Evaluation of medical ethics competencies in rheumatology: local experience during national accreditation process.

INTRODUCTION: Rheumatologists are the primary healthcare professionals responsible for patients with rheumatic diseases and should acquire medical ethical competencies, such as the informed consent process (ICP). The objective clinical structured examination is a valuable tool for assessing clinical competencies. We report the performance of 90 rheumatologist trainees participating in a station designed to evaluate the ICP during the 2018 and 2019 national accreditations. METHODS: The station was validated and represented a medical encounter in which the rheumatologist informed a patient with systemic lupus erythematosus with clinically active nephritis about renal biopsy. A trained patient-actor and an evaluator were instructed to assess ICP skills (with a focus on kidney biopsy benefits, how the biopsy is done and potential complications) in obtaining formal informed consent, delivering bad news and overall communication with patients. The evaluator used a tailored checklist and form. RESULTS: Candidate performance varied with ICP content and was superior for potential benefit information (achieved by 98.9% of the candidates) but significantly reduced for potential complications (37.8%) and biopsy description (42.2%). Only 17.8% of the candidates mentioned the legal perspective of ICP. Death (as a potential complication) was omitted by the majority of the candidates (93.3%); after the patient-actor challenged candidates, only 57.1% of them gave a clear and positive answer. Evaluators frequently rated candidate communications skills as superior (≥80%), but ≥1 negative aspect was identified in 69% of the candidates. CONCLUSIONS: Ethical competencies are mandatory for professional rheumatologists. It seems necessary to include an ethics competency framework in the curriculum throughout the rheumatology residency.

Ethical Framework for Including Research Biopsies in Oncology Clinical Trials: American Society of Clinical Oncology Research Statement.

In contrast to clinical biopsies, where tissue is collected to inform patient care, research biopsies are performed for scientific purposes to potentially enhance understanding of the biologic bases of cancer and drug action, thereby improving diagnosis and treatment, but they may offer no direct benefit to participants and have known risks. The widespread use of research biopsies that do not have the potential to directly benefit participants has come under scrutiny, with critics raising ethical concerns related to the adequacy of participant protections, informed consent, and participant understanding of the risks and benefits, as well as the scientific impact of research biopsies on drug development and treatment. This manuscript presents the American Society of Clinical Oncology's (ASCO's) ethical framework for incorporation of research biopsies in trials. The framework provides guidance on the circumstances to include optional and mandatory biopsies, as well as provides recommendations to stakeholders on necessary steps for improving the conduct of research biopsies overall.

Ideology and Palliative Care: Moral Hazards at the Bedside.

Palliative care has had a long-standing commitment to teaching medical students and other medical professionals about pain management, communication, supporting patients in their decisions, and providing compassionate end-of-life care. Palliative care programs also have a critical role in helping patients understand medical conditions, and in supporting them in dealing with pain, fear of dying, and the experiences of the terminal phase of their lives. We applaud their efforts to provide that critical training and fully support their continued important work in meeting the needs of patients and families. Although we appreciate the contributions of palliative care services, we have noted a problem involving some palliative care professionals' attitudes, methods of decisionmaking, and use of language. In this article we explain these problems by discussing two cases that we encountered.

Underreporting of Research Biopsies from Clinical Trials in Oncology.

Purpose: Research biopsies are frequently incorporated within clinical trials in oncology and are often a mandatory requirement for trial enrollment. However, limited information is available regarding the extent and completeness of research biopsy reporting.Experimental Design: We identified a cohort of therapeutic clinical trials where research biopsies were performed between January 2005 and October 2010 from an IR database at our institution. Clinical trial protocols were compared with the highest level of corresponding publication as a manuscript or registry report.Results: A total of 866 research biopsies were performed across 46 clinical trials, with a median of 8 patients biopsied/trial and 19 biopsies collected/trial. After a median follow-up time of 4.3 years from trial completion, 36 of 46 trials (78%) reported trial results: published manuscripts (n = 35), or registry report (n = 1). A total of 635 conducted biopsies were reported in 18 of the 46 trials (39%). Six (33%) of these 18 trials underreported the number of biopsies performed. Of 33 trials with mandatory research biopsies, 13 (39%) trials reported on these biopsies. Biopsy complications occurred in 8 trials [n = 39 patients, 6 grade 3/4 adverse events (AE)] but only 1 trial reported these. Factors associated with biopsy reporting included a larger number of biopsies (P ≤ 0.001) and serial biopsies (P < 0.001). Twelve of 16 (75%) trials with >12 biopsies performed reported on these biopsies compared with only 20% (6/30) that performed ≤12 biopsies.Conclusions: Despite ethical obligations to report research biopsies, the majority (61%) of trials do not report results from research biopsies. Complications are rarely reported in these studies. Improved reporting of results and AEs from research biopsies is needed. Clin Cancer Res; 23(21); 6450-7. ©2017 AACR.

