Motivational Drivers in Implant Therapy: A Novel Treatment Motivation Scale.

Aim This study aims to assess patient motivation during implant therapy using the newly developed implant treatment motivation scale. Materials and methods A questionnaire study was conducted, consisting of 15 questions designed to explore the motivating factors behind patients' decision to undergo implant therapy. A total of 50 patients about to undergo implant treatment at the Departments of Periodontology, Oral and Maxillofacial Surgery, and Prosthodontics participated in the study.  Results Analysis revealed a consistently high level of motivation (intrinsic and extrinsic) among all patients undergoing implant therapy. Conclusions The findings highlight the crucial role of motivation in treatment-seeking behavior, emphasizing the importance of dentists in motivating and guiding patients through the process of implant therapy.

Role of Clinical Pharmacology in Diversity and Inclusion in Global Drug Development: Current Practices and Industry Perspectives: White Paper.

The 2022 United States Food and Drug Administration (US FDA) draft guidance on diversity plan (DP), which will be implemented through the Diversity Action Plans by December 2025, under the 21st Century Cures Act, marks a pivotal effort by the FDA to ensure that registrational studies adequately reflect the target patient populations based on diversity in demographics and baseline characteristics. This white paper represents the culminated efforts of the International Consortium of Quality and Innovation (IQ) Diversity and Inclusion (D&I) Working Group (WG) to assess the implementation of the draft FDA guidance by members of the IQ consortium in the discipline of clinical pharmacology (CP). This article describes current practices in the industry and emphasizes the tools and techniques of quantitative pharmacology that can be applied to support the inclusion of a diverse population during global drug development, to support diversity and inclusion of underrepresented patient populations, in multiregional clinical trials (MRCTs). It outlines strategic and technical recommendations to integrate demographics, including age, sex/gender, race/ethnicity, and comorbidities, in multiregional phase III registrational studies, through the application of quantitative pharmacology. Finally, this article discusses the challenges faced during global drug development, which may otherwise limit the enrollment of a broader, potentially diverse population in registrational trials. Based on the outcomes of the IQ survey that provided the current awareness of diversity planning, it is envisioned that in the future, industry efforts in the inclusion of previously underrepresented populations during global drug development will culminate in drug labels that apply to the intended patient populations at the time of new drug application or biologics license application rather than through post-marketing requirements.

A Comparative Cytocompatibility Assessment of Leukocyte-Platelet-Rich Fibrin (L-PRF) and Injectable Platelet-Rich Fibrin (I-PRF) on the Pre-osteoblastic MG-63 Cell Line in Chronic Periodontitis Patients: An In Vitro Study.

Aim The aim of the study is to assess the cellular viability of various concentrations of different platelet concentrates on pre-osteoblastic MG-63 cells. Materials and methods In this in-vitro experiment, blood samples from 21 individuals with chronic periodontitis were taken and centrifuged according to Choukroun and Miron's protocol to prepare L-PRF and I-PRF, respectively. The methyl thiazolyl tetrazolium (MTT) test was used to determine the viability of 0%, 1%, 2%, 4%, 8%, 10%, and 20% concentrations of L-PRF and I-PRF on MG-63 cells. Results The 20% L-PRF had the lowest percentage of cell viability (90.429±2.06), and the 1% I-PRF had the highest percentage (98.918±0.54), with no statistically significant difference (p>0.05). Conclusion According to the findings of the current study, both L-PRF and I-PRF provide favorable outcomes in terms of the viability of MG-63 cells in chronic periodontitis patients that may be utilized for regenerative purposes such as periodontal osseous defects and mucogingival surgeries. Incorporating these platelet concentrates with bone grafts results in enhanced regenerative outcomes.

Next-generation phenotyping: introducing phecodeX for enhanced discovery research in medical phenomics.

