An idea has been brewing quietly for years among doctors, healthcare policy wonks, medical journal editors, and others who make it their business to keep a close eye on the workings of the pharmaceutical industry. In recent months, ordinary citizens, and the politicians who want their votes have become fired up about the issue, too, and the new pressure could help make the idea a reality: Pharmaceutical companies may soon be required to register their clinical trials and publicly disclose the results, whether they show a drug in a positive, negative, or lukewarm light.
The industry says it is willing to register some trials on a voluntary basis. But a battle over which studies should be made public, and at what stage the protocols and results should be revealed, is almost certainly forthcoming. Drug companies worry that revealing too much too soon could tip off competitors. Legislation is pending, however, and top medical journals have recently banded together, refusing to publish trials that are not registered in a public database.
The issue caught the media's attention in June when New York Attorney General Eliot Spitzer charged GlaxoSmithKline with suppressing data for its blockbuster antidepressant, Paxil. The data suggest that Paxil might not be effective in children and could even increase the risk of suicidal thinking in some patients, Spitzer said. The allegation hit the headlines, and, picking up on the public's anger, legislators vowed to force drug firms to be more open about negative study results.
GlaxoSmithKline settled with the attorney general in August. The company paid $2.5 million and agreed to create a publicly accessible online database that would house summaries of all its clinical trials. In early October, citing the GSK case as an impetus, a group of lawmakers introduced the Fair Access to Clinical Trials (FACT) Act, which is an effort to increase the transparency of clinical trials for drugs, biologics, and medical devices.
The legislation's sponsors include Sen. Chris Dodd (D-Conn.), Sen. Edward Kennedy (D-Mass.), Rep. Edward Markey (D-Mass.), and Rep. Henry Waxman (D-Calif.). Waxman is already well known to the pharmaceutical industry for coauthoring a landmark bill that made it easier for inexpensive generic medications to compete with brand-name drugs.
The 48-page bill calls for a mandatory, electronic clinical-trial registry to be run by the government. The bill would require companies to post information about a study before patient enrollment begins and to publish a summary of the results – whether positive, negative, or inconclusive – once the study is complete. The registry would operate as an expansion of clinicaltrials.gov, which houses a database established in 1997 that is run by the government's National Library of Medicine. Currently, only studies of drugs for serious diseases must be registered in the database, and companies are not required to provide results of the trials.
The FACT Act would require all US Phase II, III, and IV trials to be registered, with updates provided every six months until a summary of the final results is posted. Study sponsors who fail to comply would face civil penalties of up to $10,000 per day and would be ineligible to receive government grant money or contracts. In addition, Institutional Review Boards (IRBs), the committees responsible for green-lighting studies before enrollment begins, would be instructed to withhold approval for unregistered studies.
Because the FACT Act was introduced just before Congress adjourned, the bill is unlikely to be acted on for some time. The legislation will need to be reintroduced when the next Congress convenes in January, and it will almost certainly be the subject of lengthy hearings before any action is taken. "Anything introduced so late in the Congress is a demonstration, a march up the hill," says Burt Rein, a partner in the Washington, DC, law firm of Wiley Rein & Fielding, who has expertise in healthcare law. "But this is Mr. Waxman's way of saying, 'I'm going to bring it back."'
STRIKING A BALANCE
Pharmaceutical Research and Manufacturers of America (PhRMA), the industry's main trade group, isn't saying much about the new legislation yet. However, it seems a good bet that the group will raise objections to the proposed requirements once Congressional debate begins, in part because drug companies are worried about tipping off competitors to what they're working on.
"Companies are not going to want to disclose a protocol in a public venue so that competitors will have a good understanding of their drug-development program," said Alan Goldhammer, PhRMA's associate vice president for regulatory affairs, in September during a panel sponsored by the American Enterprise Institute, a Washington, DC-based conservative think-tank. "This is going to be one of the real significant issues between PhRMA and its member companies and where we've seen some of the proposals come in."
Rep. Markey says that the FACT Act strikes "a careful balance" between protecting proprietary information and guarding the public health. "The FACT Act explicitly forbids the government from disclosing any trade secrets and ensures that the information available to the public in the databank is limited to very basic summary information about the trial," he says. "Since we are particularly concerned about protecting the earliest stages of drug development, the FACT Act exempts Phase I trials from this registry and also provides that definitions of the primary and secondary outcomes of a trial not be disclosed until after the trial has been completed."
