Journal of the National Cancer Institute Advance Access originally published online on January 8, 2008
JNCI Journal of the National Cancer Institute 2008 100(2):90-91; doi:10.1093/jnci/djm314
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© Oxford University Press 2008.
NEWS |
Federal Drug Agency Gets Flack About Human Subjects Protections in Clinical Trials
The federal agency responsible for approving new drugs and medical devices is under fire for not doing enough to protect human subjects in research.
A recent federal report concludes that the U.S. Food and Drug Administration lacks ways to keep track of research on people and fails to conduct enough inspections. The FDA responded by saying that human subject protection is a complicated business. While it agreed with some of the report's findings, it also said that it conducts as many inspections as it can and that even the threat of inspections ensures safe treatment of patients. Clinical investigators, on the other hand, worry that the publicity the report generated could reduce the number of patients willing to participate in a clinical trial system that they believe is safe enough and already thin on volunteers.
In the September report, the inspector general for the U.S. Department of Health and Human Services criticized the FDA for a poor showing in its efforts to protect human research subjects. The inspector general reported that the FDA has no way to keep track of all the clinical trials and review boards that monitor the trials. Also, the agency has no way to keep track of the inspections it performs or the legal authority to oversee other researchers who might be involved in clinical trials but who are not the principal investigator. The inspector general also thought that inspecting 1% of trials was inadequate. For example, the FDA has only 200 inspectors to monitor 350,000 investigators using people in research. The report recommended how the FDA could improve, including creating a database to track inspections and getting the legal authority to oversee colleagues and subordinates of principal investigators.
The FDA pointed out in comments to the report that the organization is already modernizing its human subject protection protocols with the kinds of databases that the report recommends. But the agency also contended that the report focused too much on inspections that are to be conducted after a trial is in progress. "Inspections are but one narrow part," the FDA responded, saying that the initial review of protocols is also important. "In order to ensure the highest degree of human subject protection, [the] FDA carefully scrutinizes all protocols submitted to the agency and will require sponsors to revise protocols as necessary, thus ensuring the greatest protection of human subjects before a clinical investigation even begins."
Research on humans is an incredibly important part of medical science and is only becoming more vital, says hematologist Edward Benz Jr., M.D., president of the Dana-Farber Cancer Institute in Boston. "As we learn more about the genetic basis of drugs, what a drug is useful for can only be tested in humans. The limits of animal studies are becoming more of an issue. Animals have the same genes, but their genes don’t interact with drugs the same way," he says.
While recognizing that problems exist, some cancer researchers and ethicists were generally supportive of the FDA. Some say that the FDA is doing what it can and others say institutional review boards (IRBs) already do a good job of protecting human subjects. They are interested in using the report to open a broader dialogue about how to address protecting human participants in clinical studies as researchers learn more about disease in the future.
"My reaction was that it would be good if the FDA did the things that were recommended in the report," says Rebecca Dresser, J.D., a Washington University lawyer who is an expert on the FDA's regulation of drugs and devices. "But the FDA is held responsible for so many things, and it's so underfunded. And Congress hasn’t provided the money and personnel it needs to get done what it needs done."
Some researchers say that not all cancer research suffers from the issues found in the report. For example, NCI-designated cancer centers have put a great deal of time and money into ensuring the safety of patients, including IRBs, scientific review committees, and data safety and monitoring boards, Benz says. "We spend $10 million a year at Dana-Farber for protection of human subjects."
Role of IRBs
Part of the issue is that the FDA doesn’t oversee most federally funded clinical cancer research—that job is left to Department of Health and Human Service's Office of Human Research Protections (OHRP). That agency requires universities, hospitals, and other research organizations to set up IRBs and register them. The OHRP is then responsible for monitoring the IRBs.
IRBs, which approve, monitor, and review human research trials, are charged with exposing potential conflicts of interest of clinicians serving as investigators, says Joseph Fins, M.D., F.A.C.P., who is chief of medical ethics at Weill Medical College of Cornell University in Ithaca, N.Y. This situation creates the potential for an adversarial dynamic. "The adversarial strategy is necessary but not sufficient" to protect subjects, he says.
IRBs are protecting subjects, but they do so based on paper, not on observing behavior, Dresser says. "IRBs rely on investigators to be honest. If unexpected problems crop up, the researcher tells the IRB. An IRB doesn’t go out and police this."
While the OHRP monitors the IRBs, the FDA most often oversees private companies seeking FDA approval for their drugs. But when researchers want FDA approval for new drugs or label changes, the agency doesn’t actually monitor their human-based research itself, Dresser says. They check only to see if a privately funded company has gotten IRB approval for human trials. And when the company comes back later when it's time to market its product, the FDA again looks to see if IRBs were used.
But at least U.S. research subjects have the OHRP. The bigger problem is when drug or device trials are conducted in other countries, which don’t fall under OHRP jurisdiction. But companies still want to use the data for FDA approval. "The FDA is the only federal agency with oversight responsibilities in those cases. It's important to monitor those trials—some countries don’t have good domestic systems for protection," Dresser said.
Negative Repercussions
Benz worries that the attention given to the report will have a negative effect on getting volunteers to participate in trials. "The way the report was related in the media might have a very chilling effect on people enrolling in clinical trials," he says. "We already have a sense that people are less interested in clinical trials these days, and we don’t know why."
In defending its practices, the FDA wrote that its modernization efforts will address many of the inspector general's issues but also acknowledged that because of limited resources, "human subject protection must exist in the absence of FDA's presence during the clinical trial." The agency added that rather than performing an arbitrary number of additional inspections, they need to improve upon the inspections they do conduct.
Medical researchers and ethicists agree that oversight is critical, but they note that even in a highly regulated environment, research carries risk. "IRBs are the best that anybody has been able to think of to protect people," Benz says. "But we’re dealing with the unknown. You can do everything possible for safety, but research is like getting on a plane. Nothing is perfect."
Fins agrees. "We have to recognize there is risk in research. We need safeguards, though, not stasis," he says—safeguards, perhaps, that will let human cancer research keep flying high.
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