MOTIVATION: Phecodes are widely used and easily adapted phenotypes based on International Classification of Diseases codes. The current version of phecodes (v1.2) was designed primarily to study common/complex diseases diagnosed in adults; however, there are numerous limitations in the codes and their structure. RESULTS: Here, we present phecodeX, an expanded version of phecodes with a revised structure and 1,761 new codes. PhecodeX adds granularity to phenotypes in key disease domains that are under-represented in the current phecode structure-including infectious disease, pregnancy, congenital anomalies, and neonatology-and is a more robust representation of the medical phenome for global use in discovery research. AVAILABILITY AND IMPLEMENTATION: phecodeX is available at https://github.com/PheWAS/phecodeX.

Single-Dose Pharmacokinetics and Metabolism of the Oral Decongestant Phenylephrine HCl in Children and Adolescents.

INTRODUCTION: Pediatric data for phenylephrine, a decongestant used in cold medicines, are limited. This study characterized the pharmacokinetics and metabolism of phenylephrine HCl in children aged 2-17 years. METHODS: Forty-one children experiencing nasal congestion were dosed orally with phenylephrine HCl from 2.5 to 10 mg using a modified weight-age schedule. Plasma from blood samples collected up to 4.5 h after dosing was analyzed for phenylephrine. Urine collected over 24 h was analyzed for phenylephrine and metabolites. Blood pressure and pulse were measured after each blood sampling, and electrocardiograms were recorded before and after dosing. Pharmacokinetic parameters were estimated using noncompartmental methods. RESULTS: Mean phenylephrine total exposure (AUC∞) for children aged 2-5, 6-11, and 12-17 years was 672, 830, and 1020 pg∙h/mL, and mean maximum concentration (Cmax) was 477, 589, and 673 pg/mL, respectively. Times to peak concentration (Tmax) ranged from 0.17 to 1.5 h, and elimination half-life (t½,ß) was short from 1.2 to 1.6 h. Oral clearance (CL/F) increased with age, but with allometric scaling for body size, this trend reversed as scaled clearance (CL/F,scaled) was modestly higher in youngest children. No clinically relevant changes in vital signs or electrocardiograms were observed. CONCLUSION: A dosing schedule with additional weight-age increments would provide more consistent systemic concentrations as children age and receive the next higher dose. No developmental delays in clearance mechanisms were apparent when oral clearance was scaled for body size. Phenylephrine pharmacokinetics and metabolism were consistent with adult data, although AUC∞ for the youngest group and Cmax for all pediatric groups were lower. Single doses of phenylephrine HCl were well tolerated. TRIAL REGISTRATION: Clintrials.gov NCT00762567, registered 30 September 2008.

Differential Engagement by Race/Ethnicity in Experimental Trials of Mental Health Treatment Interventions: A Systematic Review.

Objective: Research on mental health interventions, largely from observational studies, suggests that individuals who are Black, Indigenous, and People of Color (BIPOC) have lower treatment engagement than non-Latino Whites. This systematic review focuses on prospective, experimental treatment trials, which reduce variability in patient and intervention characteristics and some access barriers (eg, cost), to examine the association of race/ethnicity and engagement.Data Sources: A systematic search of PubMed and PsycINFO through May 2020 using terms covering mental health treatment, engagement, and race/ethnicity.Study Selection: US-based, English-language, prospective experimental (including quasi-experimental) trials of adults treated for DSM-defined mental disorders were included. Studies had to compare engagement (treatment initiation and retention, medication adherence) across 2 or more ethnoracial groups. Fifty-five of 2,520 articles met inclusion criteria.Data Extraction: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and the Cochrane Collaboration bias-risk assessment tool were used to report study findings.Results: Twenty-nine articles (53%) reported significant ethnoracial engagement differences, of which 93% found lower engagement among BIPOC groups compared largely to non-Latino Whites. The proportion of significant findings was consistent across quality of studies, covariate adjustments, ethnoracial groups, disorders, treatments, and 4 engagement definitions. Reporting limitations were found in covariate analyses and disaggregation of results across specific ethnoracial groups.Conclusions: Prospective experimental treatment trials reveal consistently lower BIPOC engagement, suggesting persisting disparities despite standardized study designs. Future research should improve inclusion of understudied groups, examine covariates systematically, and follow uniform reporting and analytic practices to elucidate reasons for these disparities.

