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Breast cancer is one of the tumors with the highest prevalence rate among women in the world, and its BRCA1/2 gene is a common mutation site. Talazoparib, as a targeted PARP inhibitor, can effectively control the occurrence and development of breast cancer with BRCA1/2 gene mutation, and play a therapeutic role. Based on the findings from the Phase III EMBRACE trial (NCT01945775 clinical trial), our analysis reveals that the talazoparib group demonstrated a significant extension in progression-free survival, along with improved response markers and patient-reported outcomes when compared to conventional therapies. This study aims to assess the cost-effectiveness of talazoparib for treating advanced breast cancer with germline BRCA1/2 mutations and HER2 negativity, considering the perspectives of health services in China and the United States. The results obtained will serve as a valuable reference for promoting rational drug utilization and enhancing medical resource efficiency. To evaluate the cost-effectiveness of Talazoparib more scientifically and provide clinicians with chemotherapy options, this paper developed a Markov model based on the EMBRACA clinical trial (clinical Trails.gov No., NCT01945775) to simulate the survival events of breast cancer patients in the Talazoparib group and the standard treatment group. The state transition probability and clinical data of breast cancer patients during treatment were extracted from the phase III EMBRACA clinical trial. The cost data generated during the treatment process comes from local hospital pricing, other references, and expert consultation. This article uses US dollars to calculate the treatment cost and incremental cost-effectiveness ratio. Health outcomes are expressed in Quality Adjusted Life Years (QALYs). In addition, Outcomes were measured in quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio, which robustness was evaluated by deterministic and probabilistic sensitivity analyses. This article establishes a Markov model for single-item sensitivity analysis. The results show that the economic benefits of using Talazoparib as a new treatment strategy in both China and the United States are higher than other drugs, and it is cost-effective. Compared to the control group, the incremental cost incurred by the Talazoparib treatment group in China was $2484.48/QALY, with an incremental QALY of 1.5. However, Talazoparib in the United States holds a dominant position, saving costs of $10,223.43 and increasing QALYs by 1.5. The clinical treatment effect of Talazoparib group in BRCA1/2 mutant advanced breast cancer patients is better than that of the standard treatment group, and the progression free survival period is significantly prolonged. From the perspective of medical and health services in China and the United States, the Talazoparib group is more economical than the standard treatment group in treating patients with BRCA1/2 mutant advanced breast cancer. [ABSTRACT FROM AUTHOR]

The ICH E17 guidelines (2014–2017) on Multiregional Clinical Trials (MRCT) was a joint effort by the regulators and industry to facilitate simultaneous global drug development and registration through taking a strategic approach for clinical trials. In other words, the objective was to reduce the time it takes to bringing medications to patients around the world through minimizing unnecessary duplication of local or regional studies, which may add the regulatory burden to cost and time of bringing new therapies to patients. Under the auspices of ICH, training materials were created and provided to various stakeholders. Despite the successful promotion of the benefits of ICH E17 MRCT guidelines across the different regions, the uptake of some concepts (e.g., pooling strategy) in the ICH E17 guidelines has been slow. This paper describes various factors which could affect the conduct of MRCT at a global level, including ambiguity in definition of "region" (in MRCT), new regulatory requirements to enroll a diverse patient population, the use of decentralized clinical trials, use of data sources other than randomized clinical trials (e.g., use of Real Word Data), and the impact of the COVID-19 pandemic on the conduct of MRCT. [ABSTRACT FROM AUTHOR]

Use of robust, quantitative tools to measure patient perspectives within product development and regulatory review processes offers the opportunity for medical device researchers, regulators, and other stakeholders to evaluate what matters most to patients and support the development of products that can best meet patient needs. The medical device innovation consortium (MDIC) undertook a series of projects, including multiple case studies and expert consultations, to identify approaches for utilizing patient preference information (PPI) to inform clinical trial design in the US regulatory context. Based on these activities, this paper offers a cogent review of considerations and opportunities for researchers seeking to leverage PPI within their clinical trial development programs and highlights future directions to enhance this field. This paper also discusses various approaches for maximizing stakeholder engagement in the process of incorporating PPI into the study design, including identifying novel endpoints and statistical considerations, crosswalking between attributes and endpoints, and applying findings to the population under study. These strategies can help researchers ensure that clinical trials are designed to generate evidence that is useful to decision makers and captures what matters most to patients. [ABSTRACT FROM AUTHOR]

The aim of the present study was to perform a critical reflection about intervention options for bruxism reduction in children and adolescents. Search was conducted based on the PICO-structured question: "What are the intervention options to reduce bruxism in children/adolescents?". No language, year, or study design restrictions were imposed. Studies reporting interventions to reduce bruxism in children (< 10) and adolescents (10 to 19 years old) were included. Reviews and letters to editors were not included. From 2723 records, 17 papers were included. Included studies were primarily randomized clinical trials performed in Brazil (35.3%) and using different criteria for the diagnosis of bruxism. Reduction in self-reported bruxism and headaches associated with bruxism were observed in studies that used medications (hydroxyzine/trazodone/flurazepam), occlusal splints, orthodontic interventions, and psychological and physical therapy interventions. Reduction in Rhythmic Masticatory Muscle Activity was observed with the use of the occlusal splint and in orthodontic interventions. Alternative treatments (medicinal extracts such as Melissa officinalis-L) have shown inconclusive results.Conclusions: Several intervention options are available to inhibit or reduce bruxism activity. The respective indication, contraindications, and side effects of each treatment option must be assessed individually and carefully, taking into account that bruxism is not considered a disorder in otherwise healthy individuals.What is known• Biological and psychological factors have been strongly correlated to the development of bruxism• Bruxism prevalence ranging from 6 to 50% in childrenWhat is new• Reduction in self-reported bruxism and headaches associated with bruxism were observed in studies that used medication (Hydroxyzine/ Trazodone/ Flurazepam), occlusal splints, orthodontic interventions, psychological, and physical therapy interventions• A reduction in Rhythmic Masticatory Muscle Activity was observed with the use of the occlusal splint and orthodontic interventions. Alternative treatments (medicinal extracts such as Melissa officinalis L) show inconclusive results in respect of the reduction in bruxism. [ABSTRACT FROM AUTHOR]

Background: Digital health technologies (DHTs) can facilitate the execution of de-centralized trials that can offer opportunities to reduce the burden on participants, collect outcome data in a real-world setting, and potentially make trial populations more diverse and inclusive. However, DHTs can also be a significant source of electronic waste (e-waste). In recognition of the potential health and environmental impact from DHT use in trials, private and public institutions have recently launched initiatives to help measure and manage this e-waste. But in order to develop sound e-waste management policies, it will be necessary to first estimate the current volume of e-waste that results from the use of DHTs in trials. Materials and Methods: A Web Ontology Language (OWL)-compliant ontology of DHTs was created using a list of 500 DHT device names derived from a mixture of public and private sources. The U.S. clinical trials registry, ClinicalTrials.gov, was then queried to identify and classify trials using any of the devices in the ontology. The ClinicalTrials.gov records from this search were then analyzed to characterize the volume and properties of trials using DHTs, as well as estimating the total volume of individual DHT units that have been provisioned (or are planned to be provisioned) for clinical research. Results: Our ontology-driven search identified 2326 unique clinical trials with a reported "actual" enrollment of 200,947 participants and a "planned" enrollment of an additional 4,094,748 participants. The most-used class of DHTs in our ontology was "wearables," (1852 trials), largely driven by the use of smart watches and other wrist-worn sensors (estimated to involve 149,391 provisioned devices). The most-used subtype of DHTs in trials was "subcutaneous" devices (367 trials), driven by the prevalent use and testing of glucose monitors (estimated to involve 17,666 provisioned devices). Conclusion: Thousands of trials, involving hundreds of thousands of devices, have already been completed, and many more trials (potentially involving millions more devices) are planned. Despite the great opportunities that are afforded by DHTs to the clinical trial enterprise, if the industry lacks the ability to track DHT use with sufficient resolution, the result is likely to be a great deal of e-waste. A new ontology of DHTs, combined with rigorous data science methods like those described in this paper, can be used to provide better information across the industry, and in turn, help create a more sustainable and equitable clinical trials enterprise. [ABSTRACT FROM AUTHOR]

