Method of Blood Pressure Measurement in Neonates and Infants: A Systematic Review and Analysis.

OBJECTIVES: To determine the recommended blood pressure (BP) measurement methods in neonates after systematically analyzing the literature regarding proper BP cuff size and measurement location and method. STUDY DESIGN: A literature search was conducted in MEDLINE, PubMed, Embase, Cochrane Library, and CINAHL from 1946 to 2017 on BP in neonates <3 months of age (PROSPERO ID CRD42018092886). Study data were extracted and analyzed with separate analysis of Bland-Altman studies comparing measurement methods. RESULTS: Of 3587 nonduplicate publications identified, 34 were appropriate for inclusion in the analysis. Four studies evaluating BP cuff size support a recommendation for a cuff width to arm circumference ratio of approximately 0.5. Studies investigating measurement location identified the upper arm as the most accurate and least variable location for oscillometric BP measurement. Analysis of studies using Bland-Altman methods for comparison of intra-arterial to oscillometric BP measurement show that the 2 methods correlate best for mean arterial pressure, whereas systolic BP by the oscillometric method tends to overestimate intra-arterial systolic BP. Compared with intra-arterial methods, systolic BP, diastolic BP, and mean arterial pressure by oscillometric methods are less accurate and precise, especially in neonates with a mean arterial pressure <30 mm Hg. CONCLUSIONS: Proper BP measurement is critical in neonates with naturally lower BP and attention to BP cuff size, location, and method of measurement are essential. With decreasing use of intra-arterial catheters for long-term BP monitoring in neonates, further studies are urgently needed to validate and develop oscillometric methodology with enhanced accuracy.

The importance of herbal medicine use in the German health-care system: prevalence, usage pattern, and influencing factors.

BACKGROUND: Prevalence rates for herbal medicine (HM) have been increasing worldwide. However, little is known about prevalence, user characteristics, usage pattern and factors influencing HM usage for the general German population. METHODS: A nationwide online survey on HM usage was conducted in Germany. The 2906 participants were categorised into three groups: the ones who used HM in the last 12 months, the ones who did not use HM in the last 12 months but in their lifetime, and the ones who did not use HM until now. Data were analysed by descriptive statistics, Chi Square tests and binary hierarchical logistic regression analyses. RESULTS: Prevalence rates of HM were found to be very high for the general German population. Self-medication appeared as a common praxis, when at the same time HM users responded that they do not inform their physician about it, rate their knowledge about HM as somewhat poor, and use the internet as the most frequent source of information. The HM user in the last 12 months was found to include people that were more likely female, highly educated, privately insured, employed, and engaged in a more health-oriented lifestyle. While certain sociodemographic- and health-related variables influence HM usage vs. non-usage, they explain variance only to a limited extent. For distinguishing the user in the last 12 months vs. the less recent user who did not use HM in the last 12 months, ratings on different reasons for HM usage were found to perform better as predictors than sociodemographic- and health-related variables. CONCLUSIONS: This study demonstrated that HM usage plays an essential role in the German health-care system. Furthermore, the HM usage pattern may be potentially harmful for patients, as it included self-medication, little knowledge on interaction- and side-effects of HM, and a lack of communication with physicians about the usage. Moreover, prediction of HM usage in the previous year is impacted by variables beyond conventional sociodemographic- and health-related ones. In view of the high prevalence rates of HM in Germany, medical as well as health service providers should be aware of these issues.

What motivates new, established and long-term users of herbal medicine: is there more than push and pull?

