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OBJECTIVE: This systematic review provides an overview of psychiatric medications in the late stages of development (Phase III clinical trials) as of June 1, 2024. It details the mechanisms of action, efficacy, dosing, and adverse effects of these medications. METHODS: We searched the PubMed database for Phase III studies of psychiatric medications published until June 1, 2024, using the keywords psychiatric OR psychopharm* AND medic* OR pharm*. Our review encompassed medications currently undergoing Phase III clinical trials and those that have completed Phase III but are awaiting approval from the United States Food and Drug Administration (FDA). We independently analyzed the identified studies and reached a consensus on the medications to be included in this systematic review. RESULTS: As of June 1, 2024, a total of 89 pipeline drug trials were identified, including nine for schizophrenia, five for bipolar disorders, 25 for depressive disorders, 11 for anxiety disorders, five for post-traumatic stress disorder (PTSD), one for obsessive compulsive disorder (OCD), two for eating disorders, two for sleep-wake disorders, three for sexual dysfunctions, one for substance-related and addictive disorders, 22 for neurocognitive disorders, and three for neurodevelopmental disorders, specifically attention deficit hyperactivity disorder (ADHD). CONCLUSION: The psychiatric medications in the pipeline as of June 1, 2024, demonstrate significant promise in treating psychiatric disorders.

If two or more doses are employed in a Phase III clinical trial to compare to placebo, it is believed that the multiple doses can strengthen the understanding of a drug’s effect and increase the confidence in drug’s effect if consistent evidence is observed. In this article, a new approach is proposed to adjust formultiplicity introduced by multiple doses in phase III studies. Instead of dividing the significance level in the tests of individual doses, the new approach requires certain consistency to be demonstrated between themultiple active doses. The rejection regions of the new approach focus on the area of demonstrating consistent evidence,which is different fromthe rejection region of the Bonferroni correction. Detailed comparisons for the rejection regions between the Bonferroni and the new approach are provided. The comparisons explain how multiple doses can be used to strengthen the evidence without splitting the significance level. The rejection regions in the consistency-basedmethod can help statisticians understand the role of multiplicity adjustment in study design and drug evaluation comprehensively. [ABSTRACT FROM AUTHOR]

Abstract Background Older patients are underrepresented in the clinical trials that determine the standards of care for oncological treatment. We conducted a review to identify whether there have been age-restrictive inclusion criteria in clinical trials over the last twenty five years, focusing on patients with metastatic gastroesophageal cancer. Methods A search strategy was developed encompassing Embase, PubMed and The Cochrane Library databases. Completed phase III randomised controlled trials evaluating systemic anti-cancer therapies in metastatic gastroesophageal malignancies from 1st January 1995 to 18th November 2020 were identified. These were screened for eligibility using reference management software (Covidence; Veritas Health Innovation Ltd). Data including age inclusion/exclusion criteria and median age of participants were recorded. The percentage of patients ≥ 65 enrolled was collected where available. The change over time in the proportion of studies using an upper age exclusion was estimated using a linear probability model. Results Three hundred sixty-three phase III studies were identified and screened, with 66 trials remaining for final analysis. The majority of trials were Asian (48%; n = 32) and predominantly evaluated gastric malignancies, (86%; n = 56). The median age of participants was 62 (range 18–94). Thirty-two percent (n = 21) of studies specified an upper age limit for inclusion and over half of these were Asian studies. The median age of exclusion was 75 (range 65–80). All studies prior to 2003 used an upper age exclusion (n = 12); whereas only 9 that started in 2003 or later did (17%). Among later studies, there was a very modest downward yearly-trend in the proportion of studies using an upper age exclusion (-0.02 per year; 95%CI -0.05 to 0.01; p = 0.31). Fifty-two percent (n = 34) of studies specified the proportion of their study population who were ≥ 65 years. Older patients represented only 36% of the trial populations in these studies (range 7–60%). Conclusions Recent years have seen improvements in clinical trial protocols, with many no longer specifying restrictive age criteria. Reasons for poor representation of older patients are complex and ongoing efforts are needed to broaden eligibility criteria and prioritise the inclusion of older adults in clinical trials.

