Development and validation of a tool to assess researchers' knowledge of human subjects' rights and their attitudes toward research ethics education in Saudi Arabia.

BACKGROUND: Researchers must adhere to ethical and scientific standards in their research involving human subjects; therefore, their knowledge of human subjects' rights is essential. A tool to measure the extent of this knowledge is necessary to ensure that studies with participants are conducted ethically and to enhance research integrity. Currently, no validated instrument is available for such an assessment. Therefore, the primary purpose of this study is to develop a reliable and valid instrument to assess researchers' knowledge of human subjects' rights in clinical settings, as well as a reliable and valid measure of their attitudes toward clinical research ethics education in Saudi Arabia. METHODS: The current study involves the development of a questionnaire about the rights of human subjects in research and the researchers' attitudes toward research ethics education. The content was developed based on an extensive review of research ethics guidelines. A panel of experts tested the questionnaire for face validity (n = 5) and content validity (n = 8). The reliability of the questionnaire was established by a split-half reliability coefficient and item analysis among a sample (n = 301) of clinical researchers. RESULTS: Face validity demonstrated that the questionnaire was quick to complete and easy to answer. The global content validity indices (S-CVIs) were greater than 0.78 for all questionnaire sections; the split-half reliability coefficient was 0.755 for knowledge items; Cronbach's alpha was 0.77 for researchers' attitudes, showing good internal consistency. The difficulty index ranged from 12.0% to 98.7% for all knowledge items. Most questions were at an acceptable level of reliability and discrimination criteria. The final version of the questionnaire contained 89 items, distributed as 15 questions on demographic and professional characteristics, 64 questions items on knowledge, and 10 items on attitudes. CONCLUSIONS: The questionnaire is a valid and reliable tool to assess biomedical researchers' knowledge of human subjects' rights and their attitudes toward research ethics education. This instrument could help address the gap in researchers' knowledge of the rights and facilitate the development of educational intervention programs to set appropriate learning objectives.

Widespread use of pure and impure placebo interventions by GPs in Germany.

AIM: To collect data on the use of placebo interventions by GPs in Germany. METHODS: A questionnaire was mailed to 400 randomly selected GPs in Bavaria. Non-responders were reminded by telephone after 4 weeks and were given a second copy of the questionnaire after a further 3 weeks. RESULTS: In all, 208 completed questionnaires were returned. The majority of GPs (88%) have used a placebo at least once in their practice; 45% have used pure placebos, such as saline injections and sugar pills, at least once last year; the median frequency of use was 5 [interquartile range (IQR), 2-10]. The use of impure placebos during the past year was more common: 76% of GPs have used impure placebos, i.e. medical interventions that have pharmacological or physical activity but have no intrinsic effect (e.g. pharmacological or physical action) on the patient's disease or its symptoms, with a median frequency of 20 times per year (IQR, 10-50). The main reason for the use of placebo was a possible psychological effect, followed by the expectation of patients to receive a treatment. For the majority of GPs placebo interventions were ethically justified if they were used for a possible psychological effect. CONCLUSIONS: Placebo interventions are a widely accepted part of medical treatment in German general practices and are used primarily for their psychological effects. Impure placebos are used much more frequently than pure placebos.

The use of pure and impure placebo interventions in primary care - a qualitative approach.

BACKGROUND: Placebos play an important role in clinical trials and several surveys have shown that they are also common in daily practice. Previous research focused primarily on the frequency of placebo use in outpatient care. Our aim was to explore physicians' views on the use of placebos in daily practice, whereby distinction was made between pure placebos (substances with no pharmacological effect, e.g. sugar pills) and impure placebos (substances with pharmacological effect but not on the condition being treated, e.g. antibiotics in viral infections or vitamins). METHODS: We performed semi-structured interviews with a sample of twelve primary care physicians (PCPs). The interview addressed individual definitions of a placebo, attitudes towards placebos and the participants' reasons for prescribing them. The interviews were transcribed and analysed using qualitative content analysis. RESULTS: The definition of a placebo given by the majority of the PCPs in our study was one which actually only describes pure placebos. This definition, combined with the fact that most impure placebos were not regarded as placebos at all, means that most of the participating PCPs were not aware of the extent to which placebos are used in daily practice. The PCPs stated that they use placebos (both pure and impure) mainly in the case of non-severe diseases for which there was often no satisfactory somatic explanation. According to the PCPs, cases like this are often treated by complementary and alternative therapies and these, too, are associated with placebo effects. However, all PCPs felt that the ethical aspects of such treatment were unclear and they were unsure as to how to communicate the use of placebos to their patients. Most of them would appreciate ethical guidelines on how to deal with this issue. CONCLUSIONS: Many PCPs seem to be unaware that some of the drugs they prescribe are classified as impure placebos. Perceptions of effectiveness and doubts about the legal and ethical aspects of the use of placebos by PCPs may discourage their application. Dissemination of guidelines and consensus papers may be one approach, but it has to be acknowledged that the topic itself is in conflict with the PCPs' perception of themselves as professional and reliable physicians.

Frequency and circumstances of placebo use in clinical practice--a systematic review of empirical studies.

BACKGROUND: The use of placebo interventions outside clinical trials is ethically, professionally and legally controversial. Little is known about the frequency and circumstances of placebo use in clinical practice. Our aim was to summarize the available empirical studies addressing these issues. METHODS: We searched PubMed and EMBASE from inception to July 2009 in order to identify cross-sectional surveys, qualitative or longitudinal studies among health care professionals, students or patients which investigated at least one of the following issues--frequency of placebo use or attitudes to, or motivations for, the use of placebo interventions. At least two reviewers extracted information on the study methods, participants and findings. Descriptive summaries were prepared in an iterative process by at least two reviewers per study. RESULTS: Twenty-two studies from 12 different countries met the inclusion criteria. