 8:1, 5-8, 2001.
3. R. Kirschstein, "Medicine ...The intersection of research, training, and care," John E. Chapman Lectureship on the Ecology of Medicine and Medical Education, Vanderbilt University, April 6, 2001. www.nih.gov/about/director/speeches/040001.htm.-->