FDA experiences with a centralized statistical monitoring tool.

The U.S. Food and Drug Administration (FDA) has broadly supported quality by design initiatives for clinical trials - including monitoring and data validation - by releasing two related guidance documents (FDA 2013 and 2019). Centralized statistical monitoring (CSM) can be a component of a quality by design process. In this article, we describe our experience with a CSM platform as part of a Cooperative Research and Development Agreement between CluePoints and FDA. This agreement's approach to CSM is based on many statistical tests performed on all relevant subject-level data submitted to identify outlying sites. An overall data inconsistency score is calculated to assess the inconsistency of data from one site compared to data from all sites. Sites are ranked by the data inconsistency score (-log10p,where p is an aggregated p-value). Results from a deidentified trial demonstrate the typical data anomaly findings through Statistical Monitoring Applied to Research Trials analyses. Sensitivity analyses were performed after excluding laboratory data and questionnaire data. Graphics from deidentified subject-level trial data illustrate abnormal data patterns. The analyses were performed by site, country/region, and patient separately. Key risk indicator analyses were conducted for the selected endpoints. Potential data anomalies and their possible causes are discussed. This data-driven approach can be effective and efficient in selecting sites that exhibit data anomalies and provides insights to statistical reviewers for conducting sensitivity analyses, subgroup analyses, and site by treatment effect explorations. Messy data, data failing to conform to standards, and other disruptions (e.g. the COVID-19 pandemic) can pose challenges.

Response of lion demography and dynamics to the loss of preferred larger prey.

Large carnivores are experiencing range contraction and population declines globally. Prey depletion due to illegal offtake is considered a major contributor, but the effects of prey depletion on large carnivore demography are rarely tested. We measured African lion density and tested the factors that affect survival using mark-recapture models fit to six years of data from known individuals in Kafue National Park (KNP), Zambia. KNP is affected by prey depletion, particularly for large herbivores that were preferred prey for KNP lions a half-century ago. This provides a unique opportunity to test whether variables that explain local prey density also affect lion survival. Average lion density within our study area was 3.43 individuals/100 km2 (95% CI, 2.79-4.23), which was much lower than lion density reported for another miombo ecosystem with similar vegetation structure and rainfall that was less affected by prey depletion. Despite this, comparison to other lion populations showed that age- and sex-specific survival rates for KNP lions were generally good, and factors known to correlate with local prey density had small effects on lion survival. In contrast, recruitment of cubs was poor and average pride size was small. In particular, the proportion of the population comprised of second-year cubs was low, indicating that few cubs are recruited into the subadult age class. Our findings suggest that low recruitment might be a better signal of low prey density than survival. Thus, describing a lion population's age structure in addition to average pride size may be a simple and effective method of initially evaluating whether a lion population is affected by prey depletion. These dynamics should be evaluated for other lion populations and other large carnivore species. Increased resource protection and reducing the underlying drivers of prey depletion are urgent conservation needs for lions and other large carnivores as their conservation is increasingly threatened by range contraction and population declines.

Do protection gradients explain patterns in herbivore densities? An example with ungulates in Zambia's Luangwa Valley.

Ungulate populations face declines across the globe, and populations are commonly conserved by using protected areas. However, assessing the effectiveness of protected areas in conserving ungulate populations has remained difficult. Using herd size data from four years of line transect surveys and distance sampling models, we modeled population densities of four important herbivore species across a gradient of protection on the edge of Zambia's South Luangwa National Park (SLNP) while accounting for the role of various ecological and anthropogenic variables. Our goal was to test whether protection was responsible for density dynamics in this protection gradient, and whether a hunting moratorium impacted herbivore densities during the studies. For all four species, we estimated lower densities in partially protected buffer areas adjacent to SLNP (ranging from 4.5-fold to 13.2-fold lower) compared to protected parklands. Density trends through the study period were species-specific, with some species increasing, decreasing, or remaining stable in all or some regions of the protection gradient. Surprisingly, when controlling for other covariates, we found that these observed differences were not always detectably related to the level of protection or year. Our findings highlight the importance of accounting for variables beyond strata of interest in evaluating the effectiveness of a protected area. This study highlights the importance of comprehensively modeling ungulate population density across protection gradients, identifies lands within an important protection gradient for targeted conservation and monitoring, documents prey depletion and expands our understanding on the drivers in a critical buffer area in Zambia.

Comparing methods for clinical investigator site inspection selection: a comparison of site selection methods of investigators in clinical trials.

