When decisions about a new intervention are being made, the “net clinical benefit” of the intervention needs to be assessed. This requires balancing all the reported benefits and side effects of the intervention. The adverse events experienced in a trial must be known in sufficient detail for their severity and relationship to treatment allocation to be judged. Reporting of such events is the subject of item 19 of the CONSORT statement (Box 1).1

The definition of adverse events (AEs) adopted by the International Conference on Harmonization (ICH) is shown in Box 2; it is designed to document all untoward events occurring in a clinical trial.2,3 AEs are thus both those events for which there is a known or plausible association with treatment and those for which there is none. Adverse drug reactions (ADRs) are those AEs that may reasonably be attributed to the medication (Box 2), distinguishing between medications that are used in accordance with their marketing approval (eg, in the approved dose, patient population and indication) or not.2,3 AEs are also classified as being serious or non-serious (Box 2 and Box 3).

Standard schemes used to classify AEs, usually by body system, allow for easier comparison between different trial results and between different treatment options. Examples include the International classification of diseases,4 and the Medical dictionary for regulatory activities.5 Some classifications also grade severity of AEs, such as the Common terminology criteria for adverse events (CTCAE) system of the United States National Cancer Institute,6 which has five grades of severity, ranging from 1 (mild) to 5 (death).

To reliably report on AEs, procedures must be in place from the beginning of a trial for systematically recording and reporting them.2 All investigators participating in a clinical study, and their respective human research ethics committees (HRECs), must have been provided with an investigator’s brochure which includes all relevant information known about the safety, efficacy and pharmacodynamics of the investigational drug, and a description of the possible risks and adverse drug reactions associated with the drug and similar products.2

Good clinical practice guidelines require investigators to report immediately to the trial sponsor any serious AEs that occur during the conduct of a trial.2 In turn, many countries require the study sponsor to then report these to national regulatory authorities. An AE which is considered to be a serious unexpected adverse drug reaction7 must be notified by the sponsor to relevant regulatory authorities as an “expedited” SAE within 7 days of awareness for events that were fatal or life-threatening, and within 15 days for others.3 ICH guidelines for good clinical practice, as adopted internationally, also specify that all serious unexpected adverse drug reactions should be reported to the relevant HRECs.7

It is not possible to assess the significance of AEs from reports in which the treatment allocation remains blinded and the number of participants exposed to the trial medications is unknown. Hence, Data and Safety Monitoring Boards (with the ability to review events and their frequencies unblinded, if preferred) are an important (although insufficiently used8) mechanism for protecting the safety of trial participants9 and for ensuring that studies are stopped as soon as it becomes clear that the trial intervention is beneficial or harmful.10,11

Patient selection can influence the rates of AEs. It is important that the trial population is described adequately so that clinicians can assess the risk of a particular treatment for an individual patient. It is also important that the mechanisms used to elicit reporting of AEs are documented. Volunteered reports of AEs can give incidences of AE markedly different from those ascertained through checklists or diaries.13,14

A statement in the results section of a publication that “no adverse events were observed on the trial medication” without details in the methods section of the steps taken to ascertain AEs is difficult to interpret. What is less apparent is how difficult it really is to convey useful information on the types, severity and incidences of the AEs observed. Even large, multicentre studies published in first-rate journals can fail to report the number of patients who withdrew because of side effects of the trial medication. For example, a large study on the efficacy of irbesartan in preventing the development of nephropathy in patients with type 2 diabetes and microalbuminuria has the following description of the AEs observed:

In the report, the AEs that led to discontinuation were not described. Furthermore, it was unclear whether they were related to the condition being treated, to the trial medication, or to intercurrent illnesses.

Guidelines have been developed to help researchers give useful information about AEs for reporting, both in general1 and for particular classes of trial, such as chemotherapy19 or postoperative analgesia.13 The need for such guidelines is evident from studies of adequacy of AE reporting. In one evaluation of reporting of safety data from clinical trials of HIV treatment, the severity of AEs was regarded as adequately defined in only a third of trials.20 In a subsequent study in other clinical areas, only 39% of trials adequately reported clinical adverse effects and only 29% adequately reported laboratory-determined toxicity.21 Other studies show similar rates of deficiencies in AE reporting in a variety of circumstances.22-25 These deficiencies are serious, as they can prevent clinicians from being able to provide patients with balanced information about the scale and scope of risks associated with different treatment strategies.

Even when AEs have been well described, retrieving data about them can be problematic — of a sample of 37 trials indexed on MEDLINE or EMBASE known to present AE data, only 49% could be found by searching for text words such as “adverse event”, “side effect” or “h(a)emorrhage”, while adding indexing terms relevant to AEs only improved retrieval to 78%.17

Large randomised controlled trials and meta-analyses of randomised controlled trials are very effective in distinguishing AEs that are caused by the underlying condition from those that are related to the intervention. They can provide clinicians with unbiased information about the frequency and severity of adverse effects at a time when a drug or procedure is new. While other mechanisms for obtaining safety data are needed to detect AEs that are too rare to be detected by even the largest studies (Box 5), or that occur in groups of patients who would normally be excluded from trials (eg, because of illness severity, comorbid conditions or the need for potentially confounding therapies), these do not allow clinicians to quantify the risk of a treatment26 and can give markedly different impressions of the incidence of adverse drug reactions compared with those obtained from randomised clinical trials.27 Only proper reporting of AEs from randomised controlled trials allows adequate assessment of the potential net clinical benefits of interventions.

3 Severity and causality of adverse events (AEs)

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* Or more severe than previously known. NSAE = non-serious adverse event; SAE = serious adverse event; SADR = serious adverse drug reaction.