Historical Control Data Research Articles

PSXII-20 Use of Statistical Process Control to Evaluate the Effect of Isoquinoline Alkaloids Supplementation on Productive Performance of Growing-Finishing Pigs

Abstract Statistical process control (SPC) is a statistical method that can be used to evaluate the production variation in swine operations, thus facilitating decision making. The objective of this study was to evaluate the effect of plant-derived isoquinoline alkaloids (IQs) supplementation on production performance of growing-finishing pigs by using SPC.The experiment was carried out in a commercial swine integration in Spain. Historical control (calibration) data was compiled from 2017 to June 2020. During this period, all animals received a standard commercial diet. During the treatment period, which started in July 2020 and lasted until February 2021, all pigs were fed the standard diet supplemented with 1 kg/t feed of a plant-based IQ product (Phytobiotics Futterzusatzstoffe GmbH, Eltville, Germany), from day 70 of life until slaughter. Data recorded during both, historical control and treatment periods included feed conversion ratio (FCR), average daily gain (ADG, g/d), average daily feed intake (ADFI, g/d), cost of medicines (Euro/pig), runts (%) and mortality rate (%). SPC tools were used to monitor the previously described performance parameters. CUSUM control charts were obtained for all parameters and for each nutritional and health cluster to show the evolution or the changes of each parameter. The results showed that pigs supplemented with IQs had a lower FCR, increased ADG and reduced cost in medications as compared to the control period (p ≤ 0.05; Table 1). SPC methods were successfully implemented to evaluate the effect of IQs supplementation on growth performance of grow-finish pigs. The results of the study indicated that IQs supplementation improved FCR and ADG, whereas the cost of medication was significantly reduced. Therefore, IQs supplementation in pigs from day 70 of life until slaughter could be a good strategy to improve the efficiency and profitability of the production system.

Preparatory work on how to report, use and interpret historical control data in (eco)toxicity studies

Preparatory work on how to report, use and interpret historical control data in (eco)toxicity studies

Lack of direct bone effect of tofacitinib, a JAK inhibitor, in juvenile rats and evaluation of the association between offspring growth and femur length

Bone has recently emerged as a target organ for some Janus kinase (JAK) inhibitors in adult and/or juvenile animal toxicity studies. Oral administration of tofacitinib, a JAK inhibitor, was not associated with clinical or macroscopic effects on bone growth and development in a rat juvenile animal study (JAS) with tofacitinib dosing starting on postnatal day (PND) 21. However, given that previous JAS did not include a targeted evaluation of bone, inclusive of microscopic examination, an additional rat JAS was conducted to further assess this risk. In this subsequent JAS, administration of tofacitinib from PND 7–49 or from PND 21–49 did not result in any direct effects on bone, with no histologic effects on developing bone. The only bone effect in this JAS was nonadverse shorter femur length, which was not considered to be a direct effect of tofacitinib, but rather an indicator of growth delay, as this was associated with lower body weights. There were no effects on femur length or body weight after a 2-month recovery period. To further explore the relationship between body weight and femur length, historical control data were analyzed from control rats in other JAS. This analysis clearly demonstrated that shorter femur length can occur as an indirect effect that is highly associated with lower body weight, consistent with what was observed in the JAS with tofacitinib. These analyses provide a robust and valuable data set to support the interpretation of such data in JAS, and further support the lack of direct effects of tofacitinib on bone growth and development. As with the previously conducted juvenile studies with tofacitinib, the additional JAS did not identify any special JAS-based concerns for use in pediatric patients as young as 2 years of age.

CLRM-17 USE OF EXTERNAL CONTROL DATA FOR PLANNING AND ANALYZING GBM TRIALS: READY FOR PRIME TIME?