Currently, many confirmatory randomized clinical trials (RCTs) with predictive markers have taken the all‐comers approach because of the difficulty in developing predictive markers that are biologically compelling enough to apply the enrichment approach to restrict the patient population to a marker‐defined subgroup. However, such a RCT with weak marker credentials can conclude that the new treatment is efficacious only in the subgroup, especially when the primary analysis demonstrates some treatment efficacy in the subgroup, but the overall treatment efficacy is not significant under a control of study‐wise alpha rate. In this article, we consider conditional estimation of subgroup treatment effects, given the negative result in testing the overall treatment efficacy in the trial. To address the problem of unstable estimation due to the truncation in the distribution of the test statistic on overall treatment efficacy, we propose a new approach based on a weighted likelihood for the truncated distribution. The weighted likelihood can be derived by invoking a randomized test with a smooth critical function for the overall test. Our approach allows for point and interval estimations of the conditional effects consistently based on the standard maximum likelihood inference. Numerical evaluations, including simulations and application to real clinical trials, and guidelines for implementing our methods with R‐codes, are provided. [ABSTRACT FROM AUTHOR]

Background/Aim: The number of coronavirus disease 2019 deaths and cases continues to increase globally. Novel therapies are urgently needed to treat patients with coronavirus disease 2019. We sought to provide a critical review of trials designed during the coronavirus disease 2019 pandemic. Our primary goal was to provide a critical review of the landscape of clinical trials designed to address the coronavirus disease 2019 pandemic. Specifically, we were interested in assessing the design of phase II/III and phase III interventional trials. Methods: We utilized the ClinicalTrials.gov database to include trials registered between 1 December 2019 and 11 April 2021 to survey the current landscape of clinical trials for coronavirus disease 2019. Variables extracted included: National Clinical Trial number, title, location, sponsor, study type, start date, completion date, gender group, age group, primary outcome, secondary outcome, overall status, and associated references. Results: About 57% of studies were interventional, 14.5% were phase III trials, and the majority of the therapeutic trials included hospitalized patients. There were 52 primary composite outcomes and 285 unique interventions spanning 10 drug classes. The outcomes, disease severity, and comparators varied substantially across trials, and the trials were often too small to be definitive. Conclusion: These findings are relevant as we strongly advocate for global coordination of efforts through the use of common platforms that enable harmonizing of endpoints, collection of common key variables and clear definition of disease severity to have clinically meaningful results from clinical trials. [ABSTRACT FROM AUTHOR]

Pivotal cancer trials often fail to yield evidence in support of new therapies thought to offer promising alternatives to standards-of-care. Conducting randomized controlled trials in oncology tends to be considerably more expensive than studies of other diseases with comparable sample size. Moreover, phase III trial design often takes place with a paucity of survival data for experimental therapies. Experts have explained the failures on the basis of design flaws which produce studies with unrealistic expectations. This article presents a framework for predicting outcomes of phase III oncology trials using Bayesian mediation models. Predictions, which arise from interim analyses, derive from multivariate modeling of the relationships among treatment, tumor response, and their conjoint effects on survival. Acting as a safeguard against inaccurate pre-trial design assumptions, the methodology may better facilitate rapid closure of negative studies. Additionally the models can be used to inform re-estimations of sample size for under-powered trials that demonstrate survival benefit via tumor response mediation. The methods are applied to predict the outcomes of two colorectal cancer studies. Simulation is used to evaluate and compare models in the absence versus presence of reliable surrogate markers of survival. [ABSTRACT FROM AUTHOR]

In recent years, different studies have highlighted the importance of B cells in the pathophysiology of multiple sclerosis (MS): they secrete cytokines to modulate the inflammatory environment, present antigens for the activation of T lymphocytes, and they secrete antibodies contributing to the destruction of the myelin sheath. Combined, these findings have lead to new possible means for treating MS. In this review, we provide an up-to-date overview of the characteristics of ofatumumab (aka Kesimpta), and the differences between this drug and the other anti-CD20 monoclonal antibodies used to treat MS. The evolution of disease-modifying treatment algorithms in MS underlines the importance of starting treatment as soon as the diagnosis is defined, and with adequate 'treatment intensity.' Monoclonal antibodies and other aggressive treatments are now considered as an option at the clinical presentation of the disease, based to the prognostic profile emerging through clinical and paraclinical investigations. The recent adoption of new diagnostic criteria allows for the early diagnosis of MS. This, together with the availability of disease-modifying therapies (DMTs), such as ofatumumab, with a good efficacy/safety profile and which are easy to administer, could contribute to significant improvements in the long-term prognosis of MS. [ABSTRACT FROM AUTHOR]

