Estimand framework: Are we asking the right questions? A case study in the solid tumor setting

The estimand framework requires a precise definition of the clinical question of interest (the estimand) as different ways of accounting for “intercurrent” events post randomization may result in different scientific questions. The initiation of subsequent therapy is common in oncology clinical trials and is considered an intercurrent event if the start of such therapy occurs prior to a recurrence or progression event. Three possible ways to account for this intercurrent event in the analysis are to censor at initiation, consider recurrence or progression events (including death) that occur before and after the initiation of subsequent therapy, or consider the start of subsequent therapy as an event in and of itself. The new estimand framework clarifies that these analyses address different questions (“does the drug delay recurrence if no patient had received subsequent therapy?” vs “does the drug delay recurrence with or without subsequent therapy?” vs “does the drug delay recurrence or start of subsequent therapy?”). The framework facilitates discussions during clinical trial planning and design to ensure alignment between the key question of interest, the analysis, and interpretation. This article is a result of a cross-industry collaboration to connect the International Council for Harmonisation E9 addendum concepts to applications. Data from previously reported randomized phase 3 studies in the renal cell carcinoma setting are used to consider common intercurrent events in solid tumor studies, and to illustrate different scientific questions and the consequences of the estimand choice for study design, data collection, analysis, and interpretation.     

Improving early phase oncology clinical trial design: An opportunity for statisticians

This short communication supports that rule-based study designs such as the ‘3 + 3’ study design are still being used in early phase oncology development programs despite their inferior performance to model-based and model-assisted designs. Statisticians have an opportunity to shape and improve early phase oncology drug development programs by introducing newer, more efficient study designs that estimate the Optimal Biological dose to their oncology trialist colleges.     

Enhancing Collaborative Leadership in Palliative Social Work in Oncology

The Institute of Medicine (IOM) Report—Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs—provided recommendations for meeting the palliative care needs of our growing population of older Americans. The IOM report highlights the demand for social work leadership across all aspects of the health care delivery system. Social workers are core interdisciplinary members of the health care team and it is important for them to be well prepared for collaborative leadership roles across health care settings. The ExCEL in Social Work: Excellence in Cancer Education &; Leadership education project was created as a direct response to the 2008 Institute of Medicine. (2008). Cancer care for the whole patient: Meeting psychosocial health needs. Washington, DC: National Academies Press. [Google Scholar] IOM Report. This article highlights a sampling of palliative care projects initiated by outstanding oncology social work participants in the ExCEL program. These projects demonstrate the leadership of social workers in palliative care oncology.     

How to choose a time zero for patients in external control arms

When a sponsor carries out a single-arm trial of a novel oncology compound, it may wish to assess the efficacy of the compound via comparison of overall survival to an external control arm, constructed using patients included in some retrospective registry. If efficacy of the novel compound is compared to efficacy of physician's choice of chemotherapy, patients in the retrospective registry might qualify for inclusion in the external control arm at multiple different points in time, when they receive different chemotherapy treatments. For example, a patient might qualify at the start of their second, third and fourth lines of therapy. From the start of which line of therapy should this patient's survival be compared to survival of participants in the single-arm trial? Some sponsors have elected to include patients in the external control arm from the last available line of therapy in the retrospective database. Another possibility is to randomly select a line of therapy for each external control arm patient from among those available. In this paper, we show, via probabilistic arguments and also via simulation based on real data, that both of these methods give rise to a bias in favor of the single-arm trial. We further show that this bias can be avoided by instead including external control arm patients multiple times in the external control arm, once for each time they receive qualifying treatment.     

Recommendations for Hospice Care to Terminally Ill Cancer Patients: A Phenomenological Study of Oncologists' Experiences

The aim of this exploratory study was to better understand oncologists' experiences and their perceptions of hospice care as an end-of-life treatment choice for terminally ill cancer patients. To describe this experience, semi-structured qualitative interviews were conducted using phenomenological methods with nine oncologists. Four themes emerged from the data analysis: (a) feelings of discomfort and relief, (b) being different from others, (c) experience with nonhospice patients, and (d) factors influencing the decision to recommend hospice. Future research and a flexible interdisciplinary practice model are suggested to better assist with end-of-life care decision making and recommendations for hospice care with oncologists and their terminally ill cancer patients are presented.     

Integrating Gestalt psychotherapy into social work practice with adult oncology patients

This article will provide an examination of Gestalt psychotherapy and its application to adult cancer patients. Gestalt psychotherapy can be utilized as a psychosocial intervention targeted to meet the needs of oncology patients. The following article will examine Gestalt therapy theory and review basic principles to utilize in clinical practice. The authors will highlight the populations to which Gestalt has been applied, and additional case vignettes will demonstrate concrete ways to incorporate this theory into practice with oncology patients.     

