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Industry-Funded Versus Publicly Funded Trials: Are the Standards the Same?

Tom Reynolds

The rise of randomized controlled trials as the gold standard for answering important clinical questions tops many lists of key advances in scientific medicine during the past half century.

In recent years, along with rapid growth in the number of trials testing new drugs or new uses for existing drugs, a major shift has occurred in how these trials are funded and carried out. Twenty years ago, most trials in the United States were supported by the National Institutes of Health and conducted at academic medical centers.

Now, the majority of trials are paid for by the drug’s manufacturer. Trials can involve a hundred or more centers and thousands of patients. They are carried out in academic medical centers, public and private hospitals, and private physician practices. How has this shift and industry’s increased involvement in it affected the clinical trials system?

Many clinical trials today are conducted or managed by contract research organizations (CROs), profit-making companies that serve the pharmaceutical, biotechnology, and medical device industries. Some large CROs offer a full range of services including chemical synthesis, preclinical and clinical testing, submission of data to the U.S. Food and Drug Administration, and packaging and marketing of drugs. Others focus on specific aspects of the drug development process. The largest CRO, Quintiles Transnational of Research Triangle Park, N.C., reported revenues of $1.66 billion in 2000.

In a lecture at the NIH in May, Marcia Angell, M.D., former New England Journal of Medicine editor and now senior lecturer in the Department of Social Medicine at Harvard Medical School, Boston, called for the abolition of for-profit CROs. Either an independent public agency should be created to fill the role of CROs, she said, "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."



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Dr. Marcia Angell (Courtesy of Harvard Medical School)

 
"It’s not so much the source of the funding as the terms of the funding," Angell said in an interview. "Where it used to be arm’s-length, now the drug companies are tying strings to their grants: we’ll design the study, we’ll keep the data, we’ll write the paper and decide whether it’s published or not. That gives them enormous control over the evaluation of their own drugs."

Jeff Trewhitt, a spokesman for the Pharmaceutical Research and Manufacturers of America (PhRMA), countered that stringent FDA criteria for drug approval make it irrelevant who is performing the trial—all must meet the same standards.

"It does nobody any good to play fast and loose with the scientific data. If you do not have sound scientific credibility, you are going to hurt yourself not only with patients and doctors, but also with the FDA, which has to approve your products to get on the market."

Richard A. Gams, M.D., is president and chief executive officer of Prologue Research International, a CRO in Columbus, Ohio, that focuses on oncology drugs, and former director of developmental therapeutics at Ohio State University Comprehensive Cancer Center. He echoed PhRMA’s statements.



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Dr. Richard A. Gams

 
"The pharmaceutical industry is a highly regulated industry," he said. "There are hundreds of people looking over our shoulders. . . . There are standard operating procedures in place, you’re audited by quality assurance groups . . . and if things don’t check out, if we don’t have absolute documentation and source verification, none of it is acceptable" to FDA.

"Nothing like that exists in academic research," he added. Gams has been on auditing teams for NIH contract sites, and he said that their quality assurance was rather relaxed—"nothing like the kind of scrutiny that the quality assurance people in industry give."

Bertram A. Spilker, M.D., Ph.D., PhRMA’s senior vice president for scientific and regulatory affairs, added that Angell exaggerates and misrepresents the CROs’ involvement in clinical research. CROs carry out 80% to 90% of phase I trials, he said, but in 95% of phase II and III trials the companies act only as "coordinating middle men" between drug companies and the academic or community physicians who actually treat the patients.



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Dr. Bertram A. Spilker

 
Gams said that for the most part, CROs are not replacing academic researchers but are performing functions that drug companies used to do in-house, such as data management, data analysis, reporting, and quality control. His company, Prologue, was spun off from Ohio State but is now independent and works with clinical investigators at Ohio State and many other universities who treat the patients on the trials.

Too Many Trials?

Critics also charge that competition among companies has brought about too many trials that are aimed at approval or expanded application of "me-too" or "copycat" drugs—agents that are very similar to a competitor’s product already on the market.

"I can’t see any scientific reason for 40,000 to 60,000 clinical trials," a range commonly estimated for current trials, Angell said. "There are almost certainly way too many. One reason is to get copycat drugs approved and to do post-marketing studies of those drugs to find some small difference that can be exploited in marketing."

