Randomised controlled trials and 'unexpected' adverse events associated with newly released drugs : improvements in pharmacovigilance systems are necessary for real-time identification of patient safety risks

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.

Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs

Consistent with its highest abundance in humans, cytochrome P450 (CYP) 3A is responsible for the metabolism of about 60% of currently known drugs. However, this unusual low substrate specificity also makes CYP3A4 susceptible to reversible or irreversible inhibition by a variety of drugs. Mechanism-based inhibition of CYP3A4 is characterised by nicotinamide adenine dinucleotide phosphate hydrogen (NADPH)-, time- and concentration-dependent enzyme inactivation, occurring when some drugs are converted by CYP isoenzymes to reactive metabolites capable of irreversibly binding covalently to CYP3A4. Approaches using in vitro, in silico and in vivo models can be used to study CYP3A4 inactivation by drugs. Human liver microsomes are always used to estimate inactivation kinetic parameters including the concentration required for half-maximal inactivation (K(I)) and the maximal rate of inactivation at saturation (k(inact)).Clinically important mechanism-based CYP3A4 inhibitors include antibacterials (e.g. clarithromycin, erythromycin and isoniazid), anticancer agents (e.g. tamoxifen and irinotecan), anti-HIV agents (e.g. ritonavir and delavirdine), antihypertensives (e.g. dihydralazine, verapamil and diltiazem), sex steroids and their receptor modulators (e.g. gestodene and raloxifene), and several herbal constituents (e.g. bergamottin and glabridin). Drugs inactivating CYP3A4 often possess several common moieties such as a tertiary amine function, furan ring, and acetylene function. It appears that the chemical properties of a drug critical to CYP3A4 inactivation include formation of reactive metabolites by CYP isoenzymes, preponderance of CYP inducers and P-glycoprotein (P-gp) substrate, and occurrence of clinically significant pharmacokinetic interactions with coadministered drugs.Compared with reversible inhibition of CYP3A4, mechanism-based inhibition of CYP3A4 more frequently cause pharmacokinetic-pharmacodynamic drug-drug interactions, as the inactivated CYP3A4 has to be replaced by newly synthesised CYP3A4 protein. The resultant drug interactions may lead to adverse drug effects, including some fatal events. For example, when aforementioned CYP3A4 inhibitors are coadministered with terfenadine, cisapride or astemizole (all CYP3A4 substrates), torsades de pointes (a life-threatening ventricular arrhythmia associated with QT prolongation) may occur.However, predicting drug-drug interactions involving CYP3A4 inactivation is difficult, since the clinical outcomes depend on a number of factors that are associated with drugs and patients. The apparent pharmacokinetic effect of a mechanism-based inhibitor of CYP3A4 would be a function of its K(I), k(inact) and partition ratio and the zero-order synthesis rate of new or replacement enzyme. The inactivators for CYP3A4 can be inducers and P-gp substrates/inhibitors, confounding in vitro-in vivo extrapolation. The clinical significance of CYP3A inhibition for drug safety and efficacy warrants closer understanding of the mechanisms for each inhibitor. Furthermore, such inactivation may be exploited for therapeutic gain in certain circumstances.

Antidepressants and suicidal thought

The association of antidepressants with suicidal thought in people aged up to 25 year is a thorny issue. Balancing risk with benefit must always be at the core of any decision to treat and when the risk is an increased risk of suicide then a balanced decision can be difficult to make. Some clinicians who have been successfully treating patients using antidepressants have felt skepticism with these studies, finding them to be not reflective of their personal clinical experience. It may be wondered by some whether highlighting the link between suicidal thoughts and antidepressants may paradoxically lead to an increase in suicide by reducing the number of cases treated, however there is no evidence that this has occurred.

The association between antidepressants and suicidal thought may be unpalatable, but as with all new research the only way it can be judged is by the evidence to support it. The weight of evidence to demonstrate the association between antidepressants and suicidal thought in young people is convincing although the risk is low, estimated at one case of emerging suicidal ideation or suicide attempt for every 143 pediatric patients treated [1]. This risk is too low to displace antidepressants as the first line of treatment for depression but is too high a risk to be ignored. The risk is also too low to be recognized based on clinical experience alone as it is low enough to be imperceptible amongst suicides which occur due to depressive illness independent of antidepressant treatment. Only large studies are sufficiently powered to detect suicidal thought associated with antidepressant treatment. Clearly further studies would be helpful, especially if they can help characterize those at greatest risk. This is why the study by Lucy Goldsmith and Joanna Moncrieff in this issue of Current Drug Safety is an important step towards improving our understanding of antidepressant safety. These researchers find a link between increased suicidal impulses and emotional blunting and emotional instability.

