November 29, 2004
Contracts Keep Drug Research Out of Reach
ast December, medical school researchers went to a professional meeting in Puerto Rico with a sense of urgency. Federal drug regulators were reviewing unpublished data from their studies on the use of antidepressants in children and adolescents to see if the drugs increased suicide risks.
The group included many of the researchers whose published positive findings had helped persuade doctors to prescribe antidepressants like Paxil, Zoloft and Prozac to young patients. Now, faced with growing safety questions, the researchers had been trying for months to gather all the test data about those and similar drugs to see if they had missed a pattern not apparent in any single trial.
But they could get only pieces of that information.
Some drug companies refused to turn over data to the group, even though these researchers had helped come up with it, the researchers recalled. In other cases, they could not freely share their own data with colleagues who had not worked on a test. The reason, they said, was that medical schools, in agreeing to run the tests, had signed agreements with the drug makers that kept the data confidential.
Academic institutions and researchers are widely viewed as the impartial, independent heart of the system this country uses to test drugs and medical devices. But that independence often comes with strings attached, sometimes making those institutions and their researchers obstacles to the exchange and discussion of test results. The upshot is that doctors may not get all the information they need. In the wake of revelations about unpublished test data showing the potential risks of pediatric antidepressants, some doctors have stopped prescribing them. And even doctors who continue to prescribe the drugs question why they were kept in the dark.
"I think it would have been more helpful for everyone to have known what was going on at the time that it was happening," Dr. Robert Feder, a psychiatrist in Manchester, N.H., said.
In recent months, the outrage over the withheld antidepressant data has led calls for change and promises of some. Drug companies, faced with widespread criticism about their handling of test information, have promised to release more of it. Legislation has been introduced in Congress that would require all makers of drugs and medical devices to list clinical trials and their results in a public database.
Critics say, however, that academic institutions and their researchers need to examine their own practices because they share part of the blame.
The problem starts with the terms of the contracts that some universities sign for clinical trials, but of equal importance is how researchers choose to describe study results and even whether they pursue publication.
"People who are blaming this all on industry are missing the point," said Dr. Robert M. Califf, associate vice chancellor for clinical research at Duke University Medical Center. "I think that academia is part of the problem right now and not part of the solution."
Virtually all the pediatric antidepressant studies were run in part at medical schools, and in many cases the tests were led by academic scientists. But while one study of the drug Paxil, which showed positive results in depressed children, was published, another study showing that it was ineffective was not submitted to a medical journal. In addition, studies involving other antidepressants, like the drugs Remeron and Serzone, were also not published.
Makers of drugs and medical devices frequently turn to medical schools and academic teaching hospitals to run clinical trials and recruit patients for them. The industry pays many academic institutions millions of dollars annually to run such trials; the involvement of a leading academic researcher in an industry-sponsored test gives it both prestige and credibility. Medical researchers who attract studies reap the benefits of such rainmaking with bigger research budgets and career advancement.
Drug companies say that because they pay for a trial they own the data it generates. They say that contract clauses - including ones for confidentiality - are not intended to suppress possibly negative trial findings but to make sure that data is properly analyzed before it is released.
A look at the work of one medical school researcher, Dr. Karen Dineen Wagner, shows the challenges and possible pitfalls such research can entail. For example, from 1998 to 2001, university records show, Dr. Wagner was one of several academic researchers participating in more than a dozen industry-financed pediatric trials of antidepressants and other types of drugs. While some of the results were published, many were not.
Issues related to data disclosure vary between medical schools. Some schools take tougher stands on issues like confidentiality and test publication than others, and academic researchers in well-established fields like cardiology have more power in negotiating clinical trial agreements than those in relatively new ones like child psychiatry.
Leading academic research centers like Duke University and the Cleveland Clinic can often even dictate contract terms when they coordinate a trial by collecting data from various study sites and analyzing it. But Dr. Califf noted that Duke had far less ability to set terms when it was simply one site in a trial being run at many academic and private test centers, which is the way most drug trials are run.
How Trials Work
At one time, academic institutions dominated drug testing. But over the last decade, a private testing industry made up of doctors in private practice and clinics that recruit patients for studies has sprung up. Increasingly, private companies rather than universities coordinate the testing of a drug at different centers.
While industry financing of clinical trials has increased, for example, the share of it going to academic institutions has fallen to 35 percent in 2002 from 70 percent in 1991, according to Thompson CenterWatch, a Boston company that covers the testing industry.
Government financing of medical research has grown, too. But about 90 percent of that money goes to 40 of the country's 125 medical schools, said Dr. David Korn, an executive of the Association of American Medical Colleges. In addition, the government tends to finance basic medical research, not studies of drugs seeking regulatory approval or tests for potential new uses of medications already on the market or their potential use in different types of patients.
Specialists like Dr. Korn said that some medical schools, because of their reliance on industry money, might not negotiate aggressively over contract provisions for fear that companies would take test work elsewhere.
