Abstract
Adverse drug events are one of the major causes of morbidity in developed countries, yet the drugs involved in these events have been trialled and approved on the basis of randomised controlled trials (RCTs), regarded as the study design that will produce the best evidence. Though the focus on adverse drug events has been primarily on processes and outcomes associated with the use of these approved drugs, attention needs to be directed to the way in which the RCT study design is structured. The implementation of controls to achieve internal validity in RCTs may be the very controls that reduce external validity, and contribute to the levels of adverse drug events associated with the release of a new drug to the wider patient population. An examination of these controls, and the effects they can have on patient safety, underscore the importance of knowing about how the clinical trials of a drug are undertaken, rather than relying only on the recorded outcomes. As the majority of new drugs are likely to be prescribed to older patients who have one or more comorbidities in addition to that targeted by a new drug, and as the RCTs of those drugs typically under-represent the elderly and exclude patients with multiple comorbidities, timely assessment of drug safety signals is essential. It is unlikely that regulatory jurisdictions will undertake a reassessment of safety issues for drugs that are already approved. Instead, reliance has been placed on adverse drug event reporting systems. Such systems have a very low reporting rate, and most adverse drug events remain unreported, to the eventual cost to patients and healthcare systems. This makes it essential for near real-time systems that can pick up safety signals as they occur, so that modifications to the product information (or removal of the drug) can be implemented.
Highlights
The list of drugs with regulatory approval subsequently implicated in adverse drug events (ADEs) in large numbers of patients continues to grow [1,2,3]
The elephant in the room, as far as newly approved drugs and patient safety is concerned, could be what has happened in the preapproval clinical trial processes, and the extent to which the randomised controlled trials (RCTs) study design can be unintentionally manipulated in ways that avoid finding evidence of patient safety signals
Using rofecoxib as an illustration, it is interesting to see that cardiovascular (CVD) endpoints were adjudicated in early clinical trials that were submitted to the Food and Drug Administration (FDA), but adjudication of these endpoints in later trials was modified when it appeared that the drug could be associated with thrombotic morbidity [22,23]
Summary
The list of drugs with regulatory approval subsequently implicated in adverse drug events (ADEs) in large numbers of patients continues to grow [1,2,3]. Analyses of ADEs often focus on events surrounding the patient, the prescribing staff, the pharmacy staff, the administering staff, and the choice of drug, and many ADEs are associated with such procedural considerations. These considerations often start with the assumption that the drug per se has been approved for safe use in the marketplace in accordance with the approved directions. The root cause of a patient’s ADE may lie in the design of the randomised controlled trials (RCTs) that supported the approval of that drug for marketing.
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