Circulating tumour DNA sequence analysis as an alternative to multiple myeloma bone marrow aspirates.

The requirement for bone-marrow aspirates for genomic profiling of multiple myeloma poses an obstacle to enrolment and retention of patients in clinical trials. We evaluated whether circulating cell-free DNA (cfDNA) analysis is comparable to molecular profiling of myeloma using bone-marrow tumour cells. We report here a hybrid-capture-based Liquid Biopsy Sequencing (LB-Seq) method used to sequence all protein-coding exons of KRAS, NRAS, BRAF, EGFR and PIK3CA in 64 cfDNA specimens from 53 myeloma patients to >20,000 × median coverage. This method includes a variant filtering algorithm that enables detection of tumour-derived fragments present in cfDNA at allele frequencies as low as 0.25% (median 3.2%, range 0.25-46%). Using LB-Seq analysis of 48 cfDNA specimens with matched bone-marrow data, we detect 49/51 likely somatic mutations, with subclonal hierarchies reflecting tumour profiling (96% concordance), and four additional mutations likely missed by bone-marrow testing (>98% specificity). Overall, LB-Seq is a high fidelity adjunct to genetic profiling of bone-marrow in multiple myeloma.

Establishing proof of mechanism: Assessing target modulation in early-phase clinical trials.

Since modulation of the putative target and the observed anti-tumor effects form the basis for the clinical development of a molecularly targeted therapy, early-phase clinical trials should be designed to demonstrate proof-of-mechanism in tissues of interest. In addition to establishing safety and the maximum tolerated dose, first-in-human clinical trials should be designed to demonstrate target modulation, define the proposed mechanism of action, and evaluate pharmacokinetic-pharmacodynamic relationships of a new anti-cancer agent. Assessing target modulation in paired tumor biopsies in patients with solid tumors presents multiple challenges, including procedural issues such as patient safety, ethical considerations, and logistics of sample handling and processing. In addition, the availability of qualified biomarker assay technologies, resources to conduct such studies, and real-time analysis of samples to detect inter-species differences that may affect the determination of optimal sampling time points must be taken into account. This article provides a discussion of the challenges that confront the practical application of pharmacodynamic studies in early-phase clinical trials of anti-cancer agents.

Pediatric Oncology Provider Views on Performing a Biopsy of Solid Tumors in Children with Relapsed or Refractory Disease for the Purpose of Genomic Profiling.

BACKGROUND: Patients with relapsed and refractory solid tumors have a poor prognosis. Recent advances in genomic technology have made it feasible to screen tumors for actionable mutations, with the anticipation that this may provide benefit to patients. METHODS: Pediatric oncologists were emailed an anonymous 34-question survey assessing their willingness to offer a rebiopsy to patients with relapsed disease for the purpose of tumor genomic profiling. They were presented with two scenarios evaluating morbidity and invasiveness of the procedures using the clinical examples of medulloblastoma and Ewing sarcoma. RESULTS: A total of 195 pediatric oncologists responded to the questionnaire. Morbidity and invasiveness of the procedure demonstrated significant differences in provider willingness to refer their patients for rebiopsy. The pretest probability was a major variable influencing provider willingness to offer a rebiopsy. Respondents were more likely to offer a rebiopsy if the likelihood was high that the results would have an impact on clinical management than if the biopsy was for histologic confirmation alone (mean 89 vs. 56 %; p = 0.017). Compared with the rate of a rebiopsy for histologic confirmation, significantly fewer providers were willing to offer a rebiopsy if they were led to believe the likelihood of finding an actionable mutation was low (mean 45 vs. 56 %; p = 0.021). CONCLUSION: The scenario showed that the pretest probability of finding an actionable mutation was influential in determining provider willingness to offer a rebiopsy for the purpose of tumor genomic profiling. Further research is warranted to evaluate the benefit of tumor genomic profiling in terms of patient outcomes.