Treating clinicians are urged to monitor for risk of suicide after initiation of antidepressant treatment, typically more frequently for the first four weeks of treatment and as indicated thereafter. However, if there is no history of suicidal thought or attempt and the patient does not admit to suicidal thought, suicidality may be missed by the treating clinician, ending in tragedy. Studies that provide new insights into this serious problem may lead to improvements in the effectiveness of monitoring patients for suicide risk, ultimately leading to better outcomes for patients.

Debating the evidence : oral contraceptives containing drospirenone and risk of blood clots

Skepticism is an essential quality in science. We doubt, re-examine and demand the highest quality of evidence. However, sometimes this puts us in an awkward situation. How much evidence do we need before we act? This dilemma is a constant problem in drug safety. Treatment decisions are always a balance of risks and benefits and there may be a paucity of evidence about rare or very rare adverse events.

Alcohol and drug use in Australian male sex workers: its relationship to the safety outcome of the sex encounter

This paper describes the self-reporting patterns of alcohol and drug consumption among male sex workers (MSWs) in three Australian cities during commercial sex encounters, and examines to what extent alcohol and drugs are used and whether this is related to the safe/unsafe outcome of the commercial sex encounter. One hundred and eighty-six MSWs from Brisbane, Sydney and Melbourne completed a diary following each commercial sex encounter over a two-week period. MSWs reported 2,087 commercial sex encounters during the study period. Alcohol or drug consumption was reported in 50.5% of the encounters.

Safety and efficacy of routine postoperative ibuprofen for pain and disability related to ectopic bone formation after hip replacement surgery (HIPAID): a randomised control trial

Objectives To determine the benefits and risks of a non-steroidal anti-inflammatory drug (NSAID) as prophylaxis for ectopic bone formation in patients undergoing total hip replacement (or revision) surgery.
Design Double blind randomised placebo controlled clinical trial, stratified by treatment site and surgery (primary or revision).
Setting 20 orthopaedic surgery centres in Australia and New Zealand.
Participants 902 patients undergoing elective primary or revision total hip replacement surgery.
Intervention 14 days' treatment with ibuprofen (1200 mg daily) or matching placebo started within 24 hours of surgery.
Main outcome measures Changes in self reported hip pain and physical function 6 to 12 months after surgery (Western Ontario and McMaster University Arthritis index).
Results There were no significant differences between the groups for improvements in hip pain (mean difference -0.1, 95% confidence interval -0.4 to 0.2, P = 0.6) or physical function (-0.1, -0.4 to 0.2, P = 0.5), despite a decreased risk of ectopic bone formation (relative risk 0.69, 0.56 to 0.83) associated with ibuprofen. There was a significantly increased risk of major bleeding complications in the ibuprofen group during the admission period (2.09, 1.00 to 4.39).
Conclusions These data do not support the use of routine prophylaxis with NSAIDs in patients undergoing total hip replacement surgery.
Trial registration NCT00145730.

Implementation of a medication guideline to improve medication safety for patients

Although the incidence of medication error remains unknown, in Australian hospitals, they are thought to occur in 5-20 % of drug administrations 1. Not surprisingly, international debate has focused on the mechanisms to improve the safety of patients. Thus a new National Inpatient Medication Chart (NIMC) was endorsed to improve communication and reduce medication errors 2. This study aimed to investigate the documentation practices of clinicians following the implementation of a medication guideline and NIMC.
A pre and post-test design was used to evaluate the adoption of and adherence to the medication guideline at Western Health, an 850 bed healthcare network in Australia. Audits of inpatient medication charts (N=265) were conducted at 3 months prior to and repeated 4 months (N=290) after implementation. The pre-test data was used to formulate an interdisciplinary organizational strategy that included mandatory education for all clinical staff, practice reminders, decision prompts, a telephone hotline for support, an intranet information website and electronically distributed Frequently Asked Questions.
Pre and post implementation audits highlighted areas of potential medication error. The post-test showed an overall trend towards improvement in documentation. There were significant improvements in 4 critical practices: Drug name clear (p=0.0003); Drug dose clear (p=0.0002); Prescribed frequency equals documented frequency (p=0) and; No signature by administrator (p=0).
The majority of documentation errors showed poor attention to detail and would be considered a slip or lapse in skill based judgment 3. Although this study was designed to evaluate documentation practices, future research should include observation methods to increase our understanding of the context behind the judgments such as work place interruptions, skill mix and knowledge levels. While evidence based guidelines enable work, they are not the actual work or substance of patient care. Organisational systems can assist in preventing unconscious aberrations that lead to error.

