The pharmaceutical industry has repeatedly violated federal law by failing to disclose the existence of large numbers of its clinical trials to a government database, according to the Food and Drug Administration.
Doctors and patients say that compliance with the law would go a long way toward addressing their growing concerns that they are not being given the full picture about the effectiveness of many drugs because they are not told about drug trials that fail. The issue has gained urgency with recent disclosures that the publicly available research on treating children with antidepressants obscured the fact that in most studies, the drugs were no better than sugar pills. Drugmakers chose not to publish those studies.
The 1997 law is so little known that scientific journal editors and professional medical associations have recently debated whether to create a system of private incentives for disclosure of trials. When she was told the law already requires companies to register trials, Catherine DeAngelis, editor in chief of the Journal of the American Medical Association, said, "That's a surprise to me. Tell me why it's not enforced."
Although the law was primarily passed for other reasons, DeAngelis said it could very well address her concerns.
The FDA acknowledges it has not enforced the law -- officials said the statute did not spell out penalties or explicitly give the agency authority to crack down on violators.
An FDA analysis found that in 2002 only 48 percent of trials of cancer drugs had been registered, and a preliminary review now indicates the listing rate for drugs for some other serious diseases is in the single digits. Some companies have listed no studies; some trials are listed without identifying the sponsoring company or the drug being tested.
As of Friday, the database, ClinicalTrials.gov, listed 5,754 ongoing studies, but only 13 percent were industry sponsored. The federal government, mainly the National Institutes of Health, accounted for 55 percent. Those proportions are in stark contrast to the true picture, DeAngelis said. "Over 80 percent of trials are funded by for-profit companies, not by the government," she said.
FDA officials said they are re-examining whether they have the power to step in. Members of Congress are also considering adding enforcement provisions to the law, which was part of the FDA Modernization Act of 1997.
The registry was begun in 1998 and the ClinicalTrials.gov site went online in February 2000, said Alexa McCray, director of biomedical communications at the National Library of Medicine, which hosts the registry. Since then, nearly 11,000 trials have been registered from all 50 states and 90 countries. Virtually all studies sponsored by the National Institutes of Health are listed, and industry trials started coming in after March 2002, when the FDA issued a formal "guidance" on implementing the law.
Although some companies say they are amenable to wider disclosure, the patient advocacy group that fought the hardest to create the requirement predicted it would never be enforced.
"Obviously it needs an enforcement mechanism attached to it," said Abbey S. Meyers, president of the National Organization for Rare Disorders. "I can guarantee you, however, that the full force of the drug industry will stop it. They don't want you to know about clinical trials that fail. They are afraid what it will do to their stock price. A lot of trials are for drugs already on the market, and it would ruin their sales if the news got out."
The Pharmaceutical Research and Manufacturers of America countered that the registry had initially been slow to list industry-sponsored trials, and that companies started supplying the information after the FDA issued its guidance. Alan Goldhammer, PhRMA's associate vice president for regulatory affairs, said he had heard anecdotally that companies are now fully complying with the law.
But Theresa Toigo, director of the FDA's Office of Special Health Issues, painted a different picture. "Many pharmaceutical trials are not participating in ClinicalTrials.gov or are not fully participating," she wrote in a recent report in the Journal of Biolaw and Business. Responding to assertions by PhRMA that the 2002 data do not reflect the current situation, she said, "It's not like we've seen a big increase in the monthly submissions of privately sponsored protocols."
Sen. Edward M. Kennedy (D-Mass.), who helped create the registry in 1997, plans to seek revisions to enforce the registration requirement and to find a way to report study results.
Meyers and Paul Kim, a former Kennedy staff member who now works for the law firm Foley Hoag LLP, said the original purpose of the registry was to link patients who wanted to join clinical trials with the researchers.
The law required companies to register all effectiveness trials, known as Phase 2, 3 or 4 studies, for serious and life-threatening diseases. In 2002 , the FDA defined "serious" diseases broadly, including everything from AIDS and cancer to arthritis, depression and diabetes.
Some companies have boasted to stockholders of having many ongoing studies in the pipeline but not listed any with the registry. Forest Laboratories Inc., which recently touted results for an Alzheimer's disease drug called memantine and last month published a children's depression study showing positive results for its antidepressant Celexa, has no trials registered. Company spokesman Charles Triano said the law does not require companies to register trials if other drugs are available for the same disease.
Triano said the company did not need to list its trials of memantine, a new class of Alzheimer's drug, because the FDA had not given it the "fast-track" status reserved for breakthrough medicines and deadly diseases with limited treatments.
The FDA's Toigo said the law required companies to register trials whether or not medicines exist for the disease. "It doesn't say anything about existing drugs on the market," she said.
Although 246 pharmaceutical and biotech companies had ongoing trials in the database Friday, about half listed just one. GlaxoSmithKline had five, but spokesman Rick Koenig said many of the company's trials are not listed under the company's name. "We didn't understand that to be a requirement or the sort of information that is of use to a patient looking into where that patient might enroll in a trial," he said.
Toigo said the FDA's 2002 guidelines called for companies to include their names.
Journal editor DeAngelis, who is helping spearhead an editors' initiative to get all trials registered, said a government-enforced registry would be vastly superior to any system of private incentives. "It will come as a surprise to the vast majority of your readers," she said about the law's requirements. "I had personally assumed it was only for federally funded clinical trials."
Toigo said her analysis of industry compliance, which she hopes to complete by the end of the year, will examine whether more than 2,000 trials submitted to the FDA by companies seeking approval for medicines in 2002 had been properly listed.
Companies are hesitant to register trials because they want to control data, said Kay Dickersin, a professor at Brown University who has sought such data for two decades. Some are worried that trade secrets will leak out, or that a competitor will poach on patient networks. Others don't want patients to petition them for medicines on "compassionate grounds."
One way to increase registration, said Dickersin, is for patients to insist trials be registered before participating. Drummond Rennie, a professor at the University of California in San Francisco, added that physicians who conduct trials for companies "should examine their consciences" before agreeing to let trials be kept secret.
"If I buy a camera and the thing falls apart, it's a lemon, I shrug and say I'm never going back to that firm," said Rennie, who is also deputy editor at JAMA. "But if I get a drug and it makes me worse, it can kill me or maim me.
"We give pharmaceutical companies a lot of tax advantages and a whole lot of support in the Congress and a good business environment and patent protection," he said. "They owe us more information."