An increase in the number of identified therapeutic cancer targets achieved through recent biomedical research has resulted in the generation of a large number of molecules that need to be tested further. Current development of (anticancer) drugs is a rather inefficient process that for an average new molecule takes around 10–15 years. It is also a challenging process as it is associated with high costs and a low rate of approval. It is known that less than 10% of new molecular entities entering clinical Phase I testing progress beyond the investigational programme and reach the market; this probability is even lower for anticancer agents. In 2003, the US Food and Drug Administration (US FDA) declared the urgent need for new toolkits to improve the critical development path that leads from scientific discovery to the patient. In this scenario, Phase 0 (zero) trials should allow an early evaluation in humans of pharmacokinetic and pharmacodynamic profiles of test compounds through administration of sub-pharmacological doses and for a short time period to a low number of humans. Typically, Phase 0 studies have no therapeutic or diagnostic intent. Owing to the low doses administered and the low risk of toxicity, shorter preclinical packages to support these studies are required. Phase 0 trials have been proposed to help in making an early selection of promising candidates for further evaluation in Phase I–III trials, providing a potentially useful instrument for drug discovery, particularly in the field of oncology. Phase 0 studies are expected to reduce costs of drug development, and to limit the preclinical in vitro and in vivo testing and the time period of drug development. However, there are also concerns about the utility and feasibility of Phase 0 studies. In January 2006, guidelines on exploratory investigational new drug studies in humans have been published by the US FDA, and currently a Phase 0 programme is ongoing at the National Cancer Institute to evaluate the impact (feasibility and utility) of Phase 0 studies on drug development. In Europe, a Position Paper produced by the Evaluation of Medicinal Products (EMEA) in 2004 raised the possibility of a reduced preclinical safety package to support early microdose clinical studies, and, as announced by a recent Concept Paper on medicinal products published by the committee for medicinal products for human use of the EMEA, EMEA's guidelines on Phase 0 studies are expected shortly. The true impact of Phase 0 studies on the drug development process as well as on the safety needs to be carefully explored.British Journal of Cancer (2007) 97, 577–581. doi:10.1038/sj.bjc.6603925 www.bjcancer.com Published online 28 August 2007 [ABSTRACT FROM AUTHOR]

An important health policy issue is the low rate of patient enrollment into clinical trials, which may slow down the process of clinical trials and discourage their supply, leading to delays in innovative life-saving drug treatments reaching the general population. In the US, patients' cost of participating in a clinical trial is considered to be a major barrier to patient enrollment. In order to reduce this barrier, some states in the US have implemented policies requiring health insurers to cover routine care costs for patients enrolled in clinical trials. This paper evaluates empirically how effective these policies were in increasing the supply of clinical trials and speeding up their completion, using data on cancer clinical trials initiated in the US between 2001 and 2007. Our analysis indicates that the policies did not lead to an increased supply in the number of clinical trials conducted in mandate states compared to non-mandate states. However, we find some evidence that once clinical trials are initiated, they are more likely to finish their patient recruitment in a timely manner in mandate states than in non-mandate states. As a result, the overall length to completion was significantly shorter in mandate states than in non-mandate states for cancer clinical trials in certain phases. The findings hint at the possibility that these policies might encourage drug innovation in the long run. [ABSTRACT FROM AUTHOR]

Childhood psychological morbidity places both short-term and long-term costs on families, health services, social services, voluntary organizations, and society as a whole. Internationally, there have been few economic evaluations alongside clinical trials of population-based interventions to improve child mental well-being. This paper sets out a number of trade-offs relevant to the evaluation of the costs and benefits of multisectoral interventions to improve child mental well-being. These trade-offs have relevance for those who fund research, those who conduct research, and those who make policy decisions. The paper sets out a conceptual model for the economic evaluation of population-based interventions to improve child mental health. Finally, the paper argues that with the advent of “joined up” public policy and the breakdown of traditional ring-fenced budgets for health and social care, there is now, more than ever before, an opportunity for the research community to generate guidance for multisectoral collaborative interventions to promote the mental well-being of children and their families. [ABSTRACT FROM AUTHOR]

This paper presents empirical data on motivation to join an HIV prevention trial of vaginal microbicide gels in Malawi and Zimbabwe, and participant assumption of a preventive misconception. Interviews were conducted with women participating in the trial and their male partners. Most of the female participants were able to adequately describe basic aspects of the trial design. HIV counseling and testing were primary reasons motivating women's participation, and male partners' support of the trial. 29% of women and 20% of men also provided indications of a preventive misconception, attributing gel use and trial participation to avoiding HIV infection. [ABSTRACT FROM AUTHOR]

Objectives: The objective of this paper was to describe primary care prescribers' perspectives on electronic prescribing drug alerts at the point of prescribing.Design: We used a mixed-method study which included clinician surveys (web-based and paper) and focus groups with prescribers and staff.Participants: Prescribers (n = 157) working in one of 64 practices using 1 of 6 e-prescribing technologies in 6 US states completed the quantitative survey and 276 prescribers and staff participated in focus groups.Measurements: The study measures self-reported frequency of overriding of drug alerts; open-ended responses to: "What do you think of the drug alerts your software generates for you?"Results: More than 40% of prescribers indicated they override drug-drug interactions most of the time or always (range by e-prescribing system, 25% to 50%). Participants indicated that the software and the interaction alerts were beneficial to patient safety and valued seeing drug-drug interactions for medications prescribed by others. However, they noted that alerts are too sensitive and often unnecessary. Participant suggestions included: (1) run drug alerts on an active medication list and (2) allow prescribers to set the threshold for severity of alerts.Conclusions: Primary care prescribers recognize the patient safety value of drug prescribing alerts embedded within electronic prescribing software. Improvements to increase specificity and reduce alert overload are needed. [ABSTRACT FROM AUTHOR]

