An international initiative to create a collaborative for pharmacovigilance in hospice and palliative care clinical practice

Background: Medication registration currently requires evidence of safety and efficacy from adequately powered phase 3 studies. Pharmacovigilance (phase 4 studies, postmarketing data, adverse drug reaction reporting) provide data on more widespread and longer term use. Historically, voluntary reporting systems for pharmacovigilance have had low reporting rates, relying on ad hoc reporting and retrospective chart reviews, or prospective registries have often been limited to specific drugs or clinical conditions. Furthermore, these data are often irrelevant in hospice and palliative care due to the timeliness of which such data become available and the unique characteristics of our population and prescribing: compounding comorbidities, progressive organ failure, accumulation of symptom-specific medications, tendency to attribute toxicity to disease progression, use of old, off-patent medications, and incorporation of evolving evidence. There is a need for prospective, systematic pharmacovigilance in hospice and palliative care. Method: Here we describe an international, Web-based, 128-bit secure initiative to collect pharmacovigilance data documenting net clinical benefit and safety of common medications. The intention is for a diverse and large group of clinical units to record data prospectively on a small deidentified consecutive cohort of patients started on the medication of interest. A new medication would be studied every 3 months. Three key time points (different for each medication) will be assessed for each patient, collecting easily codefiable data at baseline, a point at which clinical benefit should be experienced, and a point at which short- to medium-term toxicities may occur. Toxicities can additionally be recorded at any time they occur. Data collection will take a maximum of 10 minutes per patient. Conclusion: The intention is to create an efficient, relevant system to improve hospice and palliative care with maximally generalizable results

Pharmacovigilance in hospice/palliative care: Net effect of haloperidol for delirium

Introduction: Prescribing practice in hospice/palliative care is largely extrapolated from other areas of clinical practice, with few studies of net medication effects (benefits and harms) in hospice/palliative care to guide prescribing decisions. Hospice/palliative care patients differ in multiple ways from better studied participant groups, hence the applicability of studies in other participant groups is uncertain. Haloperidol, a butyrophenone derivative and dopamine antagonist, is commonly prescribed for nausea, vomiting, and delirium in hospice/palliative care. Its frequent use in delirium occurs despite little evidence of the effect of antipsychotics on the untreated course of delirium. The aim of this study was to examine the immediate and short-term clinical benefits and harms of haloperidol for delirium in hospice/palliative care patients. Method: A consecutive cohort of participants from 14 centers across four countries who had haloperidol commenced for delirium were recruited. Data were collected at three time points: baseline, 48 hours (clinical benefits), and day 10 (clinical harms). Investigators were also able to report clinical harms at any time up to 14 days after it was commenced. Results: Of the 119 participants included, the average dose was 2.1 mg per 24 hours; 42 of 106 (35.2%) reported benefit at 48 hours. Harm was reported in 14 of 119 (12%) at 10 days, the most frequent being somnolence (n=11) and urinary retention (n=6). Seven participants had their medication ceased due to harms (2 for somnolence and 2 for rigidity). Approximately half (55/119) were still being treated with haloperidol after 10 days. Conclusion: Overall, 1 in 3 participants gained net clinical benefit at 10 days. © Copyright 2013, Mary Ann Liebert, Inc. 2013

Pharmacovigilance in hospice/palliative care: Net effect of haloperidol for delirium

Introduction: Prescribing practice in hospice/palliative care is largely extrapolated from other areas of clinical practice, with few studies of net medication effects (benefits and harms) in hospice/palliative care to guide prescribing decisions. Hospice/palliative care patients differ in multiple ways from better studied participant groups, hence the applicability of studies in other participant groups is uncertain. Haloperidol, a butyrophenone derivative and dopamine antagonist, is commonly prescribed for nausea, vomiting, and delirium in hospice/palliative care. Its frequent use in delirium occurs despite little evidence of the effect of antipsychotics on the untreated course of delirium. The aim of this study was to examine the immediate and short-term clinical benefits and harms of haloperidol for delirium in hospice/palliative care patients. Method: A consecutive cohort of participants from 14 centers across four countries who had haloperidol commenced for delirium were recruited. Data were collected at three time points: baseline, 48 hours (clinical benefits), and day 10 (clinical harms). Investigators were also able to report clinical harms at any time up to 14 days after it was commenced. Results: Of the 119 participants included, the average dose was 2.1 mg per 24 hours; 42 of 106 (35.2%) reported benefit at 48 hours. Harm was reported in 14 of 119 (12%) at 10 days, the most frequent being somnolence (n=11) and urinary retention (n=6). Seven participants had their medication ceased due to harms (2 for somnolence and 2 for rigidity). Approximately half (55/119) were still being treated with haloperidol after 10 days. Conclusion: Overall, 1 in 3 participants gained net clinical benefit at 10 days. © Copyright 2013, Mary Ann Liebert, Inc. 2013

