Search

We provide guidance for conducting clinical trials with Indigenous children in the United States. We drew on extant literature and our experience to describe 3 best practices for the ethical and effective conduct of clinical trials with Indigenous children. Case examples of pediatric research conducted with American Indian, Alaska Native, and Native Hawaiian communities are provided to illustrate these practices. Ethical and effective clinical trials with Indigenous children require early and sustained community engagement, building capacity for Indigenous research, and supporting community oversight and ownership of research. Effective engagement requires equity, trust, shared interests, and mutual benefit among partners over time. Capacity building should prioritize developing Indigenous researchers. Supporting community oversight and ownership of research means that investigators should plan for data-sharing agreements, return or destruction of data, and multiple regulatory approvals. Indigenous children must be included in clinical trials to reduce health disparities and improve health outcomes in these pediatric populations. Establishment of the Environmental Influences on Child Health Outcomes Institutional Development Award States Pediatric Clinical Trials Network (ECHO ISPCTN) in 2016 creates a unique and timely opportunity to increase Indigenous children's participation in state-of-the-art clinical trials. [ABSTRACT FROM AUTHOR]

Virtual clinical trials (VCT) are technology driven new approach to conduct the trials in a digital platform. Conducting clinical trials virtually is an option to avoid the problems faced by the researchers in the traditional method, such as delay in recruitment, delay in site start up activities, problems in distribution of study materials, delay in ethical committee review process, suspension of hospital activities and lack of clarity on regional restrictions of movement. Despite the benefits, VCTs has limitation such as unclear regulatory framework, problems in data protection, and biased recruitment of study population as VCTs enroll study participants with some technical knowledge. Research that needs continuous medical intervention by the health care team also cannot be performed virtually. To avoid unethical practices in virtual conduct of clinical trials, ethical guidelines on VCTs also needs to developed and implemented for the same. [ABSTRACT FROM AUTHOR]

A region-specific appendix to the Randomized, Embedded, Multifactorial Adaptive Platform trial for Community-Acquired Pneumonia (REMAP-CAP) is presented. The region to which the appendix applies is Europe. Interventions domains include antibiotics, macrolide duration, corticosteroid, antivirals and ventilation. Also mentioned are ethical and regulatory issues in Europe.

A region-specific appendix to the Randomized, Embedded, Multifactorial Adaptive Platform trial for Community-Acquired Pneumonia (REMAP-CAP) is presented. The countries to which the appendix applies are Australia and New Zealand. Interventions domains include antibiotics, macrolide duration, corticosteroid, antivirals and ventilation. Also mentioned are ethical and regulatory issues for each region.

A region-specific appendix to the Randomized, Embedded, Multifactorial Adaptive Platform trial for Community-Acquired Pneumonia (REMAP-CAP) is presented. The country to which the appendix applies is Canada. Interventions domains include antibiotics, macrolide duration, corticosteroid, antivirals and ventilation. Also mentioned are ethical and regulatory issues in Canada.

Implementing the National Institutes of Health's (NIH's) new single institutional review board (IRB) policy has caused a paradigm shift in IRB review across the country. IRBs and human research protection programs are looking more closely at their processes for ceding review and developing procedures to handle local review when relying on a single IRB. This article describes an NIH‐funded network that proactively instituted a central IRB (CIRB) in 2012, anticipating the NIH future mandate. Lessons learned are described. There was a steep learning curve for IRBs and participating sites. IRB submission workload burden shifted from study teams to the data coordinating center, which created new workflow challenges, especially preparing hundreds of consent documents centrally. Despite difficulties encountered with CIRB review, this network is now fully functioning under a CIRB model. Further review and experience are needed to determine whether this shift in IRB review has eliminated duplicative review or regulatory burden from study teams. [ABSTRACT FROM AUTHOR]

This article takes a standpoint based in the human and social sciences to examine a decisive time in any research related to HIV-AIDS, ie, when healthy, seronegative individuals agree to take part in preventive clinical trials. The context of recruitment for such trials has been changing over the past several decades: the normalization of the epidemic after a period of sensationalism, the change in focus of social communities to other causes, the changes in the disease from a therapeutic point of view (new drug treatments and preventive drugs), the absence of compensation for participation in trials, the absence of any direct health benefits for the participants, and the fear of volunteers or the people in their lives of the idea of transforming their healthy body into a postexperimental body. Research on the prevention of HIV seems to be dependent on the consent of a limited number of people and groups because their reasons for taking part in such experiments, which are just as much personal as they are for the sake of science, are necessarily very particular. How can healthy individuals be recruited for preventive HIV trials? What is the social basis and what kind of mediation is involved in a mutual understanding between trial participants and investigators? Such questions are answered by the authors in this book, who approach the issues from a multidisciplinary and diachronic perspective. [ABSTRACT FROM AUTHOR]

ABSTRACT The inability to reach agreement on what clinical ethics consultants' expertise consists of has generated a theoretical crisis for this field of practice. After briefly examining some recent articles on this subject, this essay focuses on the recent work of a Swedish political scientist, Maria Hedlund, who has addressed herself specifically to the political issues that claims of ethics expertise pose to democratic deliberations, and to how epistocratic claims of ethics expertise can coexist with democratic beliefs about moral expertise. Following Hedlund's lead, I conclude that at least two additional problems remain: (1) identifying ethics experts; and (2) reconciling the practice of clinical ethics consultation with philosophical issues about moral testimony. [ABSTRACT FROM AUTHOR]

