Utility of real-world evidence in biosimilar development.

Biosimilar development refers to the process of creating a biologic drug that is similar to an existing approved biologic drug, also known as a reference drug. Due to the complex nature of biologics drugs and the inherent variability in their manufacturing process biosimilars are not identical but highly similar to the reference drug in terms of quality, safety, and efficacy. Efficacy and safety trials for biosimilars involve large numbers of patients to confirm comparable clinical performance of the biosimilar and the reference product in appropriately sensitive clinical indications and for appropriate sensitive endpoints. The objective of a biosimilar clinical data is to address slight differences observed at previous steps and to confirm comparable clinical performance of the biosimilar and the reference product. In recent years with advances in big data computing, there has been increasing interest to incorporate the totality of information from different data sources (e.g. Real World data and published literature) in design and conduct of clinical trial to support regulatory objectives. The biosimilar development is an ideal framework for utilization of Real-World Evidence in design of trials as potentially large amount of data are available for the reference dug. Hence there may be an opportunity to use RWD in establishing, improving or validating equivalence margins (EQM) for biosimilar designs, specifically in the case there is no historical published data in the intended sensitive population. In this article, we propose a variation of matching method that seems promising to identify the matched set from a real-world data for which the effect size of targeted endpoint would be comparable to historical data. We believe this is a reasonable approach because in design stage, we can view covariates and secondary endpoints as data feature that can be used in a matching method. This approach was illustrated through a case study which indicated the estimate of the primary endpoint is within 1% of published results and thus RWD may be used to justify or estimate the equivalence margin. To ensure consistent results we recommend using this approach in different indications and endpoint scenarios. Thus utilization of RWD/RWE can provide an important opportunity to increase access to biologic therapies, reducing cost by repurposing existing data.

The use of real-world data for clinical investigation of effectiveness in drug development.

With the growing interest in leveraging real-world data (RWD) to support effectiveness evaluations for new indications, new target populations, and post-market performance, the United States Food and Drug Administration has published several guidance documents on RWD sources and real-world studies (RWS) to assist sponsors in generating credible real-world evidence (RWE). Meanwhile, the randomized controlled trial (RCT) remains the gold standard in drug evaluation. Along this line, we propose a hybrid two-stage adaptive design to evaluate effectiveness based on evidence from both RCT and RWS. At the first stage, a typical non-inferiority test is conducted using RCT data to test for not-ineffectiveness. Once not-ineffectiveness is established, the study proceeds to the second stage to conduct an RWS and test for effectiveness using integrated information from RCT and RWD. The composite likelihood approach is implemented as a down-weighing strategy to account for the impact of high variability in RWS population. An optimal sample size determination procedure for RCT and RWS is introduced, aiming to achieve the minimal expected sample size. Through extensive numerical study, the proposed design demonstrates the ability to control type I error inflation in most cases and consistently maintain statistical power above the desired level. In general, this RCT/RWS hybrid two-stage adaptive design is beneficial for effectiveness evaluations in drug development, especially for oncology and rare diseases.

Analysis of innovative two-stage seamless adaptive design with different endpoints and population shift.

In recent years, clinical trials utilizing a two-stage seamless adaptive trial design have become very popular in drug development. A typical example is a phase 2/3 adaptive trial design, which consists of two stages. As an example, stage 1 is for a phase 2 dose-finding study and stage 2 is for a phase 3 efficacy confirmation study. Depending upon whether or not the target patient population, study objectives, and study endpoints are the same at different stages, Chow (2020) classified two-stage seamless adaptive design into eight categories. In practice, standard statistical methods for group sequential design with one planned interim analysis are often wrongly directly applied for data analysis. In this article, following similar ideas proposed by Chow and Lin (2015) and Chow (2020), a statistical method for the analysis of a two-stage seamless adaptive trial design with different study endpoints and shifted target patient population is discussed under the fundamental assumption that study endpoints have a known relationship. The proposed analysis method should be useful in both clinical trials with protocol amendments and clinical trials with the existence of disease progression utilizing a two-stage seamless adaptive trial design.

On the use of RWD in support of regulatory submission in drug development.

