When New York Attorney General Eliot Spitzer accused GlaxoSmith-Kline of suppressing information regarding the effectiveness and safety of Paxil in adolescents last June, the push for a mandatory...
When New York Attorney General Eliot Spitzer accused GlaxoSmith-Kline of suppressing information regarding the effectiveness and safety of Paxil in adolescents last June, the push for a mandatory, public clinical trial database, fueled by the subsequent Vioxx controversy, gained momentum. But despite the media coverage, statements from professional organizations, and public outcry, the past year has been rather quiet with regard to real action on this issue. While the efforts of the Pharmaceutical Research and Manufacturers of America (PhRMA), the International Committee of Medical Journal Editors (ICMJE; includes JAMA, NEJM, and The Lancet), Congress, and various pharmaceutical companies—all of whom have made strides in publishing more clinical trials results—should not be downplayed, the development of a mandatory, centralized public clinical trials database does not appear to be on the horizon. MD Net Guide followed up with the key players in the public clinical trial database debate to see what actions have been taken over the last year to make clinical research more transparent.
There are currently more than 300 registries for clinical trials, including registries of trials that are still recruiting patients, such as www.clinicaltrials.gov, but no repositories that include unpublished data resulting from trials. Types of proposed registries run the gamut from those that would show all data from all studies for all drugs, to those that would only show data for drugs that have already been approved and are on the market. The scientific and advocacy communities want a registry and results database that is as open and transparent as possible, calls for pharmaceutical companies to register a trial as soon as it is created and starts accruing patients, and follows products’ progress from early phases to completion. Arguments from the pharmaceutical industry, meanwhile, state that such a degree of transparency would potentially jeopardize proprietary trade information and that only selective data should be available. While a federal database for open clinical trials already exists (www.clinicaltrials.gov) and drug manufacturers are technically required by law to post some of their studies there, enforcement of the law is weak. The Food and Drug Modernization Act of 1997 mandates and regulates the reporting of clinical trials involving serious or life-threatening diseases to the federal government, but the law does not specify penalties for entities that fail to comply with these regulations. Continuing non-compliance with this law, as well as the controversy surrounding Vioxx and other drugs that have lead to deadly, but preventable, consequences for patients, are fueling the push for a centralized, public clinical trials registry. Leading this effort are the various professional organizations, such as the American Medical Association, the ICMJE, the Association of American Medical Colleges, and patient advocacy groups.
Proponents of a public clinical trials registry and results database often cite ethical concerns over the apparent bias toward positive results in the literature. “What we know from the literature about what works and what doesn’t is biased in favor of things working,” said Kay Dickersin, PhD, associate professor, Brown University, in the AAMC Reporter last August. Further, significant time and money could be wasted on repeating lines of inquiry that have already been investigated in studies for which results are not published. Perhaps most important, however, are the ramifications of incomplete data in treatment decision making. “Physicians need complete and unbiased information about the safety and effectiveness of the treatments they prescribe for their patients,” AMA Trustee Ronald M. Davis, MD, said in a House Com-mittee on Energy and Commerce, Subcommittee on Oversight and Investigations hearing last Septem-ber. “A centralized clinical trials registry would improve physician and researcher access to this information.” Further, Dr. Davis believes that registration should be a condition of trial approval by Institutional Review Boards.
The AMA recently called on the Department of Health and Human Services to establish a centralized registry for clinical trials conducted in the US. The AMA recommends that it should include phase II and III clinical trials that evaluate a new drug, biologic, or medical device, post-marketing studies, and other trials designed to test a therapeutic intervention; identifying information such as the name of the trial sponsor, sources of funding, a unique identifier, and contact information for the persons responsible for the clinical trial; and trial purpose and objective, methodology, the population and diseases being studied, and the dates the trial began and ended in a simple, easy-to-understand format.
Last September, the ICMJE announced that member journals will require, as a condition of con-sideration for publication, registration in a public trials registry While the ICMJE does not advocate one particular registry, its member journals will require authors to record their trial in a registry that meets several criteria, including free, open, and public accessibility; management by a not-for-profit organization; a mechanism to ensure the validity of the registration data; and the ability to be electronically searched. According to a spokesperson for NEJM, the September JAMA editorial from the ICMJE sparked a number of meetings between the World Health Organization, members of the pharmaceutical industry, and medical experts in an attempt to reach an agreement on the issue. To date, however, there are no clear outcomes from these meetings, and the situation appears to be in flux. The industry contends that databases such as the ones required by the journals could compromise trade secrets, particularly in the early stages of drug testing. The industry also puts the blame for lack of access to studies showing unfavorable results on the journals themselves, claiming that journals are not apt to accept papers that show negative or ambiguous results.