Each year thousands of individuals enrol in clinical trials as healthy volunteers to earn money. Some of them pursue research participation as a full-time or at least a part-time job. They call themselves professional or semiprofessional guinea pigs. The practice of paying healthy volunteers raises numerous ethical concerns. Different payment models have been discussed in literature. Dickert and Grady argue for a wage-payment model. This model gives research subjects a standardised hourly wage, and it is based on an assumption that research participation is morally indistinguishable from other forms of unskilled labour. In this paper, I will challenge this assumption. I will argue that human guinea pigging has particular characteristics which taken together make it significantly different from other forms of labour. (1) Participation in research is skill-independent. Healthy volunteers are valuable not because they are skilful persons, but because they are human bodies. (2) The role of research volunteers is mainly passive. They are not asked to produce goods or deliver services. They are paid for enduring unpleasant, painful and risky interventions performed by investigators. (3) Research volunteering involves inherent risks and uncertainties, and subjects have little or no control over their minimisation and materialisation. I conclude that participation in clinical research is a specific kind of activity. It is more like renting out one's body to strangers, than working. Thus, research participation should not be treated on par with other forms of employment. [ABSTRACT FROM AUTHOR]

Clinical research is predicated ethically on the authentic voluntarism of individuals who choose to enroll in human studies. Existing literature has focused on aspects of informed consent for clinical research other than voluntarism. The objective of this study was to compare the perspectives of clinical research participants who are in good health and who are ill regarding voluntarism -related aspects of informed consent and to assess situational influences that enable voluntarism in the process of obtaining clinical research consent. A 23-item written survey, the Informed Consent Questionnaire (ICQ), was administered in a “piggyback” semi-structured interview study of ill and healthy volunteers enrolled in IRB-approved clinical research studies. A total of 150 (60 mentally ill, 43 physically ill, and 47 healthy) clinical research participants participated . Respondents expressed positive views of their experiences with the informed consent processes for their respective clinical research protocols and respondents strongly endorsed items related to voluntarism irrespective of their illness type (range of means = [3.9, 4.8]). Ill participants more highly endorsed items relating to informed consent conditions (mentally ill vs healthy: 0.54 on a 5-point scale, P value = 0.01) (physically ill vs. healthy: 0.47 on a 5-point scale, P value = 0.01). The favorable views of clinical research participants regarding their experience of giving informed consent to enroll in a study were not surprising. Contrary to our a priori hypothesis, healthy individuals did not feel as positively as their ill counterparts. [ABSTRACT FROM AUTHOR]

The article offers information regarding payment-related policies and practices of institutional review boards (IRBs) and also offers information on regulations governing human-subjects research and bioethical guidelines. It mentions that the U.S. Food and Drug Administration (FDA) guidance ties payment to coercion and undue influence and suggests that payment might undermine consent. It presents considerations for investigators proposing payment offers.

The article reports that in Presurgical Trials uses clinical care for solid malignancies. The treatment of many solid tumors involves performing an initial biopsy. Discussion onthe ethical challenges of presurgical trials which includes therapeutic misconception and interference with therapy and nongeneralizability of outcomes are presented.

In 2001, DePuy, a wholly-owned subsidiary of Johnson & Johnson (J&J/DePuy), initiated a seeding study called the “Multi-center, Prospective, Clinical Evaluation of Pinnacle Acetabular Implants in Total Hip Arthroplasty” (PIN Study). J&J/DePuy designed this study to develop new business opportunities during the launch of their Pinnacle Hip System (PHS) and generate survivorship data for marketing. This article, the first review of a seeding trial for a medical device, examines internal company documents relating to the PIN Study; the analysis herein focuses on the integrity of J&J/DePuy’s research practices in conception, implementation, and analysis. J&J/DePuy violated the study protocol and manipulated data; consented participants in violation of standards protecting human subjects; and did not secure Institutional Review Board approval for all study sites. J&J/DePuy used PIN Study results as the “fundamental selling point” for the PHS. Medical device seeding trials are distinct from previously-documented pharmaceutical seeding trials because companies can profit directly from device sales and because these studies may be the first clinical evaluation of the device (as was the case for the PIN Study). Seeding trials are malleable marketing projects, not rigorous scientific studies. Regulatory bodies, physicians, and others should be vigilant for persuasive marketing accounts disguised as science. [ABSTRACT FROM PUBLISHER]

What and where is ethics in gene therapy? Historical debates have identified a set of ethical issues with the field, and current regulatory systems presume a discrete ethics that can be achieved or protected. Resisting attempts at demarcation or resolution, we use the notions of “ordinary” or “everyday” ethics to develop a better understanding of the complexities of experimental gene therapy for patients, families, and practitioners and create richer imaginings of ethics in the gene therapy sphere. Drawing on ethnographic research in several clinical trials, we show that patients/parents can acquire some control in difficult medical situations, and practitioners can attune their care to their patients’ needs. The human provenance of gene therapy practice, and the irreducible sociality of ethics, means that understanding the ethics of this medical field also requires understanding the everyday worlds and relationships of those at its heart. [ABSTRACT FROM PUBLISHER]

