Translation of nonclinical to clinical safety findings for 27 biotherapeutics.

Human adverse drug reactions (ADRs), and in vivo nonclinical adverse and nonadverse findings, were identified in 27 biotherapeutic programs and placed into organ categories to determine translation. The sensitivity of detecting human ADRs was 30.8% with a positive predictive value (PPV) of 53.3% for nonclinical adverse findings; sensitivity increased to 67.3% and PPV fell to 35.0% when including nonadverse findings. Nonclinical findings were associated with a greater likelihood of a human ADR in that organ category, especially for adverse findings [positive likelihood ratio (LR+) >10 (lower 95% confidence interval [CI] of >5)]. The specificity and negative predictive value (NPV) were very high (>85%). A lack of nonclinical findings in an organ category was associated with a lower likelihood of a human ADR in that organ category. About 40-50% of human ADRs and nonclinical adverse findings, and about 30% of nonclinical nonadverse findings, were attributed to pharmacology. Slightly more than half of the human ADRs with a translating nonclinical finding had findings in animals that could be considered very similar. Overall, 38% of nonclinical findings translated to a human ADR at the organ category level. When nonclinical findings did not translate to humans, the cause was usually higher exposures or longer dosing in animals. All programs with human ADRs attributed to immunogenicity also had nonclinical adverse or nonadverse findings related to immunogenicity. Overall, nonclinical adverse and nonadverse findings were useful in predicting human ADRs, especially at an organ category level, and the majority of human ADRs were predicted by nonclinical toxicity studies.

Adherence to dietary guidelines and associated factors among rural Australian cancer survivors: a cross-sectional study.

PURPOSE: This study aimed to explore levels of adherence to dietary guidelines, and factors associated with dietary guideline adherence, among rural Australian cancer survivors. METHODS: A cross-sectional study was undertaken. We recruited a convenience sample of adults with cancer who attended the chemotherapy day unit or allied health appointments at a rural hospital in Baw Baw Shire, Victoria, Australia, between August 2017 and December 2021. Dietary guideline adherence was assessed by cross-referencing participants' responses to an adapted version of the Dietary Questionnaire for Epidemiological Studies with dietary recommendations in Australian dietary guidelines. Binary logistic regression was used to assess factors associated with dietary guideline adherence for fruits and whole red meats. RESULTS: There were 107 rural cancer survivors (median age, 67 years). Dietary guideline adherence was highest for alcohol (88%) followed by whole red meats (63%), fruits (56%), processed red meats (24%), cereals/breads/grains (7%), and vegetables (4%). Relative to those aged < 65 years, 65-74-year-olds had 5.7-fold greater odds (adjusted odds ratio (aOR) = 5.74, 95% confidence interval (CI) = 1.91-17.17) of adhering to the dietary guideline for fruits. Relative to those who had completed/ceased treatment, participants who were currently receiving treatment had 78% lower odds (aOR = 0.22, 95% CI = 0.09-0.59) of adhering to the dietary guideline for fruits. CONCLUSION: This study contributes preliminary data on adherence to dietary guidelines and associated factors among rural Australian cancer survivors. Dietary guideline adherence varied across food groups and was mostly low, albeit not markedly worse than Australia's national population for the fruits and vegetables groups. The mostly low adherence in our sample suggests a potential need to increase provision of dietary information, supportive care screening, and, wherever necessary, dietetics referrals, assessments, and interventions among rural cancer survivors. Larger, longitudinal studies of adherence to dietary guidelines and/or tailored, cancer-specific dietary recommendations should be undertaken in future.

Differences in cancer clinical trial activity and trial characteristics at metropolitan and rural trial sites in Victoria, Australia.

