Antidepressants and children debate yields lessons for IRBs 

IRBs seen as checking point in clinical trials registry

The recent warnings that children using certain antidepressants may be at increased risk to become suicidal — and charges that previous studies pointing out the problem were kept from public view — have reverberated throughout the research community.

The controversy could have a long-term impact on the work of IRBs — from their participation in a new recommended clinical trials registry to causing boards to review such issues as placebo controls, say those who have studied the issue.

The antidepressant debate also reinforced the need for careful study of drugs first being used with children, says Richard Gorman, MD, FAAP, chair of the American Academy of Pediatrics’ Committee on Drugs, and a member of an FDA advisory panel that recommended a so-called black box warning on antidepressant drug labels.

"[Antidepressant use] was something that we had a real sense of comfort with, from the fact that it had such a long, widely used and minimally reported side-effect profile in the adult population," he says. "IRBs, as they move forward in their reviewing and questioning and examining protocol design and safety monitoring, have to remember that these drugs have not been studied in this population before.

"Pediatricians say over and over again, Kids are not little adults.’ This was a case where children turned out not to be little adults," Gorman says. "I think that’s a message to take home as a cautionary tale — to remember that drugs, widely used, perceived as safe in the adult population, when they’re studied in children may have different benefit profiles and different risk profiles."

Currently, Prozac (fluoxetine) is the only drug that is FDA-approved for use in children and adolescents for the treatment of major depressive disorders. However, a number of other antidepressants have been prescribed for children off-label.

In October, the FDA issued a public health advisory, warning that children and adolescents being treated with antidepressants are at increased risk for suicidal thoughts and behavior. The agency directed drug manufacturers to add a black box warning to the labeling.

The labels would warn health professionals of the risk and advise them to closely monitor young patients taking the drugs.

The FDA’s Psychopharmacologic Drugs Advisory Committee and Pediatric Drugs Advisory Committee jointly recommended the new warnings after reviewing evidence from two dozen clinical trials and listening to testimony from physicians and from parents whose children committed suicide after being treated with antidepressants.

There were no suicides among the children in the clinical trials that the panel reviewed — an important point, reports Robert M. Nelson, MD, PhD, associate professor of anesthesia and pediatrics at The Children’s Hospital of Philadelphia, also a member of the FDA panel.

He says because the children in the trials were being closely monitored, he would conclude that getting the drugs within the research setting was much safer than getting them as an off-label use.

"I think both the public and the IRBs need to be cognizant of the fact that the choices here are not between research and don’t use the drug at all. They’re between research and off-label use," Nelson says.

He says just because an IRB disapproves a carefully controlled pediatric study of an antidepressant drug doesn’t mean the drug won’t be dispensed off-label to children — even at its own institution.

"I realize that IRBs don’t think they’re supposed to evaluate the sort of policy implications of what they’re doing," Nelson says. "But on the other hand, I don’t think we can put blinders on and ignore the fact that that’s the choice."

New registries could involve IRBs

Earlier this year, New York Attorney General (AG) Eliot Spitzer sued GlaxoSmithKline, manufacturer of Paxil (paroxetine), one of the drugs involved in the review. He alleged that the drug company withheld studies that had suggested a possible increased risk of suicidality.

In August, GlaxoSmithKline signed a consent order with Spitzer’s office. While the company called the AG’s charges "unfounded," the company agreed to continue posting on-line all company-sponsored clinical studies of Paxil in children and to create a clinical trials registry to provide Internet access to clinical trial data on its marketed medicines.

The drive for a publicly accessible clinical trials registry for all pharmaceutical research is proceeding on various fronts:

  • The trade group Pharmaceutical Research and Manufacturers of America (PhRMA) announced the creation of an on-line database, www.clinicalstudyresults.org, containing information about the clinical trial results of studies sponsored by its members.
  • The International Committee of Medical Journal Editors announced in September that researchers will have to register their clinical trials with a publicly accessible database to have their reports considered for publication in any of the top-tier medical journals. That requirement would affect research that begins enrollment after July 1, 2005; studies already under way would have to register by Sept. 13, 2005.
  • The Fair Access to Clinical Trials Act was introduced in both houses of Congress in October. The bill would require researchers to report all results from clinical trials for drugs and medical devices, using the existing www.Clinicaltrials.gov database. Most importantly for IRBs, the act would mandate participation in the registry as a prerequisite for IRB approval.

