Clinical Relevance of Dissolution Testing in Quality by Design

Quality by design (QbD) has recently been introduced in pharmaceutical product development in a regulatory context and the process of implementing such concepts in the drug approval process is presently on-going. This has the potential to allow for a more flexible regulatory approach based on understanding and optimisation of how design of a product and its manufacturing process may affect product quality. Thus, adding restrictions to manufacturing beyond what can be motivated by clinical quality brings no benefits but only additional costs. This leads to a challenge for biopharmaceutical scientists to link clinical product performance to critical manufacturing attributes. In vitro dissolution testing is clearly a key tool for this purpose and the present bioequivalence guidelines and biopharmaceutical classification system (BCS) provides a platform for regulatory applications of in vitro dissolution as a marker for consistency in clinical outcomes. However, the application of these concepts might need to be further developed in the context of QbD to take advantage of the higher level of understanding that is implied and displayed in regulatory documentation utilising QbD concepts. Aspects that should be considered include identification of rate limiting steps in the absorption process that can be linked to pharmacokinetic variables and used for prediction of bioavailability variables, in vivo relevance of in vitro dissolution test conditions and performance/interpretation of specific bioavailability studies on critical formulation/process variables. This article will give some examples and suggestions how clinical relevance of dissolution testing can be achieved in the context of QbD derived from a specific case study for a BCS II compound.     

乙型肝炎肝组织血管病变组织及免疫组织化学的研究

乙型肝炎(HB)已成为我国危害最大的社会公共卫生问题.近年来,我们在分析、研究国内外有关病毒性肝炎文献后选择了以HB患者肝组织活检观察为主的研究方法,从肝组织学随访中研究各型HB肝实质变性坏死及肝纤维组织增生的动态变化规律[1-8],采用组织化学(组化)及免疫组织化学(免疫组化)染色方法对肝组织内HBsAg,HBcAg表达[3],不同类型纤维组织增生情况,血清HBeAg与抗-HBe转换及透明质酸,色氨酸代谢变化[9-13],进行了深入研究.     

Using behavioural insights to increase HIV self‐sampling kit returns: a randomized controlled text message trial to improve England's HIV self‐sampling service

Objectives

The aim of the study was to determine whether behaviourally informed short message service (SMS) primer and reminder messages could increase the return rate of HIV self‐sampling kits ordered online.

Methods

The study was a 2 × 2 factorial design randomized control trial. A total of 9585 individuals who ordered a self‐sampling kit from www.freetesting.hiv different SMS combinations: 1) standard reminders sent days 3 and 7 after dispatch (control); 2) primer sent 1 day after dispatch plus standard reminders; 3) behavioural insights (BI) reminders (no primer); or 4) primer plus BI reminders. The analysis was restricted to individuals who received all messages (n = 8999). We used logistic regression to investigate independent effects of the primer and BI reminders and their interaction. We explored the impact of sociodemographic characteristics on kit return as a secondary analysis.

Results

Those who received the primer and BI reminders had a return rate 4% higher than that of those who received the standard messages. We found strong evidence of a positive effect of the BI reminders (odds ratio 1.13; 95% confidence interval 1.04–1.23; P = 0.003) but no evidence for an effect of the primer, or for an interaction between the two interventions. Odds of kit return increased with age, with those aged ≥ 65 years being almost 2.5 times more likely to return the kit than those aged 25–34 years. Men who have sex with men were 1.5–4.5 times more likely to return the kit compared with other sexual behaviour and gender identity groups. Non‐African black clients were 25% less likely to return the kit compared with other ethnicities.

Conclusions

Adding BI to reminder messages was successful in improving return rates at no additional cost.     

影响压迫疗法一致性的因素

从业医师时常报道下肢溃疡病人坚持治疗非常困难,尽管对治疗难度有多大了解较少。本文介绍了从业医师如何提供关于下肢溃疡病人有效护理,讨论了压迫疗法的选择,如何影响一致性。评估和一致性从业者常发现处理如下问题较困难:病人不接受治疗方案、病情治疗困难和病人缺乏进步思想。促进一致性需要从业医师去养成一个与患者敏锐的医患关系,认识患者的问题。选择合适的疗法一篇关于压迫疗法综述的结论是:①在压迫治疗方面有较高的压力(35~45mmHg)优于低的压力(15~25 mmHg);②具有弹性和无弹性的多层绷带方法,优于单层方法,对特定的病人用最佳…     

