Defining ‘therapeutic value’ of medicines: a scoping review

ObjectivesIn recent years, discussions on the importance and scope of therapeutic value of new medicines have intensified, stimulated by the increase of prices and number of medicines entering the market. This study aims to perform a scoping review identifying factors contributing to the definition of the therapeutic value of medicines.DesignScoping review.Data sourcesWe searched the MEDLINE, CINAHL, Embase, Business Source Premier, EconLit, Regional Business News, Cochrane, Web of Science, Scope and Pool databases through December 2020 in English, German, French, Italian and Spanish.Eligibility criteriaStudies that included determinants for the definition of therapeutic value of medicines were included.Data extraction and synthesisData were extracted using the mentioned data sources. Two reviewers independently screened and analysed the articles. Data were analysed from April 2021 to May 2022.ResultsOf the 1883 studies screened, 51 were selected and the identified factors contributing to the definition of therapeutic value of medicines were classified in three categories: patient perspective, public health perspective and socioeconomic perspective. More than three-quarters of the included studies were published after 2014, with the majority of the studies focusing on either cancer disorders (14 of 51, 27.5%) or rare diseases (11 of 51, 21.6%). Frequently mentioned determinants for value were quality of life, therapeutic alternatives and side effects (all patient perspective), prevalence/incidence and clinical endpoints (all public health perspective), and costs (socioeconomic perspective).ConclusionsMultiple determinants have been developed to define the therapeutic value of medicines, most of them focusing on cancer disorders and rare diseases. Considering the relevance of value of medicines to guide patients and physicians in decision-making as well as policymakers in resource allocation decisions, a development of evidence-based factors for the definition of therapeutic value of medicines is needed across all therapeutic areas

Therapeutic Value of Drugs Granted Accelerated Approval or Conditional Marketing Authorization in the US an Europe From 2007 to 2021

IMPORTANCE: The number of drugs approved through the accelerated approval or conditional marketing authorization pathways has increased with unclear evidence of their therapeutic value. OBJECTIVES: To assess the therapeutic value of drug indications granted accelerated approval in the US or conditional marketing authorization in the European Union (EU) overall and for cancer indications. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used the public databases of the US Food and Drug Administration and the European Medicines Agency to identify all drugs (initial and supplemental indications) granted accelerated approval in the US or conditional marketing authorization (initial indications only) in the EU between January 1, 2007, and December 31, 2021. Therapeutic value ratings were obtained from national health authorities in Germany, France, and Canada. MAIN OUTCOMES AND MEASURES: Descriptive statistics were used to assess the proportion of accelerated approvals and conditional marketing authorizations overall and for cancer vs noncancer indications rated as having high added therapeutic value. RESULTS: The cohort included 146 drug indications (94 first indications, 52 supplemental indications) in the US and 58 (all first indications) in the EU. Most drugs were approved for cancer (122 [83.6%] in the US; 40 [69.0%] in the EU). Therapeutic value ratings were available for 90 drug indications (61.6%) in the US and 56 (96.6%) in the EU. Overall, 35 drug indications granted accelerated approval (38.9%) and 21 granted conditional marketing authorization (37.5%) had high added therapeutic value in the US and EU, respectively, at the time of approval. The proportions of indications rated as having high added therapeutic value were 36.0% (27 of 75) for cancer vs 53.3% (8 of 15) for noncancer indications in the US and 30.8% (12 of 39) for cancer vs 52.9% (9 of 17) for noncancer indications in the EU. CONCLUSIONS AND RELEVANCE: In this cohort study, among new drug indications approved through the accelerated approval or conditional marketing authorization pathways in the US and Europe from 2007 to 2021, 38.9% and 37.5%, respectively, demonstrated high therapeutic value. A substantially lower proportion of cancer indications than noncancer indications were rated as having high therapeutic value. Policy makers and regulators should increase enforcement of timely postapproval study completion for drugs qualifying for these pathways

Red eyes in juvenile bull sharks (Carcharhinus leucas) from Fiji

The bull shark (Carcharhinus leucas) is an apex predator with a wide distribution in tropical and warm temperate waters. This species is known to utilize freshwater systems and estuaries as nursery grounds. During a wider bull shark tagging survey in the Rewa River, Fiji, in 2017 and 2018, 27 neonate bull sharks with red eye pupils were recorded. This opportunistic observation prompted an examination of water quality parameters in the Rewa River to collect preliminary data on the potential cause of pollution. Water samples were analyzed for fecal indicator bacteria (Escherichia coli), ammonia, total nitrogen, and various metals. Results indicated high levels of E. coli contamination, as well as elevated ammonia and total nitrogen concentrations. However, due to the limited sample size and the likelihood of additional underlying causes, a definitive causal relationship could not be established. Hence, this finding stands as an opportunistic observation, detailed here for documentation and stimulation of discourse

Families With Violence Exposure and the Intergenerational Transmission of Somatization