Perinatal depression is a serious public health issue among African American adolescents who experience significant racial health disparities in addition to age-related mental and physical health risks. Perinatal depression prevention interventions that specifically target the needs of African American adolescents are warranted. The current study presents the development and preliminary results of an intervention designed to prevent perinatal depression among African American adolescents using the heuristic framework for cultural adaptations. Adaptations were applied to an existing evidence-based cognitive behavioral group intervention to develop the Mothers and Babies Course for African American Adolescents. Adaptations were guided by qualitative data collected from a focus group and individual interviews, and by existing research on specific risk and protective factors that drive engagement with and barriers to interventions for this population. The adapted intervention was piloted with 7 pregnant and 21 postpartum African American adolescent students at four different public high schools in an urban city in the United States. The Edinburgh Postnatal Depression Scale was used to assess pre- and post-intervention perinatal depression scores. Accessibility and feasibility were assessed using participant and observer evaluations, respectively. Results indicated reductions in pre- to post-intervention depression scores and high acceptability and feasibility of the pilot study. Additional adaptations of the intervention based on qualitative feedback from study participants are discussed. Future development and implementation of the intervention provides an opportunity to reduce a mental health disparity that disproportionately affects African American adolescents. Highlights: Perinatal depression is a serious public health issue among African American adolescents who experience significant racial health disparities in addition to age-related mental and physical health risks. Introduces adaptation methods and results of an intervention pilot-study designed to prevent perinatal depression among African American adolescents. The intervention was adapted from an existing evidence-based perinatal depression prevention intervention using the heuristic framework for cultural adaptations. [ABSTRACT FROM AUTHOR]

Background: Placebo-controlled trials are the most rigorous method of evaluating the safety and efficacy of investigational treatments, yet the use of a placebo control in pediatric drug development is challenging and potentially controversial. Regulations provide additional protections for children participating in human subject research and limit the amount of risk to which children may be exposed without benefit (21 CFR 50, subpart D, Additional Safeguards for Children in Clinical Investigations). The objective of this paper is to describe the US Food and Drug Administration (FDA) experience with placebo-controlled trials conducted as part of pediatric drug development programs including compliance with 21 CFR 50, subpart D. Methods: Pediatric drug development programs conducted under the Best Pharmaceuticals for Children Act (BPCA) or the Pediatric Research Equity Act (PREA) between 2012 and 2018 were reviewed. Trials that utilized a placebo control were identified and trial characteristics and risk mitigation strategies were extracted from publicly available sources. Results: During this time frame, a total of 266 products were studied under pediatric product development initiatives. Of those, 67 products (25%) were studied in 96 individual placebo-controlled trials in pediatric patients. The majority of these studies included approaches to minimize risk to children in the placebo arm, including 49 trials that utilized placebo as an add-on to known effective therapy for the disease and 48 trials that included rescue therapy in the study protocol. Conclusions: When designed and conducted appropriately, placebo-controlled trials meet requirements under current US federal regulations for the protection of children in research. [ABSTRACT FROM AUTHOR]

The After Breast Cancer Pooling Project was established to examine the role of physical activity, adiposity, dietary factors, supplement use, and quality of life (QOL) in breast cancer prognosis. This paper presents pooled and harmonized data on post-diagnosis lifestyle factors, clinical prognostic factors, and breast cancer outcomes from four prospective cohorts of breast cancer survivors (three US-based and one from Shanghai, China) for 18,314 invasive breast cancer cases diagnosed between 1976 and 2006. Most participants were diagnosed with stage I-II breast cancer (84.7%). About 60% of breast tumors were estrogen receptor (ER)+/progesterone receptor (PR)+; 21% were ER-/PR-. Among 8,118 participants with information on HER-2 tumor status, 74.8% were HER-2- and 18.5% were HER-2+. At 1-2 years post-diagnosis (on average), 17.9% of participants were obese (BMI ≥ 30 kg/m2), 32.6% were overweight (BMI 25-29 kg/m2), and 59.9% met the 2008 Physical Activity Guidelines for Americans (≥ 2.5 h per week of moderate activity). During follow-up (mean = 8.4 years), 3,736 deaths (2,614 from breast cancer) and 3,564 recurrences have been documented. After accounting for differences in year of diagnosis and timing of post-diagnosis enrollment, five-year overall survival estimates were similar across cohorts. This pooling project of 18,000 breast cancer survivors enables the evaluation of associations of post-diagnosis lifestyle factors, QOL, and breast cancer outcomes with an adequate sample size for investigation of heterogeneity by hormone receptor status and other clinical predictors. The project sets the stage for international collaborations for the investigation of modifiable predictors for breast cancer outcomes. [ABSTRACT FROM AUTHOR]

ording to the American Cancer Society, colorectal cancer (CRC) is the third most common cause of cancer related deaths in the United States. Experts estimate that about 85% of CRCs begin as precancerous polyps, early detection and treatment of which can significantly reduce the risk of CRC. Hence, it is imperative to develop population-wide intervention strategies for early detection of polyps. Development of such strategies requires precise values of population-specific rates of incidence of polyp and its progression to cancerous stage. There has been a considerable amount of research in recent years on developing screening based CRC intervention strategies. However, these are not supported by population-specific mathematical estimates of progression rates. This paper addresses this need by developing a probability model that estimates polyp progression rates considering race and family history of CRC; note that, it is ethically infeasible to obtain polyp progression rates through clinical trials. We use the estimated rates to simulate the progression of polyps in the population of the State of Indiana, and also the population of a clinical trial conducted in the State of Minnesota, which was obtained from literature. The results from the simulations are used to validate the probability model. [ABSTRACT FROM AUTHOR]

Immune tolerance-inducing therapies reprogramme immune cells to eliminate pathogenic immune responses while preserving protective immunity. The Immune Tolerance Network (ITN), sponsored by the US National Institutes of Health, was established in 1999 to evaluate new tolerance-inducing therapies and carry out mechanistic studies using a unique interactive approach in partnership with industry, academia and foundations. Ten years later, the ITN has carried out approximately 36 clinical trials and tolerance studies examining innovative tolerogenic approaches in the settings of allergy, autoimmune diseases and organ transplantation. ITN investigators have published more than 80 original research papers based on this work. This Timeline article summarizes the progress and challenges of clinical research in the ITN. [ABSTRACT FROM AUTHOR]

This paper reports baseline behavioral and biological data collected from a cohort of 535 African American HIV serodiscordant couples enrolled in the Eban study across four urban metro areas. Data were collected on (1) the prevalence of risky sexual behaviors that occur within a couple and with concurrent sexual partners, (2) the STD prevalence for each member of the couple and (3) the correlates of STDs in the male partner as well as in the female partner. Presentation of the sociodemographic characterization and HIV risk behavior profiles of African American HIV serodiscordant couples represents an important initial description of a hidden, vulnerable population. Future research should be conducted with diverse samples of African American couples (i.e., younger couples, non-stable couples) to explore other potential correlates of STD prevalence. [ABSTRACT FROM AUTHOR]

Data and safety monitoring boards (DSMBs) provide independent oversight to bio-medical clinical trials, ensuring safe and ethical treatment of research participants, data quality, and credibility of study findings. Recently, the type of research monitored by DSMBs has been expanded to include randomized clinical trials of behavioral and psychosocial interventions in community and justice based settings. This paper focuses on the development and role of a DSMB created by the National Institute on Drug Abuse (NIDA) to monitor six multi-site clinical trials conducted within the Criminal Justice–Drug Abuse Treatment Studies (CJ-DATS). We believe this is one of the first such applications of formal DSMBs in justice settings. Special attention is given to developing processes for measuring and monitoring a range of implementation issues for research conducted within criminal justice settings. Lessons learned and recommendations to enhance future DSMB work within this area are discussed. [ABSTRACT FROM AUTHOR]