For the approval of a drug product, the United States Food and Drug Administration requires substantial evidence (SE) regarding effectiveness and safety of the test drug to be provided. In recent years, the use of real-world data in support of regulatory submission of pharmaceutical development has received much attention, and real-world evidence (RWE) is treated as complementary to SE by evaluating the real-world performance of the test treatment. In this article, we start by summarizing current regulatory perspectives on drug evaluation and some potential challenges in using RWE. To test for superiority in co-primary endpoints, a two-stage hybrid RCT/RWS adaptive design that combines randomized control trial for providing SE and real-world study for generating RWE is proposed. We use superiority in effectiveness and non-inferiority in safety as an example to illustrate how to implement this design. Numerical studies have shown that the proposed design has merits in reducing the required sample size compared with traditional co-primary endpoint tests while maintaining statistical power and controlling type I error inflation. The proposed design can be implemented in drug development considering co-primary endpoints, especially for oncology and rare disease drug development.

Risk Factors for Invasive Fungal Infection in Lung Transplant Recipients on Universal Antifungal Prophylaxis.

Background: Many centers use universal antifungal prophylaxis after lung transplant, but risk factors for invasive fungal infection (IFI) in this setting are poorly described. Methods: This retrospective, single-center cohort study including 603 lung transplant recipients assessed risk factors for early (within 90 days of transplant) invasive candidiasis (IC) and invasive mold infection (IMI) and late (90-365 days after transplant) IMI using Cox proportional hazard regression. Results: In this cohort, 159 (26.4%) patients had 182 IFIs. Growth of yeast on donor culture (hazard ratio [HR], 3.30; 95% CI, 1.89-5.75) and prolonged length of stay (HR, 1.02; 95% CI, 1.01-1.03) were associated with early IC risk, whereas transplantation in 2016 or 2017 (HR, 0.21; 95% CI, 0.06-0.70; HR, 0.25; 95% CI, 0.08-0.80, respectively) and female recipient sex (HR, 0.53; 95% CI, 0.30-0.93) were associated with reduced risk. Antimold therapy (HR, 0.21; 95% CI, 0.06-0.78) was associated with lower early IMI risk, and female donor sex (HR, 0.40; 95% CI, 0.22-0.72) was associated with lower late IMI risk. Recent rejection was a risk factor for late IMI (HR, 1.73; 95% CI, 1.02-2.95), and renal replacement therapy predisposed to early IC, early IMI, and late IMI (HR, 5.67; 95% CI, 3.01-10.67; HR, 7.54; 95% CI, 1.93-29.45; HR, 5.33; 95% CI, 1.46-19.49, respectively). Conclusions: In lung transplant recipients receiving universal antifungal prophylaxis, risk factors for early IC, early IMI, and late IMI differ.

Ratios of head circumference to ventricular size vary over time and predict eventual need for CSF diversion in intraventricular hemorrhage of prematurity.

PURPOSE: Intraventricular hemorrhage (IVH) of prematurity can lead to hydrocephalus, sometimes necessitating permanent cerebrospinal fluid (CSF) diversion. We sought to characterize the relationship between head circumference (HC) and ventricular size in IVH over time to evaluate the clinical utility of serial HC measurements as a metric in determining the need for CSF diversion. METHODS: We included preterm infants with IVH born between January 2000 and May 2020. Three measures of ventricular size were obtained: ventricular index (VI), Evan's ratio (ER), and frontal occipital head ratio (FOHR). The Pearson correlations (r) between the initial (at birth) paired measurements of HC and ventricular size were reported. Multivariable longitudinal regression models were fit to examine the HC:ventricle size ratio, adjusting for the age of the infant, IVH grade (I/II vs. III/IV), need for CSF diversion, and sex. RESULTS: A total of 639 patients with an average gestational age of 27.5 weeks were included. IVH grade I/II and grade III/IV patients had a positive correlation between initial HC and VI (r = 0.47, p < 0.001 and r = 0.48, p < 0.001, respectively). In our longitudinal models, patients with a low-grade IVH (I/II) had an HC:VI ratio 0.52 higher than those with a high-grade IVH (p-value < 0.001). Patients with low-grade IVH had an HC:ER ratio 12.94 higher than those with high-grade IVH (p-value < 0.001). Patients with low-grade IVH had a HC:FOHR ratio 12.91 higher than those with high-grade IVH (p-value < 0.001). Infants who did not require CSF diversion had an HC:VI ratio 0.47 higher than those who eventually did (p < 0.001). Infants without CSF diversion had an HC:ER ratio 16.53 higher than those who received CSF diversion (p < 0.001). Infants without CSF diversion had an HC:FOHR ratio 15.45 higher than those who received CSF diversion (95% CI (11.34, 19.56), p < 0.001). CONCLUSIONS: There is a significant difference in the ratio of HC:VI, HC:ER, and HC:FOHR size between patients with high-grade IVH and low-grade IVH. Likewise, there is a significant difference in HC:VI, HC:ER, and HC:FOHR between those who did and did not have CSF diversion. The routine assessments of both head circumference and ventricle size by ultrasound are important clinical tools in infants with IVH of prematurity.