Introduction: Adults who have histories of childhood trauma have been noted to display greater somatization, dissociative symptoms and affect dysregulation. What happens in the parent-child relationship when those traumatized children become parents? A potential link to somatization in the child has been suggested by several prior studies. Children who have early attachment disturbances had more physical complaints if their mothers displayed less maternal sensitivity during observed parent-child interactions. Yet, the intergenerational link between maternal and child somatization has not been sufficiently explored in a longitudinal study in order to understand the potential impact of maternal trauma history and related psychopathology on subsequent child somatization and psychopathology. Methods: This paper examined prospective, longitudinal data of 64 mother-toddler dyads (mean age = 2.4 years, SD = 0.7) who were later studied when children had a mean age of 7 years. Mothers with and without histories of interpersonal violence (IPV; physical/sexual abuse and/or family violence exposure) were included. Mothers with IPV histories were oversampled. Linear and Poisson regression models were used to test the associations between maternal IPV-related post-traumatic stress disorder (PTSD) with maternal somatization severity when children were toddlers, and between maternal somatization and maternal interactive behaviors with child somatization by maternal report and clinician-rated assessment at school-age. Results: Maternal PTSD severity was significantly associated with increased maternal somatization severity (p = 0.031). Maternal somatization severity during the child's early childhood predicted both maternal report of child somatization (p = 0.011) as well as child thought problems (p = 0.007) when children were school-aged. No association was found between maternal somatization and child-reported psychopathology. The study did not find that maternal alexithymia, caregiving behaviors or child exposure to violence contributed significantly to the model examining the association between maternal and child somatization. Conclusion: The results are in line with the hypothesis of intergenerational transmission of somatization in the context of IPV and related maternal PTSD during formative early development. We interpret this as an expression of psychological distress from mother to child, as maternal trauma and pathology affect the caregiving environment and, thus, the parent-child relationship. The authors conclude with a discussion of implications for parent-infant and early childhood intervention

Insights Into Insular Isolation of the Bull Shark, Carcharhinus leucas (Müller and Henle, 1839), in Fijian Waters

The bull shark (Carcharhinus leucas) is a large, mobile, circumglobally distributed high trophic level predator that inhabits a variety of remote islands and continental coastal habitats, including freshwater environments. Here, we hypothesize that the barriers to dispersal created by large oceanic expanses and deep-water trenches result in a heterogeneous distribution of the neutral genetic diversity between island bull shark populations compared to populations sampled in continental locations connected through continuous coastlines of continental shelves. We analyzed 1,494 high-quality neutral single nucleotide polymorphism (SNP) markers in 215 individual bull sharks from widespread locations across the Indian and Pacific Oceans (South Africa, Indonesia, Western Australia, Papua New Guinea, eastern Australia, New Caledonia, and Fiji). Genomic analyses revealed partitioning between remote insular and continental populations, with the Fiji population being genetically different from all other locations sampled (FST = 0.034–0.044, P \u3c 0.001), and New Caledonia showing marginal isolation (FST = 0.016–0.024, P \u3c 0.001; albeit based on a small sample size) from most sampled sites. Discriminant analysis of principal components (DAPC) identified samples from Fiji as a distinct cluster with all other sites clustering together. Genetic structure analyses (Admixture, fastStructure and AssignPOP) further supported the genetic isolation of bull sharks from Fiji, with the analyses in agreement. The observed differentiation in bull sharks from Fiji makes this site of special interest, as it indicates a lack of migration through dispersal across deep-water trenches and large ocean expanses

Fishing for profit or food? Socio-economic drivers and fishers’ attitudes towards sharks in Fiji

Sharks are an important component of coastal fisheries. Accordingly, the impacts of small-scale shark fisheries are likely significant, but data, including socio-economic drivers, are often scarce. Fiji features active but largely unregulated and unmonitored artisanal fisheries. Data suggest that the country's small-scale shark fisheries have the potential to become more targeted. This study considers the socio-economic value of shark fisheries across stakeholder groups. In 2017, semi-structured interviews were conducted with 211 fishers throughout Fiji, out of which 66.8% reported catching sharks of 11 species. Of those who caught sharks, 19.9% stated to release them dead or alive, while 78.7% retained the sharks. Various reasons were cited for shark retention with the most common explanation being to meet dietary needs. Only 19.8% of the participants who retained sharks sold them, yet fishers who gain additional income from the sale of sharks had significantly higher mean maximum catch rates compared to fishers who retained sharks for consumption. Fewer fishers reported selling shark fins compared to a previous comparable survey. This study indicates a decreasing relevance of small-scale coastal shark fisheries for income generation but an increasing utilisation of shark meat as a substitute for traditional food fishes

Discovery of a multispecies shark aggregation and parturition area in the Ba Estuary, Fiji Islands