Fructus Broussonetae extract improves cognitive function and endoplasmic reticulum stress in Alzheimer's disease models

This study investigated the effects and possible targets of Fructus Broussonetiae extract,a traditional Chinese medicinal herb,on a model of Alzheimer’s disease induced by beta-amyloid peptide 25-35 and D-galactose.The results revealed that intragastric administration of Fructus Broussonetiae significantly increased the expression of immunoglobulin-binding protein,a key factor in the endoplasmic reticulum stress-signaling pathway in rat hippocampus.In contrast,the treatment significantly decreased expression levels of PKR-like endoplasmic reticulum kinase and C/EBP homologous protein,and substantially improved learning,memory and spatial recognition dysfunction in rats.This evidence indicates that Fructus Broussonetiae extract improves spatial learning and memory abilities in rats by affecting the regulation of hippocampal endoplasmic reticulum stress and activation of the apoptosis pathway.     

广西边境县性服务小姐艾滋病相关知识、行为及HIV感染现状调查分析

目的了解广西中越边境县的本土及跨境性服务小姐对艾滋病知识的知晓情况以及高危行为特征,为开展有针对性的宣传教育及干预工作提供有利的支持。方法在该边境县调查145名性服务小姐,对她们进行访谈式调查,同时检测HIV抗体以了解艾滋病病毒感染情况。结果不同类别的性服务小姐基本上了解艾滋病相关知识,答对70%以上问题的性服务小姐占81.4%;本土性服务小姐与不相识的性伴发生性关系时每次都使用安全套的比率为88.4%,跨境性服务小姐的比率为39.5%（χ2=29.3,P〈0.01）。血清学结果显示跨境性服务小姐的HIV阳性检出率为4.3%,本土性服务小姐的HIV阳性检出率为2.0%,差异无统计学意义（P=0.60）。结论本土与跨境的性服务小姐都存在感染HIV的风险,尤以跨境性服务小姐为甚,当地在将来的宣传教育及干预工作中应注意把当地的跨境性服务小姐纳入重点宣教及干预的对象。     

Multiple diagnostic task performance in CT examination of the chest

Objectives

In three experiments, we studied the detection of multiple abnormality types using the satisfaction of search (SOS) paradigm, the provision of a computer-aided detection (CAD) of pulmonary nodules and a focused nodule detection task.

Methods

51 chest CT examinations (24 that demonstrated subtle pulmonary nodules and 27 that demonstrated no pulmonary nodules) were read by 15 radiology residents and fellows under two experimental conditions: (1) when there were no other abnormalities present except test abnormalities in the exams (non-SOS condition), and (2) when other abnormalities were present in the exams (SOS condition). Trials from the two conditions were intermixed. Readers were invited to return for two sessions: one in which the SOS condition was repeated with a simulated CAD; another in which only the non-SOS condition was presented. Detection accuracy was measured using receiver operating characteristic (ROC) analysis.

Results

An SOS effect (reduced detection accuracy for the test nodules in the presence of the diverse added abnormalities) was not found. Average accuracy was much higher when the CAD prompt was provided, without cost in the detection of the added abnormalities. Accuracy for detecting nodules appearing without intermixed SOS trials was also substantially improved.

Conclusions

CT interpretation was highly task dependent. Nodule detection was poor in the general search task. Therefore, CAD may offer a greater performance improvement than demonstrated in experiments assessing CAD using focused search. The absence of SOS may be due to limited nodule detection even without other abnormalities.