At home adaptive dual target deep brain stimulation in Parkinson's disease with proportional control.

Continuous deep brain stimulation (cDBS) of the subthalamic nucleus (STN) or globus pallidus is an effective treatment for the motor symptoms of Parkinson's disease. The relative benefit of one region over the other is of great interest but cannot usually be compared in the same patient. Simultaneous DBS of both regions may synergistically increase the therapeutic benefit. Continuous DBS is limited by a lack of responsiveness to dynamic, fluctuating symptoms intrinsic to the disease. Adaptive DBS (aDBS) adjusts stimulation in response to biomarkers to improve efficacy, side effects, and efficiency. We combined bilateral DBS of both STN and globus pallidus (dual target DBS) in a prospective within-participant, clinical trial in six patients with Parkinson's disease (n = 6, 55-65 years, n = 2 females). Dual target cDBS was tested for Parkinson's disease symptom control annually over 2 years, measured by motor rating scales, on time without dyskinesia, and medication reduction. Random amplitude experiments probed system dynamics to estimate parameters for aDBS. We then implemented proportional-plus-integral aDBS using a novel distributed (off-implant) architecture. In the home setting, we collected tremor and dyskinesia scores as well as individualized ß and DBS amplitudes. Dual target cDBS reduced motor symptoms as measured by Unified Parkinson's Disease Rating Scale (UPDRS) to a greater degree than either region alone (P < 0.05, linear mixed model) in the cohort. The amplitude of ß-oscillations in the STN correlated to the speed of hand grasp movements for five of six participants (P < 0.05, Pearson correlation). Random amplitude experiments provided insight into temporal windowing to avoid stimulation artefacts and demonstrated a correlation between STN ß amplitude and DBS amplitude. Proportional plus integral control of aDBS reduced average power, while preserving UPDRS III scores in the clinic (P = 0.28, Wilcoxon signed rank), and tremor and dyskinesia scores during blinded testing at home (n = 3, P > 0.05, Wilcoxon ranked sum). In the home setting, DBS power reductions were slight but significant. Dual target cDBS may offer an improvement in treatment of motor symptoms of Parkinson's disease over DBS of either the STN or globus pallidus alone. When combined with proportional plus integral aDBS, stimulation power may be reduced, while preserving the increased benefit of dual target DBS.

Prevention of contamination after endotracheal intubation using a dedicated sleeve.

Background: Contamination of work surfaces by used laryngoscopes after endotracheal intubation is a serious infection control concern but no strategies are available to address it. We assessed if contamination of the surfaces after endotracheal intubation would be reduced when providers used a dedicated, self-erected, disposable plastic sleeve (BladePouch) to store the used laryngoscope as compared to using single gloves or double gloves and sheathing the laryngoscope with the outer gloves. Methods: Twenty participants were recruited including attending physicians, trainees and allied health care professionals. They performed endotracheal intubation on a mannequin with oral cavity coated with a dye and stored the used laryngoscope blade using single gloves, double gloves or BladePouch. Each participant used both direct and video laryngoscopes. Following intubation, dye contamination of gloves, gown and work surface was evaluated. Results: There was no difference in the contamination of gloves or gowns between the single gloves, double gloves or BladePouch groups. However, work surface contamination was significantly reduced when using BladePouch compared to single or double gloves (13% vs. 100% vs. 80% respectively, P<0.001). The odds of work surface contamination were significantly lower with BladePouch vs. single or double gloves, even when adjusted for intubation device, role and experience of participants with an adjusted odds ratio of 0.0054 (95% confidence interval: 0.0009-0.0314), P<0.001. Conclusions: In conjunction with standard precautions, the use of a dedicated plastic sleeve to store contaminated laryngoscope blade after endotracheal intubation may reduce the work surface contamination, independent of intubation device, role and experience of providers.

