Trials and Tribulations

Did sponsors of pediatric antidepressant studies sweep unfavorable results under the rug by failing to publicize ones showing product ineffectiveness? That was the line of questioning directed at medical officers from GlaxoSmithKline and Forest Laboratories by members of the House Energy and Commerce Committee at a hearing in September. The panel's most pointed questions, though, were aimed at FDA officials who had not responded adequately to requests for information.

Jill Wechsler

FDA Acting Deputy Director Janet Woodcock, in the hot seat, explained the legal curbs on what FDA can disclose and why it wanted all major antidepressants to carry the same cautions instead of allowing some manufacturers to strengthen label warnings.

Rep. Henry Waxman (D, California) said he is developing legislation to mandate drug trial registration, including information on sources of funding and anticipated timelines. He vowed to put teeth in the program by linking trial registration to institutional review bureau (IRB) protocol approval and by levying fines on noncompliant sponsors. He also threatened changes in current six-month pediatric exclusivity policy to deny patent extensions to sponsors that "don't tell the whole story." He and other legislators want to limit the provision to products that change labels as a result of new pediatric studies.

Better Late Than Never

To head off reformers, sponsors are listing more studies at ClinicalTrials.gov after years of making excuses for not doing so. Pharma companies also say they will make public clinical trial results—negative and positive—to help doctors practice better medicine.

Pushing for Disclosure

The clamor over unbalanced drug data erupted in June when New York attorney general Eliot Spitzer charged Glaxo with concealing clinical results on the safety and efficacy of the antidepressant Paxil (paroxetine) when used by children. Glaxo denied any wrongdoing but agreed in August to post on the internet summaries of all its clinical trials conducted after December 27, 2000. Spitzer also pressured Forest, marketer of the selective serotonin reuptake inhibitor Celexa (citalopram), which similarly promised to create an online registry of clinical trial results.

Open Access to NIH Research Worries Journals

Other health organizations quickly made linking trial registration to public disclosure of trial results the key issue:

• The American Medical Association (AMA) called for a comprehensive registry of all clinical trials conducted in the US to track research activity and ensure public access. Already overloaded IRBs would make public registration a condition for approving protocols, an added chore that hasn't pleased them.

• The World Health Organization (WHO) proposed to create an international clinical trials registry slated to be discussed by national health ministers in November.

• The Pharmaceutical Research and Manufacturers of America (PhRMA) announced last month that it will establish a new online database with summaries of unpublished clinical trials sponsored by members. A voluntary program limited to "hypothesis testing" studies, which exclude early-stage exploratory trials, it applies only to drugs approved in the United States, and will not require companies to list incomplete studies or provide raw data.

Eli Lilly had announced plans to post data from its trials for recently approved drugs, and Merck said it would add trial results to its listings on the FDA website. These companies and others may shift disclosure activities to PhRMA's site, where they can post more information, such as earlier or successful studies, if they so choose.

Registration Drive

While PhRMA's initiative aims to expand disclosure of clinical trial results, FDA's

ClinicalTrials.gov

. website, mandated by the FDA Modernization Act, provides a basis for registering and tracking human studies when they begin enrollment. Sponsors are required to describe the purpose of each qualifying experimental drug entering Phase II plus enrollment criteria, site locations, and point of contact.

But the site has not achieved its goals. (See "Better Late Than Never,") The failure of many companies to provide information on hundreds of eligible studies is driving efforts to strengthen the program. One idea is to have FDA post information about clinical studies on the database by extracting relevant data from investigational new drug applications (INDs). Some critics—not FDA officials or patient advocates—want to impose clinical holds or delay approvals for unlisted products.

In September, the International Committee of Medical Journal Editors, a group of 11 publications including the Journal of the American Medical Association, the New England Journal of Medicine, and Lancet, offered a new inducement. Effective July 2005, these journals will publish articles on drug trials only if the subject studies were previously listed on a public, non-profit site by the onset of patient enrollment. The editors regard comprehensive public listing of human subject studies as a necessary first step toward disclosure of research, whatever the results.

Volunteer—or What?

The most direct way for Congress to encourage complete disclosure of clinical trials data would be through FDA. But that would require new legislation.

Pharma companies filing new drug applications are already required to submit all data from all clinical studies. Much of the information is proprietary, though, and never disclosed. The Best Pharmaceuticals for Children Act of 2002 gave FDA authority to post summaries of pediatric trials, including studies that fail to lead to approved labeling. But it does not apply to adult studies. FDA issues its own review of clinical data when it approves a new drug. But the results of research that FDA never approves do not reach the medical community unless sponsors publish the data voluntarily.

Observers remain skeptical that the industry's voluntary efforts will fill the information gap. PhRMA says an independent third party will manage its research database, and according to vice-president Caroline Loew, top company executives have made an "extremely strong commitment" to the program. Manufacturers are meeting with the AMA, patient groups, and other parties to iron out specifics such as which trials should be registered and disclosed. One challenge for manufacturers will be providing information on off-label studies without promoting off-label uses. Another is listing information expeditiously despite frequent long delays in article publication.

PhRMA tried to impress upon legislators that its initiative will provide access to data immediately, while a legislative route could take years. BPCA will be up for renewal in 2007, along with FDA user fees. That gives the industry two years to carry out its registration and disclosure promises.