Advances in knowledge

CAD prompts of nodules increase the detection accuracy of nodules and decrease the time to detection—without impairing the detection accuracy—of non-nodule abnormalities.Modalities that provide multidimensional image data are now standard practice. The large number of images included in a single imaging examination may represent increased risk for failure of human perception [1,2]. As imaging technology changes, what we consider a diagnostic error also changes. The capability to find smaller and subtler lesions dramatically increases the volume of images that need to be reviewed. There are so many image data that must be inspected that an exhaustive search may not be possible in any practical time frame. We know relatively little about perception in advanced medical imaging with few studies of how observers cope with these enormous data sets. With increasing information available, human attention becomes the limiting factor in diagnostic performance. The observer''s task—the nature of abnormalities sought and diagnostic questions addressed—determines how far his/her attention will be stretched. In the current experiments, we study the effects of observer task on error in multidimensional images.This research begins with a failed experiment. Missing a second abnormality once another abnormality has been found is often called a “satisfaction of search” (SOS) error. Laboratory experiments provide an operational definition of SOS that cannot be found in retrospective accounts of errors. In this definition, the lesion that is missed because of SOS is shown to be detected in the absence of other lesions. But laboratory study of SOS effects has been limited to traditional radiography [3]. In fact, a high frequency of SOS errors has been hypothesised in retrospective studies of errors at CT [4]. Our original goal was to determine whether SOS effects occur in CT of the chest.We compared the detection accuracy for simulated, but realistic “possibly malignant” pulmonary nodules in the presence and the absence of various naturally occurring abnormalities other than pulmonary nodules. In the language of the SOS paradigm, we compared the detection accuracy for test abnormalities in the presence and the absence of added abnormalities. Each “test abnormality” was a lung mass suspicious for malignancy. Each “added abnormality” was either a pulmonary abnormality other than lung mass or an abnormality of another organ visible in the CT examination.This experiment was made possible when more complete control of the presence of both nodules and diverse native abnormalities became available by the creation of a software tool to remove, store and add abnormalities to medical images [5]. The simulated nodules inserted by this tool were designed to mimic primary lung malignancies, recognising that in many instances, particularly small nodules, distinctions between malignant and benign lesions may be difficult or impossible. These test abnormalities appeared twice, once with and once without another added abnormality. These added abnormalities were diverse, naturally occurring abnormalities that could be digitally removed. For examinations with test abnormalities, added abnormalities were removed from one version and retained in another. The test abnormality appeared in identical locations on both examinations (Figure 1). Thus, detection of the identical test abnormalities (pulmonary nodules) was measured in CT studies that were identical except for the presence of added abnormalities in the SOS condition. Our original null hypothesis was that the presence of added abnormalities would not produce any significant reduction in detection of test abnormalities (no SOS effect).Open in a separate windowFigure 1The detection of a subtle pulmonary nodule was measured in the presence of a prominent abnormality—satisfaction of search (SOS) condition—and in its absence—non-SOS condition. A pulmonary embolus (white arrow) is apparent in one condition (a) and was digitally removed in a second condition (b). The detection of the pulmonary nodule (white arrow) as seen in (c) was measured in both conditions. The pulmonary embolus is most prominent with window and level pre-set for mediastinum and the pulmonary nodule is best seen with window and level pre-set for lung.Unfortunately, detection of test pulmonary nodules was poor even without adding diverse abnormalities to CT examinations. Such low performance allows little opportunity to measure reduced performance indicating an SOS effect. We selected examples of subtle nodules for use as test abnormalities in the same way we had for many experiments with radiographs, based on the judgement of the subspecialist radiologists. All authors felt that the nodules would be found by most readers. But the nodules were too difficult for our observers, who were senior radiology residents.How could the nodules seem obvious to experts, but be nearly invisible to near experts? Judging the salience of an abnormality from the few CT slices containing it may fail to consider the navigation required to arrive at those few slices. We added a third experimental condition to study whether the nodules were actually visible to our observers when presented under the same conditions of interpretation as the experts who had selected the nodules. We provided simulated computer-aided detection (CAD) to discover whether the nodules were actually visible to observers if they were directed to them. The SOS condition was repeated as a single block of trials with CAD. Our second null hypothesis was that the test nodules would not be reported more accurately when localised by CAD than they had been in the original SOS condition.Another possible reason for the poor performance of the observers is that the subspecialists looked only for nodules when they selected them for the experiment, whereas the observer''s task was a general search. Both the experimental instructions to observers and the mixing of non-SOS and SOS trials in experimental sessions defined all abnormalities as fair game. Perhaps the general task definition itself reduces perceptional resources so far in CT interpretation that there is not much more decrement in performance that finding an abnormality can do on finding subsequent abnormalities. To study this possibility, we brought readers back for a fourth experimental condition. In this second follow-up experiment, the non-SOS condition was repeated as a single block of trials. Every non-nodule abnormality was eliminated from the task definition. Our third null hypothesis was that the test nodules appearing without any additional abnormalities would not be reported any more accurately in the “nodule-only” search task than they had been in the “general” search task.