Recently, several pharmaceutical companies have been shown to have withheld negative clinical trial results from the public. These incidents have resulted in a concerted global effort to register all trials at inception, so that all subsequent results can be tracked regardless of whether they are positive or negative. These trial registration policies have been driven in large part by concern about the pharmaceutical sector. The medical device industry is much smaller, and different from the pharmaceutical industry in some fundamental ways. This paper examines the issues surrounding registration of device trials and argues that these differences with pharmaceutical should not exempt device trials from registration. [ABSTRACT FROM AUTHOR]

Pharmacovigilance science has traditionally been a discipline focussed on the postmarketing or post-authorisation period, with due attention directed towards pre-clinical safety data, clinical trials and adverse events. As the biological sciences have evolved, pharmacovigilance has slowly shifted toward earlier, proactive consideration of risks and potential benefits of drugs in the pre- and peri-approval stages of drug development, leading to a maturing of drug safety risk management. Further advances in biology, pharmacology and improvements in computational applications to medicine have led to the development of more complex medicines previously unobtainable and have also permitted a more thorough assessment of risks and potential benefits even earlier in the development process. Elevated public concern with the safety of more sophisticated medicines, combined with new science, have led pharmaceutical innovators, regulators and healthcare professionals to collaborate to develop guidelines, which drive enhanced pharmacovigilance and safety risk management earlier in drug development.In this paper, we review international guidelines on pharmacovigilance planning applicable to the pre-approval phases of medicines development and provide author opinion on these guidelines’ potential drug safety implications. We discuss the possible evolution of a pharmaceutical industry model to respond to these guidelines; a view on multidisciplinary safety management teams is provided to encourage refinement of safety-signal identification and risk assessment early in drug development and to communicate important safety concerns to internal research efforts, patients, investigators and regulators. We further describe these functions in the context of the complexities of vulnerable populations, including the example of medicines research for paediatric populations. We also discuss the special role of epidemiology in pre-approval drug development and the impact on epidemiological science of changes to the pharmacovigilance paradigm. [ABSTRACT FROM AUTHOR]

This paper describes the process of modifying and transporting an evidence-based treatment, Interpersonal Psychotherapy for Depressed Adolescents (IPT-A), from a university setting to school-based health clinics. It addresses conceptual issues involved in the shift from efficacy to effectiveness research as well as operational issues specific to the transport of IPT-A into school-based health clinics. Consideration is given to the rationale for an IPT-A effectiveness study, methodological concerns, and the timing of the move from the "lab" to the community. The authors identify challenges and barriers to initiating effectiveness and transportability research and provide suggestions for overcoming these barriers. Recommendations for conducting research in school-based practice settings are provided. [ABSTRACT FROM AUTHOR]

One major aspect in medical research is to relate the survival times of patients with the relevant covariates or explanatory variables. The proportional hazards model has been used extensively in the past decades with the assumption that the covariate effects act multiplicatively on the hazard function, independent of time. If the patients become more homogeneous over time, say the treatment effects decrease with time or fade out eventually, then a proportional odds model may be more appropriate. In the proportional odds model, the odds ratio between patients can be expressed as a function of their corresponding covariate vectors, in which, the hazard ratio between individuals converges to unity in the long run. In this paper, we consider the estimation of the regression parameter for a semiparametric proportional odds model at which the baseline odds function is an arbitrary, non-decreasing function but is left unspecified. Instead of using the exact survival times, only the rank order information among patients is used. A Monte Carlo method is used to approximate the marginal likelihood function of the rank invariant transformation of the survival times which preserves the information about the regression parameter. The method can be applied to other transformation models with censored data such as the proportional hazards model, the generalized probit model or others. The proposed method is applied to the Veteran's Administration lung cancer trial data. [ABSTRACT FROM AUTHOR]

Traditionally in medicine, nearly all prescribing decisions were made by the treating physician. The patient had relatively little input and hardly any access to alternative sources of information bearing on that decision; the cost of the prescription was covered by the patient or by an insurer, and neither was likely to provide any feedback to the physician to shape his or her decision. Now, all that has changed. Beginning with the consumerist movement of recent decades and culminating in the explosion of health-related information on the Internet, patients are increasingly vocal participants in the prescribing decision, on both clinical and economic grounds. Payers have become participants as well, and increasingly seek to influence prescribing decisions in the light of their own economic imperatives. Added to all these cross-currents is an additional wild card: the proliferation of ‘alternative medicines,’ ‘nutraceuticals’ and other nostrums that society has placed beyond the reach of the evidence-based discourse and regulations that govern conventional drug therapy. In a country where patients struggle to cover the cost of prescription therapies proven both safe and effective in rigorous clinical trials, billions of dollars per year are spent on alternative treatments in the US, unencumbered by concerns about whether they actually work or that they might be toxic. While these patterns of communication, education, disinformation and economic influence are much more chaotic than those that prevailed in the ‘good old days,’ this very ferment may also present opportunities for improvement of rational pharmacotherapy and public health. This paper briefly outlines the above changes in patterns of communication and influence as they relate to medication use in today's industrialised world (particularly the US), and suggests both hopeful and terrifying scenarios describing where these trends might lead in the coming decade. [ABSTRACT FROM AUTHOR]

Awareness of child maltreatment as a major public health problem in the US has increased in recent years. In response, major public initiatives have been launched to fund the delivery of evidence-based programs, such as home visiting, in an effort to promote child and family functioning and health and prevent maltreatment. While promising, the number of families served by these programs remains small relative to need. Further, many families across the US are served by community-designed and supported programs for which rigorous outcome evidence has never been collected. To broaden the evidence-base on child maltreatment prevention programs, and to encourage the use of rigorous research designs in community settings, the Children's Bureau sponsored four randomized controlled trials of established programs that had a limited or no evidence base. In this introduction to a special section of Prevention Science on the prevention of child maltreatment, an overview is provided on the epidemiology of maltreatment and the funding initiative that sponsored the four trials, and a call is made for further rigorous research by prevention scientists. [ABSTRACT FROM AUTHOR]

Traditionally, US teaching hospitals have subsidised research by charging higher costs for treatment; however, this approach is being challenged. The growth of managed-care organisations, concerned about maximising profits, has led many to argue that clinical research will be damaged, whether by the loss of internal funds for research or by reductions in the numbers of patients available for studies. This review examines the evidence on which this argument is based. There is some evidence that managed-care organisations are refusing to cover patients who are involved in clinical trials, although, in general, they are receptive towards research providing that it is explicit and seen as relevant. The indirect effects of competition are, arguably, more important. Although many academic centres have established strategies to protect research funds, those working in the most competitive healthcare environments are obtaining fewer externally funded research grants. They are also publishing fewer papers and are working in climates that are seen as less supportive, with less ability to undertake research that is not externally funded. There is little evidence that managed care is reducing access to patients for clinical research. The growth of managed care is, together with certain other trends, also influencing the nature of clinical research. The overall consequences of these different factors are difficult to predict, although there are grounds for concern about recruitment and retention of junior researchers. The relationship between the various actors involved in healthcare and research is dynamic and, as pressure is excerpted in a particular direction, others adapt. It may be some time before the consequences of policies being enacted now are apparent. [ABSTRACT FROM AUTHOR]

This article explores the moral issues and the preventive and treatment deficiencies for AIDS, as well as the systematic deficiencies beginning with a discussion of the implications of chronic illnesses like AIDS, which is now recognized as a chronic illness. The paper offers a framework for understanding AIDS in relation to several important health issues. The normal sequence of steps through which treatment drugs reach the public--screening by the U.S. Federal Drug Administration and then carefully controlled clinical trials has been altered by AIDS activists, who have created a national lobby bent on changing features of the health care system. AIDS has heightened tensions around certain moral dilemmas associated with current health care policy by raising issues of personal responsibility for illness and public responsibility for preventing and treating certain illnesses.

