Therapeutic misunderstandings in modern research.

Clinical trials play a crucial role in generating evidence about healthcare interventions and improving outcomes for current and future patients. For individual trial participants, however, there are inevitably trade-offs involved in clinical trial participation, given that trials have traditionally been designed to benefit future patient populations rather than to offer personalised care. Failure to understand the distinction between research and clinical care and the likelihood of benefit from participation in clinical trials has been termed the 'therapeutic misconception'. The evolution of the clinical trials landscape, including greater integration of clinical trials into healthcare and development of novel trial methodologies, may reinforce the significance of the therapeutic misconception and other forms of misunderstanding while at the same time (paradoxically) challenging its salience. Using cancer clinical trials as an exemplar, we describe how methodological changes in early- and late-phase clinical trial designs, as well as changes in the design and delivery of healthcare, impact upon the therapeutic misconception. We suggest that this provides an impetus to re-examine the ethics of clinical research, particularly in relation to trial access, participant selection, communication and consent, and role delineation.

Perceptions about and reasons for participation in research bronchoscopy in Uganda: A qualitative analysis.

This study sought to assess perceptions towards and reasons for participation in research bronchoscopy studies in a high TB burden urban setting. Additionally, the study aimed to identify areas of pre- and post-procedural concern among healthy adults approached to participate in research bronchoscopy. A cross sectional qualitative study was undertaken at the Uganda-Case Western Reserve University Collaboration Tuberculosis Research Project Clinic at Mulago National Referral Hospital in Kampala, Uganda. In-depth interviews were conducted with participants at their pre-bronchoscopy visit (n = 17) and after they had undergone bronchoscopy (n = 23) to examine their perceptions and experiences with the procedure. Following consent, all interviews were audio recorded and later transcribed and typed in MS WORD. Local language interviews were translated into English by the social science interviewers. Qualitative analysis was performed manually following an inductive and emergent approach typical in thematic analysis. This study was approved by the Makerere University School of Social Sciences Research Ethics Committee (MAKSS REC 09.18.220) and registered with the Uganda National Council for Science and Technology (UNCST SS4785). Overall willingness to participate in bronchoscopy was high as many participants viewed the study as primarily a means of getting free health checks and determining their health status. Notably, despite extensive face to face counseling for this study coupled with the fact that our participants had been involved in prior research at the site, therapeutic misconception still played a pivotal role in willingness to participate in research bronchoscopy. Therapeutic misconception has important ethical and research implications in clinical research, which requires strategies to tackle it, even among a pool of potential participants who are knowledgeable about a disease or clinical care procedures. Continuous awareness and knowledge building about the difference between being a trial participant and therapeutic misconception must become a mainstay in trials to improve the process of informed consent for future research bronchoscopy studies.

When research becomes practice: the concept of the therapeutic misconception and challenges to consent in clinical trials.

Many factors influence patients' decisions to participate in clinical trials. For many, the primary motivation is the possibility that they might derive some benefit from participation. This is particularly true for patients with limited treatment options, such as patients with advanced cancer. While this is not surprising, it is potentially problematic if patients fail to recognise the distinction between research and clinical care (a phenomenon known as the 'therapeutic misconception'). This is becoming increasingly problematic as clinical trial designs become more complex, as clinical trials become more embedded in routine clinical care, and as trials are increasingly used by patients and clinicians to access new diagnostic platforms and therapies. We outline some of these recent trends, focusing on the cancer clinical trials landscape as this provides a good case study of the phenomenon. We conclude by making preliminary suggestions that changes to the consent process, perhaps using 'dynamic consent' platforms, might help to mitigate the therapeutic misconception and note the need for further research to guide strategies for improving communication and decision-making.

Therapeutic Misestimation in Patients with Degenerative Ataxia: Lessons from a Randomized Controlled Trial.