Racial/Ethnic Disparities in Substance Use Treatment in Medicaid Managed Care in New York City: The Role of Plan and Geography.

OBJECTIVE: The aim was to assess the magnitude of health care disparities in treatment for substance use disorder (SUD) and the role of health plan membership and place of residence in observed disparities in Medicaid Managed Care (MMC) plans in New York City (NYC). DATA SOURCE: Medicaid claims and managed care plan enrollment files for 2015-2017 in NYC. RESEARCH DESIGN: We studied Medicaid enrollees with a SUD diagnosis during their first 6 months of enrollment in a managed care plan in 2015-2017. A series of linear regression models quantified service disparities across race/ethnicity for 5 outcome indicators: treatment engagement, receipt of psychosocial treatment, follow-up after withdrawal, rapid readmission, and treatment continuation. We assessed the degree to which plan membership and place of residence contributed to observed disparities. RESULTS: We found disparities in access to treatment but the magnitude of the disparities in most cases was small. Plan membership and geography of residence explained little of the observed disparities. One exception is geography of residence among Asian Americans, which appears to mediate disparities for 2 of our 5 outcome measures. CONCLUSIONS: Reallocating enrollees among MMC plans in NYC or evolving trends in group place of residence are unlikely to reduce disparities in treatment for SUD. System-wide reforms are needed to mitigate disparities.

Re-adjudication of the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) with study-level meta-analysis of hospitalization for heart failure from cardiovascular outcomes trials with dipeptidyl peptidase-4 (DPP-4) inhibitors.

BACKGROUND: Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) assessed the cardiovascular (CV) safety of sitagliptin versus placebo on CV outcomes in patients with type 2 diabetes and CV disease and found sitagliptin noninferior to placebo. Subsequently, based on feedback from FDA, the Sponsor of the trial, Merck & Co., Inc., engaged a separate academic research organization, the TIMI Study Group, to re-adjudicate a prespecified set of originally adjudicated events. METHODS: TIMI adjudicated in a blinded fashion all potential hospitalization for heart failure (HHF) events, all potential MACE+ events previously adjudicated as not an endpoint event, and a random subset (~10%) of MACE+ events previously adjudicated as an endpoint event. An updated study-level meta-analysis of four randomized, placebo-controlled, CV outcomes trials with dipeptidyl peptidase 4 (DPP-4) inhibitors was then performed. RESULTS: After re-adjudication of potential HHF events in the intent-to-treat population, there were 224 patients with a confirmed event in the sitagliptin arm (1.05/100 person-years) and 239 patients in the placebo arm (1.13/100 person-years), corresponding to a hazard ratio (HR) of 0.94 (95% confidence interval [95% CI]: 0.78-1.13, p = .49). Concordance between the outcome of the original adjudication and the re-adjudication for HHF events was 82.7%. The meta-analysis of CV outcomes trials with DPP-4 inhibitors with placebo and involving 43 522 patients yielded an HR of 1.07 (95% CI: 0.83-1.39), with moderate heterogeneity (p = .45, I2 = 62.07%). CONCLUSION: The results of this independent re-adjudication process and analyses of CV outcomes from TECOS were consistent with the original adjudication results and overall study findings. An updated study-level meta-analysis showed no overall significant risk for HHF with DPP-4 inhibitors, but with statistical heterogeneity.

Safety and preliminary immunogenicity of JNJ-64041809, a live-attenuated, double-deleted Listeria monocytogenes-based immunotherapy, in metastatic castration-resistant prostate cancer.