BACKGROUND: The use of herbal medicine (HM) has become an essential form of treatment and it is more and more common around the world. Little is known about the reasons that drive people to initially use HM or to maintain their behaviour, and whether the so-called "push and pull factors" known in the context of decision making for complementary and alternative medicine, also play a role for HM use. Here, our goal was to provide answers to these open questions and to analyse the reasons that motivate new, established and long-term HM consumers in detail. METHODS: Thirteen reasons for HM usage, which were previously identified within a qualitative approach, were analysed quantitatively in a nationwide online survey in Germany. Data of 2,192 German HM users from the general population were grouped into new, established and long-term users. We performed a factor analysis in order to identify factors underlying the set of reasons. RESULTS: We discovered a reliable factor associated with longstanding family traditions and cultural importance of HM in Germany. This finding shows that the reasons for HM use require a three-factor structure going beyond the well-known push and pull factors that explain the use of complementary and alternative medicine. In using the identified factors for further calculations, we were able to reveal important group differences and test how the factor scores perform as predictors for the new, established and long-term choice of HM. Our results showed that a high score on the push factor is associated more with initial HM usage, while long-term HM usage is impacted more by high scores on the pull and traditional factors. CONCLUSIONS: Our exploratory survey and analysis of the reasons that underlie HM usage aimed at providing a better understanding of the decision for this treatment form. The findings of our work deliver insights for medical practitioners and health-care providers, including the role of family traditions for HM usage and the finding that new HM users are driven to use this treatment form in part because of negative aspects they associate with conventional medicine.

Why people use herbal medicine: insights from a focus-group study in Germany.

BACKGROUND: The use of herbal medicine, as one element of complementary and alternative medicine, is increasing worldwide. Little is known about the reasons for and factors associated with its use. This study derives insights for the use of herbal medicine in Germany regarding the usage aims, role played by the type of illness, reasons for preferred usage and sources of information. METHODS: Using a qualitative methodological approach, six focus groups (n = 46) were conducted. Two groups with young, middle-aged and elderly participants, respectively. After audiotaping and verbatim transcription, the data were analysed with a qualitative content analysis. RESULTS: We found that treating illnesses was the most frequently discussed aim for using herbal medicine over all age groups. Preventing illnesses and promoting health were less frequently mentioned overall, but were important for elderly people. Discussions on herbal medicine were associated with either mild/moderate diseases or using herbal medicine as a starting treatment before applying conventional medicine. In this context, participants emphasized the limits of herbal medicine for severe illnesses. Dissatisfaction with conventional treatment, past good experiences, positive aspects associated with herbal medicine, as well as family traditions were the most commonly-mentioned reasons why herbal medicine was preferred as treatment. Concerning information sources, independent reading and family traditions were found to be equally or even more important than consulting medicinal experts. CONCLUSIONS: Although herbal medicine is used mostly for treating mild to moderate illnesses and participants were aware of its limits, the combination of self-medication, non-expert consultation and missing risk awareness of herbal medicine is potentially harmful. This is particularly relevant for elderly users as, even though they appeared to be more aware of health-related issues, they generally use more medicine compared to younger ones. In light of our finding that dissatisfaction with conventional medicine was the most important reason for a preferred use of herbal medicine, government bodies, doctors, and pharmaceutical companies need to be aware of this problem and should aim to establish a certain level of awareness among users concerning this issue.

Pediatric Crohn Disease Clinical Outcome Assessments and Biomarkers: Current State and Path Forward for Global Collaboration.

OBJECTIVE: There is a pressing need for drug development in pediatric Crohn disease (CD). Our aim was to provide strategic approaches toward harmonization of current thinking about clinical outcome assessments (COAs) and biomarkers to facilitate drug development in pediatric CD. METHODS: Scientists from the United States Food and Drug Administration, European Medicines Agency, Health Canada, and the Pharmaceuticals and Medical Devices Agency of Japan had monthly teleconferences from January 2014 through May 2015. A literature review was conducted to assess the measurement properties of all existing COA tools and to evaluate the current landscape of biomarkers used in pediatric CD. Based on the findings of literature review, we reached the consensus on the strategic approaches for evaluating outcomes in pediatric CD trials. RESULTS: The pediatric Crohn's Disease Activity Index, Crohn's Disease Activity Index, and Harvey-Bradshaw's index were used in pediatric CD clinical studies. But they lack adequate measurement properties (validity, reliability, and ability to detect change of the treatment) that are required to support approval of products intended to treat pediatric CD. Biomarkers (ie, fecal lactoferrin, osteoprotegerin, and calprotectin) have shown some promise for their potential as noninvasive surrogate endpoints in CD. CONCLUSIONS: Lack of well-defined and reliable COAs presents a hurdle for global drug development in pediatric CD. It is essential to develop well-defined and reliable COAs that can measure meaningful clinical benefit for patients in terms of how they feel, function, and survive. Development of noninvasive biomarkers as reliable surrogate endpoints needs to be further explored.