BACKGROUND: The absence of effective treatments may render patients with degenerative cerebellar ataxias susceptible to a placebo response, which could affect the outcome of clinical trials. OBJECTIVE: To retrospectively examine expectations of benefit in participants of an ataxia trial and identify determinants of possible therapeutic misestimation. METHODS: Individuals with spinocerebellar ataxia type 3 who participated in a randomized, double-blind, sham-controlled trial received a custom-designed questionnaire about short-term and long-term treatment expectations, allocation preferences, and interpretation of treatment arm assignment based on the presence or absence of clinical improvement. To evaluate whether expectations were specifically related to the application of cerebellar transcranial direct current stimulation (tDCS) or more generally reflect an overly positive attitude of patients with ataxia toward trial participation and results, the last questions involved a hypothetical scenario in which an oral drug was tested against placebo with an aim identical to that of our tDCS study. RESULTS: All 20 trial participants completed the questionnaire. If allocated to the active treatment arm, 75% of patients expected short-term health benefits and 55% thought they would still have less severe ataxia at 1-year follow-up compared with baseline. After 2 weeks, an average reduction in ataxia severity of 31.5% (standard deviation, 22.2%) was anticipated. Conversely, 65% associated a lack of improvement with probable or definite allocation to the placebo group. High expectations of benefit were neither related to the type of intervention nor to clinical or demographic characteristics. CONCLUSION: Therapeutic misestimation is common in patients with degenerative ataxia and requires special attention in future trials. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Four reasons why too many informed consents to clinical research are invalid: a critical analysis of current practices.

OBJECTIVE: Informed consent (IC) is a central ethical and legal requirement for clinical research that aims to protect the autonomy of participants. To enable an autonomous decision and valid consent, adequate understanding must be ensured. However, a considerable proportion of participants do not understand the relevant aspects about participation in research, for example, approximately 45% could not name at least one risk. As such, the inadequate understanding of IC has been known for several decades, and it still constitutes a severe problem for the ethical conduct of research. Through delineating the most pressing deficits of current IC procedures that lead to insufficient understanding, we aim to encourage the discussion among stakeholders, for example, clinical researchers, and to provide the grounds for practical solutions. MAIN ARGUMENTS: (1) IC documents are too long to be read completely, thus, make it very difficult for potential participants to identify the material facts about the trial. (2) The low readability of the IC documents disadvantages persons with limited literacy. (3) The therapeutic misconception frequently prevents participants to realise that the primary purpose of clinical research is to benefit future patients. (4) Excessive risk disclosures, insufficient information about expected benefits and framing effects compromise a rational risk/benefit assessment. CONCLUSION: Due to these deficits, practices of IC in clinical research too often preclude adequate understanding of prospective participants, thus, invalidating IC. The gap between the well-specified ethical norm to enable IC and its insufficient translation into practice can no longer be accepted, as participant rights and the public trust in responsible research are at stake. Hence, immediate action is needed to address the prevailing deficits.

Therapeutic Misconception about Research Procedures: Does a Simple Information Chart Improve Understanding?

In phase I trials, some biospecimens are used both for research and patient care and some for research only. Some research participants have therapeutic misconception, assuming all biospecimens are for patient care. This study's aim was to test if a simple information chart would improve understanding of nontherapeutic research procedures. A two-arm study was conducted. Participants in the control group (C) were asked whether biospecimens were for their care, for research only, or for both. The experimental group (E) was asked the same questions but provided with a study-specific information chart labeling the purpose of each biospecimen. One hundred one patients were interviewed. In both arms, understanding that pretreatment blood draws were for patient care and research was moderate (49% for C and 62% for E). Understanding that posttreatment blood draws were for research only was significantly higher in the experimental arm (16% for C and 44% for E; p = 0.002). Providing a simple information chart may help alleviate this aspect of therapeutic misconception.

Setting the Terms for Zoonotic Diseases: Effective Communication for Research, Conservation, and Public Policy.

