How do researchers decide early clinical trials?

Launch of clinical investigation represents a substantial escalation in commitment to a particular clinical translation trajectory; it also exposes human subjects to poorly understood interventions. Despite these high stakes, there is little to guide decision-makers on the scientific and ethical evaluation of early phase trials. In this article, we review policies and consensus statements on human protections, drug regulation, and research design surrounding trial launch, and conclude that decision-making is largely left to the discretion of research teams and sponsors. We then review what is currently understood about how research teams exercise this discretion, and close by laying out a research agenda for characterizing the way investigators, sponsors, and reviewers approach decision-making in early phase research.     

Healthcare practitioners’ personal and professional values

Personal and professional values of healthcare practitioners influence their clinical decisions. Understanding these values for individuals and across healthcare professions can help improve patient-centred decision-making by individual practitioners and interprofessional teams, respectively. We aimed to identify these values and integrate them into a single framework using Schwartz’s values model. We searched Medline, Embase, PsycINFO, CINAHL and ERIC databases for articles on personal and professional values of healthcare practitioners and students. We extracted values from included papers and synthesized them into a single framework using Schwartz’s values model. We summarised the framework within the context of healthcare practice. We identified 128 values from 50 included articles from doctors, nurses and allied health professionals. A new framework for the identified values established the following broad healthcare practitioner values, corresponding to Schwartz values (in parentheses): authority (power); capability (achievement); pleasure (hedonism); intellectual stimulation (stimulation); critical-thinking (self-direction); equality (universalism); altruism (benevolence); morality (tradition); professionalism (conformity); safety (security) and spirituality (spirituality). The most prominent values identified were altruism, equality and capability. This review identified a comprehensive set of personal and professional values of healthcare practitioners. We integrated these into a single framework derived from Schwartz’s values model. This framework can be used to assess personal and professional values of healthcare practitioners across professional groups, and can help improve practitioners’ awareness of their values so they can negotiate more patient-centred decisions. A common values framework across professional groups can support shared education strategies on values and help improve interprofessional teamwork and decision-making.     

Understanding Process in Group-Based Intervention Delivery: Social Network Analysis and Intra-entity Variability Methods as Windows into the “Black Box”

Although the majority of evidence-based programs are designed for group delivery, group process and its role in participant outcomes have received little empirical attention. Data were collected from 20 groups of participants (94 early adolescents, 120 parents) enrolled in an efficacy trial of a mindfulness-based adaptation of the Strengthening Families Program (MSFP). Following each weekly session, participants reported on their relations to group members. Social network analysis and methods sensitive to intraindividual variability were integrated to examine weekly covariation between group process and participant progress, and to predict post-intervention outcomes from levels and changes in group process. Results demonstrate hypothesized links between network indices of group process and intervention outcomes and highlight the value of this unique analytic approach to studying intervention group process.     

Three dimensional fusion of electromechanical mapping and magnetic resonance imaging for real-time navigation of intramyocardial cell injections in a porcine model of chronic myocardial infarction

For cardiac regenerative therapy intramyocardial catheter guided cell transplantations are targeted to the infarct border zone (IBZ) i.e. the closest region of viable myocardium in the vicinity of the infarct area. For optimal therapeutic effect this area should be accurately identified. However late gadolinium enhanced magnetic resonance imaging (LGE-MRI) is the gold standard technique to determine the infarct size and location, electromechanical mapping (EMM) is used to guide percutaneous intramyocardial injections to the IBZ. Since EMM has a low spatial resolution, we aim to develop a practical and accurate technique to fuse EMM with LGE-MRI to guide intramyocardial injections. LGE-MRI and EMM were obtained in 17 pigs with chronic myocardial infarction created by balloon occlusion of LCX and LAD coronary arteries. LGE-MRI and EMM datasets were registered using our in-house developed 3D CartBox image registration software toolbox to assess: (1) the feasibility of the 3D CartBox toolbox, (2) the EMM values measured in the areas with a distinct infarct transmurality (IT), and (3) the highest sensitivity and specificity of the EMM to assess IT and define the IBZ. Registration of LGE-MRI and EMM resulted in a mean error of 3.01 ± 1.94 mm between the LGE-MRI mesh and EMM points. The highest sensitivity and specificity were found for UV <9.4 mV and bipolar voltage <1.2 mV to respectively identify IT of ≥5 and ≥97.5 %. The 3D CartBox image registration toolbox enables registration of EMM data on pre-acquired MRI during the EMM guided procedure and allows physicians to easily guide injections to the most optimal injection location for cardiac regenerative therapy and harness the full therapeutic effect of the therapy.     

Lenalidomide in combination with dexamethasone: effective regimen in patients with relapsed or refractory multiple myeloma complicated by renal impairment

Over the past decade, treatment options for patients with multiple myeloma (MM) have improved substantially, resulting in better response rates and prolonged overall survival (OS). Nevertheless, MM remains a challenging disease, especially if renal insufficiency (RI) or extensive pre-treatment aggravates the assignment of the optimal treatment schedule. In this retrospective study, we analyzed the outcome of lenalidomide plus dexamethasone in 167 patients with relapsed or refractory MM with focus on RI. The baseline creatinine clearance (CL_Cr) was normal in 94 patients (CL_Cr ≥ 80 ml/min), while RI was observed in 73 patients, including 40 patients with mild RI (50 ≤ CL_Cr < 80 ml/min) and 33 patients with moderate or severe RI (CL_Cr < 50 ml/min). Response rates declined depending on the severity of RI, being 67% among patients with normal kidney function, 60% among patients with mild RI and 49% among patients with moderate or severe RI. Time to progression (TTP) was significantly reduced in patients with severe RI and in case of >2 previous treatment lines. OS was not significantly different between patients with normal and impaired renal function. In contrast, the number of previous treatment lines (2 vs. <2) and the use of novel agents like bortezomib or thalidomide prior to lenalidomide plus dexamethasone therapy had a more adverse effect on OS. In conclusion, lenalidomide plus dexamethasone is an effective regimen for relapsed or refractory patients with MM complicated by RI with manageable toxicity.     