A large academic medical center like Dr. Wagner's, the University of Texas Medical Branch at Galveston, may become involved in as many as 100 new trials a year.
Officials at the Galveston center, which gets about 7 percent of its overall budget from industry-financed tests, say they do their best to win favorable contract terms for industry trials. The standard contract adopted by the University of Texas calls for member medical schools to hold study data confidential for 18 months - a period intended to allow a company to collect test data from multiple sites, analyze it and prepare it for publication. But Galveston officials say they often extend that period to two years when companies demand it.
Companies, of course, are free to release study results as soon as they choose and, in many cases, they do so promptly. But few medical schools - Galveston included - require that study findings be published or widely disseminated as a condition of taking part in a trial, according to a survey by Duke University researchers published two years ago in The New England Journal of Medicine.
"It takes two to tango, and academics are a part of this dance," said Dr. Drummond Rennie, an editor at The Journal of the American Medical Association and a longtime advocate of greater disclosure of the results of clinical trials.
Several studies of academic research have also found that investigators may overstate, unwittingly or not, test findings to please a study's sponsor or a medical journal editor. And university researchers, Dr. Wagner among them, are also sometimes paid significant amounts of money by a drug's manufacturer for work directly related to their study of that medication, creating a potential conflict of interest.
Dr. Wagner, vice chairwoman of the department of psychiatry and behavioral sciences at the Galveston center, declined to be interviewed for this article but did reply to some questions in writing. Officials of the Galveston center insisted that the industry money she received did not affect her work.
A Researcher's Role
It was hardly surprising that many manufacturers of popular antidepressants already approved for use in adults would turn to an established researcher like Dr. Wagner to test them in young patients.
In the late 1990's, she was one of a small number of researchers with experience in testing drugs intended to treat children with problems like attention deficit disorder and bipolar disorder. Over the last decade, Dr. Wagner has led or worked on some 20 studies published in medical journals, and the government has financed some of her work.
She has also attracted a large number of industry-financed studies, including those aimed at testing whether antidepressants approved for use in adults were safe and effective in children and adolescents.
Dr. Wagner's role varied in 12 industry-sponsored trials in which antidepressants were tested against placebos for depression or other problems. On three of them, including a Zoloft trial, she was a lead investigator, working with company researchers to plan, analyze and write results up for publication. On the others, her duties were limited to overseeing test patients at her clinic.
Of the 12 studies, all five of the reports claiming positive results, meaning the drug worked without worrisome side effects, that were submitted for possible regulatory approval were published. The seven other studies were inconclusive or negative, which can mean that the drug failed to work or that the test failed because of its design. (Two of them were never submitted to the Food and Drug Administration to support an application for the drug's approval.)
Because many of the antidepressant studies were unpublished, many doctors never heard about the results. Their findings were typically disclosed in limited settings, like talks at meetings of medical specialists or on a poster displayed in a room with dozens of other posters, which is a typical way of disseminating research results at professional conferences. Several researchers who worked on the pediatric antidepressant trials said that in many cases they had little incentive to submit ambiguous or failed trials to medical journals because they thought the papers would be rejected by journal editors.
One of those researchers, Dr. Neal Ryan, a professor of psychiatry at the University of Pittsburgh, said there has typically been little publishing interest in studies with inconclusive findings or those that failed to work because of study design, a type sometimes referred to as a negative study.
"No one gets famous from publishing negative studies," Dr. Ryan said.
In response to a question, Dr. Wagner wrote that in all the cases where she was the lead investigator, test results had been or would soon be published or presented at medical meetings.
It was her study of Zoloft for childhood depression, financed by Pfizer, that attracted the most attention and criticism. Results were published last summer in The Journal of the American Medical Association as the debate on pediatric antidepressant use was rising; the study concluded that the drug effectively treated depression. The finding received widespread publicity in newspapers, including The New York Times.
"This study is both clinically and statistically significant," Dr. Wagner said last year. "The medication was effective."
But some academic researchers said that the difference in improvement that the study found between young depressed patients taking Zoloft and similar patients who received a placebo - 10 percentage points - was not substantial. Asked about complaints about the trial, Dr. Wagner referred to a statement in The Journal of the American Medical Association in which she responded last year to critical letters.
In that statement, Dr. Wagner said she believed that the 10 percentage point difference was "clinically meaningful."
A Possible Conflict
In her Zoloft study, Dr. Wagner acknowledged that she had received "research support" over the years from several drug manufacturers including Pfizer, which paid $80,000 to the Galveston center in connection with the Zoloft test. But she did not state that she also received sizable payments from the company for work she did related to the study.
In a financial filing with the school in December 1999 - the same month the Zoloft trial began recruiting patients - Dr. Wagner disclosed that she had received more than $10,000 from Pfizer but did not provide further details. She did not respond to written questions about those payments. But a lawyer for the school, Christopher Johnsen, said Dr. Wagner had told him that a check of her records showed that Pfizer had paid her $20,500 during the course of the Zoloft trial.