The Pharmaceutical Research and Manufacturers of America (PhRMA) has created a website where companies can voluntarily list clinical trials they sponsored for drugs approved by the FDA. Beginning October 1, 2004, the site has been summarizing results from selected trials that were completed since October 1, 2002. But the AMA believes the voluntary nature of such a program may allow the drug industry to “play hide and seek” with clinical trials. AMA Chair J. James Rohack, MD, stated in January 2004, in reaction to the drug industry’s announcement of its plan to develop the voluntary database, that while the AMA supports these efforts to make trial information more readily available, “the AMA believes a mandatory, centralized registry is needed to fully inform patients about opportunities for participation, and enhance awareness in the physician and research community about trials that have been conducted.” Alan Goldhammer, PhD, Vice President for Regulatory Affairs at the PhRMA, however, believes that the PhRMA’s database is meeting its intended objectives. “We do not believe additional regulation is warranted as this effort appears to be adequately addressing the public’s concerns.” As such, “PhRMA has no plans to expand this database,” Dr. Goldhammer says. “PhRMA companies are taking the published PhRMA principles seriously and posting information to the website.” There are 67 drugs posted in the database to date, according to Dr. Goldhammer.
Professional organizations have recently stepped up pressure to make clinical trial results publicly available. The AMA has called for a government-run registry to en-sure that consumers and physicians can read details of industry-sponsored trials that question a drug’s safety. Delegates to the AMA’s 2004 Annual Meeting in Chicago endorsed a policy that would urge the Department of Health and Human Services to establish a comprehensive registry for all clinical trials and require every trial to have a unique identifier. The AMA has recommended that all trial data be made available through publication or an electronic data repository and offers Guidelines for Clinical Trial Registry. More recently, the Association of American Medical Colleges announced its support of a single, national, federally sponsored clinical trials registry. Jordan J. Cohen, MD, president of the AAMC, said the AAMC would like to see the federal government fund an effort under the auspices of the Secretary of the Department of Health and Human Services, with input from the FDA, the National Institutes of Health, academic and other private-sector experts, patients, doctors and other health professionals, and biopharmaceutical and other relevant industry experts. The AAMC advisory panel on research is supposed to look at proposals for clinical trials registries this month so it can make recommendations to the association. Definitive agreements or plans for the establishment of a centralized, government-run, trial results registry have yet to be made.
The pharma industry has responded to these initiatives. GSK, Forest Labs, Roche, and Eli Lilly have all developed their own online clinical trial registries and have stated that they are all working to populate these registries with trial results from studies conducted on their marketed products. Last June, Merck stated that it supports the idea of a government-run database that would keep track of all late-stage clinical drug trials from start to finish, as published in the New York Times. Merck’s website clarifies the company's position on this issue, stating its commitment to publishing all of its hypothesis- testing clinical studies, regardless of outcome, but also noting that it “does not support mandatory registration of all clinical trials at their inception, particularly pilot or exploratory studies.” As of last June, Pfizer was “not prepared to take a position” on the issue of a government-run public clinical trials registry, according to a spokesperson, who was quoted in the same article of the June 18 issue of the New York Times. Phone and e-mail messages left in an attempt to reach a Pfizer representative—to elaborate on Pfizer’s stance on the issue or its plans to publicize clinical trial results—were not returned. Coop-eration by the industry to participate in a comprehensive, centralized database is limited; members of the PhRMA are adding information to the database on a voluntary basis, and most are posting trial information on ClinicalTrials.gov, but neither of these repositories are comprehensive, and neither are enforcing participation.
Some efforts have been made on Capitol Hill to make clinical trial results more readily available; however, legislation has been referred to committee and is unlikely to reach the floor any time soon. Senator Chris Dodd (D-CT) introduced the Fair Access to Clinical Trials of 2005 (FACT) Act last February; to date, that bill has been read twice and referred to the Committee on Health, Educa-tion, Labor, and Pensions. A similar bill (HR 5252) was introduced in the House of Representatives last October by Reps. Edward J. Markey (D-MA) and Henry Wax-man (D-CA). Both bills aim to create a publicly accessible national database of clinical trial information composed of a clinical trial registry and a clinical trial results database and to promote transparency and accountability.
As the ICMJE stated in a Septem-ber 2004 editorial, “registration is only part of the means to an end; that end is full transparency with respect to performance and reporting of clinical trials.” Nearly a full year after the movement for full transparency in reporting of clinical trials began to gather steam, definitive plans to create a public, government-run, clinical trials database remain to be seen. Real action on the issue appears to be at a standstill, but we can expect to hear more about the push for a public, government-run clinical trials registry and re-sults database in the very near future. The AMA plans to revisit the issue at its House of Delegates meeting next month, when the Council of Scientific Affairs will present a report entitled “Enhanced Physician Access to Food and Drug Administration (FDA) Data.” The report will likely present recommendations for making clinical trial data more accessible.