Study protocol: A phase III randomised, double-blind, parallel arm, stratified, block randomised, placebo-controlled trial investigating the clinical effect and cost-effectiveness of sertraline for the palliative relief of breathlessness in people with chronic breathlessness

© Published by the BMJ Publishing Group Limited. Introduction: Breathlessness remains a highly prevalent and distressing symptom for many patients with progressive life-limiting illnesses. Evidence-based interventions for chronic breathlessness are limited, and there is an ongoing need for high-quality research into developing management strategies for optimal palliation of this complex symptom. Previous studies have suggested that selective serotonin reuptake inhibitors such as sertraline may have a role in reducing breathlessness. This paper presents the protocol for a large, adequately powered randomised study evaluating the use of sertraline for chronic breathlessness in people with progressive life-limiting illnesses. Methods and analysis: A total of 240 participants with modified Medical Research Council Dyspnoea Scale breathlessness of level 2 or higher will be randomised to receive either sertraline or placebo for 28 days in this multisite, double-blind study. The dose will be titrated up every 3 days to a maximum of 100 mg daily. The primary outcome will be to compare the efficacy of sertraline with placebo in relieving the intensity of worst breathlessness as assessed by a 0-100 mm Visual Analogue Scale. A number of other outcome measures and descriptors of breathlessness as well as caregiver assessments will also be recorded to ensure adequate analysis of participant breathlessness and to allow an economic analysis to be performed. Participants will also be given the option of continuing blinded treatment until either study data collection is complete or net benefit ceases. Appropriate statistical analysis of primary and secondary outcomes will be used to describe the wealth of data obtained. Ethics and dissemination: Ethics approval was obtained at all participating sites. Results of the study will be submitted for publication in peer-reviewed journals and the key findings presented at national and international conferences. Trial registration number ACTRN12610000464066

Pharmacovigilance in hospice/palliative care: Net effect of gabapentin for neuropathic pain

Objective Hospice/palliative care patients may differ from better studied populations, and data from other populations cannot necessarily be extrapolated into hospice/palliative care clinical practice. Pharmacovigilance studies provide opportunities to understand the harms and benefits of medications in routine practice. Gabapentin, a γ-amino butyric acid analogue antiepileptic drug, is commonly prescribed for neuropathic pain in hospice/palliative care. Most of the evidence however relates to nonmalignant, chronic pain syndromes (diabetic neuropathy, postherpetic neuralgia, central pain syndromes, fibromyalgia). The aim of this study was to quantify the immediate and short-term clinical benefits and harms of gabapentin in routine hospice/palliative care practice. Design Multisite, prospective, consecutive cohort. Population 127 patients, 114 of whom had cancer, who started gabapentin for neuropathic pain as part of routine clinical care. Settings 42 centres from seven countries. Data were collected at three time points-at baseline, at day 7 (and at any time; immediate and shortterm harms) and at day 21 (clinical benefits). Results At day 21, the average dose of gabapentin for those still using it (n=68) was 653mg/24h (range 0-1800mg) and 54 (42%) reported benefits, of whom 7 (6%) experienced complete pain resolution. Harms were reported in 39/127 (30%) patients at day 7, the most frequent of which were cognitive disturbance, somnolence, nausea and dizziness. Ten patients had their medication ceased due to harms. The presence of significant comorbidities, higher dose and increasing age increased the likelihood of harm. Conclusions Overall, 42% of people experienced benefit at a level that resulted in continued use at 21 days

Sertraline in symptomatic chronic breathlessness: a double blind, randomised trial

Copyright ©ERS 2019. Does sertraline provide symptomatic relief for chronic breathlessness in people with advanced disease whose underlying cause(s) are optimally treated?223 participants with chronic breathlessness (modified Medical Research Council breathlessness scale ≥2) who had optimal treatment of underlying cause(s) were randomised 1:1 to sertraline 25-100 mg (titrated upwards over 9 days) or placebo for 4 weeks. The primary outcome was the proportion who had an improvement in intensity of current breathlessness >15% from baseline on a 100-mm visual analogue scale.The proportion of people responding to sertraline was similar to placebo for current breathlessness on days 26-28 (OR 1.00, 95% CI 0.71-1.40) and for other measures of breathlessness. Quality of life in the sertraline arm had a higher likelihood of improving than in the placebo arm over the 4 weeks (OR 0.21, 95% CI 0.01-0.41; p=0.044). No differences in performance status, anxiety and depression, or survival were observed. Adverse event rates were similar between arms.Sertraline does not appear to provide any benefit over placebo in the symptomatic relief of chronic breathlessness in this patient population

