Commentary on Chen et al. (2022): The need for continued methodological research on leveraging information in secondary endpoints for more efficient RCTs.

Chen et al. (2022) recently proposed a set of estimating equations that incorporate data from secondary endpoints to improve precision in parameter estimates related to a primary endpoint. We were motivated to translate their methodology to the context of randomized controlled trials to gain precision in treatment effect estimation using data from secondary endpoints. Our results suggest that this estimator cannot gain efficiency in this context because of random treatment assignment, especially when there is a treatment effect on secondary endpoints, and that further methodological work in this area is needed.

Laboratory-based measures of executive function and daily living skills in young children with Down syndrome: informing future interventions.

BACKGROUND: Adaptive behaviour refers to the practical skills necessary for independence and is considered a high-priority intervention target for children with neurogenetic conditions associated with intellectual disability, like Down syndrome (DS). Daily living skills (DLS) are a critical aspect of adaptive behaviour, but they have received little intervention attention, possibly because they involve a wide variety of skills across many settings. The present study aimed to advance DLS intervention science by examining the concurrent and longitudinal association between DLS performances and a cognitive skillset hypothesised to support DLS skill acquisition, executive function (EF). METHODS: Participants were 71 children with DS between the ages of 2.5 and 8.7 years (M = 5.23 years; standard deviation = 1.65) who completed a battery of adapted EF tasks and a primary caregiver who completed the Vineland Adaptive Behavior Scales 3rd Edition Parent/Caregiver Comprehensive Report Form. A subset of caregivers also provided 6- and 12-month follow-up adaptive behaviour information. RESULTS: Results demonstrated a positive association between EF task performance and DLS standard scores and v-scores both concurrently and longitudinally. CONCLUSIONS: The findings have implications for potential future intervention approaches that aim to strengthen DLS performances by advancing EF skills in this population.

Familywise error for multiple time-to-event endpoints in a group sequential design.

We investigate the familywise error rate (FWER) for time-to-event endpoints evaluated using a group sequential design with a hierarchical testing procedure for secondary endpoints. We show that, in this setup, the correlation between the log-rank test statistics at interim and at end of study is not congruent with the canonical correlation derived for normal-distributed endpoints. We show, both theoretically and by simulation, that the correlation also depends on the level of censoring, the hazard rates of the endpoints, and the hazard ratio. To optimize operating characteristics in this complex scenario, we propose a simulation-based method to assess the FWER which, better than the alpha-spending approach, can inform the choice of critical values for testing secondary endpoints.

A note on familywise error rate for a primary and secondary endpoint.

Hung et al. (2007) considered the problem of controlling the type I error rate for a primary and secondary endpoint in a clinical trial using a gatekeeping approach in which the secondary endpoint is tested only if the primary endpoint crosses its monitoring boundary. They considered a two-look trial and showed by simulation that the naive method of testing the secondary endpoint at full level α at the time the primary endpoint reaches statistical significance does not control the familywise error rate at level α. Tamhane et al. (2010) derived analytic expressions for familywise error rate and power and confirmed the inflated error rate of the naive approach. Nonetheless, many people mistakenly believe that the closure principle can be used to prove that the naive procedure controls the familywise error rate. The purpose of this note is to explain in greater detail why there is a problem with the naive approach and show that the degree of alpha inflation can be as high as that of unadjusted monitoring of a single endpoint.

Treatment endpoints for chronic hepatitis D.

Management of chronic hepatitis D (CHD) has entered a new era. In this new era, the virus entry inhibitor bulevirtide has received conditional approval as a treatment for compensated CHD. Three phase 3 studies with two new compounds are ongoing for the treatment of CHD. In this context, surrogate markers of treatment efficacy have been well defined for chronic hepatitis B (CHB) (7) and chronic hepatitis C (8) but not for CHD. The aim of this review is to give a perspective on treatment endpoints in CHD. For this, we took guidance from CHB studies and tried to make suggestions which differed according to finite versus prolonged treatment durations and also took into account the different characteristics of the new compounds.

