Breaking the Trial Result Disclosure Logjam Now

The issues surrounding clinical trial transparency and disclosure of information regarding active clinical trials and clinical trial results are in the limelight as never before.

Photography: Comstock

It started with front-page headlines about the legal actions taken by New York Attorney General Eliot Spitzer against a handful of major pharmaceutical companies suspected of concealing negative trial results of marketed therapies. The issue has since snowballed to include primetime news reports and public outcries for disclosure from patient advocacy groups and influential organizations such as the American Medical Association, the International Committee of Medical Journal Editors (includes JAMA, NEJM, and others), and even the World Health Organization.

Faced with addressing this increasingly public issue, biopharmaceutical companies began taking proactive steps to make more clinical trial information available and easily accessible. Pioneering the industry's effort, Eli Lilly, GlaxoSmithKline, and Forest Labs have all developed online clinical trial registries on their corporate Web sites. The Pharmaceutical Research and Manufacturers of America (PhRMA) developed a registry with pledged support from its member companies. Even the International Federation of Pharmaceutical Manufacturers & Associations, which includes PhRMA and other industry trade groups, has developed plans for action. Most recently, Roche has begun posting what will be nearly 2000 trials for both ongoing and completed studies with a third-party commercial registry.

Almost all industry stakeholders support disclosure. However, even with all their influence, credibility, and respect in both the health professional and consumer communities, Congress would not let industry figure out the trial transparency issue on its own. Late this February, Congress took serious action.

Figure 1. Clinical trial disclosure-A rapidly changing landscape.

On February 28, 2005, Senators Charles Grassley (R-IA) and Christopher Dodd (D-CT) introduced legislation called the Fair Access to Clinical Trials Act of 2005—the FACT Act. The FACT Act calls for the current clinical trials registry located at www.clinicaltrials.gov to be rebuilt and expanded to include information about the results of clinical trials, and to apply to all clinical trials for drugs, biologics, and medical devices. A daunting task, the proposed legislation would require that:

• Trials must be registered in the data-base in order to obtain approval from a U.S.-based Institutional Review Board

• Researchers promptly disclose the objectives, eligibility criteria, sources of funding, and anticipated timeline of clinical trials

• Results of clinical trials be available to doctors and patients

• Strong enforcement mechanisms, including civil monetary penalties of up to $10,000 per day for sponsors that do not comply.

This is by far the most aggressive legislative action taken to date to force the issue of trial transparency.

Biopharmaceutical companies, as well as government researchers, are scrambling to figure out how they will respond if the legislation is ever passed with its current requirements. They are grappling with various challenges: how to collect all of the information internally and get it into the right format for posting; proper staffing for processing, posting, and maintaining this information; combatting competitors' use of detailed information to make adjustments to their own strategy; and last but not least, what results—positive or negative—are statistically significant enough to report.

Figure 2. Industry adoption takes hold.

Given the public outcry for this information, combined with the support of professional associations and trade groups, it would be easy to assume that this legislation will not only pass, but be highly effective in getting companies to bare all when it comes to information about their trials. But is legislation necessary? More importantly, will the passing of legislation result in full compliance? If history is any guide, the answer is no.

Learning from the past

In 1997 Congress passed the Food and Drug Administration Modernization Act (FDAMA), aimed at improving transparency of clinical trials information. As part of that legislation, $215 million was appropriated for creation of a public registry of clinical trials. It took nearly three years for the database to be developed and launched, finally going "live" as

clinicaltrials.gov

in April 2000.

At the time, there were an estimated 20,000 clinical trial listings posted on three existing online registries: the National Institutes of Health, the National Cancer Institutes' PDQ database, and the CenterWatch Clinical Trials Listing Service. Creation of an entirely new registry from scratch seemed frivolous, and a misuse of taxpayers' dollars. The NIH and NCI database housed nearly all government-sponsored trials, while CenterWatch.com housed nearly 8000 industry-sponsored clinical trial listings. Many believed that between these three registries the combined expertise and technologies could arrive at a solution at a fraction of the cost. Ultimately, the initiative moved forward without assistance from private industry, and the costs and timelines skyrocketed.