Biosimilars: State of Clinical and Regulatory Science.

On May 12, 2017, various issues and challenges associated with biologics were discussed during a session of the annual joint conference of Canadian Society for Pharmaceutical Sciences and Canadian Chapter of Controlled Release Society at Hyatt Regency Hotel, Montréal, QC, Canada.  An update on the Canadian regulatory guidelines for biosimilars was given, followed by viewpoints expressed by regulatory, academic and industry scientists.  Topics of discussion included: reference biologic drug, clinical considerations, immunogenicity, extrapolation and clarification of terminology, product monograph, international collaboration, switching and interchangeability, naming conventions, clinical and non-clinical evaluation, authorization of indications, statistical equivalence, the nor-switch study and biologics marketplace.

Regulatory Decision Making in Canada-Exploring New Frontiers in Patient Involvement.

Recent legislative amendments aim to enhance the transparency of the regulatory review processes about drugs, and provide public information about Health Canada's review decisions. There is also growing recognition of the value, with respect to regulatory benefit-risk assessment, of information that could be gathered from patients-the direct users of these products. Patients can provide unique insights into practical aspects of living with their disease and its treatments-as well as gaps in treatment needs. An enhanced understanding of patients' experiences and perspectives can contribute directly to better-informed decision making about these products by regulators. Health Canada is currently exploring and examining the most effective ways to collect and consider patient input in the evaluation of therapeutic products. As part of this process, Health Canada is assessing the suitability of other existing models through environmental scans, discussions with other health authorities, and pilot projects. Lessons learned from these models can inform best practices and opportunities for patient involvement when designing a model to meet Canada's needs and context. Health Canada launched a Patient Involvement Pilot Project in 2014 to simulate how input from patients, their caregivers, health care professionals, and patient groups could be collected and incorporated in the drug submission review process. This ongoing experience and continuous learning will define better how to incorporate patient input into benefit-risk assessment and regulatory decision making throughout the life cycle of therapeutic products in Canada.

Soluble components of the flagellar export apparatus, FliI, FliJ, and FliH, do not deliver flagellin, the major filament protein, from the cytosol to the export gate.

Flagella, the locomotion organelles of bacteria, extend from the cytoplasm to the cell exterior. External flagellar proteins are synthesized in the cytoplasm and exported by the flagellar type III secretion system. Soluble components of the flagellar export apparatus, FliI, FliH, and FliJ, have been implicated to carry late export substrates in complex with their cognate chaperones from the cytoplasm to the export gate. The importance of the soluble components in the delivery of the three minor late substrates FlgK, FlgL (hook-filament junction) and FliD (filament-cap) has been convincingly demonstrated, but their role in the transport of the major filament component flagellin (FliC) is still unclear. We have used continuous ATPase activity measurements and quartz crystal microbalance (QCM) studies to characterize interactions between the soluble export components and flagellin or the FliC:FliS substrate-chaperone complex. As controls, interactions between soluble export component pairs were characterized providing Kd values. FliC or FliC:FliS did not influence the ATPase activity of FliI alone or in complex with FliH and/or FliJ suggesting lack of interaction in solution. Immobilized FliI, FliH, or FliJ did not interact with FliC or FliC:FliS detected by QCM. The lack of interaction in the fluid phase between FliC or FliC:FliS and the soluble export components, in particular with the ATPase FliI, suggests that cells use different mechanisms for the export of late minor substrates, and the major substrate, FliC. It seems that the abundantly produced flagellin does not require the assistance of the soluble export components to efficiently reach the export gate.

Steps toward harmonization for clinical development of medicines in pediatric ulcerative colitis-a global scientific discussion, part 1: efficacy endpoints and disease outcome assessments.