Background: Older patients are underrepresented in the clinical trials that determine the standards of care for oncological treatment. We conducted a review to identify whether there have been age-restrictive inclusion criteria in clinical trials over the last twenty five years, focusing on patients with metastatic gastroesophageal cancer.Methods: A search strategy was developed encompassing Embase, PubMed and The Cochrane Library databases. Completed phase III randomised controlled trials evaluating systemic anti-cancer therapies in metastatic gastroesophageal malignancies from 1st January 1995 to 18th November 2020 were identified. These were screened for eligibility using reference management software (Covidence; Veritas Health Innovation Ltd). Data including age inclusion/exclusion criteria and median age of participants were recorded. The percentage of patients ≥ 65 enrolled was collected where available. The change over time in the proportion of studies using an upper age exclusion was estimated using a linear probability model.Results: Three hundred sixty-three phase III studies were identified and screened, with 66 trials remaining for final analysis. The majority of trials were Asian (48%; n = 32) and predominantly evaluated gastric malignancies, (86%; n = 56). The median age of participants was 62 (range 18-94). Thirty-two percent (n = 21) of studies specified an upper age limit for inclusion and over half of these were Asian studies. The median age of exclusion was 75 (range 65-80). All studies prior to 2003 used an upper age exclusion (n = 12); whereas only 9 that started in 2003 or later did (17%). Among later studies, there was a very modest downward yearly-trend in the proportion of studies using an upper age exclusion (-0.02 per year; 95%CI -0.05 to 0.01; p = 0.31). Fifty-two percent (n = 34) of studies specified the proportion of their study population who were ≥ 65 years. Older patients represented only 36% of the trial populations in these studies (range 7-60%).Conclusions: Recent years have seen improvements in clinical trial protocols, with many no longer specifying restrictive age criteria. Reasons for poor representation of older patients are complex and ongoing efforts are needed to broaden eligibility criteria and prioritise the inclusion of older adults in clinical trials. [ABSTRACT FROM AUTHOR]

Two pivotal, randomized, double-blind studies in a chronic dermatology disease were ongoing when the COVID-19 pandemic broke out. The trials had identical design, with four parallel treatment arms: two doses of active drug, an active comparator and placebo. When recruitment was temporarily halted due to the pandemic, both trials had already achieved over 80% of the targeted sample size. The unprecedented and unpredictable dynamic of the pandemic caused concerns about potential risks to data integrity and interpretability, which needed to be addressed. In this article, we describe some of these challenges and mitigation strategies. In particular, the complex confirmatory situation involving multiple active doses, endpoints and comparators led to a careful modification of the testing scheme to maintain the power of key endpoints and comparisons while still controlling the relevant Type I error rates. Specifically, the strategy was adjusted to perform some lower-level statistical tests in the hierarchy on the pool of both studies, taking advantage of the replicate study design. Primary endpoint comparisons against placebo and active control remained separately by study. In this article, we share our ideas and experiences in devising this risk mitigation proposal for the statistical methodology of these pivotal trials during the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Background: Newly approved, drug-modifying therapies are associated with still unknown adverse events, although clinical trials leading to approval have strict inclusion and exclusion criteria and analyse safety and efficacy. Objectives: The aim of this study was to analyse the eligibility of multiple sclerosis (MS) patients treated in routine care into the phase III clinical trial of the respective drug. Methods: In total, 3577 MS patients with 4312 therapies were analysed. Patients with primary-progressive MS were excluded. Inclusion and exclusion criteria of phase III clinical trials in relapsing–remitting MS were adopted and subsequently applied. A comparison in clinical and sociodemographic characteristics was made between patient who met the criteria and those who did not. Results: 83% of registered patients would not have been eligible to the respective phase III clinical trial. Relapse was the single most frequent criterion not fulfilled (74.7%), followed by medication history (21.2%). Conclusion: The majority of MS patients treated in routine care would not have met clinical trials criteria. Thus, the efficacy and safety of therapies in clinical trials can differ from those in the real world. Broader phase III inclusion criteria would increase their eligibility and contribute to a better generalizability of the results in clinical trials. [ABSTRACT FROM AUTHOR]

Abstract Background Despite more than 60 years of clinical trials, tuberculosis (TB) still causes a high global burden of mortality and morbidity. Treatment currently requires multiple drugs in combination, taken over a prolonged period. New drugs are needed to shorten treatment duration, prevent resistance and reduce adverse events. However, to improve on current methodology in drug development, a more complete understanding of the existing clinical evidence base is required. Methods A systematic review was undertaken to summarise outcomes reported in phase III trials of patients with newly diagnosed pulmonary TB. A systematic search of databases (PubMed, MEDLINE, EMBASE, CENTRAL and LILACs) was conducted on 30 November 2017 to retrieve relevant peer-reviewed articles. Reference lists of included studies were also searched. This systematic review considered all reported outcomes. Results Of 248 included studies, 229 considered “on-treatment” outcomes whilst 148 reported “off-treatment” outcomes. There was wide variation and ambiguity in the definition of reported outcomes, including their relationship to treatment and in the time points evaluated. Additional challenges were observed regarding the analysis approach taken (per protocol versus intention to treat) and the varying durations of “intensive” and “continuation” phases of treatment. Bacteriological outcomes were most frequently reported but radiological and clinical data were often included as an implicit or explicit component of the overall definition of outcome. Conclusions Terminology used to define long-term outcomes in phase III trials is inconsistent, reflecting evolving differences in protocols and practices. For successful future cumulative meta-analysis, the findings of this review suggest that greater availability of individual patient data and the development of a core outcome set would be desirable. In the meantime, we propose a simple and logical approach which should facilitate combination of key evidence and inform improvements in the methodology of TB drug development and clinical trials.