Background: The application of regulatory informatics to identify trends in clinical trials is a new methodology with the potential to shape drug development programs. As an endpoint in hematologic malignancies, minimal residual disease (MRD) measures the depth of response to treatment, and has been given initial attention in draft regulatory guidelines and workshops by health authorities in the EU and US. Methods: In this paper, we analyze hematologic malignancy trials by searching for terms in Trialtrove, parsing the data sets with ActivePerl, and determining significance with the statistical package R. Results: We identify trends in the use of MRD compared to other endpoints and in different indications over time from 2005 to 2014. Results show that 2 trends of endpoint and MRD use emerge over time and the use of MRD as a primary endpoint is growing. We also take a case-study approach to investigate the functional context of MRD in chronic lymphocytic leukemia and show that it is predominantly used to determine MRD-negativity and also in correlation with other endpoints. Conclusion: The application of informatics tools to regulatory science can evaluate the role and context of MRD as it evolves in the changing pharmaceutical landscape. [ABSTRACT FROM AUTHOR]

Most people with mental health disorders cannot receive timely and evidence-based care despite billions of dollars spent by healthcare systems. Researchers have been exploring using digital health technologies to measure behavior in real-world settings with mixed results. There is a need to create accessible and computable digital mental health datasets to advance inclusive and transparently validated research for creating robust real-world digital biomarkers of mental health. Here we share and describe one of the largest and most diverse real-world behavior datasets from over two thousand individuals across the US. The data were generated as part of the two NIMH-funded randomized clinical trials conducted to assess the effectiveness of delivering mental health care continuously remotely. The longitudinal dataset consists of self-assessment of mood, depression, anxiety, and passively gathered phone-based behavioral data streams in real-world settings. This dataset will provide a timely and long-term data resource to evaluate analytical approaches for developing digital behavioral markers and understand the effectiveness of mental health care delivered continuously and remotely. Measurement(s) depression • real-world behavior • anxiety • Depressed Mood • physical mobility • daily smartphone usage Technology Type(s) Smartphone Application • GPS navigation system Factor Type(s) depression level, socioeconomic indicators, demographics Sample Characteristic - Organism Homo sapiens Sample Characteristic - Environment real world setting Sample Characteristic - Location contiguous United States of America [ABSTRACT FROM AUTHOR]

Background: New treatments are being evaluated for lipodystrophy; however, limited information is available on the patient experience. Results of a prior patient panel showed that hunger and temperature-related symptoms were an issue for participants. Therefore, evaluation of any changes in these symptoms is recommended for inclusion in new treatment options. The objective of this study was to further understand the patient experience and to evaluate newly developed items of hunger and temperature regulation. Methods: Individual, in-depth telephone interviews were conducted via semi-structured discussion guide. Telephone interviews were conducted with 21 US patients with generalized lipodystrophy (GLD) or partial lipodystrophy (PLD). Eligibility requirements included self-reported PLD or GLD. Interviews included open-ended concept elicitation followed by a review of newly developed items assessing hunger, temperature sensations, and patient globals. Interviews were conducted in two rounds, with the newly developed items assessing hunger revised after each round of interviews based on participant feedback. Results: Results indicated that hunger-related symptoms were considered a current issue for greater than half (N = 11) of participants, and all but one reported this as an issue at some point in their lives. Specifically, participants most often reported symptoms of increased appetite and not feeling full. The cognitive debriefing process indicated that the hunger-related symptoms, temperature, and global impression of change and severity items were correctly interpreted and easily completed by the participants. While not a focus of the interviews, the concept elicitation results demonstrated that pain was a frequently reported and bothersome symptom in this patient population. Conclusions: This qualitative research provided evidence to support the use of clinical outcomes assessments such as hunger and temperature-related items in clinical trials. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) can be reliably diagnosed at 18 months, yet significant diagnostic delays persist in the United States. This double-blinded, multi-site, prospective, active comparator cohort study tested the accuracy of an artificial intelligence-based Software as a Medical Device designed to aid primary care healthcare providers (HCPs) in diagnosing ASD. The Device combines behavioral features from three distinct inputs (a caregiver questionnaire, analysis of two short home videos, and an HCP questionnaire) in a gradient boosted decision tree machine learning algorithm to produce either an ASD positive, ASD negative, or indeterminate output. This study compared Device outputs to diagnostic agreement by two or more independent specialists in a cohort of 18–72-month-olds with developmental delay concerns (425 study completers, 36% female, 29% ASD prevalence). Device output PPV for all study completers was 80.8% (95% confidence intervals (CI), 70.3%–88.8%) and NPV was 98.3% (90.6%–100%). For the 31.8% of participants who received a determinate output (ASD positive or negative) Device sensitivity was 98.4% (91.6%–100%) and specificity was 78.9% (67.6%–87.7%). The Device's indeterminate output acts as a risk control measure when inputs are insufficiently granular to make a determinate recommendation with confidence. If this risk control measure were removed, the sensitivity for all study completers would fall to 51.6% (63/122) (95% CI 42.4%, 60.8%), and specificity would fall to 18.5% (56/303) (95% CI 14.3%, 23.3%). Among participants for whom the Device abstained from providing a result, specialists identified that 91% had one or more complex neurodevelopmental disorders. No significant differences in Device performance were found across participants' sex, race/ethnicity, income, or education level. For nearly a third of this primary care sample, the Device enabled timely diagnostic evaluation with a high degree of accuracy. The Device shows promise to significantly increase the number of children able to be diagnosed with ASD in a primary care setting, potentially facilitating earlier intervention and more efficient use of specialist resources. [ABSTRACT FROM AUTHOR]

The current clinical trial landscape targeting Alzheimer's disease (AD) is reviewed in the context of studies completed from 2019 to 2021. This review focuses on available data for observational and phase II/III clinical trial results, which will have the most impact on the field. ClinicalTrials.gov, the United States (US) comprehensive federal registry, was queried to identify completed trials. There are currently 226 interventional clinical trials and 51 observational studies completed, suspended, terminated, or withdrawn within our selected time frame. This review reveals that the role of biomarkers is expanding and although many lessons have been learned, many challenges remain when targeting disease modification of AD through amyloid and tau. In addition, to halt or slow clinical progression of AD, new clinical and observational trials are focusing on prevention as well as the role of more diverse biological processes known to influence AD pathology. [ABSTRACT FROM AUTHOR]