The majority of the payments, Mr. Johnsen wrote in an e-mail message, were for "her efforts in developing training tapes" and other work aimed at helping researchers at different study locations uniformly assess the psychological status of test patients.
Academic researchers routinely receive speaking and consulting fees from drug companies whose products they test. But some schools put restrictions on such payments.
"We have a strict policy that you can't be consulting with a company during the course of a trial financed by that company," said Lisa Bero, a professor of clinical pharmacology at the University of California, San Francisco, and the chairwoman of her campus's advisory committee on conflicts of interest.
At San Francisco, a conflict review occurs when a researcher receives more than $500 from a company financing a clinical study, a policy Dr. Bero described as far more restrictive than other universities'.
At Galveston and many other medical schools, the financial threshold for such a review is $10,000. But Mr. Johnsen, the school lawyer, said that the Galveston center had been unable to locate any records related to a review of Pfizer's payments to Dr. Wagner. He added that the records were either lost or that the review never took place. Christine Comer, a spokeswoman for the Texas medical school, said that the school did not believe that Dr. Wagner's work was in any way affected.
"Dr. Wagner is a dedicated physician who has always exhibited the highest ethical and professional standards in her work," Ms. Comer wrote in an e-mail message.
Dr. Paul Ambrosini, a professor at Drexel University College of Medicine who worked with Dr. Wagner on the Zoloft study, said he thought its results were fairly presented. But he acknowledged that academic researchers are frequently guilty of spinning test findings, either to please a test sponsor or a journal editor or to advance their own agenda.
"Unfortunately, the goal is always to present data in a more positive light than it might hold up to be," he said. "Everyone has their own bias."
Studies of the issue suggest more bias in industry-sponsored studies. One survey of such studies, published last year in BMJ, a British medical journal, found that reports sponsored by drug makers and published in medical journals were more likely to find drugs safe and effective than studies financed by the government and other sources.
Under many academic contracts, companies have a limited amount of time to review test results prior to their publication. But if a drug maker chooses not to seek publication of a study, problems can arise. While medical schools retain the rights to publish data under the contracts they sign, they legally have the right to publish only data generated from that test site, a small piece of the entire test picture that can at times be misleading.
In rare instances, disputes over who controls test data and publication rights can end up in court. In 2000, for example, two academic researchers were sued by the maker of an experimental H.I.V. vaccine after publishing the results of a trial that showed that it did not work. The company, Immune Response, maintained that it owned the data and asserted that the researchers had failed to include relevant positive information about the vaccine, Remune, in their report. It later dropped the lawsuit.
Advocates of greater trial disclosure say universities should be doing more to ensure that all test findings are published and data from those trials are publicly available. Universities, by recruiting patients for a trial, take on a moral obligation to them, they say.
"The obligation to the patients they recruit is to make the data they contribute available to other patients so that valid treatment decisions can be made," Dr. Bero said.
A Better Way?
In January, the panel of antidepressant researchers that met a month earlier in Puerto Rico issued a report defending the effectiveness of the drugs and disputing evidence that their use increased suicidal behavior. Subsequently, the F.D.A., which had access to all the study data, determined that such a risk did exist for some depressed young patients.
Still, the pediatric researchers also made a little-noticed recommendation in their report - that all data from those trials be made publicly available.
For years, some academic researchers had been calling for such disclosure for all trials of drugs and medical devices. And in recent months, as a result of the furor over antidepressants, some drug companies have pledged that they will voluntarily release more study results, either on corporate Web sites or on a site created recently by the industry's trade group, the Pharmaceutical Research and Manufacturers Association.
But several antidepressant researchers, including Dr. Wagner, said they now supported mandatory reporting of clinical trial results in a public database operated by the federal government. Dr. Korn of the Association of American Medical Colleges said his group also backed mandatory reporting. The initiative is also supported by the American Medical Association, the nation's largest group of doctors, and by a group of leading medical journal editors.
Legislation was recently introduced in Congress that would mandate reporting of test results. But its fate is not clear. The pharmaceutical manufacturers' trade group has said it does not see the need for a reporting requirement.
Other experts say that universities should also look to their own policies. In 2002, the editor of The New England Journal of Medicine, Dr. Jeffrey M. Drazen, suggested that medical schools develop standardized contract language to govern their dealings with drug companies on issues like researchers' access to data.
"If universally adopted, such language would help safeguard the integrity of the research process," Dr. Drazen wrote.
A few years ago, representatives of the Association of American Medical Colleges held talks with drug company officials to explore the development of standardized contract terms. But the discussions fell apart about a year ago, when drug company executives balked, school officials said. Those officials added that they did not expect academic institutions to take action individually, said one of them, Dr. Adrian Dobs, a professor at the Johns Hopkins School of Medicine.
"Most universities compete with each other when it comes to money and budget," she said. "We have not been very successful in taking a united front."