Population declines in shark species have been reported on local and global scales, with overfishing, habitat destruction and climate change posing severe threats. The lack of species-specific baseline data on ecology and distribution of many sharks, however, makes conservation measures challenging. Here, we present a fisheries-independent shark survey from the Fiji Islands, where scientific knowledge on locally occurring elasmobranchs is largely still lacking despite the location’s role as a shark hotspot in the Pacific. Juvenile shark abundance in the fishing grounds of the Ba Estuary (north-western Viti Levu) was assessed with a gillnet-and longline-based survey from December 2015 to April 2016. A total of 103 juvenile sharks identified as blacktip Carcharhinus limbatus (n = 57), scalloped hammerhead Sphyrna lewini (n = 35), and great hammerhead Sphyrna mokarran (n = 11) sharks were captured, tagged, and released. The condition of umbilical scars (68% open or semihealed), mean sizes of individuals (±SD) (C. limbatus: 66.5 ± 3.8 cm, S. lewini: 51.8 ± 4.8 cm, S. mokarran 77.4 ± 2.8 cm), and the presence of these species over recent years (based on fishermen interviews), suggest that the Ba Estuary area is a critical habitat for multiple species that are classified as “Near Threatened” or “Endangered.” Specifically, the area likely acts as a parturition ground over the studied period, and potentially as a subsequent nursery area. We identified subareas of high abundance and found that temperature, salinity and depth acted as small-scale environmental drivers of shark abundance. The data suggests a tendency for species-specific spatial use, both horizontally (i.e., between sampling areas) and vertically (i.e., across the water column). These results enhance the understanding of shark ecology in Fiji and provide a scientific basis for the implementation of local conservation strategies that contribute to the protection of these threatened species

Associations Between Maternal Post-traumatic Stress Disorder and Traumatic Events With Child Psychopathology: Results From a Prospective Longitudinal Study.

Introduction: Exposure to interpersonal violence (IPV) can lead to post-traumatic stress disorder (PTSD) in mothers, and in turn adversely affect the mother-child relationship during early development, as well as the mental health of their children. Our objectives are to assess: (1) the association of maternal IPV-PTSD to child psychopathology, (2) the association of maternal IPV independently of PTSD to child psychopathology, and (3) the relationship between child exposure to violence to the psychopathology of these children. Methods: We used data from the longitudinal Geneva Early Childhood Stress Project. The sample included 64 children [mean age at Phase 1 = 2.4 (1.0-3.7) years] of mothers with or without IPV-PTSD. Data on mothers was collected during Phase 1, using the Clinical Administered PTSD Scale (CAPS), the Brief Physical and Sexual Abuse Questionnaire (BPSAQ) and the Conflict Tactics Scale (CTS2). Modules of a semi-structured diagnostic interview, and the Violence Exposure Scale were used to collect information on child at Phase 2, when children were older [mean age = 7.02 (4.7-10)]. Results: A higher CAPS score in mothers when children were toddler-age was associated with an increased risk of symptoms of attention deficit/hyperactivity disorder (ADHD; β = 0.33, p = 0.014) and PTSD in school-age children. The association between maternal IPV-PTSD and child PTSD (β = 0.48, p < 0.001) symptoms remained significant after adjustment for potential confounders. Among children, exposure to violence was associated with an increased risk of symptoms of generalized anxiety (β = 0.37, p = 0.006), major depressive (β = 0.24, p = 0.039), ADHD (β = 0.27, p = 0.040), PTSD (β = 0.52, p < 0.001), conduct (β = 0.58, p = 0.003) and oppositional defiant (β = 0.34, p = 0.032) disorders. Conclusion: Our longitudinal findings suggest that maternal IPV-PTSD during the period of child development exert an influence on the development of psychopathology in school-aged children. Mothers' IPV was associated with child psychopathology, independently of PTSD. Child lifetime exposure to violence had an additional impact on the development of psychopathology. Careful evaluation of maternal life-events is essential during early childhood to reduce the risk for the development of child psychopathology. Early efforts to curb exposure to violence in children and early intervention are both needed to reduce further risk for intergenerational transmission of trauma, violence, and related psychopathology

On the complex and dimensional relationship of maternal PTSD during early childhood and child outcomes at school-age.

Several studies have shown associations between maternal interpersonal violence-related posttraumatic stress disorder (PTSD), child mental health problems, and impaired socioemotional development. However, the existing literature lacks evidence linking constellations of risk factors such as maternal interpersonal-violence-related PTSD, psychopathology, and interactive behavior with toddlers and outcome measures at school-age. This study involved a prospective, longitudinal investigation of 62 mothers and examined the relationship between maternal variables measured when children were in early childhood (mean age 27 months), and child outcomes when children were school-age (age mean = 83.2 months) while retaining a focus on the context of maternal PTSD. To identify and weigh associated dimensions comparatively, we employed sparse canonical correlation analysis (sCCA) aimed at associating dimensions of a dataset of 20 maternal variables in early childhood with that of more than 20 child outcome variables (i.e., child psychopathology, life-events, and socioemotional skills) at school-age. Phase 1 variables with the highest weights were those of maternal psychopathology: PTSD, depressive and dissociative symptoms, and self-report of parental stress. The highest weighted Phase 2 child outcome measures were those of child psychopathology: PTSD, anxiety, and depressive symptoms as well as peer bullying and victimization. sCCA revealed that trauma-related concepts in mothers were significantly and reliably associated with child psychopathology and other indicators of risk for intergenerational transmission of violence and victimization. The results highlight the dimensional and multifaceted nature-both for mothers as well as children-of the intergenerational transmission of violence and associated psychopathology