Purpose: A universal definition for what constitutes a hernia center does not exist. The purpose of this study was to characterize hernia centers in the United States by analyzing hernia centers and their non-hernia center counterparts. Methods: A web-based search was conducted to identify defining features of hernia centers including faculty demographics and composition, research output, research funding, clinical trials, and website content. Hernia centers and non-hernia centers were compared. Results: Most hernia centers (n = 36) are in urban areas (89%) and distributed evenly across regions of the United States. Hernia centers are associated with University program types (p = 0.001) while non-hernia centers are associated with University-Affiliate (p = 0.001) and Community (p = 0.02) program types. Hernia centers are associated with Abdominal Core Health Quality Collaborative participation (p = 0.01) and Center of Excellence by the Surgical Review Corporation certification (p = 0.005). Hernia centers are associated with presence of active clinical trials (p < 0.001) and number of clinical trials (p < 0.001). Hernia centers are associated with industry-sponsored trials (p < 0.001) but are not associated with NIH-sponsored trials. Fifty percent of hernia centers have PRS faculty. The vast majority of hernia center websites describe hernias treated (92%) and repair techniques (89%). The majority of hernia center mission statements emphasize an individualized care plan (61%) and multidisciplinary care (57%). Only 39% of websites and 17% of mission statements mention research. Conclusion: In the United States, hernia centers are clinically oriented, multidisciplinary surgical teams at predominantly urban, University programs that may use this title to attract patient referrals and industry sponsorship of clinical trials. [ABSTRACT FROM AUTHOR]

As modellers push to make their models more accurate, the ability of others to understand the models can decrease, causing the models to lose transparency. When this type of conflict between accuracy and transparency occurs, the question arises, “Where do we want to operate on that spectrum?” This paper argues that in such cases we should give absolute priority to accuracy: push for whatever degree of accuracy is needed to answer the question being asked, try to maximise transparency within that constraint, and find other ways to replace what we wanted to get from transparency. There are several reasons.The fundamental purpose of a model is to help us get the right answer to a question and, by any measure, the expected value of a model is proportional to its accuracy. Ironically, we use transparency as a way to judge accuracy. But transparency is not a very powerful or useful way to do this. It rarely enables us to actually replicate the model’s results and, even if we could, replication would not tell us the model’s accuracy. Transparency rarely provides even face validity; from the content expert’s perspective, the simplifications that modellers have to make usually raise more questions than they answer. Transparency does enable modellers to alert users to weaknesses in their models, but that can be achieved simply by listing the model’s limitations and does not get us any closer to real accuracy. Sensitivity analysis tests the importance of uncertainty about the variables in a model, but does not tell us about the variables that were omitted or the structure of the model. What people really want to know is whether a model actually works. Transparency by itself can’t answer this; only demonstrations that the model accurately calculates or predicts real events can. Rigorous simulations of clinical trials are a good place to start. This is the type of empirical validation we need to provide if the potential of mathematical models in pharmacoeconomics is to be fully achieved. [ABSTRACT FROM AUTHOR]

Background: Results of 2 trials of postmenopausal hormone therapy (HT) challenged established practice patterns; 1 was not associated with changes in HT use, whereas the other was associated with substantial decline. Differential coverage by lay newspapers may have contributed to the differential impact.Objective: To examine newspaper coverage of HT before and after the publication of the Heart and Estrogen Replacement Study (HERS) in August 1998, and the main findings of the estrogen plus progestin therapy arm of the Women's Health Initiative (EPT-WHI) in July 2002.Design: Longitudinal review of newspaper articles, 1998 to 2003 (n=663).Setting: Twenty local and 6 regional/national newspapers.Measurements: Number and content of articles about HT.Results: The average number of articles about HT published during the month of the publication of the EPT-WHI was at least 8-fold greater than the number of articles published on the topic during any prior period. While the majority of articles in all periods presented information about the potential benefits of HT, information about harms became more common than information about benefits during the 2 months before the publication of the EPT-WHI, when the trial participants were notified of the early termination of the study. The presentation of specific health harms was more common after the publication of the EPT-WHI than after the publication of HERS. Few articles in any period used visual aids.Conclusions: The publication of the EPT-WHI was associated with a change in both the volume and content of newspaper coverage about HT. [ABSTRACT FROM AUTHOR]

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This paper reviews evidence that behavioral family interventions are effective at improving child-rearing in distressed families and families with children exhibiting disruptive behavior. Essential therapeutic strategies offered within a collaborative therapeutic process are identified. Exemplary materials for parents and clinicians are identified. Differences between behavioral family interventions and two popular press parenting approaches are highlighted, including the lack of empirical support for these widely used programs and the advice they offer which runs counter to behavioral approaches. Recommendations are offered for combining behavioral family interventions with other empirically supported approaches, promoting more widespread use of empirically supported treatments, such as behavioral family interventions, and the need for a public health perspective on family functioning, involving collaboration among clinicians, policy makers, and researchers. [ABSTRACT FROM AUTHOR]

Background: Differences in experiences of care reported by Asian Americans (Asians) compared to non-Hispanic Whites (Whites) may be due to lack of measurement invariance. Methods: We evaluated the three-factor structure and the equivalence of responses to the Consumer Assessment of Healthcare Providers and Systems (CAHPS®) Clinical and Group (CG-CAHPS) Adult Visit Survey 1.0 and compared care experiences of Asians and Whites. Thirteen questions were used to elicit reports about specific aspects of care and two questions assessed overall care perceptions. This analysis of the CAHPS database included 769 providers and 266,327 respondents. Most surveys (98%) were administered by mail and the rest (2%) by phone. Only 0.5% of the surveys were administered in Spanish. The sample was 64% female, 89% White and 2% Asian, 39% 65 years or older, and 32% were high school graduates or less. Results: A three-factor model was supported by categorical confirmatory factor analysis using weighted least squares with mean and variance adjustment: confirmatory fit index (CFI) = 0.99 and root mean squared error of approximation (RMSEA) = 0.03). A multi-group configural invariance model also fit the data well: (CFI = 0.993, RMSEA = 0.031). Regression models indicated that Asians reported worse access, lower scores on office staff courtesy and helpfulness and rating their doctors and were less likely to recommend their doctors to family/friends than did Whites. Conclusions: Use of the CG-CAHPS Adult Visit Survey 1.0 to assess perceptions of care by Asians and Whites is supported. Quality improvement efforts are needed to address worse experiences of care among Asians in the United States. [ABSTRACT FROM AUTHOR]

Background: Transplantation of HIV-positive (HIV+) donor organs for HIV+ recipients (HIV D+/R+) is now being performed as research in the United States, but raises ethical concerns. While patient-reported outcome measures are increasingly used to evaluate clinical interventions, there is no published measure to aptly capture patients' experiences in the unique context of experimental HIV D+/R+ transplantation. Therefore, we developed PROMETHEUS (patient-reported measure of experimental transplants with HIV and ethics in the United States). To do so, we created a conceptual framework, drafted a pilot battery using existing and new measures related to this context, and refined it based on cognitive and pilot testing. PROMETHEUS was administered 6-months post-transplant in a clinical trial evaluating these transplants. We analyzed data from the first 20 patient-participants for reliability and validity by calculating Cronbach's alpha and reviewing item performance characteristics. Results: PROMETHEUS 1.0 consisted of 29 items with 5 putative subscales: Emotions; Trust; Decision Making; Transplant; and Decision Satisfaction. Overall, responses were positive. Cronbach's alpha was > 0.8 for all subscales except Transplant, which was 0.38. Two Transplant subscale items were removed due to poor reliability and construct validity. Conclusions: We developed PROMETHEUS to systematically capture patient-reported experiences with this novel experimental transplantation program, nested it in an actual clinical trial, and obtained preliminary data regarding its performance. [ABSTRACT FROM AUTHOR]

