Eli Lilly has released a statement strongly objecting to implications made in a New York Times article that it has suppressed results of negative clinical trials.
The newspaper finger pointed Lilly and its antidepressant Prozac as a high-profile example of where such a suppression of a negative study has occured in the past, citing a research article published in The New England Journal of Medicine (NEJM). Lilly's statement said that the New York Times story was "inaccurate when it comes to Prozac - the NEJM article didn't identify a single Prozac study as unpublished". The company said: "We are committed to publicly disclosing medical research results - whether favourable or unfavourable to a Lilly medicine - in an accurate, objective and balanced manner... In December 2004, Lilly was widely recognised as the first pharmaceutical company to voluntarily launch a clinical trials registry, where we post the results of all Lilly sponsored registration clinical trials for all of our marketed products dating back to 1994, and all clinical trials for marketed products since December 2004". Meanwhile, the firm also attacked the NEJM article itself, stating that: "the two Cymbalta studies listed in an appendix to the NEJM article as "unpublished" have, in fact, been published in peer-reviewed journals. The results of HMAT-A and HMAQ-B were published twice - first in the autumn 2002 issue of Psychopharmacology Bulletin, and again in the Primary Care Companion Journal of Clinical Psychiatry in 2003. In addition, these studies were presented at one or more medical congresses that require peer review of abstract submissions and they also have been available to the general public on LillyTrials.com since 2004". The authors of the NEJM article decided not to count studies as "published" if the manuscript included data from two or more studies. "While this methodology might be suitable for an academic discussion, it's clearly not the appropriate standard for determining whether a company has been transparent in disclosing its data", said Lilly. The study that caused the controversy, titled: "Selective publication of antidepressant trials and its influence on apparent efficacy," was published in the NEJM on 17 January. Its authors stated that there was evidence of "selective reporting" throughout the drug industry: "Whether and how the studies were published was associated with the study outcome," they said, a scenario that they warned could have "adverse consequences for researchers, study participants, health care professionals, and patients". Their conclusions were based on reviews from the Food and Drug Administration (FDA) for studies of 12 antidepressant agents involving 12,564 patients.
The investigators conducted a literature search to identify published versions of the studies and for trials that were reported in the literature, the published outcomes were compared with the FDA outcomes. The researchers revealed that out of 74 FDA-registered studies, 31 per cent, accounting for 3449 study participants, were not published. While 37 studies viewed by the FDA as having positive results were published and only one study viewed as positive was not published, virtually (22) all of the studies viewed by the FDA as having negative or questionable results were not published, or published in a way that, "in our opinion, conveyed a positive outcome (11 studies)," the researchers said. There were three exceptions. "According to the published literature, it appeared that 94 per cent of the trials conducted were positive. By contrast, the FDA analysis showed that 51 per cent were positive". The study authors concluded that a bias towards the publishing of positive data was indeed apparent, although they could not "determine whether the bias observed resulted from a failure to submit manuscripts on the part of authors and sponsors, from decisions by journal editors and reviewers not to publish, or both". Following publication of the article, The American Psychiatric Association (APA) and the American Academy of Child and Adolescent Psychiatry (AACAP) renewed their call for a mandatory public registry for clinical trials. APA president Carolyn Robinowitz said: "Open access to all clinical trial data is necessary to better understand the risks and benefits of treatments". "Issues involving publication bias are not unique to psychiatry… publication bias has been well documented with cardiovascular and anti-inflammatory medications. A clinical trials registry set up and overseen by the federal government would be good for all of medicine".
According to a statement released by the two organisations, they were among the first medical specialty groups to call for the establishment of a government-run public registry for all clinical trials, regardless of results, and in 2004, they successfully brought the issue to the attention of the American Medical Association (AMA), the nation's largest physician group. "Greater transparency in the clinical trials process, particularly including open access to important data, is of significant benefit to the research community, to practitioners in the field, and to our patients," said AACAP president Robert Hendren. Indeed, the issue is by no means isolated to antidepressant drugs, but is the subject of ongoing debate within the wider pharmaceutical industry, who are experiencing thre pressure from growing public demands for transparency regarding all clinical trials after a spate of recent high-profile drug recalls, culminating in the dramatic withdrawal in 2004 of prescription painkiller Vioxx, after an independent retrospective study of the drug raised alarming cardiovascular safety concerns. Many big pharma firms, such as Eli Lilly, already maintain their own clinical trial results databases on their websites but they are not under any obligation to do so, nor is there any form of independant monitoring. There are a number of other databases where companies can willingly list trial results although there is no repository that contains the details and results of all the clinical trials in one centralised place. As such, information is often scattered, scarce and confusing for doctors and patients. Since 2005 the International Committee of Medical Journal Editors (ICMJE) has had a policy in place requiring clinical trial investigators to deposit information about trial design into one of seven "accepted" clinical trials registries before the onset of patient enrolment if they want to later have the option of publishing the results in a prominent medical journal at a later date. However, this policy only effectively manages to encourage information about the existence and design of clinically directive trials to be made publicly available, not the publishing of negative results. As of December 2007 an FDA Amendments Act (FDAAA) requires trial sponsors of all clinical trials, except those in Phase I trials and small feasibility studies of devices, to register specific information on ClinicalTrials.gov, the world's largest clinical trials registry.
Previously, the FDA Modernization Act (FDAMA) of 1997, which established the ClinicalTrials.gov, only mandated the registration of FDA-regulated efficacy drug trials for serious or life-threatening diseases or conditions. The new law not only widens the net to require that the majority of trials are registered, but also increases the amount of information that must be provided at the time of registration, requires the eventual inclusion of trials results, and imposes penalties for non-compliance. The idea behind this was to create a "public database of clinical trial data with mandatory disclosure requirements will allow consumer advocacy groups, concerned academics, and products liability litigators, along with jealous industry competitors, to expose misinformation, ultimately protecting middle class consumers".
The submission of information about the trial results will be required, but the content of and format by which this information should be provided has yet to be finalised.