Promises of nanotechnology for drug delivery to brain in neurodegenerative diseases

Brain is a delicate organ, isolated from general circulation and characterized by the presence of relatively impermeable endothelial cells with tight junctions, enzymatic activity and the presence of active efflux transporter mechanisms. These formidable obstacles often block drug delivery to the brain across the blood-brain barrier (BBB). Although several promising molecules have the potential in the in vitro settings but lack of in vivo response is probably because the molecule cannot reach the brain in a sufficient concentration. Drug delivery across the BBB is a major limitation in the treatment of central nervous system (CNS) disorders and CNS infections. This review deals with the role of nanobiotechnology in CNS drug delivery, in which three categories of carbon nanotubes, nanowires and nanoparticles (NPs) are explained. The small size of the NPs makes them an ideal choice to penetrate the BBB. Several mechanisms are involved in this process and various strategies are used. There are some concerns about the safety of NP entry in the brain that need to be resolved before human use. Although there is no approved nanotechnology-based CNS drug available the future for such neuro-nanobiotechnology based delivery system developments is promising.

Qualitative methods in early-phase drug trials : data and methods from a trial of N-acetylcysteine in schizophrenia

Objective: The pharmacokinetic profile of a drug often gives little indication of its potential therapeutic application, with many therapeutic uses of drugs being discovered serendipitously while being studied for different indications. As hypothesis-driven, quantitative research methodology is exclusively used in early-phase trials, unexpected but important phenomena may escape detection. In this context, this study aimed to examine the potential for integrating qualitative research methods with quantitative methods in early-phase drug trials. To our knowledge, this mixed methodology has not previously been applied to blinded psychopharmacologic trials.

Method: We undertook qualitative data analysis of clinical observations on the dataset of a randomized, double-blind, placebo-controlled trial of N-acetylcysteine (NAC) in patients with DSM-IV-TR–diagnosed schizophrenia (N = 140). Textual data on all participants, deliberately collected for this purpose, were coded using NVivo 2, and emergent themes were analyzed in a blinded manner in the NAC and placebo groups. The trial was conducted from November 2002 to July 2005.

Results: The principal findings of the published trial could be replicated using a qualitative methodology. In addition, significant differences between NAC- and placebo-treated participants emerged for positive and affective symptoms, which had not been captured by the rating scales utilized in the quantitative trial. Qualitative data in this study subsequently led to a positive trial of NAC in bipolar disorder.

Conclusions: The use of qualitative methods may yield broader data and has the potential to complement traditional quantitative methods and detect unexpected efficacy and safety signals, thereby maximizing the findings of early-phase clinical trial research.

A review of clozapine safety

Clozapine is a distinctive antipsychotic agent, having a unique clinical profile and an idiosyncratic safety profile. More so than with other agents, the weighting of its adverse event profile is critical, in order to counterbalance its clear clinical advantages. The safety issues with clozapine are in a number of areas, some of which are considered medical emergencies and potentially life-threatening. These include haematological (neutropenia and agranulocytosis), CNS (seizures), cardiovascular (myocarditis and cardiomyopathy), metabolic (diabetes), gastrointestinal and neuromuscular. Understanding the safety profile of clozapine allows an informed use of the agent that can maximise its clear clinical benefit and minimise the known risks.

Multifactorial influences on and deviations from medication administration safety and quality in the acute medical/surgical context

Background and Aims: Although numerous factors influence medication administration, our understanding of the interplay of these factors on medication quality and safety is limited. The aim of this study was to explore the multifactorial influences on medication quality and safety in the context of a single checking policy for medication administration in acute care.

Approach: An exploratory/descriptive study using non-participant observation and follow-up interview was used to identify factors influencing medication quality and safety in medication administration episodes (n = 30). Observations focused on nurses’ interactions with patients during medication administration, and the characteristics of the environment in which these took place. Confirmation of observed data occurred on completion of the observation period during short semi-structured interviews with participant nurses.

Findings: Findings showed nurses developed therapeutic relationships with patients in terms of assessing patients before administering medications and educating patients about drugs during medication administration. Nurses experienced more frequent distractions when medications were stored and prepared in a communal drug room according to ward design. Nurses deviated from best-practice guidelines during medication administration.

Implications: Nurses’ abilities and readiness to develop therapeutic relationships with patients increased medication quality and safety, thereby protecting patients from potential adverse events. Deviations from best-practice medication administration had the potential to decrease medication safety. System factors such as ward design determining medication storage areas can be readily addressed to minimise potential error.

Conclusions: Nurses displayed behaviours that increased medication administration quality and safety; however, violations of practice standards were observed. These findings will inform future intervention studies to improve medication quality and safety.

Is there a need for safety monitoring guidelines for antidepressant treatment?