OBJECTIVE: Cancer clinical trials (CCTs) provide access to emerging therapies and extra clinical care. We aimed to describe the volume and characteristics of CCTs available across Victoria, Australia, and identify factors associated with rural trial location. METHODS: Quantitative analysis of secondary data from Cancer Council Victoria's Clinical Trials Management Scheme dataset. DESIGN: A cross-sectional study design was used. SETTING: CCTs were available Victoria-wide in 2018. PARTICIPANTS: There were 1669 CCTs and 5909 CCT participants. MAIN OUTCOME MEASURES: Rural CCT location was assessed as a binary variable with categories of 'yes' (modified Monash [MM] categories 2-7) and 'no' (MM category 1). MM categories were determined from postcodes. The highest ('least rural') MM category was used for postcodes with multiple MM categories. RESULTS: Of 1669 CCTs, 168 (10.1%) were conducted in rural areas. Of 5909 CCT participants, 315 (5.3%) participated in rural CCTs. There were 526 CCTs (31.5%) with 1907 (32.3%) newly enrolled participants. Of 1892 newly enrolled participants with postcode data, 488 (25.8%) were rural residents. Of them, 368 (75.4%) participated in metropolitan CCTs. In a multivariable logistic regression analysis for all 1669 CCTs, odds of a rural rather than metropolitan CCT location were significantly (p-value <0.05) lower for early-phase than late-phase trials and non-solid than solid tumour trials but significantly (p-value <0.05) higher for non-industry than industry-sponsored trials. CONCLUSIONS: In Victoria, 10% of CCTs are at rural sites. Most rural-residing CCT participants travel to metropolitan sites, where there are more late-phase, non-solid-tumour and industry-sponsored trials. Approaches to increase the volume and variety of rural CCTs should be considered.

Physical activity, obesity, and quality of life among rural Australian cancer survivors: a cross-sectional study.

PURPOSE: We aimed to describe physical activity (PA), obesity, and quality of life (QoL) among rural Australian cancer survivors, assess whether total and item-specific QoL are associated with sufficient PA and obesity, and assess whether PA and obesity interact with respect to QoL. METHODS: In a cross-sectional study, convenience sampling was used to recruit adult cancer survivors via a chemotherapy day unit and allied health professionals at a rural hospital in Baw Baw Shire, Australia. Exclusion criteria were acute malnutrition and end-of-life care. PA and QoL were measured using Godin-Shephard and 7-item Functional Assessment of Cancer Therapy (FACT-G7) questionnaires, respectively. Factors associated with total and item-specific QoL were assessed via linear and logistic regression, respectively. RESULTS: Among 103 rural cancer survivors, the median age was 66 years, 35% were sufficiently physically active, and 41% presented with obesity. Mean/median total QoL scores were 17 on the FACT-G7 scale (0-28; higher scores indicate better QoL). Sufficient PA was associated with better QoL ([Formula: see text]=2.29; 95% confidence interval [CI] = 0.26, 4.33) and more energy (odds ratio [OR] = 4.00, 95% CI = 1.48, 10.78) while obesity was associated with worse QoL ([Formula: see text]=-2.09; 95% CI = -4.17, -0.01) and more pain (OR = 3.88, 95% CI = 1.29, 11.68). The PA-obesity interaction was non-significant (p-value = 0.83). CONCLUSIONS: This is the first known study conducted among rural survivors of any cancer to find sufficient PA and obesity are associated with better and worse QoL, respectively. PA, weight management, and QoL-including energy and pain-should be considered when targeting and tailoring supportive care interventions for rural cancer survivors.

Prevalence and correlates of advance care planning among Australian hospital inpatients.

The prevalence and factors associated with advance care planning (ACP) documents for Australian public hospital inpatients were determined through cross-sectional study of 123 Victorian hospitals between July 2016 and December 2018. Of the 611 786 included patients, 2.9% had an ACP document. Odds increased significantly in those comorbid, unpartnered, regional and >5 admissions, which supports future ACP conversations and document creation.

Re-evaluating the need for chronic toxicity studies with therapeutic monoclonal antibodies, using a weight of evidence approach.

