Our results show that automated searches of MEDLINE and EMBASE will not succeed in retrieving all trials with adverse effects data because:
• indexing terms for adverse effects were not assigned to some of the papers, even though they contained data on adverse effects frequencies;
• the authors made no mention of adverse effects (or related terms) in the title or abstract, although the paper itself contained numerical information about adverse effects.
This latter point explains the failure of textword searches; more importantly, it shows that manual checking of trial abstracts will not help reviewers in determining whether adverse effects data are available from a trial report.
There are several reasons for this failure to mention adverse effects in abstracts of papers or indexes of databases. Guidelines on the structured reporting of clinical trials are directed towards the reporting of therapeutic efficacy [6
]. Authors may not feel that adverse effects deserve a mention in the confined space of an abstract, especially as there are already so many other requirements about the information they need to provide.
There are no specific rules concerning what merits indexing as "drug toxicity" or "side effect" in the EMBASE database, but general guidelines are that indexing should take place if significant information relevant to clinical use is presented in the article (Jos Hageman, personal communication). Indexing terms for adverse effects in the MEDLINE database are generally assigned only to papers in which the author devotes substantive discussion to the adverse effects (Ione Auston, Beth Van Lenten, personal communication). This usually occurs only when the author considers the effects to be significant or serious. However, most trials are not powered to detect significant differences in rates of adverse effects, and serious ones tend to be rare. Furthermore, few authors actually devote substantial amounts of space to safety data [7
]. This may explain why only about half of the trials we surveyed in which adverse effects data were reported had been assigned adverse effects indexing terms.
Data on adverse effects could be more easily retrieved if trials that reported adverse effects were distinguishable in electronic databases from those that did not. However, about 23% of papers containing adverse effects data do not have any adverse effects textwords or indexing terms attached to them, and would therefore be missed by electronic searches. These papers can be identified only by using a broad search strategy with no specific adverse effects terms, followed by manual (and potentially laborious) searching of the full-text versions. We found this to be true whether we were searching for a specific adverse effect associated with a specific drug, or for all adverse effects associated with a specific drug or type of therapy.
It is important that search strategies should reliably retrieve all trials in which drug adverse effects are reported, so that we can readily access and use all the existing evidence. However, index-based searches for adverse effects may omit papers that do not report significant or serious adverse effects. Unreliable estimates of the rate or severity of drug adverse effects may occur as a result of these limitations in the current indexing system.
Although there has been some recent interest in improving the adequacy of adverse effects reporting in clinical trials [6
] the benefits of better reporting may be wasted if steps are not taken to make the data more easily available. A number of relatively simple changes to both the reporting and indexing of drug adverse effects could significantly increase the accessibility of such evidence from future publications, and allow more reliable estimates of their significance to be given to patients. As such, we make the following proposals:
1. Indexers should agree on a unified system for indexing drug adverse effects. Any trial that reports on the frequency of adverse effects needs to be indexed, even if the adverse effects were judged not significant or not severe. Information on the absence of serious adverse effects is of no less value to those who are involved in making therapeutic decisions.
2. Journals that publish structured abstracts should require authors to mention drug adverse effects in the abstract whenever they are reported in randomised controlled trials, even if no adverse drug reactions occurred in the trial.