For more than a decade, University of Maryland biochemist Adil Shamoo has been clamoring for greater protection for people enrolled in medical experiments. And for most of that time, his colleagues at research centers across the country have ignored him.

No more.

With revelation after revelation of research-related deaths and questionable practices at some of the nation's most prestigious research institutions, attitudes are changing. Shamoo now believes that, finally, major reforms are on the way.

What was considered "revolutionary rhetoric" in the early 1990s has become "the realities of 2001," said Shamoo, co-founder of Citizens for Responsible Care and Research.

What those reforms might be is not yet clear. But the Bush administration is sending strong signals of its willingness to crack down on medical research, and congressional efforts to do the same are growing.

The turnaround stems from a string of events and reports over the past two years:

• In May 1999, a federal oversight agency took an aggressive approach by temporarily shutting down research at Duke University after the school failed to respond adequately to repeated requests to properly monitor studies. In the following months, several other universities and hospitals were suspended.

• In September 1999, a healthy 18-year-old research volunteer, Jesse Gelsinger, died from drugs in a gene-therapy experiment at the University of Pennsylvania. An investigation uncovered that the researcher, Dr. James Wilson, owned 30 percent of the company whose drug was being tested. The Food and Drug Administration shut down the program after finding that the school violated regulations.

• In March of this year, The Seattle Times reported that more than 20 patients died prematurely in two experiments at the Fred Hutchinson Cancer Research Center conducted between 1981 and 1998. In both cases, patients were not fully informed about risks, alternatives and financial conflicts of interest of doctors.

• Last month, the federal government temporarily suspended research at Johns Hopkins School of Medicine after a healthy 24-year-old technician, Ellen Roche, died in an experiment. Federal officials criticized the school for using an unapproved drug, hexamethonium, for which there was evidence of risk.

More staff approved

The White House recently approved nearly doubling the staff at the federal Office for Human Research Protections from 24 to 47. The head of that watchdog agency, Dr. Greg Koski, wants to improve the system through education and private-accreditation programs, saying the government can't effectively monitor all research.

But in the past few weeks, Koski has revealed a tougher side. His move to shut down research at Johns Hopkins showed a willingness to crack down on any institution that was flouting the rules. And after initially hesitating, Koski launched an investigation into research-related deaths at Seattle's Hutchinson Center.

The trend is prompting universities and research centers to rethink how they review experiments, inform patients of risks and handle financial conflicts of interest.

"Nobody wants to go through what a dozen or so major institutions have gone through in the past couple of years," said Jonathan Moreno, a bioethicist at the University of Virginia Health System.

The biggest reforms may come from Congress. Sen. Edward Kennedy, D-Mass., chairman of the Senate health committee, and Sen. Bill Frist, R-Tenn., a doctor and former committee chairman, are working together on a bill to provide greater oversight and to strengthen protections for research participants.

"We expect to introduce it and move it through the committee as quickly as possible when the Senate reconvenes in September," said Kennedy spokesman Jim Manley. "This still is very much a priority for Sen. Kennedy."

Meanwhile, on the House side, Rep. Diana DeGette, D-Colo., and Rep. Jim Greenwood, R-Pa., are working to extend protections under federal law to all human-research subjects. Volunteers in many privately funded studies now have no federal protections.

A similar bill made little progress last year, but proponents point out that media attention is now much more intense.

Local-board problems

Criticisms of the medical-research system have been mounting for years.

Research centers rely on internal panels called institutional- review boards to evaluate whether experiments are too risky and whether patients are adequately informed of the risks. Rarely does the federal government review the process.

But it has become clear that many institutional-review boards are understaffed and overburdened. Often, they are able to give studies only a cursory review.

The Office for Human Research Protections found that Johns Hopkins couldn't even produce minutes of 18 of its most recent review meetings. When federal investigators listened to audiotapes of those meetings, they found the boards weren't reviewing most new experiments and when experiments were reviewed, board members with financial conflicts of interest weren't recusing themselves.

Johns Hopkins didn't seem to be taking the review system seriously, said Abbey Meyers, president of the National Organization for Rare Disorders, adding, "Maybe by closing it down, it will get the rest of the field to take it seriously."

Another potential target for reform: financial conflicts of interest of researchers and the institutions themselves. A growing number of prominent bioethicists are calling for stricter rules. The conflict issue looms large in the Office for Human Research Protections' investigation of the Hutchinson Center. Researchers in two major clinical trials had financial interests in drugs being tested in the experiments, but the patients enrolled in those trails had no idea.

"Patients should not have to wonder whether an investigator is motivated by financial gain, and the public should not have to wonder whether medical research can be believed," said Marcia Angell, former editor of the New England Journal of Medicine, at a government conference last fall. "The only way to deal with the problem is to eliminate it as much as possible."

Angell advocates prohibiting researchers whose work is funded by a private company from owning stock or having other financial ties to that company. She also says that private industry shouldn't have veto power in interpreting data and publishing research.

Last week, an advisory panel to the federal Department of Health and Human Services put final touches on proposed new guidelines for managing conflicts of interest. The recommendations fall far short of Angell's suggestions. For example, they encourage but don't require researchers to tell patients if they have a financial stake in the outcome of a study.

"Disclosure is a cheap and easy substitute for management of conflicts," said Mark Barnes, an attorney who represents medical centers. Barnes is a member of the National Human Research Protections Advisory Committee.

Instead, the advisory group recommends that institutions create committees to review potential conflicts, and whether financial ties might influence a study's outcome or the welfare of patients.

The recommendations are being presented as "best-practices" suggestions rather than regulations. Even so, several research groups such as the Association of American Medical Colleges and the Association of American Universities have objected to what they perceive as a rush to create guidelines that could violate researchers' privacy and discourage research.

Malcom Parks, assistant vice provost for research at the University of Washington, said in a March letter to the advisory group: "I worry that premature guidance from regulatory agencies will stifle local experimentation and creativity in managing conflicts of financial interest. Moreover, I worry the regulatory environment will become so complex and so frustrating that the public interest will suffer."

But Barnes acknowledged the need to act given the recent reports of problems.

"This is a burning issue. It's an issue of credibility and trust," he said. "It's an issue that research centers need to get out front on."

Shamoo, the longtime reform advocate, thinks the ideas discussed so far are inadequate. But he thinks the momentum will ultimately lead to major changes.

"We have made progress," he said. "What I am really happy about is that the concerns are now on the front burner."