Inspired by the American Society of Clinical Oncology's recommendations to strengthen the evidence base for older adults with cancer, the purpose of this systematic review is to identify the reporting of treatment efficacy and adverse events specific to older adults with cancer in Phase III chemo-therapeutic clinical trials. This review also investigates the frequency with which these data points were reported in the literature to identify gaps in reporting and opportunities to expand the knowledge base on clinical outcomes for older adults with cancer. Chemo-therapeutic clinical trial data published from July 1, 2016 to June 30, 2017 was reviewed. Manuscripts (n = 929) were identified based on keyword searches of EMBASE and PubMed. After removal of duplicates (n = 116) and articles that did not meet this study's inclusion criteria (n = 654), 159 articles were identified for review. Reviewed papers were published in 36 different scientific journals and included twenty-five different cancer types. Of the 159 articles, 117 (73.6%) reported age-specific medians and 75 (47.2%) included stratifications of data by age. Treatment efficacy was reported in 96.2% of the articles with 39.9% reporting effectiveness of treatment by age. Reporting of adverse events was included in 84.9% of the articles with only 8.9% reporting these events stratified by age. Results suggest inadequate reporting of treatment efficacy and adverse events as well as basic descriptive statistics about the age distribution of study subjects. Conscious efforts are needed to address these deficiencies at every level of planning and conducting clinical trials as wells as reporting outcomes stratified by age. Ultimately, standardized reporting could lead to improved treatment decisions and outcomes for older adults with cancer. [ABSTRACT FROM AUTHOR]

Ovarian cancer has a high mortality to case ratio. To improve the initial response to therapy, trials of biologic agents in combination with primary chemotherapy and as maintenance after completing chemotherapy are being conducted. Multiple trials are ongoing and this strategy has great promise. However, the changing landscape of primary treatment will make designing future trials in ovarian cancer difficult as there may not be a consensus on the optimal primary therapy. We reviewed clinicaltrials.gov for recent and ongoing phase III clinical trials that are likely to impact primary therapy in ovarian cancer. We summarized the objectives and the available data from these trials. A total of 12 potentially practice-changing, randomized phase III trials in front line ovarian cancer were identified in which a biologic therapy was added to primary chemotherapy and/or was used in the maintenance setting. These trials included PARP inhibitors (PARPi), anti-angiogenic agents, immuno-oncology agents, and combinations of these agents. Of the 12 trials, 10 are ongoing, one was terminated for futility, and one has been recently reported. All of these trials emphasize the use of maintenance targeted therapy. In addition, 7 randomized phase III trials utilizing hyperthermic intraperitoneal chemotherapy (HIPEC) were identified in the setting of upfront ovarian cancer treatment. There are multiple ongoing trials in primary ovarian cancer. These trials investigate PARPi, anti-angiogenic agents, immuno-oncology agents, combinations of these agents, and HIPEC. Many of these trials will mature within the next several years and are likely to change the primary treatment of women with ovarian cancer. • There are many trials underway with biologic agents in combination and after primary chemotherapy for ovarian cancer. • SOLO 1 has changed the standard primary therapy for women with BRCA mutated ovarian cancer. • Other trials are likely to change the standard of care for the primary treatment of ovarian cancer. [ABSTRACT FROM AUTHOR]