Since Nuremberg, the ethics of scientific research involving human beings has been for decades the source of concern and controversy. Profit-driven experimentation sponsored by the pharmaceutical industry has progressively migrated to the South, turning into a widespread phenomenon imbued with ethical challenges and dilemmas. The protection of vulnerable communities from the risks of unethical behaviour and exploitation, often associated with the outsourcing of clinical trials in developing countries, calls for respect of internationally agreed standards. This Article argues that massive experiments conducted in disregard of universal bioethical principles and human rights may amount to crimes against humanity under international criminal law. It also suggests that, in such cases, the International Criminal Court would have jurisdiction over a broad range of liable individuals, including public officials of host and sponsoring States, physicians and researchers acting in their private capacity, as well as officers and directors of pharmaceutical corporations. [ABSTRACT FROM AUTHOR]

This article deals with a Bayesian predictive approach for two-stage sequential analyses in clinical trials, applied to both frequentist and Bayesian tests. We propose to make a predictive inference based on the notion of satisfaction index and the data accrued so far together with future data. The computations and the simulation results concern an inferential problem, related to the binomial model. [ABSTRACT FROM AUTHOR]

Appropriate ethical oversight underpins the conduct of all clinical trials in Australia. In addition, clinical trials require a suitable approach to research governance in order to ensure that research is appropriately governed. However, such governance processes are often onerous and time-consuming and are not required when trial practices are more appropriately understood as standard of care clinical services. [ABSTRACT FROM AUTHOR]

The article discusses the challenges facing health insurance systems based on randomized, controlled trials (RCTs).

The article discusses the author's claim that the use of a central institutional review board (CIRB) is an essential requirement for cancer-related clinical trials as of 2017, and it mentions the legal and ethical aspects of CIRBs, as well as issues related to human subjects research involving chronic and deadly diseases. Disease-associated DNA mutations and cancer treatment research are examined, along with the costs associated with human subjects-based medical research.

During the 2014-2015 Ebola outbreak in Guinea, Liberia and Sierra Leone, many opposed the use of individually randomised controlled trials to test candidate Ebola vaccines. For a raging fatal disease, they explained, it is unethical to relegate some study participants to control arms. In Zika and future emerging infections, similar opposition may hinder urgent vaccine research, so it is best to address these questions now. This article lays out the ethical case for individually randomised control in testing vaccines against many emerging infections, including lethal infections in low-income countries, even when at no point in the trial do the controls receive the countermeasures being tested. When individual randomisation is feasible-and it often will be-it tends to save more lives than alternative designs would. And for emerging infections, individual randomisation also tends as such to improve care, access to the experimental vaccine and prospects for all participants relative to their opportunities absent the trial, and no less than alternative designs would. That obtains even under placebo control and without equipoise-requiring which would undermine individual randomisation and the alternative designs that opponents proffered. Our arguments expound four often-neglected factors: benefits to non-participants, benefits to participants once a trial is over including post-trial access to the study intervention, participants' prospects before randomisation to arms and the near-inevitable disparity between arms in any randomised controlled trial. [ABSTRACT FROM AUTHOR]

Discussion of the ethics of clinical trials in lower income countries has been dominated by concern over double standards. Most prominently, clinical trials of interventions that are less effective than the worldwide best treatment methods typically are not permitted in higher income countries. Commentators conclude that permitting such trials in lower income countries involves an ethical double standard. Despite significant attention to this concern, and its influence over prominent guidelines for research in lower income countries, there has been little analysis of what constitutes an ethical double standard in clinical research. The present article attempts to address this gap in the literature. This analysis finds that ethical double standards involve a kind of disrespect, and yields a three-step decision procedure for evaluating when trials of less than the worldwide best methods raise this concern. Application of this procedure reveals that permitting these trials in lower income countries rarely involves an ethical double standard. Instead, the real challenge is determining when clinical trials of interventions that are less effective than the worldwide best represent a permissible and effective response to differences in access to healthcare between higher income and lower income countries. To protect research subjects, without blocking clinical trials that have the potential to improve health in lower income countries, research review committees and other stakeholders should focus on this issue, not on ethical double standards. [ABSTRACT FROM AUTHOR]

Background: The treatment of displaced midshaft clavicle fractures remains controversial.Methods: We undertook a multicenter randomized controlled trial to compare effectiveness and safety between nonoperative management and ORIF (open reduction and internal fixation) for displaced midshaft clavicle fractures in adults. Three hundred and one eligible adult patients were randomized to 1 of the 2 treatment groups and followed at 6 weeks, 3 months, and 9 months after recruitment. The primary outcome was the rate of radiographically evident nonunion at 3 months following treatment. Secondary outcomes were the rate of radiographically evident nonunion at 9 months, limb function measured using the Constant-Murley Score and DASH (Disabilities of the Arm, Shoulder and Hand) score, and patient satisfaction.Results: There was no difference in the proportion of patients with radiographic evidence of nonunion at 3 months between the operative (28%) and nonoperative (27%) groups, whereas at 9 months the proportion with nonunion was significantly lower (p < 0.001) in the operative group (0.8%) than in the nonoperative group (11%). The DASH and Constant-Murley scores and patient satisfaction were all significantly better in the operative group than in the nonoperative group at 6 weeks and 3 months.Conclusions: Although at 3 months there was no evidence that surgery had reduced the rate of nonunion of displaced midshaft clavicle fractures, at 9 months nonoperative treatment had led to a significantly higher nonunion rate (11% compared with <1%). The rate of secondary surgical intervention during the trial period was 12 (11%) of the 147 patients in the nonoperative group. ORIF is a safe and reliable intervention with superior early functional outcomes and should be considered for patients who sustain this common injury.Level Of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