Purpose: Clinical performance of hernia mesh devices is poorly understood due to a lack of relevant clinical trial and real-world data (RWD). Registries offer a means to capture longitudinal data in real-world practice. This report highlights the need for data quality, completeness, and appropriate analysis methodology for more accurate and informed interpretation of RWE of medical devices.Methods: Hernia mesh registry data were used to cross-tabulate the 30-day infection rate of patients who received one of four mesh types.Results: Initial data review suggested lower infection rate for permanent mesh versus absorbable mesh. Additional registry RWD were factored into the analysis, providing more context in the interpretation of the results.Conclusions: High-quality registries can be used to generate real-world evidence (RWE) to support surveillance and other regulatory decisions. [ABSTRACT FROM AUTHOR]

Purpose: Worldwide breast cancer is the most commonly diagnosed cancer in women and often associated with a profound physiological stress reaction. Mind-body medicine modalities have been proven effective in reducing stress symptoms. This article will cover the prevalence of MBM use in women with and without breast cancer in the US population and detect predictors of MBM use in women diagnosed with breast cancer.Methods: The 2017 National Health Interview Survey (NHIS) was used to study the prevalence of breast cancer and the use of mind-body medicine (MBM) among individuals with breast cancer in the US population. Using chi-squared tests and backward stepwise multiple logistic regression analyses, predictors of MBM use in women with breast cancer in the past 12 months were identified.Results: The prevalence of breast cancer in women was 3.1%. Among women diagnosed with breast cancer, 25.2% had used MBM in the past 12 months. Spiritual meditation (14.3%), followed by yoga (9.6%), and mindfulness meditation (4.3%) were the most commonly used MBM approaches for women with breast cancer diagnosis. Only higher education independently predicted the use of MBM among them.Conclusions: In this nationally representative sample of the USA, the most common used MBM approach was spiritual meditation, while this approach is much less researched than the evidence based approaches of yoga and mindfulness meditation. Especially stressed individuals worldwide could benefit from MBM the literature suggests. Particularly in the acute survivorship stage, influencing the initial stress reaction could be beneficial. [ABSTRACT FROM AUTHOR]

Objective: Given the global and economic burden of stroke as a major cause of long-term disability, patient-reported outcomes (PRO) data from clinical trials can elucidate differential benefits/harms of interventions from patients' perspectives and influence clinical decision making in stroke care management.Methods: This systematic review examines stroke-related randomized controlled trials (RCT) published in 12 high-impact journals between 2002 and 2016 for (1) associations between trial characteristics and the reporting of PRO measures; and (2) psychometric properties of PRO instruments used in these studies. The study combines clinical trials identified in a prior review with trials identified with an updated literature search.Results: Only 34 of 159 stroke-related RCTs reported PRO measures. Among the 34 trials, most were published in rehabilitation and general medical journals, were conducted in the United States or Europe, were funded by government/non-industry sponsors, and focused on post-stroke care. Thirty-one PRO instruments were employed in these studies. Only 5 instruments were stroke-specific measures, whereas the remaining 26 instruments were generic measures. Eight instruments assessed functional status, 9 measured quality of life, and 14 assessed symptoms. The most common health domains measured were emotional status and physical function.Conclusions: This study highlights the paucity of information from patients' perspective in stroke-related RCTs. This trend may change over time as researchers increase adherence to reporting guidelines for clinical trial protocols. [ABSTRACT FROM AUTHOR]

Despite initiatives to increase the enrollment of racial and ethnic minorities into cancer clinical trials in the National Cancer Institute National Cancer Clinical Trials Network (NCCTN), participation by Latino and African American populations remain low. The primary aims of this pilot study are (1) to develop a Cultural Competency and Recruitment Training Program (CCRTP) for physician investigators and clinical research associates (CRAs), (2) to determine if the CCRTP increases cultural competency scores among physician investigators and CRAs, and (3) to determine the impact of the CCRTP on minority patient recruitment into NRG Oncology Radiation Therapy Oncology Group (RTOG) clinical trials. Sixty-seven CRAs and physicians participated in an in-person or online 4-h CRRTP training. Five knowledge and attitude items showed significant improvements from pre- to post-training. A comparison between enrolling sites that did and did not participate in the CCRTP demonstrated a pre to 1-year post-incremental increase in minority accrual to clinical trials of 1.2 % among participating sites. While not statistically significant, this increase translated into an additional 300 minority patients accrued to NCCTN clinical trials in the year following the training from those sites who participated in the training. [ABSTRACT FROM AUTHOR]

We evaluated the adherence and acceptability of a vaginal ring containing dapivirine, maraviroc, or both drugs for 28 days during a Phase I placebo-controlled trial in 48 HIV-negative sexually abstinent U.S. women aged 18-40. Adherence was assessed weekly by clinical interview and computer-assisted self-interviewing; acceptability assessment occurred at the last product-use visit. Study retention was 98 % (47/48); 94 % (45/48) reported being fully adherent with ring use during the 28-day period. Two participants experienced the ring partially coming out. Analysis was blinded and behavioral data were combined across study groups. Most women reported being very comfortable having the ring in their vagina; 44 % preferred continuous use, whereas 51 % had no preference compared to episodic use. Although a range of minor ring concerns were expressed, few were actually experienced. High adherence to and acceptability of this vaginal ring in this Phase I trial contributes to its promise as a sustained mechanism for multidrug vaginal microbicide delivery. [ABSTRACT FROM AUTHOR]

The article focuses on the publication bias against negative results from clinical trials in the U.S. Accordingly, the assessment of the number of meeting abstracts that turned into full papers reveals that a trial proving a benefit of a drug or device has much greater chance of full publication than does a trial which is showing no benefit. Moreover, publications of trials sanctioned by institutional review boards are often characterized by selective outcome reporting.

Since 1993, how to assess the causality of serious adverse events in premarketing drug clinical trials has undergone sustained regulatory evolution in the USA. In that year, an investigational drug study for chronic hepatitis B virus infection was emergently stopped after a patient suddenly exhibited hepatic failure and lactic acidosis, which later developed, along with pancreatitis and peripheral neuropathy, in several others after drug discontinuation. Five patients eventually died, including three despite emergency liver transplantation. The drug's multisystem toxicity was not predicted by preclinical animal studies, with grave injury to human mitochondria subsequently implicated. A concerned US Food and Drug Administration (FDA) created a task force whose findings would have a lasting impact on the agency's thinking. In 1994, the FDA proposed to amend its investigational new drug reporting requirements largely based on task force recommendations for ways to enhance the likelihood that sponsors and investigators would consider investigational agents as a possible cause of serious adverse events mimicking the underlying disease or concomitant drug toxicity. Then, in its 1997 final rule for expedited safety reporting requirements for drugs and biologics, the FDA advised sponsors that such reporting of serious, unexpected clinical trial cases would be expected when "there is a reasonable suspected causal relationship between the investigational product and the adverse event (i.e., the causal relationship cannot be ruled out)." This last clause was codified into the suspected adverse drug reaction definition in the FDA's 2003 safety reporting requirements for drugs and biologics proposed rule. The negatively received suspected adverse drug reaction and proposed causality standard were not adopted in the FDA's 2010 finalized investigational new drug safety reporting regulations, the agency stating that "'reasonable possibility' means there is evidence to suggest a causal relationship between the drug and the adverse event." However, such new requirements as aggregate analysis of specific events and expedited reporting of animal or in vitro data suggesting significant harm to humans, and subsequent guidance that sponsors develop "a systematic approach" to premarketing safety assessment, are among the components of the FDA's efforts to enhance determination of a "reasonable possibility" of causality. They are also philosophically consistent with the 1993 task force recommendations, and a reminder of the inherent hazards associated with the use of investigational drugs, particularly in the early stages of human study. [ABSTRACT FROM AUTHOR]