Evidence of pre-approval clinical trial supporting the granted conditional approval for novel cancer drugs in China between 2015 and 2022.

Background: Accelerated approval (AA) of novel anticancer drugs based on surrogacy has attracted considerable concern globally. China National Medical Products Administration (NMPA) also established a similar conditional approval (CA) program to accelerate the approval of novel drugs to address unmet medical needs. This cross-sectional study aimed to evaluate the pre-approval clinical trial evidence and potential challenge of cancer drugs receiving CA in China from policy implementation to 2022. Methods: The cancer drugs (initial and supplemental indications) granted CA between January 1, 2015 and December 31, 2022 using the public database of the NMPA were analyzed. The characteristics of the cancer drugs received CA were described. Primary efficacy endpoints and safety derived from the pre-approval clinical trial, including response rates (RR), progression-free survival (PFS), overall survival (OS), treatment-related serious adverse events (SAE) and Grade ≥3 adverse events (AEs) were quantitatively estimated by meta-analysis. Besides, the correlation between the surrogate endpoints and OS was estimated by the reported trial-level correlation analysis. Findings: The NMPA approved 72 cancer indications (56 new molecular entities) with CA between 2015 and 2022. 34 indications (47%) were also approved by the FDA or EMA. 74% (53/72) of cancer indications were based on a single-arm trial design while 26% (19/72) for randomized controlled trials. The pooled RR was 0.50 (95% CI: 0.45-0.55, I2 = 96%) with significant differences across cancer types and targets while the pooled hazard risk was 0.39 (95% CI: 0.28-0.53, I2 = 89%) for PFS and 0.67 (95% CI: 0.61-0.73, I2 = 0%) for OS. The pooled treatment-related SAE and Grade ≥3 AEs from single-arm designs resulted in 15% and 25%, respectively. In randomized controlled trials, the pooled treatment-related SAE and Grade ≥3 AEs observed in CA drugs and the control groups were comparable. Surrogate endpoints were widely used as the primary efficacy endpoints in the pre-approval pivotal clinical trials with 75% (54/72) for RR, 10% (7/72) for PFS, and 4% (3/72) for others. Of these, 27% (17/63) of the surrogate endpoints reported a trial-level correlation with OS; three reported high correlation (r ≥ 0.85), two reported moderate correlation (0.70 ≤ r < 0.85) and 12 reported low correlation (r < 0.70). Interpretation: The majority of novel cancer drugs that received CA were based on RR designed for single-arm trials. The reported correlations of treatment effect between the surrogate endpoints and OS used for CA were limited. Our findings highlighted that the introduction of OS or quality of life based on RCT in confirmatory clinical trials as much as feasible was essential to ensure the clinical benefits for patients. Funding: This study was supported by postdoctoral fellowship from Tsinghua-Peking Joint Centers for Life Sciences (CLS).

Innovative thinking of clinical investigation for rare disease drug development.

For the development of a test treatment or drug product, it is necessary to conduct composite hypothesis testing to test for effectiveness and safety simultaneously, since some approved drug products have been recalled due to safety concerns. One of the major issues in conducting a composite hypothesis testing for effectiveness and safety is the requirement of a huge sample size to achieve the desired power for detecting clinically meaningful differences in both safety and effectiveness. Situation can be much difficult in orphan drug development. In this article, a generalized two-stage innovative approach to test for effectiveness and safety simultaneously is proposed. Additionally, to alleviate the requirement of a large randomized clinical trial (RCT) and revealing effectiveness, real-world data is suggested to use in conjunction with RCT data for orphan drug development. The proposed approach can help investigators test for effectiveness and safety at the same time without worrying about the sample size. It also helps reduce the probability of approving a drug product with safety concerns.

