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'Abolitionist' Angell Calls for Clinical Trial Reform

By Rich McManus

On the Front Page...

Dr. Marcia Angell is a compact reddish-haired woman in whom a certain ferocity resides; perhaps it is the arch of her eyebrows that contributes to this perception. Formerly editor-in-chief of the New England Journal of Medicine — with which she was associated for 21 years — and currently senior lecturer in the department of social medicine at Harvard Medical School, she was able to confer arched brows on an audience assembled for the fourth annual James A. Shannon Lecture May 22 in Masur Auditorium.

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Speaking on "The Ethics of Clinical Trials," she argued that the ethics that used to prevail when many in the audience were in the prime of NIH careers (the event was sponsored by the NIH Alumni Association, many of whose members attended) no longer obtain, having been corrupted by investor-owned businesses whose principal interest is financial gain rather than patient care or the advance of medical science.

"James Shannon [NIH director from 1955 to 1968] was a great man who came to a great institution at exactly the right time," Angell began, "...but Dr. Shannon wouldn't even recognize today's clinical research enterprise." Two of the bedrocks of trial ethics — informed consent and "an important reason for doing the trial" — are threatened by three factors, she charged: the size and competitiveness of the modern enterprise; the strings attached to industry funding; and the "pervasiveness of financial conflicts of interest throughout the system."

Dr. Marcia Angell (l) accepts plaque commemorating her Director's Lecture from NIH acting director Dr. Ruth Kirschstein.

Not blind to therapeutic advances wrought by the new industrial colossus, Angell warned that "without major reforms, the harms may soon outweigh the benefits."

Clinical trials are now "a multibillion dollar enterprise, with millions of participants," she said. "More than 40,000 trials are now actively seeking subjects. Less than one-fifth of these trials are sponsored by NIH — most are sponsored by drug companies." Because of the way patent law works, companies regard time spent conducting trials as a delay in bringing new drugs to market, so they are hasty and indiscriminate when recruiting patients, Angell said. Over 4,000 enrollees are needed to test a single new drug, she explained. Companies pay bounties of anywhere from $500 to $15,000 per subject ("more than enough to cover costs") to load their trials, plus bonuses for rapid enrollment. Angell is concerned that researchers may stretch eligibility criteria to enroll more subjects faster.

Entities called contract research organizations (CROs) have sprung up to recruit subjects and organize community doctors into a neophyte research cadre, Angell continued. "There is an army of amateur researchers out there; more than 50,000 are registered with the Food and Drug Administration, and most of them are conducting their first trials."

Overseas, the recruitment effort is particularly aggressive. "In Africa, South America, and parts of Asia, and also eastern Europe and parts of the former Soviet Union, the bounties paid to physicians (to recruit subjects) may amount to many times the salaries of these foreign doctors," Angell reported. "In 1991, there were only two registered researchers in Africa; now there are 266."

Academic medical centers in the U.S., which traditionally conducted clinical trials, "are losing out to CROs, and now they want their business back." Financed by big pharmaceutical companies, the academic centers are now "establishing new clinical research institutes, which are really for the convenience of drug companies who want easy access to trial participants. It's an enormous, high-stakes enterprise."

Overseeing the conduct of these trials are the FDA and the HHS Office for Human Research Protections (for PHS-funded work), but both bodies delegate patient protection authority to IRBs — institutional review boards, of which there are some 3,000 to 5,000, "but no one really knows because they're not registered," Angell said. These agencies rarely conduct inspections of IRBs. Many IRBs, she charged, are investor-owned businesses whose only clients are drug companies or their agents.

Because of the Prescription Drug User Fee Act of 1992, FDA's drug review operation is now half-funded by industry, Angell said. "Drug companies are exerting influence over the evaluation of their products either directly or indirectly...FDA is beholden for its existence on companies it is supposed to regulate, and that should never be the case with a regulatory agency."

Angell said that the agreements forged with industry by many in academic medicine "compromise their scientific independence." She described three sequelae of the proliferation of such ties: Industry unduly influences the kind of research that gets done, emphasizing not new approaches to treatment, but acquisition of patents on blockbuster drugs. "Not much of real scientific or clinical value is coming out of many of these trials," she argued. "Rather, we're getting a flood of copycat drugs and fewer novel agents...This isn't so surprising when you recall that the CEOs of four of the major pharmaceutical companies are former marketing directors."

The second outcome is that "drug companies are determining how and what trials are published." In her 21 years at NEJM, Angell said it was her impression that "company-supported work was far more likely to be biased in design and analysis than NIH-supported work." The bias can be "extremely difficult to detect," she noted.

"Finally," she said, "the system is so ridden with financial conflicts of interest that the rights of human subjects may be compromised." In the much-publicized death in 1999 of research subject Jesse Gelsinger, Angell noted that the principal investigator held a 30 percent stake in the company whose drug was on trial, and his institution held a 3 percent stake.

"What we have is a system badly in need of reform," she stated. She offered several prescriptions: Take the rush out of trial enrollment by amending patent law so that patent protection starts after FDA approves a drug, not before trials even begin. "That way, trial time wouldn't cut into marketing time." Separate drug company funding from clinical testing — they should be completely independent. Ethical oversight should be separate from both testing and funding. "There should be no investor-owned CROs," she continued. "An independent public agency could function much as the CROs now do. Or, we could return trials to the academic centers, with arm's-length funding by industry. The academic centers should never have strayed from this model in the first place."

Angell asked whether the current volume of clinical trials is reasonable or defensible. "Should we ask humans to enroll in trials of trivial drugs?" Many of today's trials yield tiny differences in compounds that drug companies can exploit financially, she said. "We should be concerned that drugs have real medical value, not just marketing value."

IRBs, she continued, "should not be the creatures of any interested party — they should serve the public. It's certainly inaccurate to refer to them now as 'independent.' Regional, public IRBs should be set up, and have much the same standing as NIH study sections. Service on such panels should count in promotion decisions and tenure."

Angell urged that, in 2002, when the Prescription Drug User Fee Act comes up for reauthorization, it not be renewed; "It's the camel's nose inside the tent." She conceded that her reform suggestions will take money. "FDA needs much better funding. The regional IRBs with their increased role will also need resources. But these issues are vital public health issues. The validity of the human research enterprise must be made less vulnerable to private financial pressures."

Noting that her views have resulted in her being labeled an "abolitionist," Angell said, "I'm guilty as charged. I am aware that my position is considered unrealistic. But the price of accommodating ourselves (to conflicts of interest — in terms of scientific quality and the welfare of human subjects) is just too high. That is what is really unrealistic."


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