Off-label prescribing in palliative care – a cross-sectional national survey of Palliative Medicine doctors

Background: Regulatory bodies including the European Medicines Agency register medications (formulation, route of administration) for specific clinical indications. Once registered, prescription is at clinicians’ discretion. Off-label use is beyond the registered use. While off-label prescribing may, at times, be appropriate, efficacy and toxicity data are often lacking. Aim: The aim of this study was to document off-label use policies (including disclosure and consent) in Australian palliative care units and current practices by palliative care clinicians. Design: A national, cross-sectional survey was conducted online following an invitation letter. The survey asked clinicians their most frequent off-label medication/indication dyads and unit policies. Dyads were classified into unregistered, off-label and on-label, and for the latter, whether medications were nationally subsidised. Setting/participants: All Australian palliative medicine Fellows and advanced trainees. Results: Overall, 105 clinicians responded (53% response rate). The majority did not have policies on off-label medications, and documented consent rarely. In all, 236 medication/indication dyads for 36 medications were noted: 45 dyads (19%) were for two unregistered medications, 118 dyads (50%) were for 26 off-label medications and 73 dyads (31%) were for 12 on-label medications. Conclusions: Off-label prescribing with its clinical, legal and ethical implications is common yet poorly recognised by clinicians. A distinction needs to be made between where quality evidence exists but registration has not been updated by the pharmaceutical sponsor and the evidence has not been generated. Further research is required to quantify any iatrogenic harm from off-label prescribing in palliative care

Evaluation of the Prescribing Skills Assessment implementation, performance and medical student experience in Australia and New Zealand

Aims: The UK Prescribing Safety Assessment was modified for use in Australia and New Zealand (ANZ) as the Prescribing Skills Assessment (PSA). We investigated the implementation, student performance and acceptability of the ANZ PSA for final-year medical students. Methods:This study used a mixed-method approach involving student data (n = 6440) for 2017–2019 (PSA overall score and 8 domain subscores). Data were also aggregated by medical school and included student evaluation survey results. Quantitative data were analysed using descriptive and multivariate analyses. The pass rate was established by a modified Angoff method. Thematic analyses of open-ended survey comments were conducted. Results:The average pass rate was slightly higher in 2017 (89%) which used a different examination to 2018 (85%) and 2019 (86%). Little difference was identified between schools for the PSA overall performance or domain subscores. There was low intercorrelation between subscores. Most students provided positive feedback about the PSA regarding the interface and clarity of questions, but an average of 35% reported insufficient time for completion. Further, 70% on average felt unprepared by their school curricula for the PSA, which is in part explained by the low prescribing experience; 69% reported completing ≤10 prescriptions during training. Conclusion:The ANZ PSA was associated with high pass rates and acceptability, although student preparedness was highlighted as a concern for further investigation. We demonstrate how a collaboration of medical schools can adapt a medical education assessment resource (UK PSA) as a means for fulfilling an unmet need.</p

Pharmacokinetic/pharmacodynamic modelling approaches in paediatric infectious diseases and immunology.

Pharmacokinetic/pharmacodynamic (PKPD) modelling is used to describe and quantify dose-concentration-effect relationships. Within paediatric studies in infectious diseases and immunology these methods are often applied to developing guidance on appropriate dosing. In this paper, an introduction to the field of PKPD modelling is given, followed by a review of the PKPD studies that have been undertaken in paediatric infectious diseases and immunology. The main focus is on identifying the methodological approaches used to define the PKPD relationship in these studies. The major findings were that most studies of infectious diseases have developed a PK model and then used simulations to define a dose recommendation based on a pre-defined PD target, which may have been defined in adults or in vitro. For immunological studies much of the modelling has focused on either PK or PD, and since multiple drugs are usually used, delineating the relative contributions of each is challenging. The use of dynamical modelling of in vitro antibacterial studies, and paediatric HIV mechanistic PD models linked with the PK of all drugs, are emerging methods that should enhance PKPD-based recommendations in the future