In 2012, USA Food and Drug Administration (FDA) approved 39 new drugs, however, there are only two botanical drugs (one topical and one oral) approved by FDA since the publication of the FDA's industry guidelines for the botanical drug product in June 2004. The approval shows the Western guideline can be used for herbal medicines, authors investigate current regulation on herbal medicine clinical research, identify challenges conducting clinical trials, and seek to produce some guidance for potential investigators and sponsors considering a clinical trial in this area. Key words were formulated for searching on Medline and FDA website to locate relevant regulations for clinical research in herbal medicines to understand current environment for herbal medicine usage and examine the barriers affecting herbal medicine in clinical trials. Authors critically explore case study of the 1st FDA approved botanical drugs, Veregen (sinecatechins), green tea leaves extract, a topical cream for perianal and genital condyloma. In consideration of current regulation environment in USA, based on the findings and analysis through the literature review and Veregen case study, authors produce and propose a Checklist for New Drug Application of Herbal Medicines for potential investigators and sponsors considering in a herbal medicine clinical trial. [ABSTRACT FROM AUTHOR]

Purpose This first-in-human study evaluated the CD70-targeted antibody-drug conjugate SGN-75 in patients with relapsed or refractory CD70-positive non-Hodgkin lymphoma (NHL) or metastatic renal cell carcinoma (RCC). Methods SGN-75 was administered intravenously to 58 patients (39 RCC, 19 NHL) every 3 weeks (Q3Wk; doses escalated from 0.3 to 4.5 mg/kg) or on Days 1, 8, and 15 of 28-day cycles (weekly; doses of 0.3 or 0.6 mg/kg). Dose-limiting toxicities were evaluated during Cycle 1; treatment response was monitored every 2 cycles. Results The maximum tolerated dose of SGN-75 in RCC patients was 3 mg/kg Q3Wk. Due to toxicity concerns (idiopathic thrombocytopenic purpura in 2 NHL patients treated weekly), dose escalation in the weekly schedule was terminated; no regimen was recommended for NHL patients. The most common adverse events reported in patients treated Q3Wk ( N = 47) were fatigue (40 %), dry eye (32 %), nausea (30 %), and thrombocytopenia (26 %). The nadir for thrombocytopenia typically occurred during Cycle 1. Ocular adverse events (e.g., corneal epitheliopathy, dry eye) were reported for 57 % of patients treated Q3Wk and were generally reversible. Antitumor activity in patients treated Q3Wk included 1 complete response, 2 partial responses, and 20 stable disease. SGN-75 exposures were approximately dose proportional, with a mean terminal half-life of 10 days. Substantial depletions of CD70-positive peripheral blood lymphocytes were observed after SGN-75 treatment. Conclusions Modest single-agent activity and generally manageable adverse events were observed in heavily pretreated RCC and NHL patients. Administration Q3Wk was better tolerated than weekly dosing. Targeted ablation of CD70-positive lymphocytes was demonstrated. [ABSTRACT FROM AUTHOR]

BACKGROUND: Family and caregiver interventions typically aim to develop family members' coping and caregiving skills and to reduce caregiver burden. We conducted a systematic review of published randomized controlled trials (RCTs) evaluating whether family-involved interventions improve patient outcomes among adults with cancer. METHODS: RCTs enrolling patients with cancer were identified by searching MEDLINE, PsycInfo and other sources through December 2012. Studies were limited to subjects over 18 years of age, published in English language, and conducted in the United States. Patient outcomes included global quality of life; physical, general psychological and social functioning; depression/anxiety; symptom control and management; health care utilization; and relationship adjustment. RESULTS: We identified 27 unique trials, of which 18 compared a family intervention to usual care or wait list (i.e., usual care with promise of intervention at completion of study period) and 13 compared one family intervention to another individual or family intervention (active control). Compared to usual care, overall strength of evidence for family interventions was low. The available data indicated that overall, family-involved interventions did not consistently improve outcomes of interest. Similarly, with low or insufficient evidence, family-involved interventions were not superior to active controls at improving cancer patient outcomes. DISCUSSION: Overall, there was low or insufficient evidence that family and caregiver interventions were superior to usual or active care. Variability in study populations and interventions made pooling of data problematic and generalizing findings from any single study difficult. Most of the included trials were of poor or fair quality. [ABSTRACT FROM AUTHOR]

Purpose: In order to test the difference between group means, the construct measured must have the same meaning for all groups under investigation. This study examined the measurement invariance of responses to the patient-reported outcomes measurement information system (PROMIS) pain behavior (PB) item bank in two samples: the PROMIS calibration sample (Wave 1, N = 426) and a sample recruited from the American Chronic Pain Association (ACPA, N = 750). The ACPA data were collected to increase the number of participants with higher levels of pain. Methods: Multi-group confirmatory factor analysis (MG-CFA) and two item response theory (IRT)-based differential item functioning (DIF) approaches were employed to evaluate the existence of measurement invariance. Results: MG-CFA results supported metric invariance of the PROMIS-PB, indicating unstandardized factor loadings with equal across samples. DIF analyses revealed that impact of 6 DIF items was negligible. Conclusions: Based on the results of both MG-CFA and IRT-based DIF approaches, we recommend retaining the original parameter estimates obtained from the combined samples based on the results of MG-CFA. [ABSTRACT FROM AUTHOR]

Objective:We changed from ampicillin and gentamicin (AG) to piperacillin-tazobactam (PT) for routine treatment of suspected early-onset sepsis. The rationale for this change included ototoxic and renal toxic effects of gentamicin, resistance to gentamicin in late-onset infections and emergence of ampicillin resistant Escherichia coli. A before and after study was designed before the start of PT administration to monitor whether PT was associated with altered outcomes within the 501 to 1500 g birth weight (Very Low Birth Weight) population.Method:Both unmatched and matched comparisons of AG (2007 to 2009) and PT (2010 to 2011) exposed infants are reported. Cohorts were evaluated for initial effectiveness for congenital infections, subsequent morbidities and mortality.Results:Data from 714 patients were collected (499 AG and 215 PT in the unmatched and 301 AG and 183 PT in the matched cohorts). No significant differences in demographics or initial Apgar scores were noted in the unmatched or matched comparisons. There were significant differences in many of the outcomes of interest in both the matched and unmatched comparisons including less necrotizing enterocolitis (NEC) and less diaper rash with PT versus AG. The only adverse finding with PT was a small, but statistically significant elevation in alkaline phosphatase.Conclusions:Use of PT as the initial empiric antibiotic for very low birth weight infants was not associated with adverse microbiological outcomes. There was no increase in major morbidities. Although outcomes were superior in 1500 g infants treated with PT when compared with AG, the study design does not allow us to conclude that others will see a reduction in NEC or diaper rash if they implement this alternative. [ABSTRACT FROM AUTHOR]