Introduction: Treatment options and decisions are often based on the results of clinical trials. We have evaluated the public availability of results from completed, registered phase III clinical trials on diabetic nephropathy and current treatment options.Methods: This was a cross-sectional analysis in which STrengthening the Reporting of OBservational studies in Epidemiology criteria were applied for design and analysis. In June 2017, 34 completed phase III clinical trials on diabetic nephropathy in the ClinicalTrials. gov registry were identified and matched to publications in the ClinicalTrials.gov registry and to those in the PubMed and Google Scholar databases. If no publication was identified, the principal investigator was contacted. The ratio of published and non-published studies was calculated. Various parameters, including study design, drugs, and comparators provided, were analyzed.Results: Drugs/supplements belonged to 26 different categories of medications, with the main ones being angiotensin-converting enzyme inhibitors, angiotensin-II receptors blockers, and dipeptidyl-peptidase-4-inhibitors. Among the trials completed before 2016 (n = 32), 22 (69%) were published, and ten (31%) remained unpublished. Thus, data on 11 different interventions and more than 1000 patients remained undisclosed. Mean time to publication was 26.5 months, which is longer than the time constrictions imposed by the U.S. Food and Drug Administration Amendments Act. Most trials only showed weak effects on micro- and macroalbuminuria, with an absolute risk reduction of 1.0 and 0.3%, respectively, and the number needed to treat varied between 91 and 333, without any relevant effect on end-stage-renal disease by intensive glucose-lowering treatment. Comparison of the results, however, was difficult since study design, interventions, and the renal outcome parameters vary greatly between the studies.Conclusion: Despite the financial and human resources involved and the relevance for therapeutic guidelines and clinical decisions, about one-third of phase III clinical trials on diabetic nephropathy remain unpublished. Interventions used in published trials showed a low efficacy on renal outcome.Funding: Deutsche Forschungsgemeinschaft (DFG): SFB 1118. [ABSTRACT FROM AUTHOR]

Background: Despite more than 60 years of clinical trials, tuberculosis (TB) still causes a high global burden of mortality and morbidity. Treatment currently requires multiple drugs in combination, taken over a prolonged period. New drugs are needed to shorten treatment duration, prevent resistance and reduce adverse events. However, to improve on current methodology in drug development, a more complete understanding of the existing clinical evidence base is required.Methods: A systematic review was undertaken to summarise outcomes reported in phase III trials of patients with newly diagnosed pulmonary TB. A systematic search of databases (PubMed, MEDLINE, EMBASE, CENTRAL and LILACs) was conducted on 30 November 2017 to retrieve relevant peer-reviewed articles. Reference lists of included studies were also searched. This systematic review considered all reported outcomes.Results: Of 248 included studies, 229 considered "on-treatment" outcomes whilst 148 reported "off-treatment" outcomes. There was wide variation and ambiguity in the definition of reported outcomes, including their relationship to treatment and in the time points evaluated. Additional challenges were observed regarding the analysis approach taken (per protocol versus intention to treat) and the varying durations of "intensive" and "continuation" phases of treatment. Bacteriological outcomes were most frequently reported but radiological and clinical data were often included as an implicit or explicit component of the overall definition of outcome.Conclusions: Terminology used to define long-term outcomes in phase III trials is inconsistent, reflecting evolving differences in protocols and practices. For successful future cumulative meta-analysis, the findings of this review suggest that greater availability of individual patient data and the development of a core outcome set would be desirable. In the meantime, we propose a simple and logical approach which should facilitate combination of key evidence and inform improvements in the methodology of TB drug development and clinical trials. [ABSTRACT FROM AUTHOR]

Aims: To investigate the effect of the different eligibility criteria used by phase III clinical studies in heart failure with preserved ejection fraction (HFpEF) on patient selection, phenotype, and survival.Methods and Results: We applied the key eligibility criteria of 7 phase III HFpEF studies (Digitalis Investigation Group Ancillary, Candesartan in Patients With Chronic Heart Failure and Preserved Left-Ventricular Ejection Fraction, Perindopril in Elderly People With Chronic Heart Failure, Irbesartan in Heart Failure With Preserved Systolic Function, Japanese Diastolic Heart Failure, Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist, and Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF; ongoing]) to a typical and well-characterized HFpEF population (n = 557) seen in modern European cardiological practice. Follow-up was available for a minimum of 24 months in each patient. Increasing the number of study eligibility criteria identifies a progressively smaller group of patients from real-life practice suitable for recruitment into clinical trials; using the J-DHF criteria, 81% of our clinic patients would have been eligible, whereas the PARAGON-HF criteria significantly reduced this proportion to 32%. The patients identified from our clinical population had similar mortality rates using the different criteria, which were consistently higher than those reported in the actual clinic trials.Conclusions: Trial eligibility criteria have become stricter with time, which reduces the number of eligible patients, affecting both generalizability of any findings and feasibility of completing an adequately powered trial. We could not find evidence that the additional criteria used in more recent randomized trials in HFpEF have identified patients at higher risk of all-cause mortality. [ABSTRACT FROM AUTHOR]