Outsourcing clinical trials sponsored by pharmaceutical companies from industrialized countries to low- (middle)-income countries - summarized as transnational biomedical research (TBR) - has lead to many concerns about ethical standards. Whether study participants are particularly vulnerable is one of those concerns. However, the concept of vulnerability is still vague and varies in its definition. Despite the fact that important international ethical guidelines such as the Declaration of Helsinki by the World Medical Association or the Ethical Guidelines for Biomedical Research Involving Human Subjects by the Council of International Organizations of Medical Sciences refer to vulnerability as ethical principle, each of their approaches are different. To overcome these shortcomings, we analyze and unite different approaches of vulnerability and develop practical criteria in order to operationalize the concept especially for the context of TBR. These criteria refer to the context of a study as well as the characteristics and the current living situation of study participants. Based on a case study of an HIV-vaccine-trial conducted in India we demonstrate how those criteria can be applied in a retrospective way to identify potential ethical conflicts. The criteria can also indicate a prospective function for ethical pre-assessment. For this, we provide an outlook for three major topics: 1. Vulnerability as a normative concept: Different ways of protection; 2. The relevance of transparency and 3. Vulnerability as an instrument to increase decision participation of human subjects. [ABSTRACT FROM AUTHOR]

The article offers information on the panel discussion on "Regulatory and ethical issues in clinical research in children" held in collaboration with Indian Academy of Pediatrics and the Federation of Obstetrics and Gynecological Societies of India in April 2017 in Mumbai, India. Topics discussed include clinical pharmacology for maternal and child health; new drug development and clinical trials in children; and pediatric clinical research and drug development by pharmaceutical industry.

Most discussions concerned with advancing the just and ethical treatment of research participants in developing countries have revolved around the moral principle of autonomy and the legal doctrine of informed consent (O'Neill 2002). However, if emerging ethical concerns are to be addressed effectively, the discussion needs to expand into the domain of business ethics where arguments addressing issues such as fair/appropriate compensation, entitlement, and corporate obligations to stakeholders are commonplace. The argument I present in this paper will conclude that emerging ethical considerations regarding the treatment of research participants in developing countries have evolved well beyond the scope of the principle of informed consent and that in order to resolve these concerns more appropriately and effectively, the new default or status quo should be to consider research participants as stakeholders of the sponsoring pharmaceutical company, even after the clinical trial is completed. This conclusion is significant because although it is fair to assume that, at some point in the timeline, most stakeholder theorists already do consider research participants stakeholders of the pharmaceutical company sponsoring the trial, the completion date of the clinical trial usually signifies and marks the termination of their stakeholder status and thus any consideration of what is owed further to the research participant. [ABSTRACT FROM AUTHOR]

On 7-8th November 2016, 60 people with an interest in the 'Trials within Cohorts' (TwiCs) approach for randomised controlled trial design met in London. The purpose of this 2nd TwiCs international symposium was to share perspectives and experiences on ethical aspects of the TwiCs design, discuss how TwiCs relate to the current ethical framework, provide a forum in which to discuss and debate ethical issues and identify future directions for conceptual and empirical research. The symposium was supported by the Wellcome Trust and the NIHR CLAHRC Yorkshire and Humber and organised by members of the TwiCs network led by Clare Relton and attended by people from the UK, the Netherlands, Norway, Canada and USA. The two-day symposium enabled an international group to meet and share experiences of the TwiCs design (also known as the 'cohort multiple RCT design'), and to discuss plans for future research. Over the two days, invited plenary talks were interspersed by discussions, posters and mini presentations from bioethicists, triallists and health research regulators. Key findings of the symposium were: (1) It is possible to make a compelling case to ethics committees that TwiCs designs are appropriate and ethical; (2) The importance of wider considerations around the ethics of inefficient trial designs and (3) some questions about the ethical requirements for content and timing of informed consent for a study using the TwiCs design need to be decided on a case-by-case basis. [ABSTRACT FROM AUTHOR]

Background: Amongst several barriers to the application of quality clinical evidence and clinical guidelines into routine daily practice, poor description of interventions reported in clinical trials has received less attention. Although some studies have investigated the completeness of descriptions of non-pharmacological interventions in randomized trials, studies that exclusively analyzed physical therapy interventions reported in published trials are scarce. Objectives: To evaluate the quality of descriptions of interventions in both experimental and control groups in randomized controlled trials published in four core physical therapy journals. Methods: We included all randomized controlled trials published from the Physical Therapy Journal, Journal of Physiotherapy, Clinical Rehabilitation, and Archives of Physical Medicine and Rehabilitation between June 2012 and December 2013. Each randomized controlled trial (RCT) was analyzed and coded for description of interventions using the checklist developed by Schroter et al. Results: Out of 100 RCTs selected, only 35 RCTs (35%) fully described the interventions in both the intervention and control groups. Control group interventions were poorly described in the remaining RCTs (65%). Conclusions: Interventions, especially in the control group, are poorly described in the clinical trials published in leading physical therapy journals. A complete description of the intervention in a published report is crucial for physical therapists to be able to use the intervention in clinical practice. [ABSTRACT FROM AUTHOR]