Mouse Models of Lung Fibrosis.

The drug discovery pipeline, from discovery of therapeutic targets through preclinical and clinical development phases, to an approved product by health authorities, is a time-consuming and costly process, where a lead candidates' success at reaching the final stage is rare. Although the time from discovery to final approval has been reduced over the last decade, there is still potential to further optimize and streamline the evaluation process of each candidate as it moves through the different development phases. In this book chapter, we describe our preclinical strategies and overall decision-making process designed to evaluate the tolerability and efficacy of therapeutic candidates suitable for patients diagnosed with fibrotic lung disease. We also describe the benefits of conducting preliminary discovery trials, to aid in the selection of suitable primary and secondary outcomes to be further evaluated and assessed in subsequent internal and external validation studies. We outline all relevant research methodologies and protocols routinely performed by our research group and hope that these strategies and protocols will be a useful guide for biomedical and translational researchers aiming to develop safe and beneficial therapies for patients with fibrotic lung disease.

Impact of COVID-19 Outbreak through Telemedicine Implementation on Data Reporting During Oncology Clinical Trials.

Coronavirus disease outbreak has affected all aspect of clinical care including cancer clinical trials. To minimize exposure of frail cancer patients, an implementation of telemedicine was retained. The impact of this implementation on primary and secondary endpoints criteria of ongoing clinical trials was analyzed. Out of 128 oncology clinical trials, 25 (19%) had an implementation of teleconsultation. Poor data reporting induced mainly a bias on qualitative and descriptive primary endpoints than those assessing efficacy (80% vs 20%; p < 0.001). The integration of telemedicine and E-technologies in the medical practices and clinical trials must be designed and validated.

Weighted false discovery rate controlling procedures for clinical trials.

Having identified that the lack of replicability of results in earlier phases of clinical medical research stems largely from unattended selective inference, we offer a new hierarchical weighted false discovery rate controlling testing procedure alongside the single-level weighted procedure. These address the special structure of clinical research, where the comparisons of treatments involve both primary and secondary endpoints, by assigning weights that reflect the relative importance of the endpoints in the error being controlled. In the hierarchical method, the primary endpoints and a properly weighted intersection hypothesis that represents all secondary endpoints are tested. Should the intersection hypothesis be among the rejected, individual secondary endpoints are tested. We identify configurations where each of the two procedures has the advantage. Both offer higher power than competing hierarchical (gatekeeper) familywise error-rate controlling procedures being used for drug approval. By their design, the advantage of the proposed methods is the increased power to discover effects on secondary endpoints, without giving up the rigor of addressing their multiplicity.

Clinical research and methodology: What usage and what hierarchical order for secondary endpoints?

In a randomised clinical trial, when the result of the primary endpoint shows a significant benefit, the secondary endpoints are scrutinised to identify additional effects of the treatment. However, this approach entails a risk of concluding that there is a benefit for one of these endpoints when such benefit does not exist (inflation of type I error risk). There are mainly two methods used to control the risk of drawing erroneous conclusions for secondary endpoints. The first method consists of distributing the risk over several co-primary endpoints, so as to maintain an overall risk of 5%. The second is the hierarchical test procedure, which consists of first establishing a hierarchy of the endpoints, then evaluating each endpoint in succession according to this hierarchy while the endpoints continue to show statistical significance. This simple method makes it possible to show the additional advantages of treatments and to identify the factors that differentiate them.

Multiplicity in confirmatory clinical trials: a case study with discussion from a JSM panel.

An invited panel session was conducted in the 2012 Joint Statistical Meetings, San Diego, California, USA, to stimulate the discussion on multiplicity issues in confirmatory clinical trials for drug development. A total of 11 expert panel members were invited and 9 participated. Prior to the session, a case study was previously provided to the panel members to facilitate the discussion, focusing on the key components of the study design and multiplicity. The Phase 3 development program for this new experimental treatment was based on a single randomized controlled trial alone. Each panelist was asked to clarify if he or she responded as if he or she were a pharmaceutical drug sponsor, an academic panelist or a health regulatory scientist.