The new FDAMA legislation mandated that biopharmaceutical companies post listings in the registry for all of their ongoing trials for serious and life-threatening illnesses. Compliance with this aspect of the law would result in companies no longer needing to post many of their listings with commercial listing services. That was five years ago.

Today, there are over 1500 organizations actively posting clinical trials on commercial clinical trial Web sites. Nearly one-third of the companies posting trials are biopharmaceutical companies. There are an estimated 25,000 industry-sponsored trials listed, and traffic to these Web sites has nearly quadrupled since the year 2000. In fact, more than 12 million people will visit commercial clinical trial Web sites this year alone.

Now, some of these sites have begun to assist companies with improving transparency of their trial results. For example, CenterWatch, the oldest and perhaps largest database of active clinical trials, recently launched a trial results registry service that companies have started using as an alternative to building their own registry Web site. Many companies have been comfortable posting their trials with commercial publishers, pointing to their strong reputation and wealth of experience in data management. Nonprofit and government registries have enjoyed some success, especially when focused on a specific therapeutic area. It is surprising to learn, though, that the latest data available from the National Library of Medicine (NLM) shows that less than half the number of mandated industry-sponsored trials for serious and life-threatening illnesses are currently posted on clinicaltrials.gov.

The NLM did a tremendous job in creating an online resource that has had a positive impact in raising awareness about clinical research and making clinical trials information available to more people. The Web site is easy to find, easy to use, and includes powerful search tools and smart indices. However, the issue is whether this solution works any better than the pre-existing ones. Given the enormous dollars spent, the impressive amount of regulation supporting it, the length of time that has passed since it was created, and the disappointing level of industry compliance, it has not worked as intended.

What went wrong? It depends upon whom you ask. Many believe the reasons revolve around the sharing of intellectual property. Within protocol and result listings, a significant level of detail is required about the clinical trial. Most biopharmaceutical companies are not comfortable disclosing detailed trial data. Many of them feel that the required information goes far beyond the intended purpose of providing patients and their physicians with some basic information about the study.

Many companies feel that the level of detail required would create a self-inflicted disadvantage in the market. It would tip-off competitors about the types of drugs they are developing, outline the design of a trial, and allow competitors to adjust their own strategies accordingly. To top it off, the government wants the information up right away. Many companies argue that they are not ready to begin posting. They have to find the resources internally and develop a process for collecting, posting, and managing the data.

Unlike other clinical trial listing services, when a company posts trials on clinicaltrials.gov, the company does all the work. Therefore, many companies have to think seriously about bringing on full-time staff to get started and stay on top of this new initiative.

So what's the answer?

The fact is, companies are willing to improve transparency of their clinical trials information. Every day, companies continue to post clinical trials information online using commercial clinical trial listing services, patient advocacy groups, and health association Web sites, as well as government Web sites. The popularity of Web-based journals and health association Web sites continues to grow.

During the last eight years, tremendous improvements have been made to the accessibility of health information and information about clinical trials. The information has been available online since 1995, but most people did not have convenient access to it; truly high-speed Internet access has only been widely adopted during the last two to three years. Why, then, are we looking at passing more legislation and spending more tax dollars to build and expand government databases? Private companies with strong reputations, established infrastructure and resources, ample visibility, and broad distribution channels are willing to participate. They are being kept on the sidelines.

Is all the action to date simply Congressional grandstanding? Or is it a sincere effort at improving the quality and availability of clinical trials information? If the latter is true, then it is time for legislators and all other stakeholders to come together to develop a solution. They must place value on the existing resources that millions of patients and health professionals already turn to for this information. If the former is true, then we will find ourselves in the same situation eight years from now.

Dan McDonald* is vice president and Paul M. Molinari is alliances and licensing manager with Thomson CenterWatch, 22 Thomson Place, 36T1, Boston, MA 02210, (617) 856-5961, fax (617) 856-5901, email: daniel.mcdonald@thomson.com.

*To whom all correspondence should be addressed.