Objectives: Pragmatic trials evaluate the comparative benefits, risks, and burdens of health care interventions in real-world conditions. Such studies are now recognized as valuable to the perimarketing stage of drug development and evaluation, with early pragmatic trials (EPTs) being explored as a means to generate real-world evidence at the time of regulatory market approval. In this article, we present an analysis of the ethical issues involved in informed consent for EPTs, in light of the generally recognized concern that traditional ethical rules governing randomized clinical trials, such as lengthy informed consent procedures, could threaten the "real world" nature of such trials. Specifically, we examine to what extent modifications (waivers or alterations) to regulatory consent for EPTs would be ethical.Methods: We first identify broadly accepted necessary conditions for modifications of informed consent (namely, the research involves no more than minimal risk of harm, the research is impracticable with regulatory consent, and the alternative to regulatory consent does not violate legitimate patient expectations) and then apply those criteria to the premarket and early postmarket contexts.Results and Conclusions: The analysis shows that neither waivers nor alterations of regulatory consent for premarket EPTs will be ethically permissible. For postmarket EPTs with newly approved interventions, waivers of consent will be ethically problematic, but some studies might be conducted in an ethical manner with alterations to regulatory consent. [ABSTRACT FROM AUTHOR]

Health research has documented disparities in health and health outcomes within and between populations. When these disparities are unfair and avoidable they may be referred to as health inequities. Few trials attend to factors related to health inequities, and there is limited understanding about how to build consideration of health inequities into trials. Due consideration of health inequities is important to inform the design, conduct and reporting of trials so that research can build evidence to more effectively address health inequities and importantly, ensure that inequities are not aggravated. In this paper, we discuss approaches to integrating health equity-considerations in randomized trials by using the PROGRESS Plus framework (Place of residence, Race/ethnicity/culture/language, Occupation, Gender, Religion, Education, Socio-economic status, Social capital and "Plus" that includes other context specific factors) and cover: (i) formulation of research questions, (ii) two specific scenarios relevant to trials about health equity and (iii) describe how the PROGRESS Plus characteristics may influence trial design, conduct and analyses. This guidance is intended to support trialists designing equity-relevant trials and lead to better design, conduct, analyses and reporting, by addressing two main issues: how to avoid aggravating inequity among research participants and how to produce information that is useful to decision-makers who are concerned with health inequities. [ABSTRACT FROM AUTHOR]

There are a number of barriers that result in cancer patients not being referred for oncofertility care, which include knowledge about reproductive risks of antineoplastic agents. Without this information, clinicians do not always make recommendations for oncofertility care. The objective of this study was to describe the level of reproductive information and recommendations that clinicians have available in clinical trial protocols regarding oncofertility management and follow-up, and the information that patients may receive in clinical trials patient information sheets or consent forms. A literature review of the 71 antineoplastic drugs included in the 68 clinical trial protocols showed that 68% of the antineoplastic drugs had gonadotoxic animal data, 32% had gonadotoxic human data, 83% had teratogenic animal data, and 32% had teratogenic human data. When the clinical trial protocols were reviewed, only 22% of the protocols reported the teratogenic risks and 32% of the protocols reported the gonadotoxic risk. Only 56% of phase 3 protocols had gonadotoxic information and 13% of phase 3 protocols had teratogenic information. Nine percent of the protocols provided fertility preservation recommendations and 4% provided reproductive information in the follow-up and survivorship period. Twenty-six percent had a section in the clinical trials protocol, which identified oncofertility information easily. When gonadotoxic and teratogenic effects of treatment were known, they were not consistently included in the clinical trial protocols and the lack of data for new drugs was not reported. Very few protocols gave recommendations for oncofertility management and follow-up following the completion of cancer treatment. The research team proposes a number of recommendations that should be required for clinicians and pharmaceutical companies developing new trials. [ABSTRACT FROM AUTHOR]

Background: In respect of the principle of autonomy and the right of self-determination, obtaining an informed consent of potential participants before their inclusion in a study is a fundamental ethical obligation. The variations in national laws, regulations, and cultures contribute to complex informed consent documents for patients participating in clinical trials. Currently, only few ethics committees seem willing to address the complexity and the length of these documents and to request investigators and sponsors to revise them in a way to make them understandable for potential participants. The purpose of this work is to focus on the written information in the informed consent documentation for drug development clinical trials and suggests (i) to distinguish between necessary and not essential information, (ii) to define the optimal format allowing the best legibility of those documents. Methods: The Aide et Recherche en Cancérologie Digestive (ARCAD) Group, an international scientific committee involving oncologists from all over the world, addressed these issues and developed and uniformly accepted a simplified informed consent documentation for future clinical research. Results: A simplified form of informed consent with the leading part of 1200-1800 words containing all of the key information necessary to meet ethical and regulatory requirements and 'relevant supportive information appendix' of 2000-3000 words is provided. Conclusions: This position paper, on the basis of the ARCAD Group experts discussions, proposes our informed consent model and the rationale for its content. [ABSTRACT FROM AUTHOR]

As the number of available cancer therapies continues to grow, there is increasing interest in their impact on cancer patients' lived experiences. Screening for distress is one way to measure psychological dimensions of cancer patients' experiences, and doing so is increasingly part of standard operations at major cancer centers across the US. To date, however, most clinical trials have not adequately captured patients' experiences as part of their outcome assessments, so clinicians lack data needed to guide their responses to psychological features of patients' illness experiences. As distress becomes the "sixth vital sign" in routine cancer care, we argue that clinical trials should assess patients' experiences in the same way that they robustly screen for adverse events and toxicities. New interventions are needed to address distress. [ABSTRACT FROM AUTHOR]

