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Clinical Trial Transparency: Registries, Databases Raise Questions, Stir Debate

Steve Benowitz

Although clinical trial registries and results databases have enjoyed renewed support among many patients and their advocates, physicians, scientists, and government officials, there is no shortage of opinions about what they should include and how they should be implemented and used. Complicating matters is the fact that there are more than 350 different registries, many run by single institutions or organizations.

Clinical trial registries have been around for decades, but several events in the last 2 years—including questions about the safety of using antidepressants in children and the cardiovascular safety of several cyclooxygenase 2 inhibitors—have sparked renewed interest in establishing a mandatory reporting requirement for all clinical trials. Many supporters also maintain that those trial registries or some other database system should pair up a study's results with its original protocol. (See News, Vol. 97, No. 6, p. 410, "Clinical Trials Registration Efforts Gain Some Ground.")



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Richard Schilsky

 
Proponents of registries maintain that safety issues such as those with Paxil (paroxetine) and Vioxx (rofecoxib) could have been avoided if all studies of the drugs were made public and tied in with their results. Registries that include all trials and all the related data, both positive and negative, may cut down on the bias toward publishing only positive clinical trials, and as a result provide a clearer picture of all studies of a drug, not merely those published in medical journals or presented at meetings.

From an academic investigator's point of view, there is a benefit to seeing what trials have and have not been done, said Richard Schilsky, M.D., associate dean for clinical research at the University of Chicago and chair of the Cancer and Leukemia Group B, a clinical trials cooperative group. Knowing which trials are in progress, their status, and preliminary results can help reduce redundancy and facilitate the next generation of trials. And having such information widely available may increase clinical trial participation, said Celia Fisher, Ph.D., director of the Center for Ethics Education at Fordham University.

For some, the rationale behind registries comes down to the public's right to know. "The public has a lot of investment in clinical trials," said Kay Dickersin, Ph.D., professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health. "Patients sign consent forms about contributing to the public good and general medical knowledge. They have a right to see information about the trial and results be available."



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Kay Dickersin

 
Registry, Database Limitations

But is more always better? Does increased availability of trial information and results really translate into better-informed consumers? With thousands of clinical trials in the mix, the goal of greater trial "transparency" brings a litany of potential problems.

While acknowledging the potential benefits of increased trial openness, Felix Gyi, Pharm.D., questions the value of more data. "Data without perspective is still data, and not information," said Gyi, chief executive officer of Chesapeake Research Review Inc., a Columbia, Md.–based organization that provides consultation, education, and training in human research subjects protections and independent institutional review board (IRB) services.

"Just to say you want data available to hold people accountable and responsible on the surface sounds like a good thing," said Gyi. "But transparency just for the sake of transparency isn't. Just because data are out there, we are not necessarily better informed."

On some level, making such information available in a database might be useful to researchers—but not necessarily to patients and patient groups, which have been vocal in the call for clinical trial registries.

"[Clinical trial protocols] are communication tools for researchers and physicians, written to be scientifically accurate and precise—and extremely complicated," said Maurie Markman, M.D., vice president for clinical research at the University of Texas M. D. Anderson Cancer Center in Houston. Eligibility criteria can be complex, for example. "What does it mean to have prior treatment with X but not Y? What does a grade 2 tumor mean?" he said. "What are the differences between an active and a placebo-controlled trial? It can be frustrating to patients and their families to think information is available and to find out it isn't always. It can be an overwhelming amount of data."

He questions whether having trial results published in a database will be useful to patients. "They may have different reasons for wanting such information, but it doesn't always translate into knowledge they can easily deal with." M. D. Anderson, he noted, has its own trial registry for patients and also registers its trials with clinicaltrials.gov.

Fisher agrees about the need for some sort of filtering mechanism. Each company seems to have its own rationale and rules for posting data, she said. Trial results that find their way to the Internet prior to publication and U.S. Food and Drug Administration review might not be helpful to the average person. "There are many studies that were designed well, but because of patient attrition and other reasons, don't necessarily turn out the way they might have otherwise," she noted. "Consumers and most practitioners don't have the scientific expertise to look at the data and methodology and say, ‘This is why it turned out this way and can't be conclusive.’"

At the same time, posted information could be misused. "If you don't understand the nature of trials and what they mean, it's easy to come to wrong conclusions," said Gary L. Stiles, M.D., executive vice president and chief medical officer of Wyeth Pharmaceuticals in Collegeville, Pa., which maintains its own registry of clinical trials that will available next year in addition to registering trials with clinicaltrials.gov and the database maintained by the Pharmaceutical Research and Manufacturers of America (PhRMA).

He said that it's probably not widely recognized by the public that more than one study is typically required to prove the effectiveness of a drug, for example. "A negative study could be picked up while a drug is under development and could inappropriately set public opinion that drug X is worthless," he said. "The public needs to recognize that drugs are variable in patient response, and multiple studies are needed. Negative studies are not surprising for some drugs."

Misleading data might influence treatment decisions as well. Although physician groups maintain that trial results can help doctors assess information to make treatment decisions, clinical decision making isn't necessarily improved by having unfiltered evidence available, Gyi said. "How many doctors would take the time to look through raw data and analyze it, then make a treatment decision?"

Industry Concerns

Although most registries, including clinicaltrials.gov, don't require registration of early, phase I studies, the call by some to register all trials is a concern for the pharmaceutical industry, which continues to be wary about the potential lack of protection of intellectual property. Posting information on unapproved therapies, for example, and exploratory studies could hurt such protections. Even candidate drugs that fail in exploratory trials can yield important insights to other research directions and form the basis for future trials. Whereas many companies tend to have some ideas of what competitors have in the development pipeline, specifics about investigational agents may not always be widely known.

Fisher noted that the biotechnology industry is particularly "nervous" about trial transparency because premature reports could hurt investments in companies that rely on very few products.

But pharmaceutical companies that sponsor clinical trials are seemingly committed to making some efforts toward increased transparency. "Companies recognize the importance of trial transparency" and of building public trust, said Caroline Loew, Ph.D., vice president for scientific and regulatory affairs at PhRMA.

PhRMA, which launched its registry site, clinicalstudyresults.org in October 2004, provides summary results of pharmaceutical company trials, though only a small fraction of such trials have been posted. Many companies, such as GlaxoSmithKline and Eli Lilly, put results in their own databases. Loew noted that many such registries were created with physicians in mind, to ensure that they "had the whole picture of drug safety."

But according to some, that commitment has limitations. "It's clear that there have been less than enthusiastic responses from some companies," noted Edward Campion, M.D., senior deputy editor of the New England Journal of Medicine. "Some companies will say they will participate in registering trials, but then put in vague, sometimes useless information."

"Information about interventions tested and outcomes examined, sample size used, even the scientific title of the study are elements that PhRMA would like to see suppressed or at least held in escrow until a later time," Dickersin added. "This calls into question the purpose of trial registration."

Although IRBs can play an important role in meeting a goal of greater trial transparency, "the push needs to be in the public's understanding and expectations of how drugs are brought to the market and what we do with them," Gyi said. "Fewer than 5% of cancer patients participate in research. Trial registration might be a noble thing, but it doesn't really have an impact yet in areas we want it to, such as in recruitment and in enhancing protection of people participating in research."



             
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