Background During the past two decades, the number and complexity of clinical trials have risen dramatically increasing the difficulty of choosing sites for inspection. FDA's resources are limited and so sites should be chosen with care. Purpose To determine if data mining techniques and/or unsupervised statistical monitoring can assist with the process of identifying potential clinical sites for inspection. Methods Five summary-level clinical site datasets from four new drug applications (NDA) and one biologics license application (BLA), where the FDA had performed or had planned site inspections, were used. The number of sites inspected and the results of the inspections were blinded to the researchers. Five supervised learning models from the previous two years (2016-2017) of an on-going research project were used to predict site inspections results, i.e., No Action Indicated (NAI), Voluntary Action Indicated (VAI), or Official Action Indicated (OAI). Statistical Monitoring Applied to Research Trials (SMARTTM) software for unsupervised statistical monitoring software developed by CluePoints (Mont-Saint-Guibert, Belgium) was utilized to identify atypical centers (via a p-value approach) within a study.Finally, Clinical Investigator Site Selection Tool (CISST), developed by the Center for Drug Evaluation and Research (CDER), was used to calculate the total risk of each site thereby providing a framework for site selection. The agreement between the predictions of these methods was compared. The overall accuracy and sensitivity of the methods were graphically compared. Results Spearman's rank order correlation was used to examine the agreement between the SMARTTM analysis (CluePoints' software) and the CISST analysis. The average aggregated correlation between the p-values (SMARTTM) and total risk scores (CISST) for all five studies was 0.21, and range from -0.41 to 0.50. The Random Forest models for 2016 and 2017 showed the highest aggregated mean agreement (65.1%) amongst outcomes (NAI, VAI, OAI) for the three available studies. While there does not appear to be a single most accurate approach, the performance of methods under certain circumstances is discussed later in this paper. Limitations Classifier models based on data mining techniques require historical data (i.e., training data) to develop the model. There is a possibility that sites in the five-summary level datasets were included in the training datasets for the models from the previous year's research which could result in spurious confirmation of predictive ability. Additionally, the CISST was utilized in three of the five site selection processes, possibly biasing the data. Conclusion The agreement between methods was lower than expected and no single method emerged as the most accurate.

A Comparison of Pediatric and Adult Safety Studies for Antipsychotic and Antidepressant Drugs Submitted to the United States Food and Drug Administration.

OBJECTIVE: To examine the differences in the adverse drug reaction (ADR) profile of antipsychotic and antidepressant agents between pediatric and adult patients in studies submitted to the Food and Drug Administration (FDA) during the drug development process. STUDY DESIGN: Clinical trials in adult and pediatric patients were conducted by sponsors as part of the drug development programs for antipsychotic and antidepressant agents, and ADR information was collected as part of those trials and submitted to the FDA. Data collection was conducted by reviewing publicly available FDA-authored reviews and FDA-approved product labels for 10 drugs with an antipsychotic or an antidepressant indication from 2007 to 2017. RESULTS: There were 308 drug and ADR combinations for the 10 drugs and drug combinations with 113 (36.7%) having a significantly different incidence in pediatric patients compared with adults. Sixty-eight (60.2%) of these ADRs had a significantly higher incidence in pediatric patients than in adults. Sedation was higher in 6 of the 10 drugs and drug combinations with risk differences ranging from 9.6 to 36.6%. CONCLUSIONS: This analysis indicates that there were significant differences between the pediatric and adult safety profiles of antipsychotic and antidepressant drugs. Sedation was the major ADR associated with the use of atypical antipsychotic drugs in pediatric patients. Clinicians caring for children should consider the ADR profile when prescribing antipsychotics and antidepressants in pediatric patients.

Foraging investment in a long-lived herbivore and vulnerability to coursing and stalking predators.

Allocating resources to growth and reproduction requires grazers to invest time in foraging, but foraging promotes dental senescence and constrains expression of proactive antipredator behaviors such as vigilance. We explored the relationship between carnivore prey selection and prey foraging effort using incisors collected from the kills of coursing and stalking carnivores. We predicted that prey investing less effort in foraging would be killed more frequently by coursers, predators that often exploit physical deficiencies. However, such prey could expect delayed dental senescence. We predicted that individuals investing more effort in foraging would be killed more frequently by stalkers, predators that often exploit behavioral vulnerabilities. Further these prey could expect earlier dental senescence. We tested these predictions by comparing variation in age-corrected tooth wear, a proxy of cumulative foraging effort, in adult (3.4-11.9 years) wildebeest killed by coursing and stalking carnivores. Predator type was a strong predictor of age-corrected tooth wear within each gender. We found greater foraging effort and earlier expected dental senescence, equivalent to 2.6 additional years of foraging, in female wildebeest killed by stalkers than in females killed by coursers. However, male wildebeest showed the opposite pattern with the equivalent of 2.4 years of additional tooth wear in males killed by coursers as compared to those killed by stalkers. Sex-specific variation in the effects of foraging effort on vulnerability was unexpected and suggests that behavioral and physical aspects of vulnerability may not be subject to the same selective pressures across genders in multipredator landscapes.