BACKGROUND: The safety and immunogenicity of JNJ-64041809 (JNJ-809), a live-attenuated, double-deleted Listeria monocytogenes (LADD Lm)-based immunotherapy targeting 4 relevant prostate cancer antigens, was evaluated in a phase 1 study in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: Men with progressive mCRPC who had received ≥2 prior approved therapies were enrolled. Primary study objectives were to determine the recommended phase 2 dose (RP2D) and to evaluate the safety and immunogenicity of JNJ-809. RESULTS: A total of 26 patients received JNJ-809 (1 × 108 CFU (n = 6); 1 × 109 CFU (n = 20)). No dose-limiting toxicities were reported, and 1 × 109 CFU was selected as the RP2D. The most common adverse events (AEs) reported were chills (92%), pyrexia (81%), and fatigue (62%). The most frequent grade ≥3 AEs were lymphopenia (27%) and hypertension (23%). Serious AEs were reported in 27% of patients including 1 patient with grade 3 intestinal obstruction. JNJ-809 transiently induced peripheral cytokines, including interferon-γ, interleukin-10, and tumor necrosis factor-α. Of the 7 patients evaluable for T cell responses at the 1 × 109 CFU dose, evidence of post-treatment antigenic responses were observed in 6 to the Listeria antigen listeriolysin O and in 5 to ≥1 of the 4 encoded tumor antigens. Best overall response was stable disease in 13/25 response-evaluable patients. The study was terminated early as data collected were considered sufficient to evaluate safety and immunogenicity. CONCLUSIONS: JNJ-809 has manageable safety consistent with other LADD Lm-based therapies. Limited antigen-specific immune responses were observed, which did not translate into objective clinical responses.

Subcutaneous daratumumab in Asian patients with heavily pretreated multiple myeloma: subgroup analyses of the noninferiority, phase 3 COLUMBA study.

The phase 3 COLUMBA study demonstrated noninferiority of subcutaneous daratumumab (DARA SC) to intravenous daratumumab (DARA IV) in relapsed or refractory multiple myeloma. We present a subgroup analysis of Asian patients from COLUMBA. Eligible patients had ≥ 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or were double refractory. Co-primary endpoints were overall response rate (ORR) and maximum trough concentration (Ctrough). Secondary endpoints included rates of infusion-related reactions, progression-free survival, and patient-reported satisfaction with therapy. Sixty-seven Asian patients (DARA SC, n = 30; DARA IV, n = 37) were randomized, including 42 Japanese patients (DARA SC, n = 18; DARA IV, n = 24). Comparable ORRs for DARA SC versus DARA IV were seen in the Asian cohort (66.7% vs 43.2%) and Japanese-only cohort (61.1% vs 54.2%), including patients weighing ≤ 65 kg. Similarity of Ctrough was seen in both Asian and Japanese-only cohorts; the ratio of the geometric mean of the Ctrough concentrations for DARA SC/DARA IV was 143.96% (90% confidence interval (CI), 112.03-185.00%) and 148.02% (90% CI, 113.32-193.34%), respectively. The Asian cohort (both treatment groups) and Japanese-only cohort (DARA SC group) experienced higher rates of grade 3/4 cytopenias compared with the global COLUMBA population, occurring predominantly in patients of low bodyweight; no patients discontinued treatment due to cytopenias. The Cancer Therapy Satisfaction Questionnaire results generally favored DARA SC. In the Asian and Japanese-only cohorts, DARA SC was comparable to DARA IV. The efficacy, pharmacokinetic, safety, and satisfaction results were generally consistent with the global COLUMBA population regardless of patient bodyweight. ClinicalTrials.gov Identifier: NCT03277105.

Exposure-Response and Population Pharmacokinetic Analyses of a Novel Subcutaneous Formulation of Daratumumab Administered to Multiple Myeloma Patients.