Antidepressants are amongst the most commonly prescribed classes of drugs and their use continues to grow. The World Health Organisation estimates that depression effects approximately 121 million people worldwide, with 26 million people receiving some form of medical care for depression [1]. A large number of these people will be treated with antidepressants. Moreover, antidepressants are commonly administered to special populations, such as the elderly, children and women during reproductive life stages. Depression is also commonly associated with comorbid physical illnesses [2], being overweight [3], tobacco smoking [4], poor diet [5] and lack of physical activity [6]. Large numbers of people being treated, often with vulnerabilities, increases the likelihood of adverse drug reactions to antidepressant treatment.

Occupational health and safety among commercial sex workers

The concept of occupational health and safety (OHS) for commercial sex workers has rarely been investigated, perhaps because of the often informal nature of the workplace, the associated stigma, and the frequently illegal nature of the activity. We reviewed the literature on health, occupational risks, and safety among commercial sex workers. Cultural and local variations and commonalities were identified. Dimensions of OHS that emerged included legal and policing risks, risks associated with particular business settings such as streets and brothels, violence from clients, mental health risks and protective factors, alcohol and drug use, repetitive strain injuries, sexually transmissible infections, risks associated with particular classes of clients, issues associated with male and transgender commercial sex workers, and issues of risk reduction that in many cases are associated with lack of agency or control, stigma, and legal barriers. We further discuss the impact and potential of OHS interventions for commercial sex workers. The OHS of commercial sex workers covers a range of domains, some potentially modifiable by OHS programs and workplace safety interventions targeted at this population. We argue that commercial sex work should be considered as an occupation overdue for interventions to reduce workplace risks and enhance worker safety.

Exploring in-hospital adverse drug events using ICD-10 codes

 Abstract
Objective Adverse drug events (ADEs) during hospital admissions are a widespread problem associated with adverse patient outcomes. The ‘external cause’ codes in the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) provide opportunities for identifying the incidence of ADEs acquired during hospital stays that may assist in targeting interventions to decrease their occurrence. The aim of the present study was to use routine administrative data to identify ADEs acquired during hospital admissions in a suburban healthcare network in Melbourne, Australia.

Methods Thirty-nine secondary diagnosis fields of hospital discharge data for a 1-year period were reviewed for ‘diagnoses not present on admission’ and assigned to the Classification of Hospital Acquired Diagnoses (CHADx) subclasses. Discharges with one or more ADE subclass were extracted for retrospective analysis.

Results From 57 205 hospital discharges, 7891 discharges (13.8%) had at least one CHADx, and 402 discharges (0.7%) had an ADE recorded. The highest proportion of ADEs was due to administration of analgesics (27%) and systemic antibiotics (23%). Other major contributors were anticoagulation (13%), anaesthesia (9%) and medications with cardiovascular side-effects (9%).

Conclusion Hospital data coded in ICD-10 can be used to identify ADEs that occur during hospital stays and also clinical conditions, therapeutic drug classes and treating units where these occur. Using the CHADx algorithm on administrative datasets provides a consistent and economical method for such ADE monitoring.

What is known about the topic? Adverse drug events (ADEs) can result in several different physical consequences, ranging from allergic reactions to death, thereby posing a significant burden on patients and the health system. Numerous studies have compared manual, written incident reporting systems used by hospital staff with computerised automated systems to identify ADEs acquired during hospital admissions. Despite various approaches aimed at improving the detection of ADEs, they remain under-reported, as a result of which interventions to mitigate the effect of ADEs cannot be initiated effectively.

What does this paper add? This research article demonstrates major methodological advances over comparable published studies looking at the effectiveness of using routine administrative data to monitor rates of ADEs that occur during a hospital stay and reviews the type of ADEs and their frequency patterns during patient admission. It also provides an insight into the effect of ADEs that occur within different hospital treating units. The method implemented in this study is unique because it uses a grouping algorithm developed for the Australian Commission on Safety and Quality in Health Care (ACSQHC) to identify ADEs not present on admission from patient data coded in ICD-10. This algorithm links the coded external causes of ADEs with their consequences or manifestations. ADEs identified through the use of programmed code based on this algorithm have not been studied in the past and therefore this paper adds to previous knowledge in this subject area.

What are the implications for health professionals? Although not all ADEs can be prevented with current medical knowledge, this study can assist health professionals in targeting interventions that can efficiently reduce the rate of ADEs that occur during a hospital stay, and improve information available for future medication management decisions.

“Pma sounds fun” : negotiating drug discourses online

 In 2007, a young woman, Annabel Catt, died after consuming a capsule sold as “ecstasy” that contained para-methoxyamphetamine. In this paper, we describe how this death was depicted in online drug-user communities and illustrate how the meanings of drug use are negotiated in online settings. News articles, public online discussions, and online fieldwork formed the data. This paper demonstrates how dominant drug discourses may be resisted by drug users, drawing on theories of health resistance and Kane Race’s concept of counterpublic health. Online environments may offer ways of engaging people who use drugs that acknowledge both pleasure and safety. The study’s limitations are noted.