Drug Safety

Adverse drug reactions (ADRs) represent a significant burden to the NHS, accounting for 6.5% of all UK hospital admissions [1] and costing more than £650m annually [2]. An estimated 2% of ADRs requiring hospitalisation prove fatal [1]. The University of Liverpool has unparalleled expertise in drug safety, having been awarded the NHS Chair in Pharmacogenetics (http://www.liv.ac.uk/researchintelligence/issue32/pharmacogenetics.htm) and the MRC Centre for Drug Safety Sciences (http://www.liv.ac.uk/drug-safety/). The former is a programme of large, well designed observational studies aimed at identifying genetic markers that could be used to predict ADRs to several commonly used drugs including antiplatelets, non-steroidal anti-inflammatory drugs, anti-epileptic drugs, and corticoid steroids. Given the vast number of genetic variants explored in a pharmacogenetic study the risk of false positive discoveries is significant, thus novel findings are understandably interpreted with caution. Replication in an independent cohort is fundamental, however in many cases regulatory authorities insist on evidence of clinical validity and utility of the genetic marker from a randomised controlled trial (RCT) before a genetic marker is approved for clinical use.

An example of such a trial, to evaluate whether pre-prescription genotyping improves the effectiveness and safety of warfarin is currently being coordinated from The University of Liverpool, funded through the EU FP7 framework [3]. The trial implements a straightforward two-armed RCT design, made possible given that the primary outcome of interest is time spent within therapeutic range on the basis that being above or below range increases risk of adverse events. However, in most situations where ADRs are under consideration, outcome will be developing the ADR. Given the high probability that this will be a rare event, the sample size required for a RCT will likely be prohibitively large. Novel trial methodologies capable of providing robust evidence of clinical validity and utility are thus urgently required such that predictive genetic markers, as well as other biomarkers, can confidently be incorporated into clinical practice.

In addition, research had been undertaken to provide important evidence about the incidence and nature of ADRs in children in both an acute admissions [4] and in-patient setting [5]. This work has been funded through an NIHR programme grant (ADRIC – Adverse Drug Reactions in Children) (http://www.adric.org.uk/). This project has also looked at understanding how ADRs might be better detected, assessed and prevented. New causality [6] and avoidability tools have been developed to help aide this process.

To complement previous work that has investigated the problem of outcome reporting bias in efficacy outcomes [7], a project funded by the Medical Research Council Methods Panel is currently under way to investigate this problem in harm outcomes (ORBIT II). Important harm outcomes maybe subject to outcome reporting bias where trialists prefer to focus on the positive benefits of an experimental intervention. The aim of this project is to raise the awareness of this type of bias in order to help improve the ability of decision makers to make informed decisions that consider both benefits and harms of an intervention in an unbiased way.

[1] Pirmohamed M, James S, Meakin S, Green C, Scott AK, et al. (2004) Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ 329: 15-19

[2] Davies EC, Green CF, Taylor S, Williamson PR, Mottram DR, et al. (2009) Adverse Drug Reactions in Hospital In-Patients: A Prospective Analysis of 3695 Patient-Episodes. PLoS ONE 4: e4439.

[3] van Schie RMF, Wadelius M, Kamali F, Daly AK, Manolopoulos VG, et al. (2009) Genotype-guided dosing of coumarin derivatives: the European pharmacogenetics of anticoagulant therapy (EU-PACT) trial design. Pharmacogenomics 10: 1687-1695.

[4] Gallagher RM, Mason JR, Bird KA, Kirkham JJ, Williamson PR, Peak M, Nunn AJ, Turner MA, Pirmohamed, Smyth RL. Adverse drug reactions causing admission to a paediatric hospital. (submitted to PLoS ONE)

[5] Thiesen S, Conroy EJ, Bellis JR, Bracken LE, Mannix HL, Bird KA et al. Incidence, characteristics and risk factors of Adverse Drug Reactions (ADRs) in hospitalised children – a prospective observational cohort study of 6601 admissions (submitted to the Lancet).

[6] Gallagher RM, Kirkham JJ, Mason JR, Bird KA, Williamson PR, Nunn AJ, Turner MA, Smyth RL, Pirmohamed M. Development and inter-rater reliability of the Liverpool adverse drug reaction causality assessment tool. PLoS ONE (2011); 6(12): e28096.

[7] Kirkham JJ, Dwan KM, Altman DG, Gamble C, Dodd S, Smyth R, Williamson PR. The impact of outcome reporting bias in randomised controlled trials on a cohort of systematic reviews. BMJ (2010); 340:c365.


Trial Methodology Research