To support registration of monoclonal antibodies (mAbs) for chronic indications, 6-month toxicity studies have historically been conducted. Experience with mAb development has shown a relatively benign and well-understood safety profile for this class, with most toxicity findings anticipated based on pharmacology. We evaluated whether a 6-month toxicity study is necessary to assess the long-term safety of mAbs. Data on First-in-Human (FIH)-enabling and chronic toxicity studies were shared for 142 mAbs submitted by 11 companies. Opportunities to further optimize study designs to reduce animal usage were identified. For 71% of mAbs, no toxicities or no new toxicities were noted in chronic studies compared to FIH-enabling study findings. New toxicities of potential concern for human safety or that changed trial design were identified in 13.5% of cases, with 7% being considered critical and 2% leading to program termination. An iterative, weight-of-evidence model which considers factors that influence the overall risk for a mAb to cause toxicity was developed. This model enables an evidence-based justification, suggesting when 3-month toxicity studies are likely sufficient to support late-stage clinical development and registration for some mAbs.

The use of recovery animals in nonclinical safety assessment studies with monoclonal antibodies: further 3Rs opportunities remain.

Assessment of reversibility from nonclinical toxicity findings in animals with potential adverse clinical impact is required during pharmaceutical development, but there is flexibility around how and when this is performed and if recovery animals are necessary. For monoclonal antibodies (mAbs) and in accordance with ICH S6(R1) if inclusion of recovery animals is warranted, this need only occur in one study. Data on study designs for first-in-human (FIH)-enabling and later-development toxicity studies were shared from a recent collaboration between the NC3Rs, EPAA, Netherlands Medicines Evaluation Board (MEB) and 14 pharmaceutical companies. This enabled a review of practices on recovery animal use during mAb development and identification of opportunities to reduce research animal use. Recovery animals were included in 68% of FIH-enabling and 69% of later-development studies, often in multiple studies in the same program. Recovery groups were commonly in control plus one test article-dosed group or in all dose groups (45% of studies, each design). Based on the shared data review and conclusions, limiting inclusion of recovery to a single nonclinical toxicology study and species, study design optimisation and use of existing knowledge instead of additional recovery groups provide opportunities to further reduce animal use within mAb development programs.

Rural community-based nurses' self-reported knowledge and skills in the provision of psychosocial care to palliative and end-of-life clients and carers.

OBJECTIVE: This study examined rural community-based nurses' self-reported knowledge and skills in the provision of psychosocial care to rural residing palliative and end-of-life clients and carers. We further sought to determine correlates of knowledge gaps to inform workforce education and planning. METHOD: Nurses from a rural area of Victoria, Australia, were invited to complete an electronic questionnaire rating their knowledge against 6 national palliative care standards and 10 screening and assessment tools. A 5-point scale of (1) No experience to (5) Can teach others was used to rate knowledge. Results were classified into three categories: practice gaps, areas of consolidation, and strengths. Descriptive and logistical regression was used to analyze data. RESULTS: A total of 122 of 165 nurses (response rate = 74%) completed the survey. Of these nurses, 87% were Registered Nurses, 43% had ≥10 years' experience in palliative care, and 40% had palliative care training. The majority of practices across the standards and screening and assessment tools were rated as knowledge strengths (N = 55/67, 82%). Gaps and areas of consolidation were in the use of client and carer assessment tools, the care of specific populations such as children, supporting carers with appropriate referrals, resources, and grief, and facilitating the processes of reporting a death to the coroner. Lack of formal training and lower years of experience were found to be associated with practice gaps. SIGNIFICANCE OF RESULTS: Our study found rural nurses were confident in their knowledge and skills in the majority of psychosocial care. As generalist nurses make up the majority of the rural nursing workforce, further research should be undertaken on what educational strategies are needed to support and upskill rural community-based nurses to undertake formal training in palliative care.

Functional outcomes following an in-hospital cardiac arrest: A retrospective cohort study.

