All clinical trial sponsors will be required to register all publicly and privately sponsored clinical trials with the existing government clinical trials registry, www.clinicaltrials.gov, before the first patient is enrolled in the trial.
In June 2004, New York State's Attorney General Eliot Spitzer filed a lawsuit charging that GlaxoSmithKline PLC committed fraud by withholding negative information and misrepresenting data about the benefits and harms of Paxil use in teenagers and children with depression.1 At issue was the alleged suppression of 4 studies that showed an increased risk of suicidality in children and adolescents treated with the drug. According to the suit, an internal 1999 GlaxoSmithKline document suggested that the company planned to "manage the dissemination of data in order to minimize any potential negative commercial impact."
Spitzer was not alone in questioning the pharmaceutical industry's unwillingness to divulge negative efficacy or adverse-event data. When at least one FDA staffer and a few independent scientific reviewers examined a more complete data set, they found an association between suicidality and antidepressant use in children, but their analysis was deemed controversial.2 The antidepressant issue made its way through heated FDA and congressional hearings. By the time it was over, the FDA had mandated new black box warnings stating that an increased risk of suicidality had been observed in children treated with these drugs.3
Last fall, the Vioxx story added more fuel to the fire concerning whether drug companies should report adverse events and negative efficacy data. In a perspectives paperpresented in the October 2004 issue of the New England Journal of Medicine, Eric Topol, MD, a cardiologist at the Cleveland Clinic Foundation, attacked both Merck and the FDA for dragging their feet on examining cardiovascular events in a clinical trial.4,5 These examples now are seen as emblematic of pharmaceutical companies' selective release of clinical trials data, which makes findings about their drugs--at times--look more positive than they are.6,7
Journal editors also have weighed in on the matter. To ensure that trial reports published in peer-reviewed journals accurately reflect the trials' hypotheses, study design, study population, and patient outcomes, the International Committee of Medical Journal Editors is now insisting that prospective journal authors enter their trial in the federal government's clinical trials database, www.clinicaltrials.gov, before the first patient is enrolled. In addition, at that time, they must clearly outline their study design, patient population, hypotheses, intention to treat outcome measures, and intended length of study, among other requirements.8,9
Also, legislation is pending in the US House of Representatives and Senate that, if passed, could make clinical trials data far more transparent and reveal adverse outcomes and negative efficacy findings sooner.
Long before this issue took off last year, as far back as 30 years ago, a small core of proponents for evidence-based medicine pressed for compulsory registration of clinical trials.10 Such registration would minimize publication bias--ie, the overrepresentation of positive outcome studies published in the peer-reviewed literature.11 This effort was ignored until the World Health Organization (WHO) and the peer-reviewed journal, Current Controlled Trials, announced on April 2, 2004, that "from today, all randomized controlled trials approved by the WHO ethics review board will be assigned an International Standard Randomised Controlled Trial Number (ISRCTN), a unique number that provides a means of identifying and unambiguously tracking a trial throughout its life cycle."
United States Representatives Edward Markey (D-MA) and Henry Waxman (D-CA) have cosponsored the Fair Access to Clinical Trials (FACT) Act. Crafted last fall, the legislation was scheduled to reach the House floor in June. In the Senate, Sen Christopher Dodd (D-CT) introduced S.470 earlier this year. Sen Charles Grassley (R-IA), chairman of the Senate Finance Committee, Sen Ron Wyden (D-OR), and Sen Tim Johnson (D-SD) are cosponsors.
The goals of the legislation are to ensure that physicians, patients, and the public have full access to information on ongoing clinical trials and their results--whether negative or positive, whether revealing beneficial or harmful effects of the drug under study, whether published or not. The FACT Act would mandate that all government-supported and privately funded clinical trials enter the registry.
Entering trials into www.clinicaltrials.gov would be mandatory for Institutional Review Board approval. Provisions are included for updating. If results are not posted in a timely (yet to be determined) fashion, sponsors could be subjected to fines of $10,000 per day.
Stephen C. Reingold, PhD, former vice president for research at the National Multiple Sclerosis Society, commented: "There are trial databases out there, but reporting is spotty. . . . This is one of the most stringent remedies yet proposed."
NEW MEDICAL JOURNAL POLICIES
The International Committee of Medical Journal Editors has been working alongside advocates to provide more useful registries for clinicians and the lay public. In September 2004, the committee released new information for authors submitting clinical trials reports. It was underscored in a June 9 New England Journal of Medicine editorial titled "Is this clinical trial fully registered?--A statement from the International Committee of Medical Journal Editors."9 Thirteen editors signed the editorial.