Statistical Evaluation of Responder Analysis in Stem Cell Clinical Trials.

BACKGROUND: In evaluating treatment efficacy, there is an ongoing discussion about which endpoint is more efficient to represent the treatment effect. Absolute change (AC) is the difference between before and after treatment, while relative change (RC) is the AC relative to the baseline value. Principal investigators sometimes support the credibility of relative change, but the FDA is more likely to support absolute change. Therefore, whether these two endpoints can be translated or combined is worth investigating in order to satisfy both parties. METHODS: In this article, a motivating example is presented to show that the choice of endpoint will result in different conclusions. The compared relationship of AC and RC is discussed in terms of required sample size, power, and precision. A new type of responder endpoint that combines the concepts of AC and RC is proposed. The comparative relationship regarding sample size, power, and precision of the proposed responder endpoint and the original two endpoints are also investigated. RESULTS: As a result, the performance of AC and RC is highly dependent on the choice of threshold that is often informed based on minimum clinically important difference or other clinical experience. Therefore, an absolute translation between them is hard to achieve. Inspired by the concept of responder analysis, three types of responder endpoints are proposed and discussed. The pattern of the third type of responder endpoint is having higher power, higher precision, and less required sample size in estimating the treatment effect compared to AC and RC within a range of thresholds. This advantage becomes more obvious when applying higher AC and RC thresholds and lower [Formula: see text] threshold. CONCLUSION: The proposed endpoint incorporates the information from the AC and RC endpoints and could be another wise choice when designing clinical trials especially when there is no absolute preference between AC and RC.

Two-Year Clinical and Radiographic Outcomes for Percutaneous Lumbar Interbody Fusion With an Expandable Titanium Cage Through Kambin's Triangle Without Facetectomy.

BACKGROUND: There has been heightened interest in performing percutaneous lumbar interbody fusions (percLIFs) through Kambin's triangle, an anatomic corridor allowing entrance into the disc space. However, due to its novelty, there are limited data regarding the long-term benefits of this procedure. Our objective was to determine the long-term efficacy and durability of the percutaneous insertion of an expandable titanium cage through Kambin's triangle without facetectomy. METHODS: A retrospective review of patients undergoing percLIF via Kambin's triangle using an expandable titanium cage was performed. Demographics, visual analog scale (VAS) scores, Oswestry Disability Index (ODI), radiographic measurements, perioperative variables, and complications were recorded. VAS, ODI, and radiographic measurements were compared with baseline using the generalized estimating equations assuming normally distributed data. Fusion was assessed with computed tomography (CT) at 1 and 2 years after the procedure. RESULTS: A total of 49 patients were included. Spondylolisthesis, lumbar lordosis (LL), sacral slope, pelvic tilt, and anterior/posterior disc space height were all significantly improved postoperatively at each time point of 3, 6, 12, and 24 months (P < 0.001). Pelvic incidence-LL mismatch decreased significantly at each follow-up (P < 0.001) with a mean reduction of 4° by 24 months. VAS back scores reduced by >2 points at the 6, 12, and 24 month follow-ups. ODI scores reduced by >15 points at the 12- and 24-month follow-ups. Of the patients who had 1- and 2-year CT images, fusion rates at those time points were 94.4% (17/18) and 87.5% (7/8), respectively. The mean annual rate of surgically significant adjacent segment disease was 2.74% through an average follow-up of 2.74 years. CONCLUSION: These results highlight that percLIF, a procedure done without an endoscope or facetectomy, can be performed using an expandable titanium cage through Kambin's triangle with excellent radiographic and clinical results. CLINICAL RELEVANCE: percLIF via Kambin's triangle is a safe and succesful procedure with long-term improvements in both clinical and radiographic outcomes.

Evaluation of clinical trial designs for novel anticancer drugs in China: A cohort study of drugs approved between 2015 and 2021.

