Incorporating adverse event relatedness into dose-finding clinical trial designs

Dose-finding designs estimate the dose level of a drug based on observed adverse events. Relatedness of the adverse event to the drug has been generally ignored in all proposed design methodologies. These designs assume that the adverse events observed during a trial are definitely related to the drug, which can lead to flawed dose-level estimation. We incorporate adverse event relatedness into the so-called continual reassessment method. Adverse events that have ‘doubtful’ or ‘possible’ relationships to the drug are modelled using a two-parameter logistic model with an additive probability mass. Adverse events ‘probably’ or ‘definitely’ related to the drug are modelled using a cumulative logistic model. To search for the maximum tolerated dose, we use the maximum estimated toxicity probability of these two adverse event relatedness categories. We conduct a simulation study that illustrates the characteristics of the design under various scenarios. This article demonstrates that adverse event relatedness is important for improved dose estimation. It opens up further research pathways into continual reassessment design methodologies.

Honesty about adverse event : more honoured in the breach than in the observance?

Part of the chapter: "Sale of Sperm, Health Records, Minimally Conscious States, and Duties of Candour" Although ethical obligations and good medical practice guidelines clearly contemplate open disclosure, there is a dearth of authority as to the nature and extent of a legal duty on Australian doctors to disclose adverse events to patients.

Beliefs underlying the intention to donate again among first-time blood donors who experience a mild adverse event

Using the belief basis of the theory of planned behavior (TPB), the current study explored the rate of mild reactions reported by donors in relation to their first donation and the intention and beliefs of those donors with regard to returning to donate again. A high proportion of first-time donors indicated that they had experienced a reaction to blood donation. Further, donors who reacted were less likely to intend to return to donate. Regression analyses suggested that targeting different beliefs for those donors who had and had not reacted would yield most benefit in bolstering donors’ intentions to remain donating. The findings provide insight into those messages that could be communicated via the mass media or in targeted communications to retain first-time donors who have experienced a mild vasovagal reaction.

Action following the discovery of a global association between the whole genome and adverse event risk in a clinical drug-development programme

Observation of adverse drug reactions during drug development can cause closure of the whole programme. However, if association between the genotype and the risk of an adverse event is discovered, then it might suffice to exclude patients of certain genotypes from future recruitment. Various sequential and non-sequential procedures are available to identify an association between the whole genome, or at least a portion of it, and the incidence of adverse events. In this paper we start with a suspected association between the genotype and the risk of an adverse event and suppose that the genetic subgroups with elevated risk can be identified. Our focus is determination of whether the patients identified as being at risk should be excluded from further studies of the drug. We propose using a utility function to? determine the appropriate action, taking into account the relative costs of suffering an adverse reaction and of failing to alleviate the patient's disease. Two illustrative examples are presented, one comparing patients who suffer from an adverse event with contemporary patients who do not, and the other making use of a reference control group. We also illustrate two classification methods, LASSO and CART, for identifying patients at risk, but we stress that any appropriate classification method could be used in conjunction with the proposed utility function. Our emphasis is on determining the action to take rather than on providing definitive evidence of an association. Copyright (C) 2008 John Wiley & Sons, Ltd.

Who, when and where? Identification of patients at risk of an in-hospital adverse event: Implications for nursing practice

Patients who suffer an adverse event (AE) are more likely to die or suffer permanent disability. Many AEs are preventable. Nurses have long played a pivotal role in the prevention of AEs. Much of the literature to date pertains to the role of nurses in the prevention of AEs such as falls, pressure areas and deep vein thrombosis. Prominent risk factors for AEs are the presence of physiological abnormality, failure to recognize or correct physiological abnormality, advanced patient age and location of patient room. Ongoing physiological assessment of patients is a nursing responsibility and the assessment findings of nurses underpin many patient care decisions. The early recognition and correction of physiological abnormality can improve patient outcomes by reducing the incidence of AEs, making nurses' ability to identify, interpret and act on physiological abnormality a fundamental factor in AE prediction and prevention. This paper will examine the role of nurses in AE prevention, using cardiac arrest as an example, from the perspective of physiological safety; that is, accurate physiological assessment and the early correction of physiological abnormality.