Randomized controlled trials (RCT) have been the gold standard for evaluating medical treatments for many decades. Randomization reduces systematic biases resulting from treatment or patient selection, whereby the improvement in clinical outcomes may be attributed to the experimental therapy under study. However, RCTs are often criticized for requiring large sample sizes and taking a long time to complete. For newly diagnosed glioblastoma (GBM), the clinical trial landscape has seen little progress since the establishment of the standard of care (SOC) by Stupp. Given the urgent need for better therapies, it has been argued that data collected from patients treated with the SOC from past GBM trials can provide high-quality external control data to supplement concurrent control arm in future trials, thereby increasing drug development efficiency by reducing the number of patients treated with SOC. Herein we consider a new design approach that leverages historical control data in the design and analysis of phase 3 GBM trials. At the first stage, patients are randomized with an equal probability to standard (concurrent control) arm and experimental arm. An interim analysis entails an outcome comparison between the concurrent and external control arms. If comparability is established, the external control data are carried forward to be combined with concurrent control data at the second stage where the randomization ratio is adapted to favor the experimental therapy, thereby reducing the number of patients treated in the concurrent control arm. Using completed phase 3 GBM trials, we elucidate the potential gain in design efficiency and draw caution to scenarios where it may fall short on meeting statistical criteria. We highlight practical challenges in its implementation and conclude that the new method is not ready for definitive phase 3 GBM studies at the current time. This work represents a critical appraisal of this new concept in GBM.

A Comparison of Historical Control Data From Cynomolgus Macaques (Macaca Fascicularis) of Chinese, Cambodian, and Vietnamese Origin.

Cynomolgus macaques, the most commonly utilized nonhuman primate in nonclinical toxicology studies, are acquired from purpose-bred colonies across various geographic locations, including China, Cambodia, and Vietnam. Importation challenges and limited availability have restricted animals suitable for inclusion in nonclinical studies. The coronavirus disease 2019 (COVID-19) outbreak further stressed supply chains, reducing the ability to source animals from a singular location to complete a drug development program. These challenges raised concerns of increased variability in study endpoints due to heterogeneity of animals and that this could subsequently impact historical control data and toxicology study interpretation. To investigate the impact of Chinese, Vietnamese, or Cambodian geographic origin on standard nonclinical toxicology study endpoints, historical control data from studies conducted at a single facility from 2005 to 2020 were compiled and evaluated for the following: clinical observations, body weight, ophthalmoscopic examinations, and clinical and anatomic pathology data. Study populations consisted of 2- to 5-year-old cynomolgus macaques sourced from China (n = 750 males/741 females), Cambodia (n = 282 males/271 females), and Vietnam (n = 122 males/120 females). Interpretation of the various data demonstrated no notable differences in standard toxicology study endpoints or background findings among cynomolgus macaques originating from China, Cambodia, or Vietnam.

Evaluation of phase 2 single-arm two-stage trials in glioblastoma and brain tumor.

e14033 Background: Oncology clinical trials have shown the lowest success rate on Phase 2 and the highest median expense in a new drug to market. We aimed to assess the appropriate implementation of single-arm two-stage Phase 2 trials with other critical design issues of phase 2 single-arm trials such as selection of primary endpoint and historical control rates, and challenges of the blood-brain barrier, and to suggest guidelines to handle design issues related to single-arm Phase 2 trials in Neuro-Oncology. Methods: Two researchers searched with the key words of “phase 2 single arm two-stage design in glioblastoma” through PubMed.gov, clinicaltrials.gov, and Google Scholar to examine study designs of (i) study information, (ii) two-stage design parameters, (iii) rejection numbers and sample size for each stage. Design issues in primary endpoints, historical controls, and challenges on brain tumor trials were discussed with the effect of adaptive design on two-stage designs, and several guidelines on these issues were suggested for investigators in Phase 2 single-arm Neuro-Oncology trials. Results: Almost 50% of single-arm two-stage studies failed to provide key information related to study designs and sample size calculation, even wrong power analysis and interpretation. Response rate and progression-free survival are used as popular surrogate endpoints for overall survival. It is time to evaluate other potential endpoints like post-progress survival and hazard ratio, and usefulness of co-primary endpoint. Investigators should keep transparency of the trials by fully providing and citing historical data source. If there exist large variabilities among existing historical data, meta-analysis can be a good option to accurately estimate the historical control. Conclusions: The appropriate selection on primary endpoint(s) and historical control data, incorporation of adaptive designs if necessary, and right application of two-stage design might help overcoming the challenges on low success rates in new therapeutic oncology trials. Furthermore, the new paradigm of Phase 0 trial might be one potential tool to overcome the challenges with insufficient penetration of therapeutic agents across the blood-brain barrier and limitations in the applicability of animal models to the human condition in glioblastoma and Neuro-Oncology.