OBJECTIVES: There is a pressing need for drug development in pediatric ulcerative colitis (UC). Lack of scientific consensus on efficacy endpoints and disease outcome assessments presents a hurdle for global drug development in pediatric UC. Scientists from 4 regulatory agencies convened an International Inflammatory Bowel Disease Working Group (i-IBD Working Group) to harmonize present thinking about various aspects of drug development in pediatric UC globally. METHODS: The i-IBD Working Group was convened in 2012 by scientists from the US Food and Drug Administration, European Medicines Agency, Health Canada, and the Pharmaceuticals and Medical Devices Agency of Japan. The members of this group considered reasons for differences in their acceptance of efficacy endpoints and disease activity indices used in pediatric UC, reviewed the available literature, and developed consensus opinions regarding approaches for evaluating outcomes in pediatric UC trials. RESULTS: There is lack of harmonization in using efficacy endpoint and outcome assessments including disease activity indices to assess clinical benefit in pediatric UC trials. Many disease activity indices have been developed, but their biometric properties, such as responsiveness, reliability, and validity, have not been properly validated. Biomarkers, such as fecal calprotectin and lactoferrin, are being investigated for their potential as noninvasive surrogate endpoints in UC. CONCLUSIONS: Consensus on the efficacy endpoints, disease activity indices, and outcome assessments is needed for globalization of pediatric UC trials. The i-IBD Working Group offers several perspectives to facilitate harmonization across regions. The development of noninvasive biomarkers as reliable surrogate endpoints needs to be explored further.

Steps toward harmonization for clinical development of medicines in pediatric ulcerative colitis-a global scientific discussion, part 2: data extrapolation, trial design, and pharmacokinetics.

OBJECTIVES: To facilitate global drug development, the International Pediatric Inflammatory Bowel Disease Working Group (i-IBD Working Group) discussed data extrapolation, trial design, and pharmacokinetic (PK) considerations for drugs intended to treat pediatric ulcerative colitis (UC), and considered possible approaches toward harmonized drug development. METHODS: Representatives from the US Food and Drug Administration, European Medicines Agency, Health Canada, and the Pharmaceuticals and Medical Devices Agency of Japan convened monthly to explore existing regulatory approaches, reviewed the results of a literature search, and provided perspectives on pediatric UC drug development based on the available medical literature. RESULTS: Although pediatric UC, when compared with UC in adults, has a similar disease progression and response to intervention, the similarity of the exposure-response relation has not been adequately established. Consequently, clinical endpoints should be selected to optimally assess efficacy in children. The inclusion of a placebo control in pediatric trials to assure assay sensitivity may be appropriate under limited circumstances. In clinical studies, although the drug under investigation could provide possible direct benefit, placebo treatment should present no more than a minor increase over minimal risk to children with UC. CONCLUSIONS: Partial extrapolation of efficacy from informative adult studies may be appropriate. Placebo-controlled efficacy trials are scientifically and ethically appropriate for pediatric UC given appropriate patient selection and the use of early escape. Clinical studies in pediatric UC may include initial dose-finding studies and exposure-response modeling followed by an efficacy and safety study to further explore the exposure-response relation.

Factors influencing the use of natural health products, in particular for concentration and cognition in Germany.