BACKGROUND/PURPOSE: Whilst much is known about the survival outcomes of patients that suffer an in-hospital cardiac arrest (IHCA) in Australia very little is known about the functional outcomes of survivors. This study aimed to describe the functional outcomes of a cohort of patients that suffered an in-hospital cardiac arrest (IHCA) and survived to hospital discharge in a regional Australian hospital. METHODS: This is a single-centre retrospective observational cohort study conducted in a regional Australian hospital. All adult patients that had an IHCA in the study hospital between 1 Jan 2017 and 31 Dec 2019 and survived to hospital discharge were included in the study. Functional outcomes were reported using the Modified Rankin Scale (mRS), a six-point scale for which increasing scores represent increasing disability. Scores were assigned through a retrospective review of medical notes. RESULTS: Overall, 102 adult patients had an IHCA during the study period, of whom 50 survived to hospital discharge. The median age of survivors was 68 years, and a third had a shockable initial arrest rhythm. Of survivors, 47 were able to be assigned both mRS scores. At discharge, 81% of patients achieved a favourable functional outcome (mRS 0-3 or equivalent function at discharge equal to admission). CONCLUSIONS: Most survivors to hospital discharge following an IHCA have a favourable functional outcome and are discharged home. Although these results are promising, larger studies across multiple hospitals are required to further inform what is known about functional outcomes in Australian IHCA survivors.

A data visualisation method for assessing exposure misclassification in case-crossover studies: the example of tricyclic antidepressants and the risk of hip fracture in older people.

BACKGROUND: The case-crossover design is suited to medication safety studies but is vulnerable to exposure misclassification. Using the example of tricyclic antidepressants and the risk of hip fracture, we present a data visualisation tool for observing exposure misclassification in case-crossover studies. METHODS: A case-crossover study was conducted using Australian Government Department of Veterans' Affairs claims data. Beneficiaries aged over 65 years who were hospitalised for hip fracture between 2009 and 2012 were included. The case window was defined as 1-50 days pre fracture. Control window one and control window two were defined as 101-150 and 151-200 days pre fracture, respectively. Patients were stratified by whether exposure status changed when control window two was specified instead of control window one. To visualise potential misclassification, each subject's tricyclic antidepressant dispensings were plotted over the 200 days pre fracture. RESULTS: The study population comprised 8828 patients with a median age of 88 years. Of these subjects, 348 contributed data to the analyses with either control window. The data visualisation suggested that 14% of subjects were potentially misclassified with control window one while 45% were misclassified with control window two. The odds ratio for the association between tricyclic antidepressants and hip fracture was 1.18 (95% confidence interval = 0.91-1.52) using control window one, whereas risk was significantly increased (odds ratio = 1.43, 95% confidence interval = 1.11-1.83) using control window two. CONCLUSIONS: Exposure misclassification was less likely to be present with control window one than with an earlier control window, control window two. When specifying different control windows in a case-crossover study, data visualisation can help to assess the extent to which exposure misclassification may contribute to variable results.

Classic and evolving approaches to evaluating cross reactivity of mAb and mAb-like molecules - A survey of industry 2008-2019.

Monoclonal antibodies (mAbs) and mAb derivatives have become mainstay pharmaceutical modalites. A critical assessment is to ascertain the specificity of these molecules prior to human clinical trials. The primary technique for determining specificity has been the immunohistochemistry (IHC)-based "Tissue Cross-Reactivity" (TCR) assay, where the candidate molecule is applied to > 30 tissues to look for unexpected staining. In the last few years, however, non-IHC array-based platforms have emerged that allow for screening 75-80% of the human membrane proteome, indicating a viable alternative and/or addition to the IHC methods. The preclinical sciences subcommittee of the Biotechnology Innovation Organization (BIO), "BioSafe", conducted a survey of 26 BIO member companies to understand current sponsor experience with the IHC and array techniques. In the last ten years, respondents noted they have conducted more than 650 IHC TCR assays, largely on full length mAbs, with varying impacts on programs. Protein/cell arrays have been utilized by almost half of the companies and sponsors are gaining familiarity and comfort with the platform. Initial experience with recent versions of these arrays has been largely positive. While most sponsors are not prepared to eliminate the IHC TCR assay, growing experience with these alternatives allows them to confidently choose other approaches with or without TCR assays.