We report the population pharmacokinetic (PK) and exposure-response analyses of a novel subcutaneous formulation of daratumumab (DARA) using data from 3 DARA subcutaneous monotherapy studies (PAVO Part 2, MMY1008, COLUMBA) and 1 combination therapy study (PLEIADES). Results were based on 5159 PK samples from 742 patients (DARA 1800 mg subcutaneously, n = 487 [monotherapy, n = 288; combination therapy, n = 199]; DARA 16 mg/kg intravenously, n = 255 [all monotherapy, in COLUMBA]; age, 33-92 years; weight, 28.6-147.6 kg). Subcutaneous and intravenous DARA monotherapies were administered once every week for cycles 1-2, once every 2 weeks for cycles 3-6, and once every 4 weeks thereafter (1 cycle is 28 days). The subcutaneous DARA combination therapy was administered with the adaptation of corresponding standard-of-care regimens. PK samples were collected between cycle 1 and cycle 12. Among monotherapy studies, throughout the treatment period, subcutaneous DARA provided similar/slightly higher trough concentrations (Ctrough ) versus intravenous DARA, with lower maximum concentrations and smaller peak-to-trough fluctuations. The PK profile was consistent between subcutaneous DARA monotherapy and combination therapies. The exposure-response relationship between daratumumab PK and efficacy or safety end points was similar for subcutaneous and intravenous DARA. Although the ≤65-kg subgroup reported a higher incidence of neutropenia, no relationship was found between the incidence of neutropenia and exposure, which was attributed, in part, to the preexisting imbalance in neutropenia between subcutaneous DARA (45.5%) and intravenous DARA (19%) in patients ≤50 kg. A flat relationship was observed between body weight and any grade and at least grade 3 infections. The results support the DARA 1800-mg subcutaneous flat dose as an alternative to the approved intravenous DARA 16 mg/kg.

Subcutaneous daratumumab plus standard treatment regimens in patients with multiple myeloma across lines of therapy (PLEIADES): an open-label Phase II study.

Daratumumab is a CD38-targeting monoclonal antibody approved for intravenous (IV) infusion for multiple myeloma (MM). We describe the Phase II PLEIADES study of a subcutaneous formulation of daratumumab (DARA SC) in combination with standard-of-care regimens: DARA SC plus bortezomib/lenalidomide/dexamethasone (D-VRd) for transplant-eligible newly diagnosed MM (NDMM); DARA SC plus bortezomib/melphalan/prednisone (D-VMP) for transplant-ineligible NDMM; and DARA SC plus lenalidomide/dexamethasone (D-Rd) for relapsed/refractory MM. In total, 199 patients were treated (D-VRd, n = 67; D-VMP, n = 67; D-Rd, n = 65). The primary endpoints were met for all cohorts: the ≥very good partial response (VGPR) rate after four 21-day induction cycles for D-VRd was 71·6% [90% confidence interval (CI) 61·2-80·6%], and the overall response rates (ORRs) for D-VMP and D-Rd were 88·1% (90% CI 79·5-93·9%) and 90·8% (90% CI 82·6-95·9%). With longer median follow-up for D-VMP and D-Rd (14·3 and 14·7 months respectively), responses deepened (ORR: 89·6%, 93·8%; ≥VGPR: 77·6%, 78·5%), and minimal residual disease-negativity (10-5 ) rates were 16·4% and 15·4%. Infusion-related reactions across all cohorts were infrequent (≤9·0%) and mild. The median DARA SC administration time was 5 min. DARA SC with standard-of-care regimens demonstrated comparable clinical activity to DARA IV-containing regimens, with low infusion-related reaction rates and reduced administration time.

Scientific diligence for oncology drugs: a pharmacology, translational medicine and clinical perspective.

Increasingly, new drug development by major pharmaceutical companies relies on in-licensing of innovative therapies. Often there are limited data accompanying these novel entities. By focusing on scientific principles and generating key preclinical and clinical data, discovery companies can improve their valuations. From the lens of a large pharmaceutical company, we highlight key scientific aspects that are assessed to mitigate risk in valuations and deal terms. Our focus is on clinical development aspects for oncology drugs by stage of development. However, these lessons apply equally to other therapeutic areas.

Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial.