Management strategies and outcomes of acute coronary syndrome (ACS) during Covid-19 pandemic

BackgroundThe COVID-19 outbreak represents a significant challenge to international health. Several studies have reported a substantial decrease in the number of patients attending emergency departments with acute coronary syndromes (ACS) and there has been a concomitant rise in early mortality or complications during the COVID-19 pandemic. A modified management system that emphasizes nearby treatment, safety, and protection, alongside a closer and more effective multiple discipline collaborative team was developed by our Chest Pain Center at an early stage of the pandemic. It was therefore necessary to evaluate whether the newly adopted management strategies improved the clinical outcomes of ACS patients in the early stages of the COVID-19 pandemic.MethodsPatients admitted to our Chest Pain Center from January 25th to April 30th, 2020 based on electronic data in the hospitals ACS registry, were included in the COVID-19 group. Patients admitted during the same period (25 January to 30 April) in 2019 were included in the pre-COVID-19 group. The characteristics and clinical outcomes of the ACS patients in the COVID-19 period group were compared with those of the ACS patients in the pre-COVID-19 group. Multivariate logistic regression analyses were used to identify the risk factors associated with clinical outcomes.ResultsThe number of patients presenting to the Chest Pain Center was reduced by 45% (p = 0.01) in the COVID-19 group, a total of 223 ACS patients were included in the analysis. There was a longer average delay from the onset of symptom to first medical contact (FMC) (1176.9 min vs. 625.2 min, p = 0.001) in the COVID-19 period group compared to the pre-COVID-19 group. Moreover, immediate percutaneous coronary intervention (PCI) (80.1% vs. 92.3%, p = 0.008) was performed less frequently on ACS patients in the COVID-19 group compared to the pre-COVID-19 group. However, more ACS patients received thrombolytic therapy (5.8% vs. 0.6%, p = 0.0052) in the COVID-19 group than observed in the pre-COVID-19 group. Interestingly, clinical outcome did not worsen in the COVID-19 group when cardiogenic shock, sustained ventricular tachycardia, ventricular fibrillation or use of mechanical circulatory support (MCS) were compared against the pre-COVID-19 group (13.5% vs. 11.6%, p = 0.55). Only age was independently associated with composite clinical outcomes (HR = 1.3; 95% CI 1.12–1.50, p = 0.003).ConclusionThis retrospective study showed that the adverse outcomes were not different during the COVID-19 pandemic compared to historical control data, suggesting that newly adopted management strategies might provide optimal care for ACS patients. Larger sample sizes and longer follow-up periods on this issue are needed in the future.

The Influence of Geographical Origin, Age, Sex, and Animal Husbandry on the Spontaneous Histopathology of Laboratory Cynomolgus Macaques (Macaca Fascicularis): A Contemporary Global and Multisite Review of Historical Control Data.

