Protocol for the development of a tool (INSPECT-SR) to identify problematic randomised controlled trials in systematic reviews of health interventions.

INTRODUCTION: Randomised controlled trials (RCTs) inform healthcare decisions. It is now apparent that some published RCTs contain false data and some appear to have been entirely fabricated. Systematic reviews are performed to identify and synthesise all RCTs that have been conducted on a given topic. While it is usual to assess methodological features of the RCTs in the process of undertaking a systematic review, it is not usual to consider whether the RCTs contain false data. Studies containing false data therefore go unnoticed and contribute to systematic review conclusions. The INveStigating ProblEmatic Clinical Trials in Systematic Reviews (INSPECT-SR) project will develop a tool to assess the trustworthiness of RCTs in systematic reviews of healthcare-related interventions. METHODS AND ANALYSIS: The INSPECT-SR tool will be developed using expert consensus in combination with empirical evidence, over five stages: (1) a survey of experts to assemble a comprehensive list of checks for detecting problematic RCTs, (2) an evaluation of the feasibility and impact of applying the checks to systematic reviews, (3) a Delphi survey to determine which of the checks are supported by expert consensus, culminating in, (4) a consensus meeting to select checks to be included in a draft tool and to determine its format and (5) prospective testing of the draft tool in the production of new health systematic reviews, to allow refinement based on user feedback. We anticipate that the INSPECT-SR tool will help researchers to identify problematic studies and will help patients by protecting them from the influence of false data on their healthcare. ETHICS AND DISSEMINATION: The University of Manchester ethics decision tool was used, and this returned the result that ethical approval was not required for this project (30 September 2022), which incorporates secondary research and surveys of professionals about subjects relating to their expertise. Informed consent will be obtained from all survey participants. All results will be published as open-access articles. The final tool will be made freely available.

Rebalancing commercial and public interests in prioritizing biomedical, social and environmental aspects of health through defining and managing conflicts of interest.

Biomedical research is intended to benefit human beings and their health. Toward that end, scientific norms involve examining and criticizing the work of others and prioritizing questions that should be studied. Yet, in areas of health research where industry is active, it has often utilized well-honed strategies aimed at evading scientific standards and at dominating the research agenda, largely through its financial support and lack of transparency of its research practices. These tactics have now been documented to uniformly support industry products. Commercial entities are aided in this pursuit by public policy that has significantly embedded commercial interests and agendas into federal research funding and infrastructure. Therefore, to understand the resulting landscape and its effect on priority in health research agendas, traditional definitions of individual conflicts of interest (COI) and the less well developed institutional COI must be supplemented by a new construct of structural COI, largely operating as intellectual monopolies, in support of industry. These arrangements often result in financial and reputational resources that assure dominance of commercial priorities in research agendas, crowding out any other interests and ignoring justified returns to the public from investment of its tax dollars. There is no sustained attention to mechanisms by which public interests can be heard, normative issues raised, and then balanced with commercial interests which are transparently reported. Focus on research supporting approval of commercial products ignores social and environmental determinants of health. Commercial bias can invalidate regulatory research protections through obscuring valid risk-benefit ratios considered by IRBs.

Protocol for the development of a tool (INSPECT-SR) to identify problematic randomised controlled trials in systematic reviews of health interventions.

Introduction: Randomised controlled trials (RCTs) inform healthcare decisions. It is now apparent that some published RCTs contain false data and some appear to have been entirely fabricated. Systematic reviews are performed to identify and synthesise all RCTs that have been conducted on a given topic. While it is usual to assess methodological features of the RCTs in the process of undertaking a systematic review, it is not usual to consider whether the RCTs contain false data. Studies containing false data therefore go unnoticed and contribute to systematic review conclusions. The INSPECT-SR project will develop a tool to assess the trustworthiness of RCTs in systematic reviews of healthcare related interventions. Methods and analysis: The INSPECT-SR tool will be developed using expert consensus in combination with empirical evidence, over five stages: 1) a survey of experts to assemble a comprehensive list of checks for detecting problematic RCTs, 2) an evaluation of the feasibility and impact of applying the checks to systematic reviews, 3) a Delphi survey to determine which of the checks are supported by expert consensus, culminating in 4) a consensus meeting to select checks to be included in a draft tool and to determine its format, 5) prospective testing of the draft tool in the production of new health systematic reviews, to allow refinement based on user feedback. We anticipate that the INSPECT-SR tool will help researchers to identify problematic studies, and will help patients by protecting them from the influence of false data on their healthcare.

Should the Regulation of Research Misconduct Be Integrated with the Ethics Framework Promulgated in The Belmont Report?