Purpose Success in the era of value-based payment will depend on the capacity of health systems to improve quality while controlling costs. Comparative quality performance review can be used to drive improvements in surgical outcomes and thereby reduce costs. We sought to determine the efficacy of a comparative quality performance review to improve a surgeon-level measure of surgical oncologic quality, that is the positive surgical margin rate at the time of radical prostatectomy. Materials and Methods Eight surgeons who performed consecutive radical prostatectomies at a single high volume institution between January 1, 2015 and December 31, 2015 were included in analysis. Individual surgeons were provided with confidential report cards every 6 months detailing their case mix, case volume and pT2 radical prostatectomy positive surgical margin rate relative to 1) their own self-matched data, 2) the de-identified data of their colleagues and 3) institutional aggregate data during the study period. Positive surgical margin rates were compared before and after intervention. Hierarchal logistic regression analysis was used to examine the association of study period on the odds of positive surgical margins, adjusted for prostate specific antigen level and National Comprehensive Cancer Network® risk group. Results Overall, 1,822 (1,392 before and 430 after intervention) radical prostatectomies were performed that met study inclusion criteria. The aggregate departmental unadjusted positive surgical margin rates were 10.6% and 7.4% in the pre-intervention and post-intervention groups, respectively. After adjusting for higher risk cancer in the post-intervention group, there was a significant protective association of post-intervention status on positive margins (OR 0.64, 95% CI 0.43–0.97, p = 0.03). All 5 surgeons with positive surgical margin rates higher than the aggregate department rate in the pre-intervention period showed improvement after intervention. Conclusions Comparative quality performance review can be implemented at the surgeon level and can promote improvement in an objective measure of surgical oncology quality. [ABSTRACT FROM AUTHOR]

Background: Improving the effectiveness and efficiency of research informed consent is a high priority. Some express concern about longer, more complex, written consent forms creating barriers to participant understanding. A recent meta-analysis concluded that randomized comparisons were needed. Methods: We conducted a cluster-randomized non-inferiority comparison of a standard versus concise consent form within a multinational trial studying the timing of starting antiretroviral therapy in HIV+ adults (START). Interested sites were randomized to standard or concise consent forms for all individuals signing START consent. Participants completed a survey measuring comprehension of study information and satisfaction with the consent process. Site personnel reported usual site consent practices. The primary outcome was comprehension of the purpose of randomization (pre-specified 7.5% non-inferiority margin). Results: 77 sites (2429 participants) were randomly allocated to use standard consent and 77 sites (2000 participants) concise consent, for an evaluable cohort of 4229. Site and participant characteristics were similar for the two groups. The concise consent was non-inferior to the standard consent on comprehension of randomization (80.2% versus 82%, site adjusted difference: 0.75% (95% CI -3.8%, +5.2%)); and the two groups did not differ significantly on total comprehension score, satisfaction, or voluntariness (p>0.1). Certain independent factors, such as education, influenced comprehension and satisfaction but not differences between consent groups. Conclusions: An easier to read, more concise consent form neither hindered nor improved comprehension of study information nor satisfaction with the consent process among a large number of participants. This supports continued efforts to make consent forms more efficient. Trial registration: Informed consent substudy was registered as part of START study in clinicaltrials.gov #, and EudraCT # 2008-006439-12 [ABSTRACT FROM AUTHOR]

Several studies of deep brain stimulation (DBS) of the fornix or the nucleus basalis of Meynert have been recently conducted in people with Alzheimer's disease, with several recruiting participants <65 and thus have early-onset Alzheimer's disease (EOAD). Although EOAD accounts for less than 5.5% of AD cases, ethical considerations must still be made when performing DBS trials including these participants since a portion of people with EOAD, especially those possessing autosomal-dominant mutations, have an atypical and more aggressive disease progression. These considerations include appropriate patient selection and signing of an informed consent for genetic testing; appropriate study design; potential outcomes that people with EOAD could expect; and accurate interpretation and balanced discussion of trial results. Finally, recommendations for future DBS for AD trials will be made to ensure that EOAD patients will not experience avoidable harms should they be enrolled in these experimental studies. [ABSTRACT FROM AUTHOR]

Background: Improving informed consent to participate in randomized clinical trials (RCTs) is a key challenge in cancer communication. The current study examines strategies for enhancing randomization comprehension among patients with diverse levels of health literacy and identifies cognitive and affective predictors of intentions to participate in cancer RCTs.Methods: Using a post-test-only experimental design, cancer patients (n = 500) were randomly assigned to receive one of three message conditions for explaining randomization (ie, plain language condition, gambling metaphor, benign metaphor) or a control message. All statistical tests were two-sided.Results: Health literacy was a statistically significant moderator of randomization comprehension ( P = .03). Among participants with the lowest levels of health literacy, the benign metaphor resulted in greater comprehension of randomization as compared with plain language ( P = .04) and control ( P = .004) messages. Among participants with the highest levels of health literacy, the gambling metaphor resulted in greater randomization comprehension as compared with the benign metaphor ( P = .04). A serial mediation model showed a statistically significant negative indirect effect of comprehension on behavioral intention through personal relevance of RCTs and anxiety associated with participation in RCTs ( P < .001).Conclusions: The effectiveness of metaphors for explaining randomization depends on health literacy, with a benign metaphor being particularly effective for patients at the lower end of the health literacy spectrum. The theoretical model demonstrates the cognitive and affective predictors of behavioral intention to participate in cancer RCTs and offers guidance on how future research should employ communication strategies to improve the informed consent processes. [ABSTRACT FROM AUTHOR]