To investigate the influence of geographical origin, age, and sex on toxicologically relevant spontaneous histopathology findings in cynomolgus macaques (Macaca fascicularis), we performed a comparative analysis of historical control data (HCD) from 13 test sites that included 3351 animals (1645 females and 1706 males) sourced from Mauritius, China, Vietnam, and Cambodia, aged from 2 to 9.5 years, and from 446 toxicology studies evaluated between 2016 and 2021. The most common findings were mononuclear infiltrates in the kidney, liver, brain, and lung, which showed highest incidences in Mauritian macaques, and heart, salivary glands, and gastrointestinal tract (GIT), which showed highest incidences of mononuclear infiltrates in mainland Asian macaques. Developmental and degenerative findings were more common in Mauritian macaques, while lymphoid hyperplasia and lung pigment showed higher incidences in Asian macaques. Various sex and age-related differences were also present. Despite origin-related differences, the similarities in the nature and distribution of background lesions indicate that macaques from all geographical regions are suitable for toxicity testing and show comparable lesion spectrum. However, in a toxicity study, it is strongly recommended to use animals from a single geographical origin and to follow published guidelines when using HCD to evaluate and interpretate commonly diagnosed spontaneous lesions.

Using horseshoe prior for incorporating multiple historical control data in randomized controlled trials.

Meta-analytic approaches and power priors are often used to incorporate historical controls into the analysis of a current randomized controlled trial. In this study, we propose a method for incorporating multiple historical controls based on a horseshoe prior, which is a type of global-local shrinkage prior. The method assumes that historical controls follow the same distribution as the current control. In the case in which only a few historical controls are heterogeneous, we consider them to follow a potentially biased distribution from the distribution of the current control. We analyze two clinical trial examples with binary and time-to-event endpoints and conduct simulation studies to compare the performance of the proposed and existing methods. In the analysis of the clinical trial example, the posterior standard deviation of the treatment effect is decreased by the proposed method by considering the bias between the current control and heterogeneous historical control. In the scenarios in which the current and historical controls follow the same distribution, the statistical power using the proposed method is higher than that using existing methods. The proposed method is advantageous when few or no heterogeneous historical controls are expected.

A Simple Approach to Incorporating Historical Control Data in Clinical Trial Design and Analysis

A Simple Approach to Incorporating Historical Control Data in Clinical Trial Design and Analysis

Statistical analysis of avian reproduction studies

Avian reproduction studies for regulatory risk assessment are undergoing review by regulatory authorities, often leading to requests for statistical re-analysis of older studies using newer methods, sometimes with older study data that do not support these newer methods. We propose detailed statistical protocols with updated statistical methodology for use with both new and older studies and recommend improvements in experimental study design to set up future studies for robust statistical analyses. There is increased regulatory and industry attention to the potential use of benchmark dose (BMD) methodology to derive the endpoint to be used in avian reproduction studies for regulatory risk assessment. We present benefits and limitations of this BMD approach for older studies being re-evaluated and for new studies designed for with BMD analysis anticipated. Model averaging is recommended as preferable to model selection for BMD analysis. Even for a new study following the modified experimental design analyses, with BMD methodology will only be possible for a restricted set of response variables. The judicious use of historical control data, identification of outlier data points, increased use of distributions more consistent with the nature of the data collected as opposed to forcing normality-based methods, and trend-based hypothesis tests are shown to be effective for many studies, but limitations on their applicability are also recognized and explained. Updated statistical methodologies are illustrated with case studies conducted under existing regulatory guidelines that have been submitted for product registrations. Through the adoption of alternative avian reproduction study design elements combined with the suggested revised statistical methodologies the conduct, analyses, and utility of avian reproduction studies for avian risk assessments can be improved.

Bayesian adaptive randomization design incorporating propensity score-matched historical controls.