The new specifications apply to all trials that begin enrollment on or after July 1, 2005, as well as ongoing trials that are still under way as of September 15, 2005. For trials to be considered for publication in a research journal, authors must enter their trial in the registry before the trial begins.
According to the revised guidelines published in the Journal of the American Medical Association, "each manuscript should clearly state an objective or hypothesis; the design and methods (including the study setting and dates, patients or participants with inclusion and exclusion criteria, or data sources, and how these were selected for the study); the essential features of any interventions; the main outcome measures; the main results of the study; a comment section that discusses the results in context with the published literature and addresses study limitations; and the conclusions."12
Neurology editor Richard C. Griggs, MD, and Archives of Neurology editor Roger N. Rosenberg, MD, said that their journals intend to follow suit. Annals of Neurology editor Richard T. Johnson, MD, was not available for comment, but managing editor Sheila Rose Garrity, JD, MBA, indicated that the journal would follow the new policy.
PHARMACEUTICAL INDUSTRY RESPONDS
Since September 2004, many pharmaceutical companies, including Merck, GlaxoSmithKline, and Eli Lilly have voluntarily pledged to list ongoing and newly accruing hypothesis-testing and postmarketing clinical trials on the federal government's trials registry.13-15
Merck spokesperson Craig Buchholz said that the company will make all of its hypothesis-testing trials available on www.clinicaltrials.gov and that the company intends to "follow the spirit" of the registry. Merck has its own "results" database on the Internet, and Pharmaceutical Research and Manufacturers of America also has established a Web database of clinical results, www.ClinicalTrialsResults.org, to which any member drug company can submit results.16,17
What remains unclear is exactly what the companies intend to submit and how useful their alternative sites will be. Drummond Rennie, West Coast editorof the Journal of the American Medical Association, said that registration at the inception of the trial is key. "If it is done then--before any results--the sponsor's marketing department won't make results disappear when they don't like them. A promise to publish is well and good and important," said Rennie, "but it's unbelievable."
In a commentary that appeared in the Journal of the American Medical Association, Rennie wrote: "The worst outcome would be for some companies to forestall legislation by announcing individual registers that are obscure, hard to access, idiosyncratic in the sorts of data they post, contain only what marketing departments allow them to contain, and are temporary and dependent on the company's institutional memory and will."11
Many neurology research investigators have said that greater access to clinical trials information is essential for sound clinical decision making and that it is ethical. "Imagine saying you have a safer car when everybody is hiding their crash tests," said Lawrence M. Brass, MD, professor of neurology at Yale University School of Medicine. "We have an obligation to make clinical trials data available--whether it is NIH, industry, whether the intervention worked, was helpful, or caused harm."
Peter Whitehouse, MD, PhD, director of integrative studies at Case Western Reserve University, said that academics should not sign clauses that prevent them from publishing data from industry-sponsored trials. In addition, he pointed out that when persons volunteer for a study, they believe that they are contributing to science and that the results will be known. "It is simply unethical for those results to disappear," he said.
One argument that companies have made about disclosing information to publicly funded registries is that it would reveal their trade secrets. Karl Kieburtz, MD, professor of neurology at the University of Rochester in New York State, said: "It seems like an exaggeration to me. Phase 2 and 3 trials are in the public domain anyway. Clearly, if patent rights were an issue, we couldn't have pioneered a clinical trial."
Publishing negative trials and minimizing publication bias is an admirable goal, but there are other reasons why studies with negative results do not make it into print. Brass contended: "Journals want to make news--and put simply--negative findings are not sexy: they don't make headlines." Kieburtz said that he has found it very difficult to get peer-review approval on well-designed trials with negative findings.
Researchers have their own concerns about publishing negative studies. "Investigators who depend on getting new grants might feel that they cannot afford to take the risk of reporting negative results," said Barry Oken, MD, associate professor of neurology at Oregon Health Sciences University in Portland. According to Oken, research sponsors might be more likely to fund investigators who report positive results.
When trials are negative or some adverse events are reported, sorting out the benefit-to-risk ratio is difficult. On June 2, The Boston Globe reported that Biogen Idec told the FDA that a progressive multifocal leukoencephalopathy (PML) might have developed in a fourth patient who had been receiving Tysabri.18 Neurologists and patients had high hopes for the drug in the treatment of multiple sclerosis (MS), and many were disappointed when the drug was taken off the market in February after 2 cases of PML--one of them resulting in death--were reported (see Hope, Then Disappointment, for Multiple Sclerosis Therapy, Applied Neurology, April 2005, pp 18-19).
"How do you decide when there are too many adverse events, when there is too much signal?" said Whitehouse. "These are value judgments that are not so easy to make."