China has greatly facilitated the approval of many novel anticancer drugs since the drug regulatory reform in 2015. Here, we review the clinical trial designs used in pivotal clinical trials for approved anticancer agents in China from 2015 to 2021. Overall, 79 new molecular entities (NMEs) with 140 anticancer indications were identified. Of these, adaptive randomized controlled trial (RCT) designs were used most frequently in pivotal clinical trials (n = 83, 49%), followed by single-arm design trials (n = 52, 30%) and traditional RCT design trials (n = 36, 21%). The single-arm trials and adaptive RCTs can significantly shorten clinical trial duration compared with traditional RCT designs. Our findings showed that novel clinical trial designs were widely used in China to accelerate the launch of anticancer drugs.

MyKidneyCoach, Patient Activation, and Clinical Outcomes in Diverse Kidney Transplant Recipients: A Randomized Control Pilot Trial.

Kidney transplant (KT) recipients who are not actively engaged in their care and lack self-management skills have poor transplant outcomes, which are disproportionately observed among Black KT recipients. This pilot study aimed to determine whether the MyKidneyCoach app, an mHealth intervention that provides self-management monitoring and coaching, improved patient activation, engagement, and nutritional behaviors in a diverse KT population. Methods: This was a randomized, age-stratified, parallel-group, attention-control, pilot study in post-KT patients. Participants were randomized into the attention-control with access to MyKidneyCoach for education and self-management (n = 9) or the intervention with additional tailored nurse coaching (n = 7). Feasibility, acceptability, and clinical outcomes were assessed. Results: The acceptability of MyKidneyCoach by System Usability Scale was 67.5 (95% confidence interval [CI], 59.1-75.9). Completion rates based on actively using MyKidneyCoach were 81% (95% CI, 57%-93%) and study retention rate of 73%. Patient activation measure significantly increased overall by a mean of 11 points (95% CI, 3.2-18.8). Additionally, Black patients (n = 7) had higher nutrition self-efficacy scores of 80.5 (95% CI, 74.4-86.7) compared with 75.6 (95% CI, 71.1-80.1) in non-Black patients (n = 9) but lower patient activation measure scores of 69.3 (95% CI, 56.3-82.3) compared with 71.8 (95% CI, 62.5-81) in non-Black patients after 3 mo. Conclusions: MyKidneyCoach was easy to use and readily accepted with low attrition, and improvements were demonstrated in patient-reported outcomes. Both Black and non-Black participants using MyKidneyCoach showed improvement in self-management competencies; thus, this intervention may help reduce healthcare inequities in KT.

The price, efficacy, and safety of within-class targeted anticancer medicines between domestic and imported drugs in China: a comparative analysis.