Factors Associated With Quality of Life Among People Living With a Stoma in Nonmetropolitan Areas.

BACKGROUND: Interruption of gastrointestinal continuity through surgical formation of a stoma can be lifesaving. However, it is also typically associated with reduced quality of life (QoL). Although past research has investigated QoL among people living with a stoma, no known studies have investigated stoma-related QoL, specifically among nonmetropolitan residents who may experience distinct health issues compared with their metropolitan counterparts. OBJECTIVES: The aim of the study was to investigate the level of and factors associated with QoL among people living with a stoma in nonmetropolitan Australia. METHODS: In a cross-sectional survey, 678 adults with colostomy, ileostomy, and/or urostomy and with membership in a regional Victorian stoma association were given the City of Hope Quality of Life Questionnaire for a Patient With an Ostomy (QOL-O). Total QoL score was calculated and described before categorization into quintiles. Patient factors associated with quintiles of QoL were assessed using univariable and multivariable proportional odds ordinal logistic regression, with a 95% confidence interval excluding 1.00 denoting statistical significance. RESULTS: Overall, 311 regional ostomy association members (46%) responded to any QOL-O questions; 285 members responded to >80% of QOL-O questions and contributed data to the study. Their median age was 73 years, and 60% were male. The median total QoL score was 6.9 on a scale of 0-10, where a higher number indicates better QoL. Factors independently associated with better QoL in the multivariable model were working full/part time, no poststoma clothing change, poststoma sexual activity, and older age. Factors independently associated with worse QoL were poststoma depression and a stoma location issue. DISCUSSION: People living with a stoma in nonmetropolitan Australia reported moderate-to-high QoL. Better QoL was identified in those who worked, had no poststoma clothing change, were sexually active poststoma, and were older. Worse QoL was seen in those who had poststoma depression and stoma location issues. Healthcare providers could influence stoma-related QoL by identifying risk factors and tailoring interventions toward individuals in nonmetropolitan settings.

Comparative nonclinical assessments of the biosimilar PF-06410293 and originator adalimumab.

Adalimumab, a recombinant fully human monoclonal antibody targeting tumor necrosis factor (TNF), is approved in the United States and Europe to treat various inflammatory and autoimmune indications. Biosimilars are approved biologics highly similar, but not identical, to approved biotherapeutics. To support clinical development of PF-06410293, an adalimumab biosimilar, nonclinical studies evaluated the structural, functional, toxicologic, and toxicokinetic similarity to originator adalimumab sourced from the United States (adalimumab-US) and European Union (adalimumab-EU). Structural similarity was assessed by peptide mapping. Biologic activity was measured via inhibition of TNF-induced apoptosis and Fc-based functionality assessments. In vivo nonclinical similarity was evaluated in a toxicity study in cynomolgus monkeys administered subcutaneous PF-06410293 or adalimumab-EU (0 or 157 mg/kg/week). Peptide mapping demonstrated PF-06410293, adalimumab-US, and adalimumab-EU had identical amino acid sequences. Comparative functional and binding assessments were similar. Effects of PF-06410293 and adalimumab-EU were similar and limited to pharmacologically mediated decreased cellularity of lymphoid follicles and germinal centers in spleen. Toxicokinetics were similar; maximum plasma concentration and area-under-the-concentration-time curve ratio of PF-06410293:adalimumab-EU ranged from 1.0 to 1.2. These studies supported PF-06410293 entry into clinical development. Many regulatory agencies now only request nonclinical in vivo testing if there is residual uncertainty regarding biosimilarity after in vitro analytical studies.

Nonclinical assessments of the potential biosimilar PF-06439535 and bevacizumab.