Vascular Endothelial Growth Factor Levels in Childhood Acute Lymphoblastic and Myeloblastic Leukemia

Angiogenesis has been associated with the growth, dissemination and metastasis and has been shown to be a prognostic. Although there are some data suggesting that angiogenesis may have a role in the pathophysiology of leukemia, its role in patient prognosis is yet to be defined. We analyzed the expression level of vascular endothelial growth factor (VEGF), an angiogenesis promoter and its possible- prognostic value in bone marrow samples at the time of diagnosis and remission of acute childhood leukemia patients. Besides 46 patients diagnosed as ALL or AML, 16 children were also included as a control group in the study. Our data have demonstrated that VEGF levels of AML patients were found higher than the control group statistically (P = 0.022). However we could not find any significant difference between VEGF levels of diagnosis and remission in both AML and ALL groups by blastic VEGF expression (P > 0.05). In this study the higher levels of VEGF in AML patients is one of the main findings although we were not able to assess any role of VEGF in predicting prognosis in pediatric leukemia patients by evaluating blastic cell VEGF expression. These results have demonstrated that the relationship between angiogenesis or angiogenesis promoters and hematological malignancies is not clear and simple as different methods or different cells beside different angiogenesis promotors are involved to these studies. So that not only tumor cells and their cytokines but also surrounding cells and their cytokines must be taken into consideration with the standardized study methods in the further studies to obtain a promising treatment approach.     

Generic Anti-PEG Antibody Assay on ProterixBio’s (Formerly BioScale) ViBE Platform Shows Poor Reproducibility

PEGylation is a modification commonly used to increase the half-life of therapeutic proteins. The strategy for immunogenicity testing of these compounds should include methods to detect both anti-protein and anti-PEG antibodies. We previously reported a method for the detection of anti-PEG antibodies using ProterixBio’s (formerly BioScale) acoustic membrane microparticle (AMMP) technology. Our initial method development work showed the assay was capable of detecting antibodies in human serum with a sensitivity of 1 μg/mL with good reproducibility (CV?<?7%). Since the publication of this initial paper, additional experimentation was performed in an effort to validate the assay for support of clinical sample analysis. This additional data indicate that the method has high variability (CV%?>?20) and is unsuitable to support clinical sample analysis.     

Statistical and regulatory considerations in assessments of interchangeability of biological drug products

When the patent of a brand-name, marketed drug expires, new, generic products are usually offered. Small-molecule generic and originator drug products are expected to be chemically identical. Their pharmaceutical similarity can be typically assessed by simple regulatory criteria such as the expectation that the 90 % confidence interval for the ratio of geometric means of some pharmacokinetic parameters be between 0.80 and 1.25. When such criteria are satisfied, the drug products are generally considered to exhibit therapeutic equivalence. They are then usually interchanged freely within individual patients. Biological drugs are complex proteins, for instance, because of their large size, intricate structure, sensitivity to environmental conditions, difficult manufacturing procedures, and the possibility of immunogenicity. Generic and brand-name biologic products can be expected to show only similarity but not identity in their various features and clinical effects. Consequently, the determination of biosimilarity is also a complicated process which involves assessment of the totality of the evidence for the close similarity of the two products. Moreover, even when biosimilarity has been established, it may not be assumed that the two biosimilar products can be automatically substituted by pharmacists. This generally requires additional, careful considerations. Without declaring interchangeability, a new product could be prescribed, i.e. it is prescribable. However, two products can be automatically substituted only if they are interchangeable. Interchangeability is a statistical term and it means that products can be used in any order in the same patient without considering the treatment history. The concepts of interchangeability and prescribability have been widely discussed in the past but only in relation to small molecule generics. In this paper we apply these concepts to biosimilars and we discuss: definitions of prescribability and interchangeability and their statistical implementation; the relation between bioequivalence and interchangeability for small-molecule drug products; regulatory requirements and expectations of biosimilar products in various jurisdictions; possible statistical approaches to establish the similarity and interchangeability of biologic drug products; definition of other technical terms such as switchability and automatic substitution. The paper will be concluded with a discussion of the anticipated future use of interchangeability of biological drug products.     

A Novel Approach to the Nutrigenetics and Nutrigenomics of Obesity and Weight Management

Nutrigenetics and nutrigenomics, as well as diet and exercise, play an important role in the development and treatment of obesity and its comorbidities. If an individual’s susceptibility to becoming obese and their responsiveness to weight loss interventions are to be understood, then it needs to be addressed at a molecular and metabolic level, including genetic interaction. This review proposes a three-pillar approach to more fully comprehend the complexity of diet-gene interactions in obesity. Peroxisomal proliferating-activated receptor gamma (PPARG) and mitochondrial uncoupling protein-1 (UCP-1) are explored in detail. Illustrating how an understanding of nutritional biochemistry, nutrigenomics, and nutrigenetics may be the key to understanding differences observed in the obese phenotype that vary both within and across populations.