Background: Affordability to novel anticancer drugs has become a major health issue in China. It is encouraging to note that China initiated its drug regulatory reform and national price negotiation policies since 2015. As a growing number of domestic within-class targeted anticancer drugs are approved in China, it is expected that this may reduce the price of novel anticancer drugs and improve the affordability of anticancer drugs. This study aimed to evaluate the price, efficacy, and safety of the within-class anticancer drugs between domestic and imported drugs approved in China from 2010 to 2022. Methods: The domestic and imported within-class targeted drugs for solid cancers approved in China between 2010 and 2022 were extracted. We classified it as a class of anticancer drugs based on the same indication and similar biological mechanism. The published literature derived from pivotal clinical trials of these domestic and imported drugs was identified based on the review report and the latest labels issued by the China National Medical Products Administration. We evaluated the monthly treatment price at launch and the latest (2022), primary efficacy endpoint and safety between domestic and imported anticancer drugs. Meta-analyses were further employed to evaluate the efficacy and safety of the domestic and imported anticancer drugs, including pooled hazard ratios (HR) for progression-free survival (PFS), overall survival (OS), objective response rates (ORR) for solid cancers, and relative risk for serious adverse events (SAE) and Grade ≥3 adverse events (AEs). Findings: In our cohort study, 12 within-class anticancer drugs with 7 cancer diseases were analyzed, including 18 domestic (21 indications; 21 pivotal trials) and 18 imported (21 indications; 27 pivotal trials) novel anticancer drugs, respectively. The median monthly treatment price of domestic and imported drugs from the years of launch to 2022 had significantly decreased by 71% and 62%, respectively. Moreover, the median monthly treatment price of domestic targeted anticancer drugs on the market at launch ($3786 vs. $5393, P = 0.007) and the latest ($1222 vs. $2077, P = 0.011) was significantly lower than that of imported drugs. No significant differences in median PFS gains (9.0 vs. 11.0 months; P = 0.24), OS gains (9.3 vs 10.6 months; P = 0.66), and ORR (57% vs 62%, P = 0.77) of targeted anticancer drugs in their pivotal trials were observed between the domestic and imported drugs. Additionally, there was no significant difference between domestic and imported drugs in the incidence of SAE (23% vs. 24%; P = 0.41) and Grade ≥3 AEs (59% vs. 57%; P = 0.45). These findings were also further confirmed in the meta-analyses for primary efficacy endpoints and safety outcomes. Interpretation: The prices of both domestic and imported anticancer drugs significantly decreased after market entry mainly due to the role of national price negotiations. The median monthly treatment price of domestic within-class targeted anticancer drugs was significantly lower than that of imported drugs. Furthermore, the efficacy and safety of domestic anticancer drugs were comparable to that of imported drugs. This evidence implicated that the development of within-class anticancer drugs with national price negotiations in China significantly improved the affordability for patients. Funding: This study was supported by postdoctoral fellowship from Tsinghua-Peking Joint Centers for Life Sciences (CLS).

A Proposal for Post Hoc Subgroup Analysis in Support of Regulatory Submission.

BACKGROUND: In clinical trials, it is not uncommon that the primary analysis fails to achieve the study objective for demonstrating the safety and efficacy of a test treatment under investigation, while a specific sub-population analysis shows a significant positive result. In this case, whether the observed positive sub-population analysis results can be used in support of regulatory submission of the test treatment under investigation is an interesting question to both the investigator(s) and the regulatory medical/statistical reviewers. METHODS: In this article, several statistical evaluations for confirming the integrity and validity of the observed sub-population analysis results were proposed in support of the regulatory submission. Selection bias caused by looking at one subgroup is adjusted before all statistical evaluations, including reproducibility, consistency between sub-population and the entire population, generalizability between the promising sub-population and other sub-populations, and sensitivity index when there are shifts in mean and/or variability between sub-populations. The multiplicity issue is also addressed in measuring generalizability. RESULTS: A numerical example of a global (multi-regional) clinical trial was presented for illustration purposes. The choice of applying which estimation approach relies on the scale of test statistics. Recommendations for incorporating statistical evaluations in measuring sub-population analysis are provided. Finally, we proposed possible solutions such as real-world data and real-world evidence for regulatory concerns, which may increase the insufficient power. CONCLUSION: Sub-population analysis can contribute to regulatory submission if it passes the evaluation. This analysis can also support hypothesis generation and the planning of future clinical trials, though it fails to pass the measurement process.

Efficacy of Transcendental Meditation to Reduce Stress Among Health Care Workers: A Randomized Clinical Trial.