BACKGROUND: Natural health products (NHP) are an important part of the healthcare system. They are mainly non-prescription and sold over the counter, which requires active decision making by the consumer. Within the framework of the Complementary and Alternative Healthcare Model, this study aims to identify factors that influence NHP usage, in particular related to concentration and cognition (CC), a topic that concerns all ages and social classes within the population. METHODS: Data were collected by means of a representative online survey (n = 1,707) in Germany in April 2022. Three user groups were defined: NHPCC users, who used NHP for CC (12 month prevalence); nCC-NHP users, who used NHP but not for CC indications (12 month prevalence); and past NHP users, who have used NHP but not within the previous 12 months. Independent influencing variables were categorized into predisposing, enabling, need, and health service use factors. Data were analyzed with descriptive statistics, inferential statistics, and binary logistic regression models to compare NHPCC users to nCC-NHP users (model 1) and to past NHP users (model 2). RESULTS: A higher share of NHPCC and nCC-NHP users compared to past NHP users were women, self-medicated with NHP, and used information about NHP provided by health professionals or on product. Their openness-to-change value orientation was more pronounced than of past users. Compared to nCC-NHP and past NHP users, the probability of being an NHPCC user increased if an individual had more difficulties in daily attention and memory performance, made use of health professionals and literature to seek information about NHP, and used NHP for health support and illness prevention. Additionally, a female gender, NHP self-medication, and having higher values of self-transcendence were significant indicators for NHPCC usage compared to past NHP usage. CONCLUSION: NHP manufacturers, health professionals, and policymakers should be aware of the factors that lead to NHP consumption decisions and consider them in the development and optimization of healthcare strategies as well as in the marketing and communication strategies of companies producing NHP, in particular for CC. The current study can contribute to characterizing the target groups and to defining the aims and communication channels of such campaigns.

Ways of integrating eating into everyday lives - a qualitative study in Germany.

BACKGROUND: Food-related behaviour is a very complex topic. A common way to reduce complex issues to their essential content is to create a typology. In Germany, with regard to food-related behaviour, the creation of a typology has often been carried out by commercial research institutes, but also by (international) scientific institutes. The former have mostly used quantitative methods, the latter usually have a specific content focus. Within this study, we want to investigate how people integrate eating into their everyday lives while engaging with themselves and the environment, thereby living out personality development and related socialisation. METHODS: 37 qualitative interviews were conducted and evaluated by means of content-structuring qualitative analysis and type-forming qualitative content analysis. Interviewees were recruited via recruitment calls using different channels, such as newspapers or university e-mail lists. Participants over the age of seventeen were eligible to take part in the study. Both the individual action processes and the interpretation processes regarding food-related behaviour were taken into account. The final sample consisted of 20 male and 18 female participants with an age range from 18 to 83. RESULTS: The result were seven eating action types, namely: Eating as a way of life, The Relaxed, Eating as self-determination, Eating as a necessary Evil, The Adaptive, The Overstrained and The Controlled. CONCLUSIONS: We contribute to the study of food-related behaviour with the chosen qualitative method of type-building and by looking at how people integrate eating into their everyday lives. This contributes to a broader understanding of this phenomenon and complements the findings of existing commercial and academic food-related typing-building activities. Specifically, through identifying "The Overstrained" as a novel eating action type, this study adds to the literature in the field and may be a useful baseline for future research.

Neonatal blood pressure by birth weight, gestational age, and postnatal age: a systematic review.

BACKGROUND: Blood pressure is a vital hemodynamic marker during the neonatal period. However, normative values are often derived from small observational studies. Understanding the normative range would help to identify ideal thresholds for intervention to treat hypotension or hypertension. Therefore, the aim of this study was to assess observed blood pressure values in neonates who have not received any blood-pressure modifying treatments from birth to three months postnatal age and whether these vary according to birth weight, gestational age and postnatal age. METHODS: This was a systematic review. A literature search was conducted in MEDLINE, PubMed, Embase, Cochrane Library, and CINAHL from 1946 to 2017 on blood pressure in neonates from birth to 3 months of age (PROSPERO ID CRD42018092886). Unpublished data were included where appropriate. RESULTS: Of 3,587 non-duplicate publications identified, 30 were included (one unpublished study). Twelve studies contained data grouped by birth weight, while 23 contained data grouped by gestational age. Study and clinical heterogeneity precluded meta-analyses thus results are presented by subgroup. A consistent blood pressure rise was associated with increasing birth weight, gestational age, and postnatal age. In addition, blood pressure seemed to rise more rapidly in the most preterm and low birth weight neonates. CONCLUSION: Despite blood pressure increasing with birth weight, gestational age, and postnatal age, there was marked blood pressure variability observed throughout. To better define hypotension and hypertension, future studies should develop consistent approaches for factors related to blood pressure variability, including the method and timing of measurement as well as statistical control of relevant patient characteristics.