BACKGROUND: Intravenous daratumumab for treatment of patients with multiple myeloma involves a lengthy infusion that affects quality of life, and infusion-related reactions are common. Subcutaneous daratumumab is thought to be easier to administer and to cause fewer administration-related reactions. In this study (COLUMBA), we tested the non-inferiority of subcutaneous daratumumab to intravenous daratumumab. METHODS: In this ongoing, multicentre (147 sites in 18 countries), open-label, non-inferiority, randomised, phase 3 trial, we recruited adult patients (age ≥18 years) if they had confirmed relapsed or refractory multiple myeloma according to International Myeloma Working Group criteria; received at least three previous lines of therapy, including a proteasome inhibitor and immunomodulatory drug, or were double refractory to both a proteasome inhibitor and immunomodulatory drug; and had an Eastern Cooperative Oncology Group performance status score of 2 or lower. Patients were randomly assigned (1:1) by a computer-generated randomisation schedule and balanced using randomly permuted blocks to receive daratumumab subcutaneously (subcutaneous group) or intravenously (intravenous group). Randomisation was stratified on the basis of baseline bodyweight (≤65 kg, 66-85 kg, >85 kg), previous therapy lines (≤four vs >four), and myeloma type (IgG vs non-IgG). Patients received 1800 mg of subcutaneous daratumumab co-formulated with 2000 U/mL recombinant human hyaluronidase PH20 or 16 mg/kg of intravenous daratumumab once weekly (cycles 1-2), every 2 weeks (cycles 3-6), and every 4 weeks thereafter (28-day cycles) until progressive disease or toxicity. The co-primary endpoints were overall response and maximum trough concentration (Ctrough; cycle 3, day 1 pre-dose). The non-inferiority margin for overall response was defined using a 60% retention of the lower bound (20·8%) of the 95% CI of the SIRIUS trial. Efficacy analyses were done by intention-to-treat population. The pharmacokinetic-evaluable population included all patients who received all eight weekly daratumumab doses in cycles 1 and 2 and provided a pre-dose pharmacokinetics blood sample on day 1 of cycle 3. The safety population included all patients who received at least one daratumumab dose. This trial is registered with ClinicalTrials.gov, NCT03277105. FINDINGS: Between Oct 31, 2017, and Dec 27, 2018, 655 patients were screened, of whom 522 were recruited and randomly assigned (subcutaneous group n=263; intravenous group n=259). Three patients in the subcutaneous group and one in the intravenous group did not receive treatment and were not evaluable for safety. At a median follow-up of 7·5 months (IQR 6·5-9·3), overall response and Ctrough met the predefined non-inferiority criteria. An overall response was seen in 108 (41%) of 263 patients in the subcutaneous group and 96 (37%) of 259 in the intravenous group (relative risk 1·11, 95% CI 0·89-1·37). The geometric means ratio for Ctrough was 107·93% (90% CI 95·74-121·67), and the maximum Ctrough was 593 µg/mL (SD 306) in the subcutaneous group and 522 µg/mL (226) in the intravenous group. The most common grade 3 and 4 adverse events were anaemia (34 [13%] of 260 patients evaluable for safety in the subcutaneous group and 36 [14%] of 258 patients in the intravenous group), neutropenia (34 [13%] and 20 [8%]), and thrombocytopenia (36 [14%] and 35 [14%]). Pneumonia was the only serious adverse event in more than 2% of patients (seven [3%] in the subcutaneous group and 11 [4%] in the intravenous group). There was one death resulting from a treatment-related adverse event in the subcutaneous daratumumab group (febrile neutropenia) and four in the intravenous group (sepsis [n=2], hepatitis B reactivation [n=1], and Pneumocystis jirovecii pneumonia [n=1]). INTERPRETATION: Subcutaneous daratumumab was non-inferior to intravenous daratumumab in terms of efficacy and pharmacokinetics and had an improved safety profile in patients with relapsed or refractory multiple myeloma. These data could contribute to the approval of the subcutaneous daratumumab formulation by regulatory bodies. FUNDING: Janssen Research & Development.

Comparison of efficacy from two different dosing regimens of bortezomib: an exposure-response analysis.

