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Industry has grown to accept CT registries
Lack of legislation has not stopped their spread
The clinical research community has begun to accept the presence of clinical trial registries, despite lingering questions about intellectual property rights and other issues.
Since the benefits of having research transparency might outweigh the harms, some experts wonder why IRBs do not use their oversight power to promote clinical trial registration.
Registration affords investigators the opportunity to use the registries, as well as literature reviews, as part of the explanation for why a particular study is needed, says Alexander M. Capron, LLB, professor of law and medicine, Scott H. Bice Chair in Healthcare Law, Policy, and Ethics, and co-director of the Pacific Center for Health Policy and Ethics at the University of Southern California in Los Angeles, CA. Capron spoke about clinical trial registries and databases at the annual conference of the Public Responsibility In Medicine & Research (PRIM&R), held Nov. 15-19, 2006, in Washington, DC.
"It would seem to me it would be beneficial for research ethics committees to be supporters of the use of clinical trial registries," Capron says. "It happens that nobody is in a better position to advance the use of clinical trial registries than IRBs."
IRBs had a huge impact on research in terms of forcing the research community to better explain itself, and they've made research better by spending time on the fine points of informed consent, Capron notes.
However, the question that is essential to an IRB's purpose is whether research is designed in such a way that it will produce results that are scientifically important and valid, Capron says.
"Since the IRB approval is needed before any trial can commence, research ethics committees could make a requirement that before a trial can be approved, they need notification from the investigator that the trial has been registered, and 'Here's the trial registry number,'" Capron explains.
To some, that idea might seem burdensome to IRBs.
When 50 representatives from the various research stakeholders met two years ago to discuss the future of pharmaceuticals, there were presentations about clinical trial registries and the common ground regarding all of the issues surrounding the topic, recalls Celia Fisher, PhD, director of the Center for Ethics Education and a Marie Ward Doty professor of psychology at Fordham University in New York, NY. Fisher also spoke about clinical trial registries at the PRIM&R conference.
"In the first draft of the Fair Access to Clinical Trials Act, IRBs were going to serve as gatekeepers and guarantee to the Food and Drug Administration (FDA) that indeed the research would be posted on a registry," Fisher explains.
"That seemed to be an undue burden on IRBs, who don't have enough money to begin with, and that's not their area of expertise," she adds. "So everyone agreed that it probably wasn't the best route to take."
Instead, the onus of proof that a trial is registered should come from the sponsor, Fisher says.
"It would be too costly and inefficient and unfair to burden IRBs with it," she says.
The stakeholders' sessions also raised questions about the purpose of registries and databases, Fisher notes.
When the International Committee of Medical Journal Editors (ICMJE) said they would no longer accept journal articles from studies that were not registered, the rationale was that there was some kind of bias for positive results in the published studies, Fisher explains.
This didn't mean a bias was intentional, but it existed, she adds.
"The science community basically sees studies that work and have significant differences," Fisher says.
So it would provide an additional check and balance to know about more of the studies that were conducted, she says.
"So if someone submits an article to the New England Journal of Medicine (NEJM), then NEJM editors can go back to the registry to see how many of these studies have been conducted," Fisher says. "It allows for peer review that is a little more sophisticated and has more knowledge about research in this area."
On the other hand, the journal editors' decision has only limited impact on registration because studies that lack positive results won't be published, and since they won't be published, the sponsor will not have to worry about registering them, Capron says.
"The purpose of the major journals, which are requiring clinical trial registries, is to have people register at the beginning of the trial, because if they don't do that, it doesn't do any good to do it at the end," Capron says.
Although legislation, called the Fair Access to Clinical Trials (FACT) Act, now in its third version before Congress, includes registry requirements, it is unlikely it will be passed soon, Capron says.
"It seems to me it is much more likely that if the IRBs at leading institutions start saying, 'Yes, this is a part of our process that we expect,' then we'll have the change and, eventually, it will make its way into a regulation," Capron says.
The next question regarding registries has to do with how much information should be included and how it should be used, Fisher says.
At the government-funded Web site: www.ClinicalTrials.gov, anyone can search for clinical trials about a particular topic and find a list of hundreds of ongoing trials. For example, a quick search under the topic "skin cancer" reveals 953 clinical trials, almost all of which are recruiting subjects.
Investigators can register any trial that has been approved by an ethics review board and that conforms to federal regulations. Registration takes place via a Web-based data entry system called the Protocol Registration System.
The Web site conforms with requirements by the ICMJE and advises lead sponsors of multi-sponsor trials to take responsibility for registration.
This type of registration provides patients with greater access to clinical trials, but that's only one aspect of registration, Fisher says.
Opening registries to more information could raise intellectual property rights questions, she says.
For example, how do you protect the rights of a company that is developing a new medication but does not want competitors to know?
"Before a product is FDA-approved or marketed, it may be necessary to protect the name of the sponsor, the name of the drug, and aspects of the ingredients," Fisher says. "So with that kind of research, it could still be required to be registered, but it would be company X or product X."
Later, the registry information would become available when the researchers submitted an article to a journal, giving the journal permission to look inside this lock box registry, Fisher explains.
Eventually, all of the information would be made public.
"So that was one of the things I thought was a nice combination of stakeholder interest in protecting intellectual property rights, and public interest," Fisher says.
Another issue involves the publication of databases that include all of the trials, including "good" and "bad" studies, Fisher says.
"The public doesn't have the scientific education to determine what's good or bad," she says. "What would be seen as a legitimate site in which they could review data, as well as know whether or not this study is based on a sample size that is small?"
It's not that some companies engage in unethical research, but some research simply cannot be generalized, so how could a database sponsor protect against misinterpretation and findings that appear more efficacious than they are, Fisher asks.
For example, critics of the FACT Act have said that it would be difficult to evaluate trial information included in a database, she says.
"If the company itself was required to interpret it, there would be other legal issues that would arise," Fisher says. "There would have to be nonpromotional language in the database."
Also, could all of the audiences that a database serves be well-served with one database?
"I think it's a great idea, but it could really backfire if it's not done right because there would be no peer review," Fisher says. "Do we want something like Wikipedia, which is a consumer-beware site where you don't know what's right or wrong?"
Physicians and others are concerned about liability issues with a large database of trials. For instance, would a physician then be expected to check this database for every trial ever conducted for a new drug before prescribing it?
"They neither have the time nor expertise to go through that much information," Fisher says. "That's why we have medical journals, because there's a guarantee that scientists can draw upon that information."