There is evidence to suggest that purely in terms of trial design and scientific rigor, industry trials are at least equivalent to academic trials. In research published in the Lancet last year, Benjamin Djulbegovic, M.D., of the H. Lee Moffitt Cancer Center, University of South Florida, Tampa, and co-authors graded the quality of 136 randomized trials of drugs to treat multiple myeloma. Industry-funded trials received a slightly higher average quality score (a mean score of 2.94 out of a possible 5) than government- or nonprofit-funded trials (mean score 2.4).

But Frank Davidoff, M.D., clinical professor at the University of Connecticut Medical School, Farmington, and editor emeritus of Annals of Internal Medicine, noted that technical excellence does not equal scientific importance, and that many industry-sponsored trials are for trivial or ‘me too’ drugs. "And even extremely well-conducted industry trials can be, and sometimes are, reported with a definite marketing ‘spin,’" he added.



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Dr. Frank Davidoff

 
Bias in Publications

In their study of multiple myeloma trials, Djulbegovic and colleagues found that 74% of industry-funded trials favored the new therapy over standard therapy, compared with 47% of nonindustry-funded trials. Much of this difference was attributable to the fact that 60% of industry-funded studies compared the new treatment to placebo or no treatment, versus only 21% of nonindustry-funded trials. (In cancer, placebo-controlled studies are usually limited to prevention trials and to cancers with few treatment options and poor prognoses, such as multiple myeloma.)

Lisa A. Bero, Ph.D., associate professor in the Department of Clinical Pharmacy at the University of California at San Francisco, and Drummond Rennie, M.D., adjunct professor of medicine at UCSF, noted in a 1996 article that the choice of drug to be given to the control group can influence a trial’s outcome. An ideal trial would compare the new drug both with placebo and with a competing product, but this is rarely done, and placebo-only comparisons are frequently chosen to maximize chances of finding a statistically significant difference.

"By excluding comparisons with competing products, the sponsoring company can introduce a bias toward finding results that can be used to promote its products," Bero and Rennie wrote. "It is the marketing department, not the science, that is driving the research."

But Spilker pointed out that the choice of a comparison treatment varies greatly depending on the disease and other available treatments. In most cases, a placebo-controlled trial offers the most definitive test of a drug’s effectiveness, he said, because when two drugs are tested only against each other, neither drug may be superior to placebo.

Davidoff acknowledged that the pharmaceutical industry makes an easy target and sometimes is unfairly demonized. But he said the pressures of turning a profit can have negative consequences.

"There are a lot of very smart, very capable, and ethical people in industry, and I think a lot of the work is of extremely high quality," he said, "but perhaps not surprisingly, those kinds of pressures sometimes lead people to do things that serve the commercial agenda of selling drugs more than the academic agenda of finding and reporting scientific truth."

No One Immune

But neither are academic researchers immune to pressure, noted Gams. "The concept that the university researcher is independent is a myth," he said. "The fact is that promotions, tenure, being invited to international meetings, to publish papers, to get on editorial boards of major journals . . . all depend on the success of research. So to think that the university researcher is somehow purer than the driven snow and would relish the thought of reporting negative results—nothing could be further from the truth."

A group of journals including Annals of Internal Medicine, Journal of the American Medical Association, the Lancet, and the New England Journal of Medicine issued a joint editorial in September announcing that they will publish industry-sponsored trials only if the sponsors guarantee the scientific independence of the investigators. Davidoff said the decision was made in response not only to a few egregious and highly publicized cases when companies tried to block publication, but to many less well-known cases as well.

"More subtle, and probably a lot more common, are the little tweakings and the spin that are put on data—those are harder to recognize and harder to deal with," he said.

Spilker acknowledged that "there may be some examples" of the kinds of situations the journal editors are reacting to. But he said the pharmaceutical industry "supports high standards of science and medicine, and we are not against any policies that will improve the standards of scientific reporting." However, such policies should not single out industry researchers, because there may be an equal number of problems in academic research, he added.

Networks For Research

Several leading university medical centers, seeking to regain a share of the lucrative clinical research enterprise, have begun wooing pharmaceutical companies by forming networks or institutes for clinical research. They promise both the reputation of quality that comes with the university name and the expeditiousness that drug makers demand. Instead of working in separate spheres, the universities are promoting themselves as partners and colleagues with pharmaceutical companies.

This academic-industrial collaboration "completely changes what academia has always been about in the past," Davidoff said. "Is that bad? That’s an open question."

Angell was less uncertain. "What is the mission of an academic medical center?" she asked. "Surely it’s not to serve the drug companies. But increasingly that’s how the academic medical centers see themselves."



             
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