Many cancers, including breast cancer, have demonstrated prognosis and support advantages thanks to the discovery of targeted therapies. The advent of these new approaches marked the rise of precision medicine, which leads to improve the diagnosis, prognosis and treatment of cancer. Precision medicine takes into account the molecular and biological specificities of the patient and their tumors that will influence the treatment determined by physicians. This new era of medicine is accessible through molecular genetics platforms, the development of high-speed sequencers and means of analysis of these data. Despite the spectacular results in the treatment of cancers including breast cancer, described in this review, not all patients however can benefit from this new strategy. This seems to be related to the many genetic mutations, which may be different from one patient to another or within the same patient. It comes to give new impetus to the research-both from a technological and biological point of view-to make the hope of precision medicine accessible to all. [ABSTRACT FROM AUTHOR]

The key elements in recent drug development aiming toward personalized medicine involve the development of baseline predictive biomarkers to predict the responsiveness to new treatments. When biological evidence to support the biomarker hypothesis is not strong, it is particularly important to evaluate the clinical validity of a predictive biomarker based on data from clinical trials. All-comers randomized clinical trials stratified with biomarker measurements can provide the opportunity to evaluate the predictive value of the biomarker, and a test of treatment-by-biomarker interaction is applied for this purpose. If the interaction is significant, it is natural to proceed to a subgroup analysis that evaluates treatment efficacy within biomarker-based subgroups. However, estimation bias can arise when using the standard estimation method without regard to the significant interaction because of the correlation between the interaction test and subgroup analysis. In this paper, after evaluating the bias function for the standard estimators, we provide bias-corrected point and interval estimation methods, including polynomial approximations of the bias function previously developed for a fallback analysis plan. The magnitude of bias reduction and precision of the proposed estimators are assessed via simulations. Applications to biomarker-stratified, randomized phase III trials in oncology are provided. Supplementary materials for this article are available online. [ABSTRACT FROM AUTHOR]

• Across all analysed drugs, 27.2% of the patients would have been eligible for inclusion into a phase III clinical trial if all five predefined criteria were applied. • 61.5% of patiets would have been included into the respective clinical trial if the selection criterion "relapse" was dropped. • A low transferability of phase III clinical trial criteria, to patients in routine care with the exception of age, does not imply a higher risk with regard to adverse and serious adverse events. The aim of this study was to evaluate how many MS patients treated with an approved DMD in routine care would have fulfilled the inclusion and exclusion criteria of phase III clinical trial and would therefore be eligible for the respective drug trial. Further, adverse events and disease progression for these patients were compared. A comparison of patients fulfilling phase III clinical trial inclusion and exclusion criteria and those who do not with regard to sociodemographic and clinical characteristics, adverse events and disease progression. Database was the REGIMS register, a national, prospective, observational, clinical multicentre registry. 1248 MS Patients were included. 27.2% patients would have been eligible for inclusion into a phase III clinical trial of their indication. Patients who did not meet the criterion age are more likely to have a serious adverse event (SAE), whereas patients who did not fulfil the criterion relapse had a significant lower occurrence of an adverse event (AE). Non-fulfilment of other inclusion criteria (EDSS Score; medication history and MS type) did not show any significant differences in drug safety variables, AE and SAE. Our results suggest that a low transferability of phase III clinical trial criteria, to patients in routine care with the exception of age, does not imply a higher risk with regard to adverse and serious adverse events. [ABSTRACT FROM AUTHOR]

In advanced renal cell carcinoma, few randomized controlled trials involving immunotherapy plus antiangiogenic therapy have shown survival benefits relative to Sunitinib. Our meta-analysis aimed to evaluate the efficacy and safety of combined immunotherapy and antiangiogenic therapy compared to Sunitinib therapy alone in patients with advanced renal cell carcinoma. Six phase III randomized controlled trials were analyzed, including 4,119 patients. The primary endpoints were overall survival and progression-free survival, and the secondary endpoints were objective response rate and serious adverse events. The results showed that combined immunotherapy and antiangiogenic therapy significantly improved overall survival, progression-free survival, and objective response rate compared to Sunitinib alone. No significant difference was observed in adverse events between the two groups. This study suggests that combined immunotherapy and antiangiogenic therapy is a great treatment option for advanced renal cell carcinoma., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Patel et al.)

