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.     

Beneficial effects of ketogenic diets for cancer patients: a realist review with focus on evidence and confirmation

Ketogenic diets (KDs) have gained popularity among patients and researchers alike due to their putative anti-tumor mechanisms. However, the question remains which conclusions can be drawn from the available human data thus far concerning the safety and efficacy of KDs for cancer patients. A realist review utilizing a matrix analytical approach was conducted according to the RAMESES publication standards. All available human studies were systematically analyzed and supplemented with results from animal studies. Evidence and confirmation were treated as separate concepts. In total, 29 animal and 24 human studies were included in the analysis. The majority of animal studies (72%) yielded evidence for an anti-tumor effect of KDs. Evidential support for such effects in humans was weak and limited to individual cases, but a probabilistic argument shows that the available data strengthen the belief in the anti-tumor effect hypothesis at least for some individuals. Evidence for pro-tumor effects was lacking completely. Feasibility of KDs for cancer patients has been shown in various contexts. The probability of achieving an anti-tumor effect seems greater than that of causing serious side effects when offering KDs to cancer patients. Future controlled trials would provide stronger evidence for or against the anti-tumor effect hypothesis.     

Evidence-Based Practice Implementation Within a Theory of Planned Behavior Framework

Although significant progress has been made in the identification of youth evidence-based practices, the adoption of these interventions into community-based mental health care remains limited. Dissemination and implementation (DI) research has the potential to bridge this science-practice gap in clinical psychology. The theory of planned behavior (TPB) offers a useful conceptualization of individual behavior change including behavioral intention as defined by attitudes, subjective norms, and perceived behavioral control. To facilitate application of this model to DI efforts, the current study explores perspectives about using evidence-based practice from stakeholders in the field of youth mental health (including clinical supervisors, case managers, administrators at the departments of health and education, and direct service providers in clinic-based, school-based, and intensive in-home settings) within the TPB framework. A set of instrument items was created from this rich qualitative data using a rigorous mixed-method content validation approach. Instrument items are provided for future use in DI research.     

The ethics of killing human/great-ape chimeras for their organs: a reply to Shaw et al.

The aim of this paper is to critically examine David Shaw, Wybo Dondorp, and Guido de Wert’s arguments in favour of the procurement of human organs from human/nonhuman-primate chimeras, specifically from great-ape/human chimeras. My main claim is that their arguments fail and are in need of substantial revision. To prove this I first introduce the topic, and then reconstruct Shaw et al.’s position and arguments. Next, I show that Shaw et al.: (1) failed to properly apply the subsidiarity and proportionality principles; (2) neglected species overlapping cases in their ethical assessment; (3) ignored the ethics literature on borderline persons; and (4) misunderstood McMahan’s two-tiered moral theory. These mistakes render an important part of their conclusions either false or problematic to the point that they would no longer endorse them. Finally I will briefly mention a possible multipolar solution to the human organ shortage problem that would reduce the need for chimeras’ organs.     

Progress testing: critical analysis and suggested practices

Educators have long lamented the tendency of students to engage in rote memorization in preparation for tests rather than engaging in deep learning where they attempt to gain meaning from their studies. Rote memorization driven by objective exams has been termed a steering effect. Progress testing (PT), in which a comprehensive examination sampling all of medicine is administered repeatedly throughout the entire curriculum, was developed with the stated aim of breaking the steering effect of examinations and of promoting deep learning. PT is an approach historically linked to problem-based learning (PBL) although there is a growing recognition of its applicability more broadly. The purpose of this article is to summarize the salient features of PT drawn from the literature, provide a critical review of these features based upon the same literature and psychometric considerations drawn from the Standards for Educational and Psychological Testing and provide considerations of what should be part of best practices in applying PT from an evidence-based and a psychometric perspective.     

Disconnectedness from the here-and-now: a phenomenological perspective as a counteract on the medicalisation of death wishes in elderly people

When elderly people are ideating on manners to end their lives, because they feel life is over and no longer worth living, it is important to understand their lived experiences, thoughts and behaviour in order to appropriately align care, support and policy to the needs of these people. In the literature, the wish to die in elderly people is often understood from a medical, psychopathological paradigm, referred to as cognitive impairment, depressive disorder, pathological bereavement, and suicidality. In this paper, we evaluate this dominant paradigm by considering three serious limitations, namely: (1) the risk of epistemic transformation; (2) the risk of reduction; and (3) the risk of obscuring the social and cultural embeddedness. Drawing on insights from our empirical–phenomenological research on the issue of elderly and the self-chosen death, this paper argues for a phenomenological perspective to counteract the medicalisation of death wishes in elderly people.     

Positron emission tomography in imaging evaluation of staging,restaging, treatment response,and prognosis in prostate cancer

Prostate cancer is a prevalent public health problem worldwide. While imaging has played a major role in this disease, there still remain many challenges and opportunities. Positron emission tomography with various physiologically based radiotracers is fundamentally suited to interrogate this biologically and clinically heterogeneous disease along the course of its natural history. In this article, I review briefly the published evidence for the use of positron emission tomography with 18F-fluorodeoxyglucose, 11C-acetate, and 18F- or 11C-choline in the imaging evaluation of prostate cancer. Although the focus of the article will be on these radiotracers given the accumulated experience with them, but I will also comment on the outlook for the use of other emerging PET radiotracers such as those targeted to the prostate-specific membrane antigen and the amino acid metabolism pathway. It is anticipated that PET will play major role in the evaluation of prostate cancer in the current evidence-based medicine environment. There will also be exciting novel prospects for the use of therapeutic-diagnostic (theransotic) pairs in the management of patients with prostate cancer.     

Factors Driving the HIV Epidemic in Southern Africa

The HIV pandemic has disproportionately impacted sub-Saharan Africa and Southern Africa in particular. The concurrent presence of overlapping epidemic drivers likely underpins how and why the HIV epidemic is so explosive in this region, with implications for understanding approaches to reduce transmission. In this review, we discuss the relative contribution and interaction between epidemic drivers in the Southern African context, including factors both distally and proximally associated with the likelihood and degree of exposure to HIV and factors that increase the probability of transmission when exposure occurs. In particular, we focus on young women as a key population in need of HIV prevention and highlight factors that increase their risk on several levels.