Incorporating historical control data to augment the control arm in randomized controlled trials (RCTs) is one way of increasing their efficiency and feasibility when adequate RCTs cannot be conducted. In recent work, a Bayesian adaptive randomization design incorporating historical control data has been proposed to reduce sample size according to the amount of information that could be borrowed, assessed at interim assessment in respect to prior-data conflict. However, the approach does not distinguish between the two sources of prior-data conflict: (1) imbalance in measured covariates, and (2) imbalance in unmeasured covariates. In this paper, we propose an extension of the Bayesian adaptive randomization design to incorporate propensity score-matched historical controls. At interim assessment, historical controls similar to the concurrent controls in terms of measured covariates are selected using propensity score matching. Then, final sample size of the control arm is adjusted according to the extent of borrowing from the matched historical controls quantified by effective historical sample size. The conditional power prior approach and commensurate prior approach are adopted for designing the prior, and addressing prior-data conflict due to unmeasured covariate imbalance. Simulation results show that the proposed method yields reduced bias in treatment effect estimates, type I error at the nominal level, and reduced sample size while maintaining statistical power. Even when residual imbalance exists due to unmeasured covariates, the proposed method borrowed more information without risking substantially inflated type I error and bias, providing meaningful implications for use of historical controls to facilitate the conduct of adequate RCTs.

Open-label use of an aliphatic polyamine immunomodulator in patients hospitalized with COVID-19.

BackgroundEvidence-based therapies used to treat coronavirus disease (COVID-19) remain limited. Azoximer bromide (AZB; Polyoxidonium®) is an immunomodulating molecule frequently used in the Russian Federation. It offers demonstrable therapeutic benefit in upper respiratory tract infections. This study evaluated the safety and efficacy of AZB when used in combination with standard of care treatment in patients hospitalized with COVID-19.MethodsHospitalized patients with COVID-19 (n=81; nine sites) received AZB 12 mg intravenously once daily for 3 days then intramuscularly every other day until day 17. The primary endpoint included clinical status at day 15 versus baseline. Historical control data of 100 patients from a randomized, controlled, open-label trial conducted in China were included to serve as a direct control group.ResultsNotable clinical improvement, assessed by seven-point ordinal scale (OS) score and National Early Warning Score, was observed. Mean duration of hospitalization was 19.3 days. Indicators of pneumonia and lung function showed gradual recovery to normalization. No patients died but, by day 28, one patient still required respiratory support; this patient died on day 34. A higher proportion of patients receiving AZB required invasive or non-invasive ventilation (OS 5 or 6) at baseline compared with the historical control group. Improvement in mean OS score by day 14/15 was not notable in the control group (OS 3.99–3.87) but was clear in the AZB group (OS 4.36–2.90). Mean duration of hospitalization was similar in the control group (16.0 days); however, day 28 mortality was higher, at 25.0% (n=25).ConclusionAZB combined with standard of care was safe and well tolerated. An apparent clinical improvement could not be fully evaluated due to the lack of a direct control group; further assessment of AZB for the treatment of COVID-19 in a randomized, placebo-controlled study is warranted.

Safety and efficacy of MIKE-1 in patients with advanced pancreatic cancer: a study protocol for an open-label phase I/II investigator-initiated clinical trial based on a drug repositioning approach that reprograms the tumour stroma