The need for performing clinical trials to develop well-studied and appropriate medicines for inherited neurometabolic disease patients faces ethical concerns mainly raising from four aspects: the diseases are rare; include young and very young patients; the neurological impairment may compromise the capability to provide 'consent'; and the genetic nature of the disease leads to further ethical implications. This work is intended to identify the ethical provisions applicable to clinical research involving these patients and to evaluate if these cover the ethical issues. Three searches have been performed on the European regulatory/legal framework, the literature and European Union-funded projects. The European legal framework offers a number of ethical provisions ruling the clinical research on paediatric, rare, inherited diseases with neurological symptoms. In the literature, relevant publications deal with informed consent, newborn genetic screenings, gene therapy and rights/interests of research participants. Additional information raised from European projects on sharing patients' data from different countries, the need to fill the gap of the regulatory framework and to improve information to stakeholders and patients/families.Conclusion: Several recommendations and guidelines on ethical aspects are applicable to the inherited neurometabolic disease research in Europe, even though they suffer from the lack of a common ethical approach. What is Known: • When planning and conducting clinical trials, sponsors and researchers know that clinical trials are to be performed according to well-established ethical rules, and patients should be aware about their rights. • In the cases of paediatric patients, vulnerable patients unable to provide consent, genetic diseases' further rules apply. What is New: • This work discusses which ethical rules apply to ensure protection of patient's rights if all the above-mentioned features coexist. • This work shows available data and information on how these rules have been applied. [ABSTRACT FROM AUTHOR]

The ethics of health incentive research-a form of public health research-are not well developed, and concerns of justice have been least examined. In this paper, we explore what potential long term harms in relation to justice may occur as a result of such research and whether they should be considered as part of its ethical evaluation. 'Long term harms' are defined as harms that contribute to existing systematic patterns of disadvantage for groups. Their effects are experienced on a long term basis, persisting even once an incentive research project ends. We will first establish that three categories of such harms potentially arise as a result of health incentive interventions. We then argue that the risk of these harms also constitutes a morally relevant consideration for health incentive research and suggest who may be responsible for assessing and mitigating these risks. We propose that responsibility should be assigned on the basis of who initiates health incentive research projects. Finally, we briefly describe possible strategies to prevent or mitigate the risk of long term harms to members of disadvantaged groups, which can be employed during the design, conduct and dissemination of research projects. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) is an invasive neuromodulation modality that has shown early promise as a novel treatment of Alzheimer's disease (AD). Further clinical research is warranted on the basis of positive results from animal and human studies, as well as the inadequacy of existing treatments in reducing the enormous medical and financial costs of untreated AD. Nevertheless, unique ethical challenges require particular attention to elements of subject enrollment and informed consent. Study protocols should specify robust assessment and regular monitoring of subject decision-making capacity to consent to trial participation. Investigators should also assess for and mitigate therapeutic misconception (the phenomenon whereby a research participant conflates the goals of research with those of clinical treatment) and ensure that all prospective trial participants have adequate post-trial access to treatment and DBS device maintenance. In the following discussion, each issue is summarized and followed by recommendations for proper ethical procedure. We conclude by assimilating relevant ethical considerations into a decision-making algorithm designed to aid future clinical investigators of DBS for AD with the task of ethical subject enrollment. [ABSTRACT FROM AUTHOR]

The Belmont Report's distinction between research and the practice of accepted therapy has led various authors to suggest that these purportedly distinct activities should be governed by different ethical principles. We consider some of the ethical consequences of attempts to separate the two and conclude that separation fails along ontological, ethical, and epistemological dimensions. Clinical practice and clinical research, as with yin and yang, can be thought of as complementary forces interacting to form a dynamic system in which the whole exceeds the sum of its parts. Just as effective clinical practice cannot exist without clinical research, meaningful clinical research requires the context of clinical practice. We defend this thesis by triangulation, that is, by outlining how multiple investigators have reached this conclusion on the basis of varied theoretical and applied approaches. More confidence can be placed in a result if different methods/viewpoints have led to that result. [ABSTRACT FROM AUTHOR]

Clinical decisions in reproductive medicine are often made in uncertainty. To reduce uncertainty and to improve clinical decision-making, RCTs are increasingly called upon. A key concept underpinning the ethics of RCTs is equipoise. Here, we aimed to dissect the basic reasoning behind the concept of equipoise and we proposed a line of thinking delineating under which conditions it is ethical to design and execute an RCT. This might prevent a priori negative trials, reduce research waste and aid in the design of meaningful ones. It is these trials that will provide insight on how to safely and effectively assist subfertile couples. [ABSTRACT FROM AUTHOR]