Primary Endpoints in Pediatric Efficacy Trials Submitted to the US FDA.

The selection of appropriate endpoints in pediatric drug development trials is a critical aspect of trial design. Given the high pediatric trial failure rate, selecting optimal trial design elements, such as the primary efficacy endpoint, is essential to ensuring increased potential for trial success. The objectives of this study were to identify the primary efficacy endpoints measured in pediatric drug development trials submitted to the US Food and Drug Administration and to relate endpoint attributes to trial and label outcome. The analysis included pediatric pivotal efficacy studies submitted from September 2007 to July 2016 for which there was a corresponding adult trial for the same indication. Two hundred and thirty-four efficacy trials on 138 unique products studied in pediatric patients were assessed. The adult and pediatric endpoints were the same in 141 of the 234 trials (60.3%), and these trials succeeded in meeting their primary endpoint more often (122 of 141 [86.5%]) than when the adult and pediatric endpoints differed (57 of 93 [61.3%]; odds ratio, 4.03; 95%CI, 2.10-7.80). Trials that included both pediatric and adult patients succeeded more frequently than those trials that did not combine pediatric and adult patients (85 of 95 versus 94 of 139, respectively; odds ratio, 4.05; 95%CI, 1.94-9.31). No differences were observed in pediatric trial success between those using subjective and objective endpoints. Using the same endpoint in the pediatric trial as was measured in the corresponding adult trial and enrolling pediatric and adult patients in the same trial were attributes associated with trial success.

The relationship between direct predation and antipredator responses: a test with multiple predators and multiple prey.

Most species adjust their behavior to reduce the likelihood of predation. Many experiments have shown that antipredator responses carry energetic costs that can affect growth, survival, and reproduction, so that the total cost of predation depends on a trade-off between direct predation and risk effects. Despite these patterns, few field studies have examined the relationship between direct predation and the strength of antipredator responses, particularly for complete guilds of predators and prey. We used scan sampling in 344 observation periods over a four-year field study to examine behavioral responses to the immediate presence of predators for a complete antelope guild (dominated by wildebeest, zebra, and oribi) in Liuwa Plains National Park, Zambia, testing for differences in response to all large carnivores in the ecosystem (lions, spotted hyenas, cheetahs, and African wild dogs). We quantified the proportion that each prey species contributed to the kills made by each predator (516 total kills), used distance sampling on systematic line transects to determine the abundance of each prey species, and combined these data to quantify the per-capita risk of direct predation for each predator-prey pair. On average, antelopes increased their vigilance by a factor of 2.4 when predators were present. Vigilance varied strongly among prey species, but weakly in response to different predators. Increased vigilance was correlated with reduced foraging in a similar manner for all prey species. The strength of antipredator response was not detectably related to patterns of direct predation (n = 15 predator-prey combinations with sufficient data). This lack of correlation has implications for our understanding of the role of risk effects as part of the limiting effect of predators on prey.

Effects of a protection gradient on carnivore density and survival: an example with leopards in the Luangwa valley, Zambia.

Human activities on the periphery of protected areas can limit carnivore populations, but measurements of the strength of such effects are limited, largely due to difficulties of obtaining precise data on population density and survival. We measured how density and survival rates of a previously unstudied leopard population varied across a gradient of protection and evaluated which anthropogenic activities accounted for observed patterns. Insights into this generalist's response to human encroachment are likely to identify limiting factors for other sympatric carnivore species. Motion-sensitive cameras were deployed systematically in adjacent, similarly sized, and ecologically similar study areas inside and outside Zambia's South Luangwa National Park (SLNP) from 2012 to 2014. The sites differed primarily in the degree of human impacts: SLNP is strictly protected, but the adjacent area was subject to human encroachment and bushmeat poaching throughout the study, and trophy hunting of leopards prior to 2012. We used photographic capture histories with robust design capture-recapture models to estimate population size and sex-specific survival rates for the two areas. Leopard density within SLNP was 67% greater than in the adjacent area, but annual survival rates and sex ratios did not detectably differ between the sites. Prior research indicated that wire-snare occurrence was 5.2 times greater in the areas adjacent to the park. These results suggest that the low density of leopards on the periphery of SLNP is better explained by prey depletion, rather than by direct anthropogenic mortality. Long-term spatial data from concurrent lion studies suggested that interspecific competition did not produce the observed patterns. Large carnivore populations are often limited by human activities, but science-based management policies depend on methods to rigorously and quantitatively assess threats to populations of concern. Using noninvasive robust design capture-recapture methods, we systematically assessed leopard density and survival across a protection gradient and identified bushmeat poaching as the likely limiting factor. This approach is of broad value to evaluate the impacts of anthropogenic activities on carnivore populations that are distributed across gradients of protection.