Many of the world's most pressing issues, such as the emergence of zoonotic diseases, can only be addressed through interdisciplinary research. However, the findings of interdisciplinary research are susceptible to miscommunication among both professional and non-professional audiences due to differences in training, language, experience, and understanding. Such miscommunication contributes to the misunderstanding of key concepts or processes and hinders the development of effective research agendas and public policy. These misunderstandings can also provoke unnecessary fear in the public and have devastating effects for wildlife conservation. For example, inaccurate communication and subsequent misunderstanding of the potential associations between certain bats and zoonoses has led to persecution of diverse bats worldwide and even government calls to cull them. Here, we identify four types of miscommunication driven by the use of terminology regarding bats and the emergence of zoonotic diseases that we have categorized based on their root causes: (1) incorrect or overly broad use of terms; (2) terms that have unstable usage within a discipline, or different usages among disciplines; (3) terms that are used correctly but spark incorrect inferences about biological processes or significance in the audience; (4) incorrect inference drawn from the evidence presented. We illustrate each type of miscommunication with commonly misused or misinterpreted terms, providing a definition, caveats and common misconceptions, and suggest alternatives as appropriate. While we focus on terms specific to bats and disease ecology, we present a more general framework for addressing miscommunication that can be applied to other topics and disciplines to facilitate more effective research, problem-solving, and public policy.

Reassessing the measurement and presence of therapeutic misconception in a phase 1 setting.

BACKGROUND: Therapeutic misconception (TM) refers to research subjects' failure to distinguish the goals of clinical research from standard personal care. TM has traditionally been determined by questioning the patient about the research study's purpose. Recent research, however, has questioned whether TM is as prevalent as reported due to discrepancies between patient/researcher interpretations of TM questions. The authors have created an interview tool receptive to these advancements to more accurately determine the prevalence of TM. METHODS: Patients were questioned about the trial's purpose as follows: 1) "Is the trial mostly intending to help research and gain knowledge?," 2) "Is it mostly intending to help you as a person?," or 3) "Don't know." Participants were then asked what they thought this question was asking: A) "What my own intentions are for participating," B) "What the official purpose of the research study is," or C) "Not sure." A patient exhibited TM by answering that the official trial purpose was to help him or her. RESULTS: Patients (n = 98) had a mean age of 60 years, were mostly White (64%), had a combined family annual income ≥$60,000 (61%), and 49% had a college degree. Twelve of 98 patients (12%) definitely exhibited TM. This was much lower than the author's original finding of 68% in a similar cohort. Twenty-four of 98 patients (24.5%) were unclear about what one or both questions were asking and could not be categorized. CONCLUSIONS: Previously, a patient was thought to have TM if they answered that the purpose of the trial was to benefit to him or her. An additional query about how patients interpreted that question revealed only 12% definitely had TM. LAY SUMMARY: Therapeutic misconception (TM) refers to research subjects' failure to distinguish the goals of clinical research from standard personal care. TM signals a basic misunderstanding of the purpose of clinical research, threatening valid informed consent to participate in clinical trials. TM has traditionally been determined by questioning patients about their research study's purpose. Recent research, however, has questioned whether TM is as prevalent due to discrepancies between patient/researcher interpretations of TM questions. By developing an interview-tool receptive to these advancements, we report a lower TM estimate in the phase 1 setting (12%) than we found previously in a similar cohort (68%).

Professional integrity in maternal - fetal innovation and research: an essential component of perinatal medicine.

OBJECTIVES: Clinical innovation and research on maternal-fetal interventions have become an essential for the development of perinatal medicine. In this paper, we present an ethical argument that the professional virtue of integrity should guide perinatal investigators. METHODS: We present an historical account of the professional virtue of integrity and the key distinction that this account requires between intellectual integrity and moral integrity. RESULTS: We identify implications of both intellectual and moral integrity for innovation, research, prospective oversight, the role of equipoise in randomized clinical trials, and organizational leadership to ensure that perinatal innovation and research are conducted with professional integrity. CONCLUSIONS: Perinatal investigators and those charged with prospective oversight should be guided by the professional virtue of integrity. Leaders in perinatal medicine should create and sustain an organizational culture of professional integrity in fetal centers, where perinatal innovation and research should be conducted.

