Who's afraid of the WHO?

Leaks and lawsuits initiate free clinical trials register

Researchers hope there'll be no more sweeping failed trials under the carpet

By Owen Dyer

The question that immediately springs to mind is: Who would have the clout to bully recalcitrant drug companies into signing up for such a project? And who would be disinterested enough in profit to provide such a service to everyone at no cost? The World Health Organization (WHO), that's who.

FRUITFUL LABOUR
The WHO has wanted to build such a register for years, mainly to facilitate cooperation between researchers and to level the playing field between well-financed Western researchers and their poorer cousins in the developing world. But the concept's been given new impetus by the growing realization that no existing public registry actually provides a balanced overview of research into any drug whatsoever, for the simple reason that failed trials aren't publicized.

The WHO's big chance came with the announcement of New York attorney general Eliot Spitzer's lawsuit against GlaxoSmithKline over the alleged concealment of adverse results from five trials of the antidepressant paroxetine (Paxil) in children and adolescents. The negative trial data came out in 1999, when one of the participating researchers, Dr Robert Milin of the Royal Ottawa Hospital, presented the findings at a meeting of the American Academy of Child and Adolescent Psychiatry. But more damaging was a leaked company memo published in the Canadian Medical Association Journal this past February, which stated that releasing the trial data would be "commercially unacceptable."

The trials suggested that paroxetine in children brings either no benefit over placebo, or a slight increase in suicidal thoughts. In February the FDA changed warning labels on a number of antidepressants including paroxetine, to discourage their use in children.

SNUFF OUT SUPPRESSION
The obvious way to prevent negative trials data being buried is to insist that all trials be registered on a database at the outset, before anyone knows how they'll turn out. The FDA attracted criticism over the paroxetine affair because there's a law in the US that decrees that all trials should indeed be registered on an FDA database at baseline. The database exists, but only a small minority of US trials are registered there, because the FDA has never enforced the rule.

In fact, according to Kay Dickersin, director of the Center for Clinical Trials and Evidence-Based Healthcare at Brown University, the 1997 law superseded a 1993 law that set the same requirement. "The FDA lacks teeth," she says. "It's a regulatory agency, not an enforcement body." FDA spokeswoman Susan Cruzan acknowledged that the FDA had never enforced the existing provisions, adding that the organization is considering requesting additional powers from legislators and hoping to set up a meaningful US register.

WHO'S ARMY
But the WHO isn't prepared to wait. They believe their unique links to national governments can provide a global registry with enrolment enforced at the national level � now. Dr Tikki Pang, the project's director, points to the Framework Convention on Tobacco Control, which signatory nations are obliged to enforce against tobacco advertisers. "We also look to national health research organizations, to funders and to publishers," he says. "For example, ethics review boards might insist that a trial be assigned a registry number. We've talked to the Canadian Institutes of Health Research about this."

The full-blown compulsory register will take years to put together, but the WHO has a plan to fill the gap. "Our initial effort will be aimed at providing a central virtual link to other, existing databases," says Dr Pang. But he acknowledges that such an approach cannot resolve the issue of unfavourable data going unreported.

The WHO already has an embryonic central database containing all WHO-sponsored trials in the fields of reproductive health and childhood diseases. WHO-sponsored vaccine and tropical disease trials are now being added. For the moment, the organization is concentrating on new trials, but eventually old trials will be added retrospectively � including even those failed paroxetine trials.

INTO THE PUBLIC DOMAIN
"It's crucial that the register be free, and open to lay people," says Dr Pang. "The other day I received an email from a man who said his son had a rare, fatal disease and he needed to find a trial to enrol him in. I never get emails from the general public. I was sure it was a pressure group posing as a patient's relative. But I checked it out, and the email was genuine. Our register must fill that need."

The WHO will announce its new trials register at an international research conference in Mexico City on November 16. "I think we'll have something fairly solid to put forward by the November meeting," says Dr Pang. "We've approached Eliot Spitzer to do some flag-waving for us. He's really put this issue in the spotlight."