If a federally mandated registry ever becomes law, then IRBs are the logical checking point, says David Korn, MD, senior vice president for biomedical and health sciences at the Association of American Medical Colleges. But he says the plan needs to be crafted carefully, both to minimize the burden on already overburdened IRB staffers, and to avoid needless registration of trials.

Korn says requiring a researcher to register his or her clinical trial proposal before submitting it to the IRB for review could result in studies being registered that are never approved.

"There’s no point putting stuff in a registry that’s never going to happen at all," he says. "It would be better to have IRB approval conditioned on registration of that particular trial," a process Korn says could be made relatively painless by technology.

The IRB tentatively could approve the trial, but withhold formal notification for a few weeks, requiring the investigator to register the trial in whatever national registry becomes the standard, he says. The registry could have a function that automatically notifies the IRB once a trial has been registered: "Sort of like when you order something on the web, on Amazon or wherever, and you get an e-mail back."

The job of the IRB would be simply to ensure that notification from the registry gets filed with the proper trial. That could then trigger a formal notification of IRB approval to the investigators, Korn says.

"I think the IRB’s the right place to do this," he says. "And we are in an age of advanced technologies, where things that used to be very burdensome can now be done with a double-click or the press of a key. However this is set up, it should be set up to be minimally burdensome."

Gorman, a researcher who served on an IRB for 14 years, agrees that IRBs are up to the task of monitoring such a system.

"IRBs live by regulations," he says. "We are sensitive to regulations and therefore we’ll find ways to implement them without much disruption to our operations.

"This, compared to HIPAA, is nothing. HIPAA was a major nightmare; this is a little speed bump."

But what if the proposal never becomes law? Could IRBs decide on their own to refuse to approve studies that aren’t registered with a public database, or to require that results from the studies be made available to the public?

Gorman says that’s unlikely. "We have no control or power or ability to cajole, force or mandate that negative trials reach public light," he says.

Nelson notes that an IRB that requires registration could find itself at a disadvantage if the sponsor could go to another institution that doesn’t require it.

"If everybody does it, there’s not going to be a problem," he says. "But if there are holes, then individual IRBs could be put in a bind as to whether they should hold the company to this standard, knowing they might then just withdraw the protocol and go elsewhere."

But Nelson says he’s hopeful that the litigation risk introduced by Spitzer’s lawsuit against GlaxoSmithKline will lead to a standard for registration of trials and publication of all results, even if that’s not federally mandated.

"I would say that if someone doesn’t do it, there would be a way that if that drug is sold in New York, that Eliot Spitzer would go after them," Nelson says. "And I would say that’s a good thing."

Korn says it’s unclear at this point what form the publication of results might take — whether it would include a notation in the registry and, if so, what amount of detail would be required.

"Even a brief entry would at least give people a piece of information — maybe the trial failed to demonstrate what [the sponsor was] looking for, or it was costing too much money and the company lost interest," he says. "That’s a way of publishing it, putting it in a publicly accessible database that can be accessed by those who have interest in knowing about it."

Nelson says keeping track of such follow-up information could easily fit within an IRB’s existing continuing review process.

Placebo controls — important for safety

Beyond the logistics of registries and publication of results, the debate over antidepressants also points to a number of lessons for IRBs, say Nelson and Gorman.

Both say the issue underlines the importance of placebo-controlled trials when a drug is introduced to a new clinical population.

"There was a time when people would have argued, Oh, it’s unethical to give placebos when you’ve got proven effective treatment for depression,’" Nelson says. "Well, the only way these data came forward is with placebo-controlled trials. People often think of placebos purely in terms of efficacy. But placebos are part of safety evaluation, too.

"I think IRBs are going to have to think through carefully issues of research design in a much more sophisticated way and recognize that in fact, there may be important questions that need to be answered that can only be answered with the conduct of appropriately controlled trials."

Gorman says it’s also important to have studies that use real-world populations, not just narrowly controlled groups.

"On some of our IRBs, we get used to the Phase 3 pharmaceutical controlled clinical trial, which tends to be a very select, narrow population, looking for a fairly select and narrow indication," he says. "And that’s not how drugs get used when they go out into the real world. They get used in complicated people on other medicines.

"I think we need to start thinking about including those people. Excluding them is safer for the clinical trial, it’s true, but it then becomes more risky for the population when it gets generalized," Gorman adds.