Talk to Patients About: Vaccines and SIDS.

Over the years, several vaccines have been blamed for SIDS, including those for pertussis, tetanus, diphtheria, Hemophilus influenzae type B, polio, and hepatitis B. This misconception has triggered a lot of scientific study to find out if vaccines could, in fact, cause SIDS. However, multiple studies and safety reviews have concluded that the answer is no, according to the Centers for Disease Control and Prevention (CDC).

Enhancing the ethical conduct of a longitudinal cluster-randomized trial of psychosocial stimulation intervention for children with complicated severe acute malnutrition through Rapid Ethical Assessment: a qualitative study.

BACKGROUND: Informed consent is a universally accepted precondition for scientific researches involving human participants. However, various factors influence the process of obtaining authentic informed consent, and researchers particularly working in resource-poor countries often face considerable difficulties in implementing the universally recommended procedures for obtaining informed consent. We have conducted this Rapid Ethical Assessment (REA) to accommodate the local cultural norms and to understand the relevant ethical issues in the Silti community before the conduct of a cluster-randomized controlled trial. METHODS: This REA was conducted in two purposively selected Woredas/Districts and Worabe Town administration of Silti Zone. Data were collected using in-depth interviews and focus group discussions. Purposive and convenient sampling techniques were used to select respondents. Five in-depth interviews and 15 Focus Group Discussions were conducted in the Amharic language. The collected data was transcribed, translated, and analyzed using a thematic approach. RESULT: Most of the community members never heard about research and therapeutic misconception was common. In the area, the permission of people working in the formal and informal community administration is essential before approaching individuals. The male head of the household should also be involved in the decision before individual household members participate in research. Furthermore, sensitizing the community using public and religious gatherings was suggested before individual recruitment. In the consent process, delivering selected information particularly the purpose and benefits of the research was emphasized and the tendency of preferring verbal consent was documented despite the willingness of the individuals to sign on the consent form. Local health workers were identified as appropriate personnel to communicate information and the procedures of the research were found to be acceptable. However, the value of small incentives was suggested to motivate potential participants. Finally, involving all concerned stakeholders and respecting the cultural norm of the community was emphasized. CONCLUSION: Through REA, we understand the research awareness of the community, their expectation, and the cultural norms relevant to the ethical conduct of research. It enabled us to devise culturally sensitive and scientifically sound strategies to secure authentic informed consent. The process of conducting REA was found to be feasible, quick, and efficient.

A Qualitative Analysis of Ethical Perspectives on Recruitment and Consent for Human Intracranial Electrophysiology Studies.

Intracranial electrophysiological research methods, including those applying electrodes on the cortical surface or in deep structures, have become increasingly important in human neuroscience. They also pose novel ethical concerns, as human studies require the participation of neurological patients undergoing surgery for conditions such as epilepsy and Parkinson's disease. Research participants in this setting may be vulnerable to conflicts of interest, therapeutic misconception, and other threats to valid recruitment and consent. We conducted semi-structured interviews with investigators from NIH-funded studies involving recording or stimulation inside the human skull. We elicited perspectives on study recruitment and consent procedures, and analyzed transcripts using a modified grounded theory approach. We interviewed 26 investigators from 19 separate intracranial electrophysiology studies, who described two study types: opportunity studies (n = 15) and experimental trials (n = 4). Respondents described significant heterogeneity in recruitment and consent procedures, even among studies employing similar techniques. In some studies, clinician-investigators were specifically barred from obtaining consent, while in other studies clinician-investigators were specifically required to obtain consent; regulatory guidance was inconsistent. Respondents also described various models for subject selection, the timing of consent, and continuing consent for temporally extended studies. Respondents expressed ethical concerns about participants' vulnerability and the communication of research-related risks. We found a lack of consensus among investigators regarding recruitment and consent methods in human intracranial electrophysiology. This likely reflects the novelty and complexity of such studies and indicates a need for further discussion and development of best practices in this research domain.