Importance: Health care workers (HCWs) have been experiencing substantial stress and burnout, and evidence-based mitigation strategies are needed. Transcendental Meditation (TM) is a mantra meditation practice with potential efficacy in reducing stress. Objective: To assess the efficacy of TM practice in reducing stress among HCWs over a 3-month period. Design, Setting, and Participants: This single-center open-label randomized clinical trial was conducted among HCWs at an academic medical center from November 19, 2020, to August 31, 2021. Inclusion criteria comprised a score of 6 points or greater on the Subjective Units of Distress Scale and an increase of 5% or greater in baseline heart rate or an increase of 33% or greater in galvanic skin response after exposure to a stressful script. Exclusion criteria included the use of antipsychotic or ß blocker medications, current suicidal ideation, or previous TM training. Of 213 HCWs who participated in prescreening, 95 attended in-person visits, resulting in 80 eligible participants who were randomized to receive a TM intervention (TM group) or usual treatment (control group). Interventions: The TM group practiced TM for 20 minutes twice daily over a 3-month period. The control group received usual treatment, which consisted of access to wellness resources. Main Outcomes and Measures: The primary outcome was change in acute psychological distress measured by the Global Severity Index. Secondary outcomes included changes in burnout (measured by the Maslach Burnout Inventory), insomnia (measured by the Insomnia Severity Index), and anxiety (measured by the Generalized Anxiety Disorder-7 scale). Results: Among 80 participants, 66 (82.5%) were women, with a mean (SD) age of 40 (11) years. One participant (1.3%) was American Indian or Alaska Native, 5 (6.3%) were Asian, 12 (15.0%) were Black, 59 (73.8%) were White, and 3 (3.8%) were of unknown or unreported race; 4 participants (5.0%) were Hispanic, and 76 (95.0%) were non-Hispanic. A total of 41 participants were randomized to the TM group, and 39 were randomized to the control group. Participants in the TM group did not show a statistically significant decrease in psychological distress on the Global Severity Index compared with those in the control group (-5.6 points vs -3.8 points; between-group difference, -1.8 points; 95% CI, -4.2 to 0.6 points; P = .13). Compared with the control group, the TM group had significantly greater reductions in the secondary end points of emotional exhaustion (Maslach Burnout Inventory subscore: -8.0 points vs -2.6 points; between-group difference, -5.4 points; 95% CI, -9.2 to -1.6 points; P = .006), insomnia (Insomnia Severity Scale score: -4.1 points vs -1.9 points; between-group difference, -2.2 points; 95% CI, -4.4 to 0 points; P = .05), and anxiety (Generalized Anxiety Disorder-7 score: -3.1 points vs -0.9 points; between-group difference, -2.2 points; 95% CI, -3.8 to -0.5; P = .01) at 3 months. A total of 38 participants (92.7%) in the TM group adhered to home practice. Conclusions and Relevance: In this randomized clinical trial, TM practice among HCWs over a 3-month period did not result in a statistically significant reduction in the primary outcome of acute psychological distress compared with usual treatment but significantly improved the secondary outcomes of burnout, anxiety, and insomnia. These findings suggest that TM may be a safe and effective strategy to alleviate chronic stress among HCWs. Trial Registration: ClinicalTrials.gov identifier: NCT04632368.

Statistical Evaluation of Absolute Change versus Responder Analysis in Clinical Trials.

In clinical trials, the primary analysis is often either a test of absolute/relative change in a measured outcome or a corresponding responder analysis. Though each of these tests may be reasonable, determining which test is most suitable for a particular research study is still an open question. These tests may require different sample sizes, define different clinically meaningful differences, and most importantly, lead to different study conclusions. This paper aims to compare a typical non-inferiority test using absolute change as the study endpoint to the corresponding responder analysis in terms of sample size requirements, statistical power, and hypothesis testing results. From numerical analysis, using absolute change as an endpoint generally requires a larger sample size; therefore, when the sample size is the same, the responder analysis has higher power. The cut-off value and non-inferiority margin are critical which can meaningfully impact whether the two types of endpoints yield conflicting conclusions. Specifically, an extreme cut-off value is more likely to cause different conclusions. However, this impact decreases as population variance increases. One important reason for conflicting conclusions is that the population distribution is not normal. To eliminate conflicting results, researchers should pay attention to the population distribution and cut-off value selection.

Innovative Design and Analysis for PK/PD Biosimilar Bridging Studies with Multiple References.

When there are multiple reference products, (e.g., EU-approved product and US-licensed product), a pharmacokinetic/pharmacodynamic (PK/PD) bridging study is often conducted in order to bridge the clinical data from the original region (e.g., Europe) to the new region (e.g., USA) in support of the biosimilar regulatory submission in the new region. The purpose is to avoid duplicated clinical trials for clinical similarity between a proposed biosimilar product and the reference product in the new region provided that there is no ethnic concern in the two regions. In this article, some innovative statistical designs for PK/PD biosimilar bridging studies are proposed. Statistical model and methods under the proposed statistical designs are studied. Power analysis for sample size requirement based on Schuirmann's two one-sided tests procedure is also derived and compared to pairwise testing using simulation.