This is an introductory article to an occasional series that will take a close look at the clinical trials system.
If U.S. taxpayers are to foot the bill for a biomedical experiment on people, the protocol for the studyits research planmust first satisfy an institutional review board that it provides for the informed consent of the participants and sufficient safeguards of their welfare.
Composed primarily of scientists and physicians, these watchdog panels are also responsible for checking, at least once a year, on the compliance with these requirements of any study they approve.
It has been that way since 1974 when Congress imposed reforms in response to then recent revelations of ethically flawed human experiments. A federally funded study during the 1960s in which live cancer cells were injected into debilitated noncancer patients at a Brooklyn, New York, Jewish hospital without the patients knowledge was among the most egregious offenders. So was the infamous Tuskegee (Ala.) study of some 400 black men with syphilis, which was also federally funded. Begun in 1932, it denied them treatment until the press got wind of it in 1972. By then, penicillin had been known for decades to cure the disease.
In the more than a quarter century since that era, IRBs are thought to have had a salutary effect. Nonetheless, the 1996 death of Nicole Wan, a healthy young volunteer in an asthma study at the University of Rochester, and the death last June at Johns Hopkins University of Ellen Rochealso a healthy young volunteer in an asthma studyas well as the loss at the University of Pennsylvania in 1999 of 18-year-old Jesse Gelsinger in a gene transfer experiment are just three of the events that have raised doubts about the boards effectiveness. (Gelsinger had a genetic disease, but it had been mild and well controlled by diet and drugs.)
Both the increasing numbers of NIH-funded studies and the mounting aspirations of pharmaceutical and medical devices firms whose products must be clinically tested if they are to qualify for U.S. Food and Drug Administration approval mean that IRBs are riding herd on more studies than ever before (though exactly how many is unknown).
Just Overwhelmed
An unprecedented number of peoplean estimated 500,000 in the United States aloneare enrolled in clinical studies. "I serve on some IRBs," said Arthur Caplan, Ph.D., who heads the Bioethics Center at the University of Pennsylvania. "I can tell you they are just overwhelmed."
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Adding IRBs
The seemingly obvious solution would be to add an IRB or two at institutions where the existing ones are overworked. Although some centers (including Hopkins) have done this, it has not always been enthusiastically.
There are a variety of reasons for such reluctance, said Gary Chadwick, Pharm.D., who is in charge of regulatory affairs involving human subjects at the University of Rochester. Typically, one of them is that scientists and physicians at research institutions do IRB duty for nothing, but the support staff a panel must have to operate efficiently does not come free. Consequently, some research institutions seem to have willingly settled for fewer IRBs than they really need, even if it means that there will be superficial oversight of protocols.
It is true, too, that the lot of IRB chairs and members tends not to be happy anyway. At academic medical centers the system is such that promotion and prestige have, for generations, hinged on doing studies that produce publishable results. Accordingly, there is a long history of some investigators perceiving IRBs as a potential threat to their careers. But in 1980, the situation was further complicated when Congress passed the Bayh-Dole Act.
Prior to Bayh-Dole, the rights to any discovery growing out of federally funded research remained in the public domain; that is to say, the rights were retained by the U.S. government for the use of its citizens. Since 1980, researchers making discoveries and/or their host institutions can now patent them and create spin-off companies that license the patents to private industry.
Financial Implications
Whatever else the impact of this policy, its financial implications have made IRBs even less popular in much of the research community than they were already. (Since the passage of the Technology Transfer Act in 1986, researchers at NIH and other federal laboratories can also profit personally from their discoveries.)
Meanwhile, the world that IRBs were designed for in 1974 has changed. For one thing, clinical research, which used to be done almost entirely in teaching hospitals and at such federal venues as the NIH Clinical Center, is now also done in community hospitals, doctors offices, and even the occasional storefront clinic. For another, more and more clinical studies these days are multicenter and may involve dozens of sites.
Then, too, the traditional nonprofit IRB put together by a research institution that is at least partly publicly funded is no longer the only sort of IRB. In the last 20 years or so it has been joined by commercial review boards, of which there are several kinds. Most pay their members and many are set up to make a profit. Some are the subsidiaries of contract research organizations or pharmaceutical firms; others are not.
Signs of Innovation
In so varied a landscape, what are the prospects for addressing ethical issues with a single set of standards that do not greatly differ from place to place? In the current antiregulatory political climate, at least, prospects appear to be slim, particularly because the firewall between the research community and industry is now largely history.
Still, some signs of innovation are in the air. For example, the National Cancer Institute supports several groups of institutions that are organized as networks to do multicenter clinical trials. Ordinarily (primarily because of liability concerns) no two of the centers in a network have been willing to use the same consent form for the same trial. But with the NCI serving as honest broker and providing the necessary assistance, some members of these groups have agreed to try doing exactly that.
The National Committee on Quality Assurance, a Washington, D.C., group that has focused on managed care, has embarked on a somewhat similar effort for the research done by the hospitals of the Department of Veterans Affairs.
Accreditation Organization
Perhaps the most ambitious innovation, however, has been developed by Public Responsibility in Medicine and Research of Boston, which has been working with a number of groups to set up a system that will accredit IRBs.
The result will be the launch by years end of the private nonprofit Association for the Accreditation of Human Research Protection Programs, which is to be located in or near Washington. Marjorie Speers, Ph.D., will be its director. According to her, all the details have yet to be worked out. But it has already been decided that AAHRPP will be voluntary and peer-driven and use the intramural program at the NIH as the first of its pilot sites.
Speers also said the new group will be closely modeled after the Association for the Assessment and Accreditation of Laboratory Animal Care, whose headquarters is in Rockville, Md. AAALAC keeps tabs on the care of research animals in almost 800 institutions around the world.
The question on the minds of some people is whether and how quickly AAHRPP will be able to catch up.
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