Bortezomib is a first-in-class proteasome inhibitor, approved for the treatment of multiple myeloma. The originally approved dosing schedule of bortezomib results in significant toxicities that require dose interruptions and discontinuations. Consequentially, less frequent dosing has been explored to optimise bortezomib's benefit-risk profile. Here, we performed exposure-response analysis to compare the efficacy of the original bortezomib dosing regimen with less frequent dosing of bortezomib over nine 6-week treatment cycles using data from the VISTA clinical trial and the control arm of the ALCYONE clinical trial. The relationship between cumulative bortezomib dose and clinical response was evaluated with a univariate logit model. The median cumulative bortezomib dose was higher in ALCYONE versus VISTA (42·2 vs. 38·5 mg/m2 ) and ALCYONE patients stayed on treatment longer (mean: 7·2 vs. 5·8 cycles). For all endpoints and regimens, probability of clinical response correlated with cumulative bortezomib dose. Similar to results observed for VISTA, overall survival was longer in ALCYONE patients with ≥ 39·0 versus < 39·0 mg/m2 cumulative dose (hazard ratio, 0·119; P < 0·0001). Less frequent bortezomib dosing results in comparable efficacy, and a higher cumulative dose than the originally approved bortezomib dosing schedule, which may be in part be due to reduced toxicity and fewer dose reductions/interruptions.

Comparison of a transdermal contraceptive patch with a newly sourced adhesive component versus EVRA patch: A double-blind, randomized, bioequivalence and adhesion study in healthy women.

OBJECTIVE: To evaluate the bioequivalence of norelgestromin and ethinyl estradiol (NGMN-EE) and adhesion of a transdermal contraceptive patch containing a newly sourced adhesive component (test) compared with the marketed (reference) patch. STUDY DESIGN: In this randomized, double-blind, 2-way crossover study, healthy women received single 7-day application of both test and reference patches. Treatment phase included two treatment periods of 11 days each separated by a 21-day washout period starting from day of patch removal (day 8) of treatment period 1. Assessments included NGMN and EE pharmacokinetics (PK), adhesion using European Medicines Agency (EMA) 5-point scale, irritation potential and application-site reactions, and safety. Patches were bioequivalent if 90% CIs of ratios of means of test/reference for AUC168h, AUCinf, and Css fell within 80-125%. Patch adhesion was comparable if ratios of mean cumulative adhesion percentage values of test/reference were ≥90.0%. RESULTS: Seventy women were randomized; 57 completed both treatments with ≥80% adhesion (score 0-1). Bioequivalence of test and reference patches was demonstrated as 90% CI of ratio of geometric means for AUC168h, AUCinf, and Css for NGMN and EE fell within 80-125%. Both patches had similar adhesion properties (geometric mean ratio was 100.3% [90% CI, 93.2-107.9]). Similar rates of mild-to-moderate itching (11% vs 10%) and erythema events (79% vs 74%) were reported for test and reference patches, respectively, on day 8. CONCLUSIONS: The test patch with the newly sourced adhesive component is bioequivalent to the currently marketed NGMN-EE transdermal patch and has similar adhesion and irritation potential. IMPLICATIONS STATEMENT: The norelgestromin and ethinyl estradiol transdermal patch containing a newly sourced adhesive component is bioequivalent to the currently marketed patch for both active moieties. Both patches had similar adhesion, irritation potential, and safety profiles.

Oral Health-Related Quality of Life Among Publicly Insured Mental Health Service Outpatients With Serious Mental Illness.