Purpose: Although health-related quality of life (HRQL) is increasingly assessed in randomized controlled trials (RCTs), HRQL findings are not always incorporated into clinical decision making. We examined the current perspectives of oncologists on the use of HRQL findings from RCTs, and variation of these perspectives between countries and specialties. Methods: A cross-sectional e-survey of oncologist members of the NCIC Clinical Trials Group, the United Kingdom National Cancer Research Institute Clinical Studies Groups, and the Australia/New Zealand cancer clinical trials network was conducted. Respondents reported their perceptions of the usefulness of RCT HRQL outcomes for informing practice, their use of HRQL findings in practice, barriers/facilitators to this use, and preferences for HRQL data presentation in RCT publications. Chi-square tests compared responses between countries and specialties. Results: A total of 396 oncologists participated (estimated response rate: 30 %). The most frequently reported specialties were medical (46 %) and radiation (37 %) oncology. HRQL findings from RCTs were reported as useful (73 %), but were infrequently used to guide clinical decisions with patients. Perceived barriers were lack of time (67 %) and understanding (57 %), and concerns about generalizability of results (68 %). Identified facilitators included joint publication of HRQL/clinical outcomes (96 %) and summary of clinical implications of HRQL findings in RCT publications (76 %). Use of HRQL findings, perceived barriers/facilitators, and presentation preferences did not differ by country or specialty. Conclusions: Oncologists support HRQL findings from RCTs, but perceive important barriers to their use in clinical decision making, regardless of country or specialty. Combined, clear reporting of HRQL/clinical data may facilitate their clinical application. [ABSTRACT FROM AUTHOR]

Purpose. This study measured the time taken for setting up the different facets of Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO), an international phase III study being conducted in 44 participating countries. Methods. Time to regulatory authority (RA) approval, time to ethics committee/institutional review board (EC/IRB) approval, time from study approval by EC/IRB to first randomized patient, and time from first to last randomized patient were prospectively collected in the ALTTO study. Analyses were conducted by grouping countries into either geographic regions or economic classes as per the World Bank's criteria. Results. South America had a significantly longer time to RA approval (median: 236 days, range: 21-257 days) than Europe (median: 52 days, range: 0 -151 days), North America (median: 26days, range:22-30days),and Asia-Pacific (median:62 days, range: 37-75 days). Upper-middle economies had longer times to RA approval (median: 123 days, range: 21-257 days) than high-income (median: 47 days, range: 0-112 days) and lower-middle income economies (median: 57 days, range: 37-62 days). No significant difference was observed for time to EC/IRB approval across the studied regions (median: 59 days, range 0-174 days). Overall, the median time from EC/IRB approval to first recruited patient was 169 days (range: 26-412 days). Conclusion. This study highlights the long time intervals required to activate a global phase III trial. Collaborative research groups, pharmaceutical industry sponsors, and regulatory authorities should analyze the current system and enter into dialogue for optimizing local policies. This would enable faster access of patients to innovative therapies and enhance the efficiency of clinical research. [ABSTRACT FROM AUTHOR]

In a phase III multi-center cancer clinical trial or a large public health study, sample size is predetermined to achieve desired power, and study participants are enrolled from tens or hundreds of participating institutions. As the accrual is closing to the target size, the coordinating data center needs to project the accrual closure date on the basis of the observed accrual pattern and notify the participating sites several weeks in advance. In the past, projections were simply based on some crude assessment, and conservative measures were incorporated in order to achieve the target accrual size. This approach often resulted in excessive accrual size and subsequently unnecessary financial burden on the study sponsors. Here we proposed a discrete-time Poisson process-based method to estimate the accrual rate at time of projection and subsequently the trial closure date. To ensure that target size would be reached with high confidence, we also proposed a conservative method for the closure date projection. The proposed method was illustrated through the analysis of the accrual data of the National Surgical Adjuvant Breast and Bowel Project trial B-38. The results showed that application of the proposed method could help to save considerable amount of expenditure in patient management without compromising the accrual goal in multi-center clinical trials. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

It is not uncommon to have experimental drugs under different stages of development for a given disease area. Methods are proposed for use when another treatment arm is to be added mid-study to an ongoing clinical trial. Monte Carlo simulation was used to compare potential analytical approaches for pairwise comparisons through a difference in means in independent normal populations including (1) a linear model adjusting for the design change (stage effect), (2) pooling data across the stages, or (3) the use of an adaptive combination test. In the presence of intra-stage correlation (or a non-ignorable fixed stage effect), simply pooling the data will result in a loss of power and will inflate the type I error rate. The linear model approach is more powerful, but the adaptive methods allow for flexibility (re-estimating sample size). The flexibility to add a treatment arm to an ongoing trial may result in cost savings as treatments that become ready for testing can be added to ongoing studies. [ABSTRACT FROM AUTHOR]

The design, endpoints, statistical methods, and equivalence boundary for studies seeking to demonstrate clinical similarity between biologics are not standardized by any regulatory agency. We describe our experience in conducting a phase III study of a biologic product before and after a manufacturing change, focusing on statistical considerations for claiming equivalence for the dosing endpoint. We discuss and evaluate traditional statistical methods like two one-sided testing and the Kolmogorov-Smirnov test, as well as the newly proposed overlap coefficient method. We conclude that establishing clinical similarity of biologics is complex and demands more thought from regulatory agencies and the biopharmaceutical industry. [ABSTRACT FROM AUTHOR]