Usage of Natural Health Products (NHPs) for respiratory diseases: user characteristics and NHP-Consumption behavior during the Covid-19 pandemic in Germany.

BACKGROUND: Respiratory diseases (RD) can challenge healthcare systems around the globe. Natural health products (NHPs) are popular complementary and alternative medicine options for health issues concerning non-fatal RD. Little is known about the characteristics of the users of RD-NHPs and about their NHP consumption behavior during the Covid-19 pandemic in Germany. METHODS: A representative online survey was conducted in Germany in 2022. 1707 participants were classified based on having used NHPs for RD within the previous 12 months, having used NHPs but not for RD within the previous 12 months and not having used NHPs. Data were analyzed using descriptive and inferential statistical methods as well as a multinomial logistic regression model. RESULTS: Users of RD-NHPs within the previous 12 months were more likely to be employed and to consult pharmacists more often for non-fatal health issues than individuals who did not take RD-NHPs. RD-NHP users were more likely to suffer from a Covid-19 infection and to have children living in the same household than other NHP users. Compared to non-NHP users, RD-NHP users were more likely to be female, highly educated and have stronger openness-to-change value orientations. Vaccination-related behavior was no indicator of RD-NHP usage. Most RD-NHP users took NHPs in self-medication. Few reported informing their practitioner about their self-medication. Drugstores were the most visited supply source for NHPs during the pandemic, followed by pharmacies. Common information sources regarding NHPs were the products themselves and pharmacists. CONCLUSION: This study emphasized the important role of NHPs as a popular prevention and treatment option for RD. RD-NHPs were more likely used by individuals who were employed, who suffered from a RD and who consult pharmacists for non-fatal health issues. The importance of product information and pharmacies as information sources should be considered to make communication strategies about safe self-medication options with RD-NHPs more effective, which could help to reduce the burden of health facilities regarding non-fatal RD. To improve and develop future pandemic-control strategies, health professionals and policy makers should consider NHP usage behavior and provide critical information about chances and risks of self-medicated NHP consumption.

Regulatory Verification by Health Canada of Content in Recombinant Human Insulin, Human Insulin Analog, and Porcine Insulin Drug Products in the Canadian Market Using Validated Pharmacopoeial Methods Over Nonvalidated Approaches.

BACKGROUND: For diabetes mellitus treatment plans, the consistency and quality of insulin drug products are crucial for patient well-being. Because biologic drugs, such as insulin, are complex heterogeneous products, the methods for drug product evaluation should be carefully validated for use. As such, these criteria are rigorously evaluated and monitored by national authorities. Consequently, reports that describe significantly lower insulin content than their label claims are a concern. This issue was raised by a past publication analyzing insulin drug products available in Canada, and, as a result, consumers and major patient organizations have requested clarification. METHODS: To address these concerns, this study independently analyzed insulin drug products purchased from local Canadian pharmacies-including human insulin, insulin analogs, and porcine insulin-by compendial and noncompendial reversed-phase high-performance liquid chromatography (RP-HPLC) methods. RESULTS: We demonstrated the importance of using methods fit for purpose when assessing insulin quality. In a preliminary screen, the expected insulin peak was seen in all products except two insulin analogs-insulin detemir and insulin degludec. Further investigation showed that this was not caused by low insulin content but insufficient solvent conditions, which demonstrated the necessity for methods to be adequately validated for product-specific use. When drug products were appropriately assessed for content using the validated type-specific compendial RP-HPLC methods for insulin quantitation, values agreed with the label claim content. CONCLUSIONS: Because insulin drug products are used daily by over a million Canadians, it is important that researchers and journals present data using methods fit for purpose and that readers evaluate such reports critically.

Health Canada/BIOTECanada Summit on regulatory and clinical topics related to subsequent entry biologics (biosimilars), Ottawa, Canada, 14 May 2012.

