Prior to release onto the market, all new medicines must have completed a series of clinical trials with patients. These trials will have aimed to establish the safety and efficacy of the drug for the treatment of a particular disease within a selected sample of the population. This page provides a brief insight into the need for post-marketing pharmacovigilance activities.
Pre-marketing trials could have been conducted on a large scale, involving up to 10,000 subjects, or they could have been relatively small. In small trials, the study size could have ranged from only dozens to perhaps hundreds of patients, as can be the case for ‘orphan drugs’ (meaning drugs intended to treat rare diseases).
However, even after having completed rigorous pre-marketing trials, the limitations of the scale of the studies mean that the less common and rare adverse reactions (ADRs) are statistically unlikely to have been detected. For example, for a study of 10,000 patients, the absence of a report of a particular ADR occurring in the study programme means that we can be confident (at the 5% probability level) that the true rate of occurrence is less than 1 in 3,333. A statistical probability level of 1% would require a zero occurrence rate in 46,000 patients. Therefore, uncommon AEs or those with less commons rate of occurrence cannot be detected with any certainty given the limitations of sample size during the pre-marketing phase.
Pre-marketing studies of a drug may also exclude certain groups of patients, although in real-life clinical practice, the drug may be prescribed for patients from those groups. For example, clinical trials may have included patients aged 18 to 60 years old. However, the drug may then be prescribed to more elderly patients. The elderly are a population who are more sensitive to a range of adverse reactions to medicines for various reasons, including differences in metabolism and in body mass index compared with a younger population as well as a higher likelihood of non-compliance with medication and of polypharmacy. Additionally, clinical trials may exclude subjects with co-morbidities such as renal or cardiac impairment, immunodeficiency, or blood pressure anomalies etc. These conditions may put such patients at increased risk of certain ADRs and may eventually lead to the medicine being contraindicated or requiring close monitoring when used under these circumstances.
Polypharmacy is another issue which may not have been possible to adequately address during pre-marketing studies. There could have been some drug interaction studies including drug-drug interactions and investigation into the effects of food intake, but information is likely to be limited and patients taking several classes of concomitant medicines may have been excluded from the study programme, whilst such patients could be exposed to these drugs after marketing.
The initial 500,000 to 1,000,000 patients who are the first to take the new drug after it has been released onto the market represent the first large scale safety test. A robust pharmacovigilance system is clearly of pivotal importance during this particular stage of the products life cycle. Pharmacists, doctors and nurses report suspected adverse drug reactions each working day around the globe; this is known as spontaneous reporting. They may report to regulatory agencies, national or regional pharmacovigilance centres or to pharmaceutical companies. Should pharmaceutical companies receive a report of a serious suspected adverse reaction for one of their products on the market, they must report it (generally within 15 days) to the regulatory authorities according to national and international laws.
Please note this information is intended as a brief introduction for the interested lay reader and does not constitute any form of professional advice.
1. Barton L. Cobert, MD. (2007). Manual of Drug Safety and Pharmacovigilance. Massachusetts: Jones and Bartlett.
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