Clinical Research: Show Us the Data
Authors: Alberto Ocana, Eitan Amir, Bostjan Seruga
Journal: Journal of Clinical Oncology (2011)

Molecular studies are increasingly being used to identify signaling pathways and to develop new drug therapies. Use of these tools has resulted in the acquisition of extensive information, such as gene expression arrays and genome sequence data. Almost a decade ago, there were calls for such data to be made publicly available to benefit global research and permit transparency. High-impact basic science journals subsequently mandated that such data to be made publicly available before a manuscript on the data could be published. As a result, most microarray data are now easily accessible either openly or on request. In contrast, most clinical research, and particularly data collected from randomized clinical trials (RCTs), remains proprietary of the sponsor(s) of those trials and is not publicly available. Many data often remain unpublished. In this commentary, we call for increased public access to efficacy and safety data from RCTs. RCTs evaluating new drugs are usually designed with the aim of the registration of the study drug for a particular indication. Independently of drug approval proceedings, investigators submit efficacy and safety results to high-impact journals for the consideration of publication. Published reports of RCTs then represent the major guidance for the use of these drugs in everyday clinical practice. Unfortunately, the information published in such articles can be incomplete and/or outdated. Patients enrolled onto RCTs are usually highly selected and may not be representative of patients treated in general practice. Such RCTs usually have multiple exclusion criteria, which include particular comorbidities or the use of certain concomitant medications. Unfortunately, the reporting of exclusion criteria in published reports of RCTs is usually limited. Exhaustive lists of exclusion criteria and detailed information about the administration of approved therapies are available in study protocols. Several prominent journals have encouraged (eg, Journal of American Medical Association) or mandated (eg, Journal of Clinical Oncology) that the study protocol be available at the time of the submission of the manuscript. However, submitted study protocols are usually only available to editors and reviewers during the peer-review process rather than openly available to health professionals. Increased access to study protocols could allow for better selection of patients for new therapies and may allow for more accurate translation of gains demonstrated in RCTs into societal benefits. The reporting of toxicity data remains an area of concern. Some rare but potentially serious toxicities may not be detected in RCTs as a result of patient selection or of relatively short follow-up; others may be detected but either inadequately reported or not reported at all. In published reports of RCTs, threshold criteria for reporting of the most common adverse events (AEs) are usually well defined—for example, AEs of all grades occurring in 10% of patients or severe AEs occurring in 5% of patients. The capture and causation of AEs relies on the judgement of the investigators. Consequently, AEs that are infrequent but that might be clinically relevant may not be reported in the publication of RCTs. For example, in the pivotal RCT of cetuximab in head and neck cancer, investigators reported AEs that occurred in at least 10% of patients in either treatment group. Consequently, cardiopulmonary arrest, which occurred in 2% of patients treated with cetuximab in that particular RCT, was not reported, and clinicians were only alerted to this serious AE when it appeared as a black box warning in the US Food and Drug Administration drug label. In the primary publication, investigators reported that “no death was known to be related to cetuximab.” This statement contrasts with the appearance of cardiopulmonary arrest in the drug label. Furthermore, although serious toxicities may be rare in the overall population of patients, they may occur more commonly in susceptible subsets of patients. For example, in 2008, the Arimidex, Tamoxifen Alone or in Combination (ATAC) study trialists reported that ischemic cardiovascular events occurred in 4.2% of women receiving the aromatase inhibitor anastrozole. However, in the same year, the US Food and Drug Administration added a warning into the label of anastrozole that 17% of women with pre-existing ischemic heart disease experienced ischemic cardiovascular events on anastrozole in that trial. Although investigators conducted this subgroup analysis at the behest of the licensing authority, they did not report these results in the scientific literature. Results from posthoc subgroup analyses of RCTs should be interpreted cautiously, but practicing clinicians should be aware of potential serious and fatal toxicities in vulnerable subgroups. Reports of cardiotoxicity of cetuximab and anastrozole were submitted to the US Food and Drug Administration, but they were not published. When such analyses are carried out at the request of licensing authorities, data should be published in the scientific literature. Both investigators and journal editors should be compelled to report these data. The use of secondary analyses may allow for more data to be reported. Such supplementary analyses have been described for more than 20 years, but the publication of such data remains rare. The JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 29 NUMBER 9 MARCH 2