Rein says the issue of how to protect companies' competitive information should be the subject of serious debate going forward. "As we push in one direction for prompter, better disclosure and registration of clinical trials at a very early date, which is the scientific optimum, is that compatible with the financial incentives that lead people to do the research in the first place?" Rein asks. "And, if it's not, then how do you adjust the two goals?"
A VOLUNTARY ALTERNATIVE?
In an apparent effort to forestall legislation of the FACT Act, PhRMA recently launched its own database
The site has been up and running since early October and so far contains only a handful of studies. PhRMA says that all of its member companies have committed to participating and that the database will grow as time goes on. The trade group plans to hand off the management of the site to an independent party in the near future.
PhRMA spokesman Court Rosen maintains that the database was also designed with physicians' needs in mind. "When a drug application goes to the FDA, there can be a truckload of paper," he points out. "In terms of providing physicians with information that is actually useful, by and large that is information from Phases III and IV." Rosen says companies are welcome to use the database to post earlier-stage results if they believe that the data might have some bearing on clinical practice.
Ron Davis, a trustee of the American Medical Association, says that the AMA commends PhRMA for its efforts. However, the AMA would prefer to see some earlier-stage data and believes a mandatory registry is needed. "PhRMA has said they're happy to discuss these issues, but they're certainly not on board yet," he adds.
In a commentary published in
JOURNALS FLEX THEIR MUSCLES
DeAngelis is well versed in issues of clinical-trial transparency, having spearheaded a recent effort by the International Committee of Medical Journal Editors (ICMJE) to get companies to publicly register their trials. In September, the ICMJE declared that none of the 13 prestigious journals whose editors are on the committee – including
The requirement is effective for studies beginning enrollment after July 1, 2005. For trials that began enrollment before that date, registration must be completed by Sept. 13, 2005. Only Phase I studies and other trials focused on major toxicities or pharmacokenetics – the sort of studies that are rarely submitted to journals in the first place – are exempt.
Publication of study results in ICMJE journals, which are peer-reviewed and highly regarded in the scientific community, is an important tool for pharmaceutical companies. A study in a major journal can influence skeptical physicians in a way that paid advertising and pitches from sales reps can't. As a result, while it is not a legal or regulatory body, the ICMJE has considerable muscle to flex.
DeAngelis says no meetings have occurred between the committee and industry representatives to discuss concerns about the clinical trial registration requirement. "What's to discuss?" she asks. "If they've got nothing to hide, they should just do it."
The ICMJE says that currently only
RESULTS OR NO RESULTS?
Increasing Clinical Trials Transparency
Despite the tough talk, ICMJE's requirements are in one way less demanding of study sponsors than the proposals that have been put forward in the FACT Act and by groups such as the AMA. The medical editors are calling only for studies to be registered before they begin, not for results to be posted once the trials are complete.
Gregory Curfman, executive editor of
"The editors realized that by not asking for results, they were leaving a loophole. They understood that," adds Curfman. "At the same time, they felt that the simple fact that the trial would be permanently registered, with a unique ID number, would go a long way to prevent results from being buried later."
DOCTORS WEIGH IN
The AMA has its own proposal for increasing clinical-trial transparency. In June, the association called for the Department of Health and Human Services to establish a mandatory registry of US clinical trials of drugs, biologics, devices, and other medical interventions. Information about the trials would be posted before they began, and results would be added when they became available.
The AMA's proposal is similar to the FACT Act, but some of the details differ. For example, the association believes that tying IRB approval to study registration would make monetary penalties unnecessary. "The IRB link would probably obviate other sanctions, because you just can't enroll patients until you have IRB approval," says Davis. He adds that "a lot of details need to be worked out by the stakeholders," regardless of which plan is eventually adopted.
The AMA says it issued its call for a government-run registry in part because it is increasingly concerned about the role that commercial sponsorship plays in creating publication bias. Company-sponsored trials sometimes require investigators to agree to delay publication or to delete certain information before publication, the AMA points out. Also, problems with the design of some commercial studies, including an increased use of placebo rather than active controls, can make positive results appear more dramatic than they are.
"Up to now, we've had a situation where negative or inconclusive results were often unreported," Davis says. "Sometimes the sponsors don't want the results published, sometimes the researchers don't bother writing them up, or sometimes the journals aren't interested in publishing them. Of course, all this contributes to publication bias, so when people do meta-analyses, they may not find all the research that has been done. That distorts the medical literature and can harm medical practice."
Kate Fodor (