BackgroundCancer-associated fibroblasts (CAFs) are an important component of the tumour microenvironment. Recent studies revealed CAFs are heterogeneous and CAF subset(s) that suppress cancer progression (cancer-restraining CAFs [rCAFs]) must exist in addition to well-characterised cancer-promoting CAFs (pCAFs). However, the identity and specific markers of rCAFs are not yet reported. We recently identified Meflin as a specific marker of rCAFs in pancreatic and colon cancers. Our studies revealed that rCAFs may represent proliferating resident fibroblasts. Interestingly, a lineage tracing experiment showed Meflin-positive rCAFs differentiate into α-smooth muscle actin-positive and Meflin-negative CAFs, which are generally hypothesised as pCAFs, during cancer progression. Using a pharmacological approach, we identified AM80, a synthetic unnatural retinoid, as a reagent that effectively converts Meflin-negative pCAFs to Meflin-positive rCAFs. We aimed to investigate the efficacy of a combination of AM80 and gemcitabine (GEM) and nab-paclitaxel (nab-PTX) in patients with advanced pancreatic cancer.MethodsThe phase I part is a 3 + 3 design, open-label, and dose-finding study. The dose-limiting toxicity (DLT) of these combination therapies would be evaluated for 4 weeks. After the DLT evaluation period, if no disease progression is noted based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or if the patient has no intolerable toxicity, administration of AM80 with GEM and nab-PTX would be continued for up to 24 weeks. The phase II part is an open-label, single-arm study. The maximum tolerated dose (MTD) of AM80 with GEM and nab-PTX, determined in phase I, would be administered until intolerable toxicity or disease progression occurs, up to a maximum of 24 weeks, to confirm efficacy and safety.The primary endpoints are frequency of DLT and MTD of AM80 with GEM and nab-PTX in the phase I part and response rate based on the RECIST in the phase II part. Given the historical control data, we hope that the response rate will be over 23% in phase II.DiscussionStrategies to convert pCAFs into rCAFs have been developed in recent years. We hypothesised that AM80 would be a promising enhancer of chemosensitivity and drug distribution through CAF conversion in the stroma.Trial registrationClinicaltrial.gov: NCT05064618, registered on 1 October 2021.jRCT: jRCT2041210056, registered on 27 August 2021.

Parental experiences and breastfeeding outcomes of early support to new parents from family health care centres\u2014a mixed method study

BackgroundEarly parenthood is a sensitive period for parents. Parents may feel uncertain about their new roles and unsure about where to find trusted information and support. The aim of this study was to explore the association between breastfeeding and early home visits and a proactive telephone support intervention and to describe parental experiences.MethodThis study was conducted as a mixed method study with a convergent design using qualitative data from the written comments of parents, and the quantitative data consisted of demographics, breastfeeding, and Likert questions about parents’ satisfaction with the early home visit and telephone support. Historic control (2017–2018) and intervention (2019–2020) data were collected from one family health care centre, and control (2019–2020) data were collected from another family health care centre.ResultsIn total, 838 infants, 42 mothers and 38 fathers contributed to the data in the study. The intervention group had a statistically significantly earlier home visit than the control groups. Early home visits and proactive telephone support to parents with newborn infants were not associated with breastfeeding outcomes up to six months after birth, but we could not exclude the possibility that this was a consequence of our observational study design. However, the early home visit was appreciated by the parents where they received both practical and emotional support.ConclusionsAlthough the intervention was not associated with breastfeeding, the parents appreciated the service. This shows the importance of continuing to investigate how and which support parents of newborn infants need and the effects of such support, including interventions to provide optimal support to facilitate continued breastfeeding.

Abstract OT2-05-01: The HER2-RADiCAL study (Response ADaptive CAre pLan) - Tailoring treatment for HER2 positive early breast cancer