Novel sequential methods in dose-finding designs : extensions of the continual reassessment method

Dose-finding trials are a form of clinical data collection process in which the primary objective is to estimate an optimum dose of an investigational new drug when given to a patient. This thesis develops and explores three novel dose-finding design methodologies. All design methodologies presented in this thesis are pragmatic. They use statistical models, incorporate clinicians' prior knowledge efficiently, and prematurely stop a trial for safety or futility reasons. Designing actual dose-finding trials using these methodologies will minimize practical difficulties, improve efficiency of dose estimation, be flexible to stop early and reduce possible patient discomfort or harm.

Sequential monitoring of hospital adverse events when control charts fail : the example of fall injuries in hospitals

Objective To evaluate methods for monitoring monthly aggregated hospital adverse event data that display clustering, non-linear trends and possible autocorrelation. Design Retrospective audit. Setting The Northern Hospital, Melbourne, Australia. Participants 171,059 patients admitted between January 2001 and December 2006. Measurements The analysis is illustrated with 72 months of patient fall injury data using a modified Shewhart U control chart, and charts derived from a quasi-Poisson generalised linear model (GLM) and a generalised additive mixed model (GAMM) that included an approximate upper control limit. Results The data were overdispersed and displayed a downward trend and possible autocorrelation. The downward trend was followed by a predictable period after December 2003. The GLM-estimated incidence rate ratio was 0.98 (95% CI 0.98 to 0.99) per month. The GAMM-fitted count fell from 12.67 (95% CI 10.05 to 15.97) in January 2001 to 5.23 (95% CI 3.82 to 7.15) in December 2006 (p<0.001). The corresponding values for the GLM were 11.9 and 3.94. Residual plots suggested that the GLM underestimated the rate at the beginning and end of the series and overestimated it in the middle. The data suggested a more rapid rate fall before 2004 and a steady state thereafter, a pattern reflected in the GAMM chart. The approximate upper two-sigma equivalent control limit in the GLM and GAMM charts identified 2 months that showed possible special-cause variation. Conclusion Charts based on GAMM analysis are a suitable alternative to Shewhart U control charts with these data.

Lower preoperative quality of life increases postoperative risk of adverse events in women with endometrial cancer: results from the LACE trial

Objective: To examine the association between preoperative quality of life (QoL) and postoperative adverse events in women treated for endometrial cancer. Methods: 760 women with apparent Stage I endometrial cancer were randomised into a clinical trial evaluating laparoscopic versus open surgery. This analysis includes women with preoperative QoL measurements, from the Functional Assessment of Cancer Therapy- General (FACT-G) questionnaire, and who were followed up for at least 6 weeks after surgery (n=684). The outcomes for this study were defined as (1) the occurrence of moderate to severe AEs adverse events within 6 months (Common Toxicology Criteria (CTC) grade ≥3); and (2) any Serious Adverse Event (SAE). The association between preoperative QoL and the occurrence of AE was examined, after controlling for baseline comorbidity and other factors. Results: After adjusting for other factors, odds of occurrence of AE of CTC grade ≥3 were significantly increased with each unit decrease in baseline FACT-G score (OR=1.02, 95% CI 1.00-1.03, p=0.030), which was driven by physical well-being (PWB) (OR=1.09, 95% CI 1.04-1.13, p=0.0002) and functional well-being subscales (FWB) (OR=1.04, 95% CI 1.00-1.07, p=0.035). Similarly, odds of SAE occurrence were significantly increased with each unit decrease in baseline FACT-G score (OR=1.02, 95% CI 1.01-1.04, p=0.011), baseline PWB (OR=1.11, 95% CI 1.06-1.16, p<0.0001) or baseline FWB subscales (OR=1.05, 95% CI 1.01-1.10, p=0.0077). Conclusion: Women with early endometrial cancer presenting with lower QoL prior to surgery are at higher risk of developing a serious adverse event following surgery. Funding: Cancer Council Queensland, Cancer Council New South Wales, Cancer Council Victoria, Cancer Council, Western Australia; NHMRC project grant 456110; Cancer Australia project grant 631523; The Women and Infants Research Foundation, Western Australia; Royal Brisbane and Women’s Hospital Foundation; Wesley Research Institute; Gallipoli Research Foundation; Gynetech; TYCO Healthcare, Australia; Johnson and Johnson Medical, Australia; Hunter New England Centre for Gynaecological Cancer; Genesis Oncology Trust; and Smart Health Research Grant QLD Health.

