Real-World Clinical and Economic Outcomes Associated with Palbociclib for HR-Positive/HER2 Negative Metastatic Breast Cancer: A Commentary.

Despite the achieved advancement in pharmacological cancer treatments, the majority of postmenopausal women with hormone receptor-positive metastatic breast cancer (mBC) will experience disease progression. Research into alternative therapies with improved efficacy and reduced side effects has led to the development of a new class of oral anticancer medications, the cyclin-dependent kinase (CDK) 4/6 inhibitors, which include palbociclib, ribociclib, and abemaciclib. Nonetheless, there is growing evidence that the effectiveness of oral anticancer medications is sub-optimal, being influenced by low adherence, sociodemographic factors, and adverse effect profiles. In addition, there is a disconnect between the high price tags of CDK 4/6 inhibitors and their observed effectiveness, raising questions about their value. Currently, the existing knowledge base on the effectiveness and cost-effectiveness of newer oral anticancer medications in understudied populations with possible health disparities is scant. This commentary discusses what is known about palbociclib's clinical effectiveness, safety, and adherence and suggests the need for further studies of real-world effectiveness and cost-effectiveness to help establish the value of newer oncologic drugs, such as palbociclib. DISCLOSURES: No funding supported the writing of this article. The authors have nothing to disclose.

The APPROACH trial: Assessing pain, patient-reported outcomes, and complementary and integrative health.

Electronic health record data can be used in multiple ways to facilitate real-world pragmatic studies. Electronic health record data can provide detailed information about utilization of treatment options to help identify appropriate comparison groups, access historical clinical characteristics of participants, and facilitate measuring longitudinal outcomes for the treatments being studied. An additional novel use of electronic health record data is to assess and understand referral pathways and other business practices that encourage or discourage patients from using different types of care. We describe an ongoing study utilizing access to real-time electronic health record data about changing patterns of complementary and integrative health services to demonstrate how electronic health record data can provide the foundation for a pragmatic study when randomization is not feasible. Conducting explanatory trials of the value of emerging therapies within a healthcare system poses ethical and pragmatic challenges, such as withholding access to specific services that are becoming widely available to patients. We describe how prospective examination of real-time electronic health record data can be used to construct and understand business practices as potential surrogates for direct randomization through an instrumental variables analytic approach. In this context, an example of a business practice is the internal hiring of acupuncturists who also provide yoga or Tai Chi classes and can offer these classes without additional cost compared to community acupuncturists. Here, the business practice of hiring internal acupuncturists is likely to encourage much higher rates of combined complementary and integrative health use compared to community referrals. We highlight the tradeoff in efficiency of this pragmatic approach and describe use of simulations to estimate the potential sample sizes needed for a variety of instrument strengths. While real-time monitoring of business practices from electronic health records provides insights into the validity of key independence assumptions associated with the instrumental variable approaches, we note that there may be some residual confounding by indication or selection bias and describe how alternative sources of electronic health record data can be used to assess the robustness of instrumental variable assumptions to address these challenges. Finally, we also highlight that while some clinical outcomes can be obtained directly from the electronic health record, such as longitudinal opioid utilization and pain intensity levels for the study of the value of complementary and integrative health, it is often critical to supplement clinical electronic health record-based measures with patient-reported outcomes. The experience of this example in evaluating complementary and integrative health demonstrates the use of electronic health record data in several novel ways that may be of use for designing future pragmatic trials.

Applying the pragmatic-explanatory continuum indicator summary to the implementation of a physical activity coaching trial in chronic obstructive pulmonary disease.

BACKGROUND: Observational studies show that physical inactivity is associated with worse outcomes in chronic obstructive pulmonary disease (COPD). Despite practice guidelines recommending regular physical activity (PA), there are no large-scale experimental studies to confirm that patients at high risk for COPD exacerbations can increase their PA and consequently, have improved outcomes. PURPOSE: The purpose of this case study is to describe the use of a widely accepted pragmatic trials framework for the design and implementation of a pragmatic clinical trial (PCT) of PA coaching for COPD in a real-world setting. METHOD: The aim of the trial was to determine the effectiveness of a 12-month PA coaching intervention (Walk On!) compared to standard care for 2,707 patients at high risk for COPD exacerbations from a large integrated health care system. The descriptions of our implementation experiences are anchored within the pragmatic-explanatory continuum indicator summary (PRECIS-2) framework. DISCUSSION: Facilitators of PCT implementation include early and ongoing engagement and support of multiple stakeholders including patients, health system leaders, administrators, physician champions, and frontline clinicians, an organizational/setting that prioritizes positive lifestyle behaviors, and a flexible intervention that allows for individualization. Pragmatic challenges include reliance on electronic data that are not complete or available in real-time for patient identification, timing of outreach may not synchronize with patients' readiness for change, and high turnover of clinical staff drawn from the existing workforce. DISCUSSION: PRECIS-2 is a useful guide for organizing decisions about study designs and implementation approaches to help diverse stakeholders recognize the compromises between internal and external validity with those decisions.