Adverse Event Detection and Labeling in Pediatric Drug Development: Antiretroviral Drugs.

BACKGROUND: Pediatric safety studies are conducted for drugs undergoing development for use in pediatric patients. The objective of this study was to describe safety studies and compare adverse events of antiretroviral drugs between pediatric patients and adult subjects. METHODS: Pediatric and adult adverse event data were obtained from US Food and Drug Administration (FDA)-approved drug labels for 9 antiretroviral drugs with pediatric indications approved by the FDA prior to 2013. For adverse events (AEs) reported in both pediatric patients and adult subjects, the risk difference (RD) and associated confidence interval (CI) were calculated. RESULTS: Of 35 drug-AE combinations, 10 AEs were reported at statistically significantly ( P < .05) higher incidence rates in the pediatric population than in the adult population, and 3 AEs were reported at statistically significantly higher rates in the adult population than in the pediatric population. The largest differences where the risk of an AE was greater in pediatric patients than in adult subjects were for rash with efavirenz (RD = 36.24% [95% CI, 21.1 to 50.53]), diarrhea with efavirenz (RD = 24.53% [95% CI, 9.06 to 39.57]), and rash with nevirapine (RD = 16.14% [95% CI, 9.7 to 24.27]). The largest differences where the risk of an adverse event was lower in pediatric patients than in adult subjects were for headache with abacavir (RD = -12% [95% CI, -16.81 to -6.89]), diarrhea with tipranavir (RD = -11.32% [95% CI, -15.02 to -5.6]), and diarrhea with lamivudine (RD = -9.88% [95% CI, -15.91 to -3.98]). CONCLUSIONS: The adult adverse event experience provides preliminary data for pediatric drug safety, yet the specific types of adverse effects and frequencies may not be predicted in children based exclusively on adults. As adult safety data do not fully inform the pediatric safety profile, pediatric safety studies should continue to be conducted separately for drugs undergoing testing in pediatric patients.

Glucocorticoid stress responses of lions in relationship to group composition, human land use, and proximity to people.

Large carnivore populations are in global decline, and conflicts between large carnivores and humans or their livestock contribute to low tolerance of large carnivores outside of protected areas. African lions (Panthera leo) are a conflict-prone species, and their continental range has declined by 75% in the face of human pressures. Nonetheless, large carnivore populations persist (or even grow) in some areas that are occupied by humans. Lions attain locally high density in the Olkiramatian and Shompole Group Ranches of Kenya's South Rift region, despite residence by pastoralist Maasai people and their sheep, goats, and cattle. We have previously found that these lions respond to seasonal movements of people by moving away from occupied settlements, shifting into denser habitats when people are nearby, and moving into a protected conservation area when people move into the adjacent buffer zone. Here, we examined lion stress responses to anthropogenic activities, using enzyme-linked immunoassay to measure the concentration of faecal glucocorticoid metabolites in 136 samples collected from five lion groups over 2 years. Faecal glucocorticoid metabolite concentrations were significantly lower for lions in the conservation area than for lions in the human-settled buffer zone, and decreased significantly with increasing distance to the nearest occupied human settlement. Faecal glucocorticoid metabolite concentrations were not detectably related to fine-scaled variation in prey or livestock density, and surprisingly, faecal glucocorticoid metabolite concentrations were higher in the wet season, when regional prey abundance was high. Lions coexist with people and livestock on this landscape by adjusting their movements, but they nonetheless mount an appreciable stress response when conditions do not allow them to maintain adequate separation. Thus, physiological data confirm inferences from prior data on lion movements and habitat use, showing that access to undisturbed and protected areas facilitates human-lion coexistence in a broader landscape that is used by people and livestock.