Bevacizumab, a recombinant humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF), is approved for treatment of metastatic colorectal cancer, nonsquamous non-small-cell lung cancer, metastatic kidney cancer, and glioblastoma. To support clinical development of the potential bevacizumab biosimilar PF-06439535, nonclinical studies evaluated structural, functional, toxicological, and toxicokinetic similarity to bevacizumab sourced from the European Union (bevacizumab-EU) and United States (bevacizumab-US). Peptide mapping demonstrated the amino acid sequence of PF-06439535 was identical to bevacizumab-EU and bevacizumab-US. Biologic activity, measured via inhibition of VEGF-induced cell proliferation in human umbilical vein endothelial cells and binding to VEGF isoforms, was similar across the three drugs. In vivo similarity was demonstrated in cynomolgus monkeys administered intravenous PF-06439535 or bevacizumab-EU (0 or 10 mg/kg/dose twice weekly for 1 month; total of nine doses). Systemic exposure appeared similar and test article-related effects were limited to physeal dysplasia of the distal femur. The potential for non-target-mediated toxicity of PF-06439535 was evaluated in rats administered intravenous PF-06439535 (15 or 150 mg/kg/dose twice weekly for 15 days; total of five doses). Nonadverse higher liver weights and minimal sinusoidal cell hyperplasia were observed. Collectively, these studies demonstrated similarity of PF-06439535 to bevacizumab, supporting entry into clinical development.

A Synopsis of the "Influence of Epigenetics, Genetics, and Immunology" Session Part A at the 35th Annual Society of Toxicologic Pathology Symposium.

The overarching theme of the 2016 Society of Toxicology Pathology's Annual Symposium was "The Basis and Relevance of Variation in Toxicologic Responses." Session 4 focused on genetic variation as a potential source for variability in toxicologic responses within nonclinical toxicity studies and further explored how knowledge of genetic traits might enable targeted prospective and retrospective studies in drug development and human health risk assessment. In this session, the influence of both genetic sequence variation and epigenetic modifications on toxicologic responses and their implications for understanding risk were explored. In this overview, the presentations in this session will be summarized, with a goal of exploring the ramifications of genetic and epigenetic variability within and across species for toxicity studies and disseminating information regarding novel tools to harness this variability to advance understanding of toxicologic responses across populations.

Nonproliferative and Proliferative Lesions of the Gastrointestinal Tract, Pancreas and Salivary Glands of the Rat and Mouse.

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) project is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature and diagnostic criteria for nonproliferative and proliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature and diagnostic criteria for classifying lesions in the digestive system including the salivary glands and the exocrine pancreas of laboratory rats and mice. Most lesions are illustrated by color photomicrographs. The standardized nomenclature, the diagnostic criteria, and the photomicrographs are also available electronically on the Internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous and age related lesions as well as lesions induced by exposure to test items. Relevant infectious and parasitic lesions are included as well. A widely accepted and utilized international harmonization of nomenclature and diagnostic criteria for the digestive system will decrease misunderstandings among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.

Scientific and Regulatory Policy Committee Points-to-consider Paper*: Drug-induced Vascular Injury Associated with Nonsmall Molecule Therapeutics in Preclinical Development: Part I. Biotherapeutics.

Drug-induced vascular injury (DIVI) is a recurrent challenge in the development of novel pharmaceutical agents. Although DIVI in laboratory animal species has been well characterized for vasoactive small molecules, there is little available information regarding DIVI associated with biotherapeutics such as peptides/proteins or antibodies. Because of the uncertainty about whether DIVI in preclinical studies is predictive of effects in humans and the lack of robust biomarkers of DIVI, preclinical DIVI findings can cause considerable delays in or even halt development of promising new drugs. This review discusses standard terminology, characteristics, and mechanisms of DIVI associated with biotherapeutics. Guidance and points to consider for the toxicologist and pathologist facing preclinical cases of biotherapeutic-related DIVI are outlined, and examples of regulatory feedback for each of the mechanistic types of DIVI are included to provide insight into risk assessment.

Scientific and Regulatory Policy Committee Points-to-consider Paper*: Drug-induced Vascular Injury Associated with Nonsmall Molecule Therapeutics in Preclinical Development: Part 2. Antisense Oligonucleotides.