Reporting practices of pharmacodynamic studies involving invasive research procedures in cancer trials.

BACKGROUND: Tumour biopsy for pharmacodynamic (PD) study is increasingly common in early-phase cancer trials. As they are non-diagnostic, the ethical justification for such procedures rests on their knowledge value. On the premise that knowledge value is related to reporting practices and outcome diversity, we assessed in a sample of recent invasive PD studies within cancer trials. METHODS: We assessed reporting practices and outcomes for PD studies in a convenience sample of cancer trials published from 2000 to 2010 that employed invasive, non-diagnostic tissue procurement. Extracted data were used to measure outcome reporting in individual trials. Using a reporting scale we developed for exploratory purposes, we tested whether reporting varied with study characteristics, such as funding source or drug novelty. RESULTS: Reporting varied widely within and across studies. Some practices were sporadically reported, including results of all planned tests (78% trials reporting), use of blinded histopathological assessment (43% trials reporting), biopsy dimensions (38% trials reporting), and description of patient flow through PD analysis (62%). Pharmacodynamic analysis as a primary end point and mandatory biopsy had statistically significant positive relationships with overall quality of reporting. A preponderance of positive results (61% of the studies described positive PD results) suggests possible publication bias. CONCLUSION: Our results highlight the need for PD-reporting guidelines, and suggest several avenues for improving the risk/benefit for studies involving invasive, non-diagnostic tissue procurement.

Use of research biopsies in clinical trials: are risks and benefits adequately discussed?

PURPOSE: Although the incorporation of research biopsies into clinical trials is increasing, limited information is available about how study protocols and informed consents integrate and describe their use. METHODS: All therapeutic clinical trials in which image-guided research biopsies were performed from January 1, 2005, to October 1, 2010, were identified from an interventional radiology database. Data from study protocols and informed consents were extracted and analyzed. Procedural complications were recorded. RESULTS: A total of 57 clinical trials were identified, of which 38 (67%) contained at least one mandatory biopsy. The analysis of the research biopsy tumor tissue was a study end point in 95% of trials. The primary indication for a research biopsy was for integral biomarker analysis in 32% and for correlative science in 68% of trials. A statistical analytic plan for the correlative science research biopsy tumor tissue was mentioned in 26%, described as exploratory in 51%, and not mentioned in 23% of trials. For studies with mandatory biopsies, biopsy was an eligibility criterion in 71% of trials, and a statistical justification for the research biopsy sample size was present in 50% of trials. A total of 745 research biopsies were performed on 576 patients. Overall and major complication rates were 5.2% (39 of 745 biopsies) and 0.8% (six of 745 biopsies), respectively. Complication rates for intrathoracic and abdominal/pelvic solid organ biopsies were 17.1% (36 of 211 biopsies) and 1.6% (three of 189 biopsies), respectively. Site-stratified research biopsy-related risks were discussed in five consents. CONCLUSION: A better representation of the risks and benefits of research biopsies in study protocols and informed consents is needed.

Publication and reporting conduct for pharmacodynamic analyses of tumor tissue in early-phase oncology trials.

PURPOSE: In principle, nondiagnostic biopsies for pharmacodynamic (PD) studies are carried out to inform decision-making in drug development. Because such procedures have no therapeutic value, their ethical justification requires that results be published. We aimed to assess the frequency of nonpublication of PD data in early phase cancer trials and to identify factors that prevent full publication of data. METHODS: We identified a sample of early-phase cancer trials containing invasive nondiagnostic tissue procurement for PD analysis from American Society of Clinical Oncology and American Association for Cancer Research meeting abstracts published between 1995 and 2005. These trials were followed to publication to determine frequency of nonpublication of PD data. Corresponding authors on early-phase cancer trials using invasive nondiagnostic research procedures were also surveyed to identify factors preventing full publication of PD data. RESULTS: In a sample of 90 trials, 22.2% (20 trials) resulted in no trial publication. Of published trials expected to contain PD reports, 16 (17.8%) did not include any PD data, and 21 (23.3%) reported incomplete PD data. We surveyed 92 authors; nonpublication was regarded as a frequent occurrence, and the most commonly cited barrier to full publication of PD data was strategic considerations in publication (58.8% of responding authors). CONCLUSIONS: Our results suggest ways that investigators, study planners, and reviewers can improve the burden/knowledge value balance in PD studies.