Despite recent news, there have been instances of negative studies coming to light in the peer-reviewed literature, according to Lawrence S. Honig, MD, PhD, associate professor of clinical neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University School of Physicians and Surgeons. One was a study of the tumor necrosis receptor lenercept for MS19; another concerned gamma interferon, also for MS.20 Both these studies demonstrated negative efficacy data and a worsening of disease in association with therapy.
However, the time lag for reporting efficacy data that might be positive, as well as that for reporting adverse outcomes, remains a problem. A case in point is the dissemination of information on Ab immunization for Alzheimer disease. In 2002, Nature published a complaint because data were known in 2001, but no reports surfaced in the peer-reviewed journals.21 The results were not presented until the 9th International Conference on AD and Related Disorders in July 200422; the paper was not published in the peer-reviewed literature until 2005.23 Even so, Honig said that he still believes the vaccine shows promise.
The Merci clot retrieval device for ischemic stroke is an example of a medical device that made it to the market without exhaustive study. According to Brass, he and others had worried about a high 38% mortality rate in a nonrandomized, single-arm study (personal communication). These findings have led to a randomized trial that is now under way.
Fair Access to Clinical Trials Act Provisions
* All clinical trial sponsors will be required to register all publicly and privately sponsored clinical trials with the existing government clinical trials registry, www.clinicaltrials.gov, before the first patient is enrolled in the trial.
* Researchers will be required to satisfy all criteria for clinical trial reporting set out by the International Committee of Medical Journal Editors on September 8, 2004, and outlined in major journals. These include the requirement that researchers disclose the hypotheses to be tested, the primary and secondary outcome measures under study, eligibility criteria, sources of funding, and anticipated timeline of the clinical trial.
* All trials must be registered with a unique identifier number before the first patient is enrolled in the study.
* Clinical trial results, regardless of outcome, must be accessible to the scientific community, health care practitioners, and members of the public.
* The FDA will be required to make internal drug approval and safety reviews publicly available.
* Participation in the registry will be a requirement for Institutional Review Board approval. Civil monetary penalties will be imposed for noncompliance.
* The information provided to the registry will be subject to auditing for completeness and accuracy.
* Patients will have access to enrollment information about clinical trials for serious and life-threatening diseases (as established in the FDA Modernization Act of 1997) at www.clinicaltrials.gov.
* Provisions of the FACT Act will apply to clinical trials for drugs, biologics, and medical devices.
Source: Offices of Representatives Edward Markey (D-MA) and Henry Waxman (D-CA) and Senator Christopher Dodd (D-CT).
PROSPECTS FOR THE FUTURE
"This is not an issue that is going to go away," said John Noseworthy, MD, chair of the American Academy of Neurology's Science Committee, and professor and chair of the Department of Neurology, Mayo Clinic College of Medicine, in Rochester, MN. "The situation is ultimately going to change because an informed public is going to demand it. Although the Academy does not have a position on this per se, we are extra careful about conflict of interest and competing interests of our members. The Academy insists on complete financial disclosure at its scientific meetings to avoid the perception of conflict of interest or bias."
So what does it mean in the clinic? Alexander Mauskop, MD, neurologist and founder of the New York Headache Center, said: "I think that we should have all the data available--positive and negative--since we are using the drugs." However, he cautioned: "It is not pure science. We have direct-to-consumer marketing where some doctors feel obliged to give [a drug] when the patient doesn't understand the drug or when the doctor hasn't had time to review the clinical trials."
Richard Atkinson, MD, a practicing neurologist in Sacramento, CA, said that one of the biggest problems with research is the failure to disseminate results in trials for which interventions never make it to market. "It is a missed opportunity," he said. "We could gain a better understanding of the natural history of disease, which, in turn, could be used to refine new research questions."
He also favored developing a database of patients (not a registry) to which neurologists could contribute information on the effectiveness of controversial interventions, such as the use of heparin for stroke. In addition, he viewed such a database as invaluable for accumulating information on the treatment of rare diseases. Also, according to Atkinson, Web access to clinical trials would be an improvement: "If community neurologists could see where to send their patients, it would be a major help."
Of course, any solution is not always as simple as it seems. Jacqueline French, MD, professor of neurology and co-director of the Pennsylvania Epilepsy Center, University of Pennsylvania, in Philadelphia, said that posting clinical trials data to the Internet "is not a simple matter. . . . A negative trial is not a negative trial," she said, asserting that patients could easily misinterpret findings and become alarmed, and that the findings could get blown out of proportion. She also expressed concerns that research on high-risk populations could be compromised if companies thought that they had to release proprietary information.
"It would be a big mistake if people rushed to judgment. What I would love to see is for someone to hold a learned symposium, where all sides could be presented before we rush into a plan." *
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