Barriers to the conduct of randomised clinical trials within all disease areas.

BACKGROUND: Randomised clinical trials are key to advancing medical knowledge and to enhancing patient care, but major barriers to their conduct exist. The present paper presents some of these barriers. METHODS: We performed systematic literature searches and internal European Clinical Research Infrastructure Network (ECRIN) communications during face-to-face meetings and telephone conferences from 2013 to 2017 within the context of the ECRIN Integrating Activity (ECRIN-IA) project. RESULTS: The following barriers to randomised clinical trials were identified: inadequate knowledge of clinical research and trial methodology; lack of funding; excessive monitoring; restrictive privacy law and lack of transparency; complex regulatory requirements; and inadequate infrastructures. There is a need for more pragmatic randomised clinical trials conducted with low risks of systematic and random errors, and multinational cooperation is essential. CONCLUSIONS: The present paper presents major barriers to randomised clinical trials. It also underlines the value of using a pan-European-distributed infrastructure to help investigators overcome barriers for multi-country trials in any disease area.

A focused ethnography of a Child and Adolescent Mental Health Service: factors relevant to the implementation of a depression trial.

BACKGROUND: Prior to commencing a randomised controlled trial, we conducted a focused ethnography to ensure that the trial was well suited to the proposed setting. METHODS: A six-month observation of a Child and Adolescent Mental Health Service site in the North-East of England was undertaken to observe the site procedures, staff culture and patient care pathways. During this period, documentary data were collected and interviews were conducted with key informants to provide insight into staff perceptions of the proposed trial. The data were coded using thematic analysis and the resulting themes were verified by a second coder. RESULTS: Seventeen documents were collected, 158 h of observation and six formal staff interviews were undertaken. Four themes emerged from the data; non-clinically orientated variation in practice, diagnosis, capacity and staff economy. Non-clinically orientated variation in practice occurred when staff decisions were based upon resource availability rather than on clinical judgement. Diagnosis demonstrated differing staff confidence in making diagnoses and in the treatment of patients who had received a diagnosis. Capacity consisted of the time to attend training and the psychological capacity to consider or incorporate learning into practice. Staff economy was characterised by staff changes and shortages. There was significant interaction between the themes, with staff economy emerging as a central barrier to research. The results directly informed adaptations to the trial protocol. CONCLUSIONS: An ethnographic approach has provided important insights into the individual, practical and organisational boundaries into which a trial would need to be implemented.

Meeting pragmatism halfway: making a pragmatic clinical trial protocol.

Pragmatic clinical trials (PCTs) are today an increasingly prominent means of measuring the 'effectiveness' of healthcare interventions in 'real world' clinical settings, in order to produce evidence on which to base regulatory and clinical decision-making. Although several sociological studies have shown persuasively how PCTs are co-constructed within particular healthcare systems in which they are based, they have tended to focus on relatively later stages in careers of trials. The paper contributes to literature by considering how the 'real world' of the UK National Health Service (NHS) is incorporated into the design of a research protocol. Drawing on a meeting held just prior to patient recruitment for a PCT in maternal health, the paper analyses a trial collective's efforts to purify the messy domain of NHS clinical care into the orderly confines of the protocol (Law 2004), which meant satisfying demands for both scientific and social robustness (c.f. Nowotny et al. 2001). The findings show how efforts to inscribe robustness into the PCT protocol were themselves mediated through epistemic and regulatory conventions surrounding protocols as devices in healthcare research. Finally it is argued that meetings constitute an important epistemic instrument through which to settle various emerging tensions in PCT protocol design.