The federal research misconduct regulations finalized in 2005 did not incorporate important principles regarding human subjects protections articulated in The Belmont Report, yet research misconduct can involve harms to research subjects and to subsequent patients whose treatments are based on false research findings. Consistency with the Belmont principles would require assuring regular monitoring to detect research misconduct, tracing effects of research misconduct on trial participants and informing them of these effects, and assuring timely correction of published reports of research findings if research misconduct related to the study was subsequently discovered. Research misconduct has historically been viewed as a matter for the scientific community to manage; it is actually a threat to the welfare of human subjects and ethically ought to be treated as such.

Institutional Approaches to Research Integrity in Ghana.

Research misconduct (RM) remains an important problem in health research despite decades of local, national, regional, and international efforts to eliminate it. The ultimate goal of every health research project, irrespective of setting, is to produce trustworthy findings to address local as well as global health issues. To be able to lead or participate meaningfully in international research collaborations, individual and institutional capacities for research integrity (RI) are paramount. Accordingly, this paper concerns itself not only with individuals' research skills but also with institutional and national policies and governance. Such policies and governance provide an ethical scaffold for the production of knowledge and structure incentives. This paper's operational definition of research therefore draws from Institute of Medicine's articulation of health research as an inquiry that aims to produce knowledge about the structure, processes, or effects of personal health services; and from an existing health systems framework. The paper reviews the research regulatory environment and the ethics apparatus in Ghana, and describes a project jointly undertaken by Ghanaian researchers in collaboration with New York University to assess the perceived adequacy of current institutional practices, opportunities, and incentives for promoting RI.

Single-Patient Expanded Access Requests: IRB Professionals' Experiences and Perspectives.

BACKGROUND: U.S. physicians may treat a patient with an investigational drug outside of a clinical trial by using the expanded access (EA) pathway or the recently created federal right to try (RTT) pathway. The EA pathway requires physicians to get prior permission from the U.S. Food and Drug Administration (FDA) and, except in emergency cases, institutional review board (IRB) approval. The perspectives of IRB professionals on the review of single-patient EA requests have not been empirically studied. METHODS: We used a cross-sectional online survey to ascertain IRB professionals' perspectives on IRB experiences with and preparedness for review of single-patient EA requests, as well as their attitudes about the importance of IRB review of such requests. Email invitations were sent to 234 IRB professionals connected to the SMART IRB platform. Approximately half of the survey questions used a Likert scale to assess respondents' agreement with specific statements. RESULTS: Eighty-three respondents completed the survey (36.4% response rate, with 228 deliverable e-mail invitations). Of the respondents, 73.5% were affiliated with an academic medical institution; 78.3% of respondents agreed that it is important for a designated member of an IRB to review single-patient EA requests before investigational drugs are used by patients. The majority indicated that local review of the EA request was important and that a single designated reviewer was sufficient (rather than full board). Further, 86.6% felt that their IRBs were prepared to review these requests, and 9.2% indicated that not all the single-patient EA requests reviewed by their IRBs in 2017 were approved. CONCLUSIONS: A large majority of IRB professionals affiliated with the SMART IRB platform who responded to this survey felt IRB review of single-patient EA requests is important and that their IRBs were prepared to handle such requests.

Correctable Myths About Research Misconduct in the Biomedical Sciences.

A recent National Academy report on research integrity noted that policies are not evidence-based, with no formal entity responsible to attend to this deficit. Here we describe four areas of research misconduct (RM) regulations governing Public Health Service funded research that are empirically and/or ethically questionable. Policies for human subject protection, RM and conflict of interest are not harmonized, making it extremely difficult to deal with complex cases which often contain allegations in all of these areas. Second, detection of RM has depended entirely on whistleblowers in spite of evidence of significant under-reporting. Third, the scientific record is far from cleansed of the effects of falsified/fabricated work through current mechanisms of retraction. Finally, lack of fairness in the regulations may reflect lack of a Belmont Report-like document to guide ethics of RM policy. These issues are likely common in other countries. RM regulations should be harmonized with related regulations and their effectiveness tracked, open access to data for independent replication and improved statistical tests are an essential supplement to whistleblowers, correction of the scientific record will require a major effort, and further ethical analysis and guidance are as important as is empirical study for the improvement of RM regulations. Further consideration should be given to assigning current regulations for human subjects protection, RM and conflict of interest to a single authority and to the further development of a Belmont-like report of essential principles, for RM.

Commentary: Legacy of the Commission on Research Integrity.