Informed consent is one of the principal ethical requirements of conducting clinical research, regardless of the study setting. Breaches in the quality of the informed consent process are frequently described in reference to clinical trials conducted in developing countries, due to low levels of formal education, a lack of familiarity with biomedical research, and limited access to health services in these countries. However, few studies have directly compared the quality of the informed consent process in developed and developing countries using the same tool and in similar clinical trials. This study was conducted to compare the quality of the informed consent process of a series of clinical trials of an investigational hookworm vaccine that were performed in Brazil and the United States. A standardized questionnaire was used to assess the ethical quality of the informed consent process in a series of Phase 1 clinical trials of the Na-GST-1/Alhydrogel hookworm vaccine that were conducted in healthy adults in Brazil and the United States. In Brazil, the trial was conducted at two sites, one in the hookworm non-endemic urban area of Belo Horizonte, Minas, and one in the rural, resource-limited town of Americaninhas, both in the state of Minas Gerais; the American trial was conducted in Washington, DC. A 32-question survey was administered after the informed consent document was signed at each of the three trial sites; it assessed participants’ understanding of information about the study presented in the document as well as the voluntariness of their decision to participate. 105 participants completed the questionnaire: 63 in Americaninhas, 18 in Belo Horizonte, and 24 in Washington, DC. Overall knowledge about the trial was suboptimal: the mean number of correct answers to questions about study objectives, methods, duration, rights, and potential risks and benefits, was 45.6% in Americaninhas, 65.2% in Belo Horizonte, and 59.1% in Washington, DC. Although there was no difference in the rate of correct answers between participants in Belo Horizonte and Washington, DC, there was a significant gap between participants at these two locations compared to Americaninhas (p = 0.0002 and p = 0.0001, respectively), which had a lower percentage of correct answers. Attitudes towards participating in the clinical trial also differed by site: while approximately 40% had doubts about participating in Washington, DC and Belo Horizonte, only 1.5% had concerns in Americaninhas. Finally, in Belo Horizonte and Washington, high percentages cited a desire to help others as motivation for participating, whereas in Americaninhas, the most common reason for participating was personal interest (p = 0.001). Understanding of information about a Phase 1 clinical trial of an experimental hookworm vaccine following informed consent was suboptimal, regardless of study site. Although overall there were no differences in knowledge between Brazil and the US, a lower level of understanding about the trial was seen in participants at the rural, resource-limited Brazilian site. These findings demonstrate the need for educational interventions directed at potential clinical trial participants, both in developing and developed countries, in order to improve understanding of the informed consent document. [ABSTRACT FROM AUTHOR]

The article discusses updates on world health and drug industry as of January 2017. Topics covered include the first-ever list of antibiotic-resistant priority pathogens by the World Health Organization, an amendment to the WTO Trade Related Aspects of Intellectual Property Rights Agreement, and two reports launched by the Organisation for Economic Co-operation and Development concerning pharmaceutical spending and new technologies.

Ethical concerns about randomising persons to a no-treatment arm in the context of Ebola epidemic led to consideration of alternative designs. The stepped wedge (SW) design, in which participants or clusters are randomised to receive an intervention at different time points, gained popularity. Common arguments in favour of using this design are (1) when an intervention is likely to do more good than harm, (2) all participants should receive the experimental intervention at some time point during the study and (3) the design might be preferable for practical reasons. We examine these assumptions when considering Ebola vaccine research. First, based on the claim that a stepped wedge design is indicated when it is likely that the intervention will do more good than harm, we reviewed published and ongoing SW trials to explore previous use of this design to test experimental drugs or vaccines, and found that SW design has never been used for trials of experimental drugs or vaccines. Given that Ebola vaccines were all experimental with no prior efficacy data, the use of a stepped wedge design would have been unprecedented. Second, we show that it is rarely true that all participants receive the intervention in SW studies, but rather, depending on certain design features, all clusters receive the intervention. Third, we explore whether the SW design is appealing for feasibility reasons and point out that there is significant complexity. In the setting of the Ebola epidemic, spatiotemporal variation may have posed problematic challenges to a stepped wedge design for vaccine research. Finally, we propose a set of points to consider for scientific reviewers and ethics committees regarding proposals for SW designs. [ABSTRACT FROM AUTHOR]

For the 2016 end-of-the-year editorial, the PLOS Medicine editors asked 7 global health leaders to discuss developments relevant to the equitable provision of medical care to all populations. The result is a collection of expert views on ethical trial design, research during outbreaks, high-burden infectious diseases, diversity in research and protection of migrants. [ABSTRACT FROM AUTHOR]

The volume of clinical research is increasing exponentially-far beyond our ability to process and absorb the results. Given this situation, it may be beneficial to consider reducing the flow at its source. In what follows, I will motivate and critically evaluate the following proposal: researchers should conduct fewer clinical trials. More specifically, I c onsider whether researchers should be permitted to conduct only clinical research of very high quality and, in turn, whether research ethics committees (RECs) should prohibit all other, lower-quality research, even when it might appear to meet some minimal ethical standard. Following a close analysis of the social-value requirement of ethical clinical research, I argue that this proposal is defensible. The problem identified in this paper has two parts, quantity and quality, and some clarification is needed about the latter because 'quality' is a highly contested term in the medical literature. When some scholars advocate for high-quality trials, they mean large-scale, simple, explanatory randomized controlled trials. Others, including myself, have defended a different characterization of high-quality research that tends more toward pragmatic trial design and the use of methods other than RCTs. Pragmatic trials aim to provide evidence that directly supports clinical decision-making in 'usual' care settings. Unlike explanatory trials, which aim to abstract away from particular settings and patients, in the hopes of creating ideal conditions for the success of an intervention, pragmatic trials deliberately pursue knowledge of high applicability, through the use of representative subjects, clinically important questions, flexible treatment protocols, patient-oriented outcome measures, and so on. I see applicability as a marker of high-quality research. The context in which research is meant to be applied should be the context in which new interventions are evaluated. [ABSTRACT FROM AUTHOR]