Abstract: The target of novel signal transduction inhibitors may be present on normal as well as tumor cells, resulting in mechanistic adverse effects (AE) in addition to antitumor activity. As those AEs lie in the causal pathway that patients respond to the drug, may thus serve as an indicator of benefit from the drug. In this paper, we discuss issues in validating drug related AEs as predictive markers of overall survival benefit. Based on our proposed approach, we showed that erlotinib induced skin rash appears to predict a survival benefit. [Copyright &y& Elsevier]

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A pharmaceutical intervention that has received great attention in recent years for treating Alzheimer's disease (AD) is the use of antibodies targeting amyloid beta (Aβ) in the brain, as the formation of Aβ plaques is considered as being the driving force for the development and progression of AD. Recently, a Phase III trial in patients with mild-to-moderate AD has provided ambivalent evidence for the efficacy of this intervention. In this trial, the intravenous administration of bapineuzumab, a monoclonal antibody targeting Aβ in the brain, for 78 weeks led to a reduction of cerebrospinal fluid levels of phosphorylated tau and evidence for lower Aβ accumulation in the brain of AD patients who carried APOE ε4. However, this treatment did not improve clinical outcomes (e.g. the rate of cognitive decline) in these patients. Similar null results with respect to the rate of cognitive decline were found in a separate Phase III clinical trial after treatment with solanezumab. Based on these findings, one conclusion could be that antibodies targeting Aβ in the brain may unfold their highest efficacy when given before the development of clinical AD symptoms, i.e. during a period where neurodegeneration but not cognitive loss represents the major pathology. Another conclusion could be that antibody-based pharmaceutical interventions may fail to slow the progress of cognitive loss in patients who have AD because of their solely pharmaceutical therapeutic approach. Leisure activities that require patients' mental and physical abilities (e.g. exercise) are associated with a reduced risk of developing dementia. In the same manner, they may help to curb the progress of this devastating disease. Thus, combining the use of antibodies targeting Aβ with therapeutic strategies that require patients' mental and physical abilities might help tackle the neurodegenerative dynamics and cognitive loss both in patients with AD, and its prodromal state, mild cognitive impairment. [ABSTRACT FROM AUTHOR]

Neuropathic pain is characterized by abnormal hypersensitivity to stimuli (hyperalgesia) and nociceptive responses to non-noxious stimuli (allodynia). The conditions and the pathophysiological states that determine the onset of neuropathic pain are heterogeneous, such as metabolic disorders, neuropathy caused by viral infections, and autoimmune diseases affecting the central nervous system (CNS). Neuropathic pain in the general population is estimated to have a prevalence ranging between 3% and 17%. Most of the available treatments for neuropathic pain have moderate efficacy and present side effects that limit their use; therefore, other therapeutic approaches are needed for patients. In this article, the current standard of care treatment, the emerging pharmacological approaches from the completed phase III clinical trials, and the preclinical studies on novel promising therapeutic options will be reviewed.

Background: Nausea and vomiting are among the most feared side effects of chemotherapy and can prevent cancer patients from completing their treatment regimens. Rolapitant is a highly selective neurokinin-1 (NK-1) receptor antagonist with very good oral activity, central nervous system penetration and a long (180-hour) plasma half-life. Unlike other available NK-1 receptor antagonists, rolapitant does not inhibit or induce cytochrome P450 (CYP) 3A4., Methods: Findings from recent phase II and III clinical trials of rolapitant in patients receiving highly or moderately emetogenic chemotherapy are reviewed and discussed., Results: The addition of a single-dose of rolapitant to combination 5-hydroxytryptamine type 3 receptor antagonist and dexamethasone regimens provided increased protection against chemotherapyinduced nausea and vomiting, a benefit that encompassed the entire at-risk period investigated (0-120 hours after initiation of chemotherapy) in patients receiving highly or moderately emetogenic chemotherapy. Rolapitant was well tolerated by patients in these trials, with the overall frequency of treatment- related adverse events similar in patients receiving rolapitant (7.0%) and active placebo (6.3%)., Conclusion: Rolapitant's favorable toxicity profile and lack of CYP3A4-related drug-drug interactions indicate that it would be a suitable treatment for older patients or those with multiple comorbidities, who are likely to be receiving a number of concomitant medications. Future studies should focus on the role of rolapitant in the control of chemotherapy-induced nausea and vomiting in patients receiving multiple-day chemotherapy, specific chemotherapy agents or high-dose chemotherapy and stem cell support., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)