20 years ago, the Report of the Commission on Research Integrity (also known as the Ryan Commission after its chair) was submitted to the Secretary of the Department of Health and Human Services and to House and Senate Committees. As directed in enabling legislation, the Commission had provided recommendations on a new definition of research misconduct, oversight of scientific practices, and development of a regulation to protect whistleblowers. Reflecting the ethos of the time, the Commission recommended that institutions receiving Public Health Service research funding should provide oversight of all but the most egregious misconduct. The suggested definition of research misconduct was organized around misappropriation, interference and misrepresentation, which would have addressed collaborative/authorship disputes and sabotage in scientific laboratories, both of which remain unaddressed in current policy. The Commission also recommended the Whistleblower Bill of Rights and Responsibilities which would have authorized remedies for whistleblowers who experienced retaliation and sanctions against retaliators. Response from the scientific community was highly critical, and none of the Commission's recommendations was accepted. No new body has examined issues within the Commission's charge, there has been no significant Congressional or public pressure to do so, institutions have not been able to sustain standards that would have avoided current concerns about bias and irreproducibility in research, and there is still no entity in science capable of addressing issues assigned to the Commission and other urgent issues.

Institutional Review Boards as Arbiters of Expanded Access to Unapproved Drugs: Time for a Change?

Institutional review boards (IRBs) are one of the bodies charged with prospectively reviewing compassionate use, the hopefully therapeutic use of an unapproved drug in a seriously ill or dying patient who has no other treatment options. However, there are ethical issues in assigning this role to a body whose primary purpose is to review research proposals. The role of IRBs with regard to compassionate use must be examined and potentially revised.

Ethics of patient education and how do we make it everyone's ethics.

Patient education has long been central to nursing's philosophy of practice, and, because of this commitment, nurses in all practice settings have been deeply distressed with the careless and generally incomplete manner in which it is practiced in the health care system. This article examines the ethical underpinning of this distress and of this neglect in patient education and what actions nurses can take to correct this situation.

Patient adherence or patient self-management in transplantation: an ethical analysis.

Adherence of patients to transplantation regimens has been problematic. Patient self-management of the chronic diseases that frequently lead to transplantation is now the standard of practice, although that practice has been incompletely implemented. Through its focus on developing patients' skills and confidence in their ability to perform medical management, maintain important life roles, and manage the negative emotions that often accompany chronic conditions, patient self-management has the potential to support effective adherence of patients in an ethically satisfactory way. A professional decision to transplant should carry with it a commitment to help patients self-manage, including patients with low levels of literacy. Viewing adherence as patients' work to be accomplished within a framework of patient self-management offers an option for improving transplant outcomes. Testing this option is an important next step.

When is patient education unethical?

Although patient education is central to the ethical practice of nursing, it can be practiced in an ethically contested or unethical way. It is sometimes used to: forward a societal goal the individual might not have chosen; assume that patients should learn to accommodate unjust treatment; exclude the views of all except the dominant health care provider group; limit the knowledge a patient can receive; make invalid or unreliable judgments about what a patient can learn; or require a patient to change his or her identity to meet a medical ideal. Both health promotion education and manipulating patient beliefs in situations of uncertainty are ethically contested. Nussbaum's capabilities approach is used here as a moral framework through which to view the goals and practice of patient education. This provides better guidance than the current conception of patient education as an instrument to carry out the directives of medical practice.

Accountability for patient self-management of chronic conditions; ethical analysis and a proposal.

Patient self-management (PSM) of varying portions of therapy for chronic illness is expanding. However, several current conditions of practice are ethically problematic. Standards remain process-oriented, and accountability for patient outcomes and quality of practice of both patient and provider is diffuse. PSM carries important benefits but largely unmonitored potential harms. Also, access to preparation for safe PSM appears to be skewed in favour of high socio-economic classes. This condition persists even though available evidence supports the conclusion that less advantaged patients with poor disease outcomes can be taught to self-manage, albeit they require more intensive and prolonged interventions. Routine clinical use of well-validated measurement instruments could serve to develop evidence-based standards of PSM, quality improvement and effective public policy. Development of a standard dataset would facilitate description of the effectiveness of existing programmes and comparison across programmes. Such reform will require investment in the development of instruments that measure patient ability to make sound clinical judgements and sustain PSM over changed disease and social conditions. It will take advantage of modem psychometric theory, which is increasingly necessary for building the empirical base for evidence-based healthcare.

Responsibility for control; ethics of patient preparation for self-management of chronic disease.

Patient self-management (SM) of chronic disease is an evolving movement, with some forms documented as yielding important outcomes. Potential benefits from proper preparation and maintenance of patient SM skills include quality care tailored to the patient's preferences and life goals, and increase in skills in problem solving, confidence and success, generalizable to other parts of the patient's life. Four central ethical issues can be identified. 1) insufficient patient/family access to preparation that will optimize their competence to SM without harm to themselves, 2) lack of acknowledgement that an ethos of patient empowerment can mask transfer of responsibility beyond patient/family competency to handle that responsibility, 3) prevailing assumptions that preparation for SM cannot result in harm and that its main purpose is to deliver physician instructions, and 4) lack of standards for patient selection, which has the potential to exclude individuals who could benefit from learning to SM. Technology assessment offers one framework through which to examine available data about efficacy of patient SM and to answer the central question of what conditions must be put in place to optimize the benefits of SM while assuring that potential harms are controlled.