Dealing with selective dropout in clinical trials

Clinical trials in severely diseased populations often suffer from a high dropout rate that is related to the investigated target morbidity. These dropouts can bias estimates and treatment comparisons, particularly in the event of an imbalance. Methods to describe such selective dropout are presented that use the time in study distribution to generate so‐called population evolution charts. These charts show the development of a distribution of a covariate or the target morbidity measure as it changes as a result of the dropout process during the follow‐up time. The selectiveness of the dropout process with respect to a variable can be inferred from the change in its distribution. Different types of selective dropout are described with real data from several studies in metastatic bone disease, where marked effects can be seen. A general strategy to cope with selective dropout seems to be the inclusion of dropout events into the endpoint. Within a time‐to‐event analysis framework this simple approach can lead to valid conclusions and still retains conservative elements. Morbidity measures that are based on (recurrent) event counts react differently in the presence of selective dropout. They differ mainly in the way dropout is included. One simple measure achieves good performance under selective dropout by introducing a non‐specific penalty for premature study termination. The use of a prespecified scoring system to assign a weight for each works well. This simple and transparent approach performs well even in the presence of unbalanced selective dropout. Copyright © 2002 John Wiley & Sons, Ltd.     

An adaptive biomarker basket design in phase II oncology trials

The phase II basket trial in oncology is a novel design that enables the simultaneous assessment of treatment effects of one anti-cancer targeted agent in multiple cancer types. Biomarkers could potentially associate with the clinical outcomes and re-define clinically meaningful treatment effects. It is therefore natural to develop a biomarker-based basket design to allow the prospective enrichment of the trials with the adaptive selection of the biomarker-positive (BM+) subjects who are most sensitive to the experimental treatment. We propose a two-stage phase II adaptive biomarker basket (ABB) design based on a potential predictive biomarker measured on a continuous scale. At Stage 1, the design incorporates a biomarker cutoff estimation procedure via a hierarchical Bayesian model with biomarker as a covariate (HBMbc). At Stage 2, the design enrolls only BM+ subjects, defined as those with the biomarker values exceeding the biomarker cutoff within each cancer type, and subsequently assesses the early efficacy and/or futility stopping through the pre-defined interim analyses. At the end of the trial, the response rate of all BM+ subjects for each cancer type can guide drug development, while the data from all subjects can be used to further model the relationship between the biomarker value and the clinical outcome for potential future research. The extensive simulation studies show that the ABB design could produce a good estimate of the biomarker cutoff to select BM+ subjects with high accuracy and could outperform the existing phase II basket biomarker cutoff design under various scenarios.     

Analysis of progression-free survival in oncology trials: some common statistical issues

With the advent of ever more effective second and third line cancer treatments and the growing use of 'crossover' trial designs in oncology, in which patients switch to the alternate randomized treatment upon disease progression, progression-free survival (PFS) is an increasingly important endpoint in oncologic drug development. However, several concerns exist regarding the use of PFS as a basis to compare treatments. Unlike survival, the exact time of progression is unknown, so progression times might be over-estimated and, consequently, bias may be introduced when comparing treatments. Further, it is not uncommon for randomized therapy to be stopped prior to progression being documented due to toxicity or the initiation of additional anti-cancer therapy; in such cases patients are frequently not followed further for progression and, consequently, are right-censored in the analysis. This article reviews these issues and concludes that concerns relating to the exact timing of progression are generally overstated, with analysis techniques and simple alternative endpoints available to either remove bias entirely or at least provide reassurance via supportive analyses that bias is not present. Further, it is concluded that the regularly recommended manoeuvre to censor PFS time at dropout due to toxicity or upon the initiation of additional anti-cancer therapy is likely to favour the more toxic, less efficacious treatment and so should be avoided whenever possible.     

Conditional approval: discussion points from the PSI conditional approval expert group

The European Agency for the Evaluation of Medicinal Products has recently completed the consultation of a draft guidance on how to implement conditional approval. This route of application is available for orphan drugs, emergency situations and serious debilitating or life-threatening diseases. Although there has been limited experience in implementing conditional approval to date, PSI (Statisticians in the Pharmaceutical Industry) sponsored a meeting of pharmaceutical statisticians with an interest in the area to discuss potential issues. This article outlines the issues raised and resulting discussions, based on the group's interpretation of the legislation. Conditional approval seems to fit well with the accepted regulatory strategy in HIV. In oncology, conditional approval may be most likely when (a) compelling phase II data are available using accepted clinical outcomes (e.g. progression/recurrence-free survival or overall survival) and Phase III has been planned or started, or (b) when data are available using a surrogate endpoint for clinical outcome (e.g. response rate or biochemical measures) from a single-arm study in rare tumours with high response, compared with historical data. The use of interim analyses in Phase III for supporting conditional approval raises some challenging issues regarding dissemination of information, maintenance of blinding, potential introduction of bias, ethics, switching, etc.