A Data Mining Approach for the Identification of Adverse Drug Events (ADE) resulting from Drug-Drug Interactions (DDI) to improve pharmacovigilance

In the current study, epidemiology study is done by means of literature survey in groups identified to be at higher potential for DDIs as well as in other cases to explore patterns of DDIs and the factors affecting them. The structure of the FDA Adverse Event Reporting System (FAERS) database is studied and analyzed in detail to identify issues and challenges in data mining the drug-drug interactions. The necessary pre-processing algorithms are developed based on the analysis and the Apriori algorithm is modified to suit the process. Finally, the modules are integrated into a tool to identify DDIs. The results are compared using standard drug interaction database for validation. 31% of the associations obtained were identified to be new and the match with existing interactions was 69%. This match clearly indicates the validity of the methodology and its applicability to similar databases. Formulation of the results using the generic names expanded the relevance of the results to a global scale. The global applicability helps the health care professionals worldwide to observe caution during various stages of drug administration thus considerably enhancing pharmacovigilance

The role of nurses in preventing adverse events related to respiratory dysfunction: literature review

Aims. This paper reports a literature review examining the relationship between specific clinical indicators of respiratory dysfunction and adverse events, and exploring the role of nurses in preventing adverse events related to respiratory dysfunction.

Background. Adverse events in hospital are associated with poor patient outcomes such as increased mortality and permanent disability. Many of these adverse events are preventable and are preceded by a period during which the patient exhibits clearly abnormal physiological signs. The role of nurses in preserving physiological safety by early recognition and correction of physiological abnormality is a key factor in preventing adverse events.

Methods. A search of the Medline and CINAHL databases was conducted using the following terms: predictors of poor outcome, adverse events, mortality, cardiac arrest, emergency, oxygen, supplemental oxygen, oxygen therapy, oxygen saturation, oxygen delivery, assessment, patient assessment, physical assessment, dyspnoea, hypoxia, hypoxaemia, respiratory assessment, respiratory dysfunction, shortness of breath and pulse oximetry. The papers reviewed were research papers that demonstrated a relationship between adverse events and various clinical indicators of respiratory dysfunction.

Results. Respiratory dysfunction is a known clinical antecedent of adverse events such as cardiac arrest, need for medical emergency team activation and unplanned intensive care unit admission. The presence of respiratory dysfunction prior to an adverse event is associated with increased mortality. The specific clinical indicators involved are alterations in respiratory rate, and the presence of dyspnoea, hypoxaemia and acidosis.

Conclusions. The way in which nurses assess, document and use clinical indicators of respiratory dysfunction is influential in identifying patients at risk of an adverse event and preventing adverse events related to respiratory dysfunction. If such adverse events are to be prevented, nurses must not only be able to recognise and interpret signs of respiratory dysfunction, but must also take responsibility for initiating and evaluating interventions aimed at correcting respiratory dysfunction.

Using clinical trial data and linked administrative health data to reduce the risk of adverse events associated with the uptake of newly released drugs by older Australians : a model process

Background
The study was undertaken to evaluate the contribution of a process which uses clinical trial data plus linked de-identified administrative health data to forecast potential risk of adverse events associated with the use of newly released drugs by older Australian patients.

Methods
The study uses publicly available data from the clinical trials of a newly released drug to ascertain which patient age groups, gender, comorbidities and co-medications were excluded in the trials. It then uses linked de-identified hospital morbidity and medications dispensing data to investigate the comorbidities and co-medications of patients who suffer from the target morbidity of the new drug and who are the likely target population for the drug. The clinical trial information and the linked morbidity and medication data are compared to assess which patient groups could potentially be at risk of an adverse event associated with use of the new drug.

Results
Applying the model in a retrospective real-world scenario identified that the majority of the sample group of Australian patients aged 65 years and over with the target morbidity of the newly released COX-2-selective NSAID rofecoxib also suffered from a major morbidity excluded in the trials of that drug, indicating a substantial potential risk of adverse events amongst those patients. This risk was borne out in post-release morbidity and mortality associated with use of that drug.

Conclusions
Clinical trial data and linked administrative health data can together support a prospective assessment of patient groups who could be at risk of an adverse event if they are prescribed a newly released drug in the context of their age, gender, comorbidities and/or co-medications. Communication of this independent risk information to prescribers has the potential to reduce adverse events in the period after the release of the new drug, which is when the risk is greatest.

Note: The terms 'adverse drug reaction' and 'adverse drug event' have come to be used interchangeably in the current literature. For consistency, the authors have chosen to use the wider term 'adverse drug event' (ADE).