Drug-induced vascular injury (DIVI) is a recurrent challenge in the development of novel pharmaceutical agents. In recent years, DIVI has been occasionally observed in nonhuman primates given RNA-targeting therapeutics such as antisense oligonucleotide therapies (ASOs) during chronic toxicity studies. While DIVI in laboratory animal species has been well characterized for vasoactive small molecules, and immune-mediated responses against large molecule biotherapeutics have been well described, there is little published information regarding DIVI induced by ASOs to date. Preclinical DIVI findings in monkeys have caused considerable delays in development of promising new ASO therapies, because of the uncertainty about whether DIVI in preclinical studies is predictive of effects in humans, and the lack of robust biomarkers of DIVI. This review of DIVI discusses clinical and microscopic features of vasculitis in monkeys, their pathogenic mechanisms, and points to consider for the toxicologist and pathologist when confronted with ASO-related DIVI. Relevant examples of regulatory feedback are included to provide insight into risk assessment of ASO therapies.

Psychoactive medicine use and the risk of hip fracture in older people: a case-crossover study.

PURPOSE: Many factors can increase the risk of hip fracture, including medicines. Traditional observational studies have assessed the risk, but results may be confounded by unmeasured factors. The case-crossover design is an alternative approach that controls for patient-specific, time-invariant confounding factors. This study aimed to assess associations between psychoactive medicines and hip fracture in the elderly using the case-crossover method. METHODS: Data were sourced from the Australian Government Department of Veterans' Affairs healthcare claims database. The study population comprised beneficiaries aged over 65 years who were hospitalised for hip fracture between 2009 and 2012. The case-crossover method was used to compare individuals' medicine exposure immediately before hip fracture (case window) with their exposure at an earlier time (control window). Conditional logistic regression was employed to quantify associations between medicine use and hip fracture. Alternative exposure windows were assessed in sensitivity analyses. RESULTS: Eight thousand eight hundred twenty-eight patients were hospitalised for hip fracture. Their median age was 88 years, and 63% were female. Odds of hip fracture were increased for opioids (odds ratio [OR] = 1.62, 95% confidence interval [CI] = 1.42-1.84), selective serotonin reuptake inhibitors (OR = 1.54, 95% CI = 1.28-1.86) and antipsychotics (OR = 1.47, 95% CI = 1.21-1.80). There was no significant association for tricyclic antidepressants in the primary analysis (OR = 1.18, 95% CI = 0.91-1.52), but there was a significant association in the sensitivity analysis using an alternative, earlier control window (OR = 1.43, 95% CI = 1.11-1.83). CONCLUSIONS: Increased risk of hip fracture in older people was found for opioids, selective serotonin reuptake inhibitors and antipsychotics. The choice of control window influenced the result for tricyclic antidepressants.

Immunogenicity/hypersensitivity of biologics.

This continuing education course was designed to provide an overview of the immunologic mechanisms involved in immunogenicity and hypersensitivity reactions following administration of biologics in nonclinical toxicity studies, the methods used to determine whether such reactions are occurring, and the associated clinical and anatomic pathology findings. Hypersensitivity reactions have classically been divided into type I, II, III, and IV reactions; type I and III reactions are those most often observed following administration of biologics. A variety of methods can be used to detect these reactions. Antemortem methods include hematology; detection of antidrug antibodies, circulating immune complexes and complement fragments, and immunoglobulin E in serum; tests for serum complement activity; and evaluation of complement receptor 1 on erythrocytes. Postmortem methods include routine light microscopy and electron microscopy, which can demonstrate typical findings associated with hypersensitivity reactions, and immunohistochemistry, which can detect the presence of immune complexes in tissues, including the detection of the test article. A final determination of whether findings are related to a hypersensitivity reaction in individual animals or across the entire study should rely on the overall weight of evidence, as findings indicative of these reactions are not necessarily consistent across all affected animals.