In May 2012, Health Canada and other participants held a National Summit on Subsequent Entry Biologics (SEBs). Health Canada released a guidance document in March 2010 describing policy positions and data requirements for approval of SEBs. While Health Canada and health agencies in other regulatory jurisdictions are aligned on many scientific principles related to biosimilar drugs, Health Canada's specific requirements may not be widely understood by many Canadian stakeholders. The Summit provided an opportunity for education and dialog among physicians who prescribe biologics, provincial payers, and industry on the following topics: preclinical and clinical comparability studies; manufacturing and other product differences; extrapolation of indications; substitution and interchangeability of SEBs with reference biologic drugs in clinical practice; payers' current perspective; pharmacovigilance and naming. It is anticipated that the consensus reached at this meeting will further educate Canadian healthcare professionals, provincial payers, and insurers about the appropriate use of SEBs, and may be of general interest to others internationally.

Global Regulatory and Public Health Initiatives to Advance Pediatric Drug Development for Rare Diseases.

The literature thoroughly describes the challenges of pediatric drug development for rare diseases. This includes (1) generating interest from sponsors, (2) small numbers of children affected by a particular disease, (3) difficulties with study design, (4) lack of definitive outcome measures and assessment tools, (5) the need for additional safeguards for children as a vulnerable population, and (6) logistical hurdles to completing trials, especially with the need for longer term follow-up to establish safety and efficacy. There has also been an increasing awareness of the need to engage patients and their families in drug development processes and to address inequities in access to pediatric clinical trials. The year 2020 ushered in yet another challenge-the COVID-19 pandemic. The pediatric drug development ecosystem continues to evolve to meet these challenges. This article will focus on several key factors including recent regulatory approaches and public health policies to facilitate pediatric rare disease drug development, emerging trends in product development (biologics, molecularly targeted therapies), innovations in trial design/endpoints and data collection, and current efforts to increase patient engagement and promote equity. Finally, lessons learned from COVID-19 about building adaptable pediatric rare disease drug development processes will be discussed.

The first subsequent entry biologic authorized for market in Canada: the story of Omnitrope, a recombinant human growth hormone.

Omnitrope is the first Subsequent Entry Biologic (SEB)/Similar Biotherapeutic Product (SBP) filed with Health Canada, for purposes of marketing. Health Canada is the home organization of the Regulatory Authority in Canada. As the first SEB to be filed for actual review, it presented unique challenges. While the principles for the review and approval of a SEB were laid out in a "fact sheet" there remained still a guidance to be drafted. The review of the submissions proceeded in parallel with the development of the guideline. This article will provide the details of how the final decision was arrived at and how that decision validated the principles underlying the guidance document, in the absence of direct regulations specifically addressing SEBs in Canada.

Determining the Distinguishing Features of Different Eating Action Types in Germany Using a Mixed-Method Approach.

Food-related behavior is a very complex topic, as it affects the most diverse areas of life. Accordingly, wide varieties of disciplines have already dealt with the topic to understand it better. The result is that there is neither a uniform nutrition knowledge nor a uniform nutrition behavior. In order to reduce the complexity of a field of study, there is the methodical means of type-building. Both commercial and academic studies have already formed nutrition types, either by means of standardized questionnaires or with a specific content focus. However, since both individual and social aspects influence food-related behavior, we investigate how people integrate eating into their everyday life against the background of (competing) individual and social demands by focusing on the individual point of view, for which a mixed methods approach is used. Based on 42 semi-structured, problem-centered interviews conducted in Germany in 2017, we built qualitative food-related types in a first step, which are analyzed in this article using a quantitative content analysis and cross-over analysis to identify the particular distinguishing feature(s) of each type and test them for significance. The results show the prominent characteristics for each type and indicate furthermore that subjectivization, self-determination, the body as an instrument of power, adaptation to the environment and being overstrained with the own behavior are particularly prominent when it comes to eating. Moreover, we clearly identified The Overstrained and The Relaxed as independent eating action types, which we could not find anywhere else. The study shows that interventions, especially for The Overstrained and The Controlled, are necessary to achieve a relaxed approach to eating in everyday life. At the same time, systematic approaches should be used to intervene in cases of overstraining or controlled behavior.