OBJECTIVE: The study investigated factors associated with unmet need for dental care and oral health-related quality of life (OHQoL) among individuals with serious mental illness receiving outpatient care in a public mental health program serving a largely low-income population, mostly from racial-ethnic minority groups. METHODS: Cross-sectional interview data were collected from a convenience sample (N=150) of outpatients. Adjusted risk ratios (ARRs) and adjusted risk differences (ARDs) were estimated by logistic regression models to examine the independent contribution of sociodemographic and clinical factors to low OHQoL and past-year unmet dental need, defined as inability to obtain all needed dental care. RESULTS: More than half of participants reported low OHQoL (54%) and a past-year dental visit (61%). Over one-third (39%) had past-year unmet dental need. Financial barriers (ARR=3.16) and nonfinancial barriers (ARR=2.18) were associated with greater risk for past-year unmet dental need after control for age, gender, high dental anxiety, and limited English proficiency. ARDs for financial and nonfinancial barriers indicated absolute differences of 40 and 27 percentage points, respectively. Unmet dental need (ARR=1.31), xerostomia severity (ARR=1.20), and a schizophrenia spectrum diagnosis (ARR=1.33) were associated with low OHQoL, after control for age and current smoking, with ARDs ranging from 11 to 15 percentage points. CONCLUSIONS: Improving oral health promotion, oral health service access, and the integration of the mental and oral health systems may help reduce the high prevalence of low OHQoL in this population, given that low OHQoL is partly driven by unmet dental need.

Population Pharmacokinetic Analysis of Decitabine in Pediatric Patients With Acute Myeloid Leukemia.

Dacogen, the formulated product of the pharmaceutically active agent decitabine (5 aza-2'-deoxycytidine), is approved for treatment of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML). The current analysis was performed to characterize the pharmacokinetics of decitabine in pediatric patients with AML and evaluate their consistency with the PK in adult patients. A population pharmacokinetic model was developed by pooling decitabine concentration-time data from 5 adult (AML and MDS) and 2 pediatric (AML) studies. A total of 840 concentration-time data points obtained from 71 adults and 28 pediatric subjects (1 to 16 years old) were available for analysis. A 2-compartment linear pharmacokinetic (PK) model with allometric scaling using body surface area accounting for body size adequately described the PK of decitabine. After accounting for body size, decitabine pharmacokinetics were not affected by age, sex, race, dosing regimen, renal function (creatinine clearance), bilirubin, or disease type (AML or MDS) and all PK parameters (including clearance, steady-state volume of distribution, maximum concentration, time to reach maximal concentration, and terminal half-life) were comparable between adult and pediatric patients. Simulated concentration-time profiles using the final population PK model suggested that decitabine exposure at steady state was similar in adults and pediatrics for a 20 mg/m2 decitabine dose administered as a 1-hour infusion once daily. The current analysis suggests that decitabine PK is similar in pediatric AML patients and a combined adult AML and MDS population.

Why Drugs Fail in Late Stages of Development: Case Study Analyses from the Last Decade and Recommendations.

New drug development is both resource and time intensive, where later clinical stages result in significant costs. We analyze recent late-stage failures to identify drugs where failures result from inadequate scientific advances as well as drugs where we believe pitfalls could have been avoided. These can be broadly classified into two categories: 1) where science is mature and the failures can be avoided through rigorous and prospectively determined decision-making criteria, scientific curiosity, and discipline to follow up on emerging findings; and 2) where problems encountered in Phase 3 failures cannot be explained at this time, as the science is not sufficiently advanced and companies/investigators need to recognize the possibility of deficiency of our knowledge. Through these case studies, key themes critical for successful drug development emerge-understanding the therapeutic pathway including receptor and signaling biology, pharmacological responses related to safety and efficacy, pharmacokinetics of the drug and exposure at target site, optimum dose, and dosing regimen; and identification of patient sub-populations likely to respond and will have a favorable benefit-risk profile, design of clinical trials, and a quantitative framework that can guide data-driven decision making. It is essential that the right studies are conducted early in the development process to answer the key questions, with the emphasis on learning in the early stages of development, whereas Phase 3 should be reserved for confirming the safety and efficacy. Utilization of innovative technology in identifying patients based on molecular signature of their disease, rapid assessment of pharmacological response, mechanistic modeling of emerging data, seamless operational processes to reduce start-up and wind-down time for clinical trials through use of electronic health records and data mining, and development of novel and objective clinical efficacy endpoints are some concepts for improving the success rate.