Abstract Background The presence or absence of residual disease following neoadjuvant systemic anti-cancer therapy (neoSACT) for HER2-positive early breast cancer (HER2+ EBC) provides powerful prognostic information that may guide subsequent adjuvant treatment for the individual patient. Pathological complete response (pCR) following neoSACT identifies a population with excellent outcomes in whom the balance of toxicity associated with the current treatment pathway may be disproportionate to the absolute clinical benefit. Aims HER2-RADiCAL seeks to reduce the burden of toxicity and healthcare costs of treating HER2+ EBC by testing the hypothesis that pCR can be used as a functional response biomarker to select patients who can safely receive less intensive therapy, including avoiding anthracyclines, with minimal or no loss of efficacy in the population. Trial design and eligibility criteria HER2-RADiCAL is a response-directed interventional cohort (single-arm) study embedded within a real-world data driven clinical pathway model. Participants will be registered within 6 weeks of completion of breast cancer surgery. The main eligibility criteria include clinical stage T1N1 or T2N0-1 at diagnosis and locally-determined pCR (ypT0/Tis ypN0) after standard of care taxane-based (non-anthracycline) neoadjuvant chemotherapy, trastuzumab and pertuzumab. After registration participants will continue to receive trastuzumab to complete a total of 9 cycles including those (neo-)adjuvant cycles administered prior to study entry. Participants will receive no further pertuzumab nor any adjuvant chemotherapy. Statistical methods The primary clinical endpoint is relapse free interval. Recruitment of 720 participants over 3 years will provide 90% power to exclude an event rate >6.5% at 3 years. Secondary endpoints include relapse-free survival, invasive breast cancer-free survival, invasive disease-free survival, distant recurrence-free interval, breast cancer-free interval, treatment pathway adherence and cost-effectiveness. Real-world data driven clinical pathway model Health economic modelling will compare the protocol-driven study cohort with two comparator pathways: a non-response adapted maximum therapy pathway (the standard clinical pathway prior to the study) and a real-world representative pathway taken from 4-nation UK National Health Service data at the beginning and end of the study. Patient and public involvement Patient advocates have shaped the research by confirming that the main outcomes being evaluated are important to patients and that the interventional cohort design, with power to exclude an absolute risk of recurrence outwith a 2-3% margin of historical control data, is acceptable and preferable to a randomised controlled trial, which would take longer to get answers and need many more patients to be included. They have been involved in protocol design, including methodology, sample collection and patient follow-up, and their input has shaped the patient information materials and consent forms. Patient advocates will have an ongoing key role in overseeing the progress of the study as members of the Trial Management Group, and they will also have an important role in communicating the study results to patients and the public. Current status HER2-RADiCAL is planned to open at ~40 UK sites commencing in September 2021. Citation Format: Iain Macpherson, Stuart McIntosh, Lucy Kilburn, Holly Tovey, Sarah Kernaghan, Katie Goddard, Indrani Bhattacharya, Clinton Boyd, Charlotte Coles, Cliona Kirwan, Mairead Mackenzie, Ciara O’Brien, Alistair Ring, Claire Snowdon, Hilary Stobart, Duncan Wheatley, Andrew Wardley, Abeer Shaaban, Peter Hall, David Cameron, Judith Bliss. The HER2-RADiCAL study (Response ADaptive CAre pLan) - Tailoring treatment for HER2 positive early breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-05-01.

Prediction intervals for all of M future observations based on linear random effects models

In many pharmaceutical and biomedical applications such as assay validation, assessment of historical control data, or the detection of anti‐drug antibodies, the calculation and interpretation of prediction intervals (PI) is of interest. The present study provides two novel methods for the calculation of prediction intervals based on linear random effects models and restricted maximum likelihood (REML) estimation. Unlike other REML‐based PI found in the literature, both intervals reflect the uncertainty related with the estimation of the prediction variance. The first PI is based on Satterthwaite approximation. For the other PI, a bootstrap calibration approach that we will callquantile‐calibrationwas used. Due to the calibration process this PI can be easily computed for more than one future observation and based on balanced and unbalanced data as well. In order to compare the coverage probabilities of the proposed PI with those of four intervals found in the literature, Monte Carlo simulations were run for two relatively complex random effects models and a broad range of parameter settings. The quantile‐calibrated PI was implemented in the statistical software R and is available in the predint package.

Matching design for augmenting the control arm of a randomized controlled trial using real-world data

ABSTRACT Randomized clinical trials (RCTs) have often been considered as the gold standard in drug development, but they may not be fully powered due to limited patient population and can even lead to ethical concerns in rare disease studies. In situations like this, real-world data (RWD)/historical data can be utilized to augment or possibly serve as the control arm for the current trial. If a subset of subjects from the RWD/historical trial could be matched to the concurrent control arm subjects and they are deemed comparable following certain criteria, then pooling the matched subjects from the historical control arm and the concurrent control arm can boost the power. In this paper, we propose two matching methods of borrowing historical control data that not only balance key observed baseline covariates but also ensure the comparability of responses between the historical and concurrent controls. Close similarity in response variables among controls reduces Type I error inflation and provides further protection against unmeasured confounding bias, which is a major challenge in using RWD. Simulation studies are conducted to evaluate the empirical performance of the two matching methods in terms of Type I error rate and power, and an illustrative description of a planned study is presented.