Stakeholder perspectives on clinical research related to therapies for rare diseases: therapeutic misconception and the value of research.

BACKGROUND: For many rare diseases, few treatments are supported by strong evidence. Patients, family members, health care providers, and policy-makers thus have to consider whether to accept, recommend, or fund treatments with uncertain clinical effectiveness. They must also consider whether and how to contribute to clinical research that may involve receiving or providing the therapy being evaluated. OBJECTIVE: To understand why and how patients and families with rare metabolic diseases, specialist metabolic physicians, and health policy advisors choose whether to participate in studies and how they use and value research. METHODS: We conducted separate focus group interviews with each stakeholder group (three groups in total); two groups were conducted by telephone and the third was held in-person. Participants were recruited using purposive sampling. We analyzed each interview transcript sequentially using a qualitative description approach to inductively identify key themes. Several strategies to ensure credibility and trustworthiness were used including debriefing sessions after each focus group and having multiple team members review transcripts. RESULTS: Four patients/caregivers, six physicians, and three policy advisors participated. Our findings did not support conventional perspectives that therapeutic misconception (gaining access to treatment) is the main motivating factor for patients/caregivers to participate in clinical research. Rather, patients'/caregivers' expressed reasons for participating in research included advancing science for the next generation and having an opportunity to share their experiences. Patients/caregivers and physicians described the difficulties in weighing risks versus benefits of accepting treatments not well-supported by evidence. Physicians also reported feeling conflicted in their dual role as patient advisor/advocate and evaluator of the evidence. Policy advisors were primarily focused on critically appraising the evidence to make recommendations for the health system. CONCLUSIONS: Stakeholders differ in their perspectives on rare disease research but share concerns about the risks versus benefits of therapies when making individual- and population-level decisions.

Comparison of Various Phase I Combination Therapy Designs in Oncology for Evaluation of Early Tumor Shrinkage Using Simulations.

There is still a lack of efficient designs for identifying the dose response in oncology combination therapies in early clinical trials. The concentration response relationship can be identified using the early tumor shrinkage time course, which has been shown to be a good early response marker of clinical efficacy. The performance of various designs using an exposure-tumor growth inhibition model was explored using simulations. Different combination effects of new drug M and cetuximab (reference therapy) were explored first assuming no effect of M on cetuximab (to investigate the type I error (α)), and subsequently assuming additivity or synergy between cetuximab and M. One-arm, two-arm, and four-arm designs were evaluated. In the one-arm design, 60 patients received cetuximab + M. In the two-arm design, 30 patients received cetuximab and 30 received cetuximab + M. In the four-arm design, in addition to cetuximab and cetuximab + M as standard doses, combination arms with lower doses of cetuximab were evaluated (15 patients/arm). Model-based predictions or "simulated observations" of early tumor shrinkage at week 8 (ETS8) were compared between the different arms. With the same number of individuals, the one-arm design showed better statistical power than other designs but led to strong inflation of α in case of misestimated reference for ETS8 value. The two-arm design protected against this misestimation and, with the same total number of subjects, would provide higher statistical power than a four-arm design. However, a four-arm design would be helpful for exploring more doses of cetuximab in combination with M to better understand the interaction.

Common Myths and Misconceptions That Sidetrack Parkinson Disease Treatment, to the Detriment of Patients.

Parkinson disease symptoms become apparent when there has been substantial loss of brain dopamine. That is the consequence of the slow progression of the Lewy body neurodegenerative process. Replenishment of brain dopamine with levodopa therapy dates back approximately a half century and continues to be the most efficacious symptomatic treatment. Understanding the fundamentals of levodopa treatment is crucial to therapeutic success. Various myths over the years have sabotaged treatment outcomes and have discouraged primary care physicians from managing patients with Parkinson disease. That is unfortunate because in some regions, neurologists, and in particular movement specialists, are in short supply. The long history of these persistent levodopa myths and the counterarguments are the focus of this article.