Propensity score-integrated Bayesian prior approaches for augmented control designs: a simulation study

ABSTRACT Drug development can be costly, and the availability of clinical trial participants may be limited either due to the disease setting (rare or pediatric diseases) or due to many sponsors evaluating multiple drugs or combinations in the same patient population. To maximize resource utilization, sponsors may leverage patient-level control data from historical trials. However, in a study with no control arm, it is impossible to evaluate if the historical controls are an appropriate comparator for the current study. Here, instead of conducting a single-arm trial and relying solely on historical controls, we evaluate the situation where a minimal number of patients are enrolled into a control arm, which is augmented by borrowing historical control data. Propensity score (PS) methods are commonly used to minimize bias for non-randomized data. In addition, Bayesian information borrowing with PS adjustments has been proposed when it may not be reasonable to include all available historical data. This paper proposes using PS adjustment integrated with Bayesian commensurate priors to adaptively borrow information. We then evaluate the performance of different PS adjustment methods and different Bayesian priors for augmented control using simulation studies to help inform the design of future trials. In general, we find that propensity weighting or matching combined with the commensurate prior yield reasonable statistical properties across a range of scenarios. Finally, our proposed methods are applied to a real trial with a binary outcome. Abbreviations: PS: propensity score; IPTW: inverse probability of treatment weighting; ATT: average treatment effect on those who received treatment; RCT: randomized controlled trial; CDD: covariate distribution difference; ESS: effective sample size

Impact of protocolized postarrest care with targeted temperature management on the outcomes of cardiac arrest survivors without temperature management

Introduction Protocolized postarrest care that includes targeted temperature management (TTM) improves survival and neurological outcomes in cardiac arrest survivors. Whether the accumulated experience regarding the use of the protocolized approach also benefits patients who did not undergo TTM has yet to be investigated. Methods Adults (≥18 years old) with nontraumatic cardiac arrest and who survived to intensive care unit (ICU) admission were retrospectively recruited from a single tertiary medical centre from 2006 to 2009 and 2011 to 2017. Patients were excluded if they had traumatic injuries, were pregnant, did not survive to ICU admission, regained clear consciousness within 3 h after the return of spontaneous circulation, or underwent TTM. The sum of TTM cases since 2006 and before the cardiac arrest of each enrolled patient was used as a substitute index for the amount of experience accumulated from the use of protocolized TTM care. Results In total, 802 non-TTM patients were enrolled in the final analysis. The rate of survival to hospital discharge increased from 25.9% in 2006 to 33.3% in 2017. Regarding neurological recovery at hospital discharge, the incidence of favourable neurological function (cerebral performance category: 1 or 2) increased from 10.3% in 2006 to 23.5% in 2017. A multiple logistic regression indicated a significant association between the cumulative TTM case numbers and neurological outcomes in patients who did not receive TTM. Conclusions The improvement of neurological outcomes in adult nontraumatic cardiac arrest survivors who did not receive TTM was associated with the cumulative number of cases receiving protocolized TTM care. In the era of TTM, the use of only historical control data might lead to bias, which is caused by overlooking the influence of a more refined protocolized postarrest care that includes TTM. KEY MESSAGE The cumulative number of cases receiving protocolized TTM care, which we used as a substitute index for the amount of experience accumulated from the use of protocolized postarrest care that includes TTM, was associated with the improvement of neurological outcomes in adult nontraumatic cardiac arrest survivors who did not receive TTM.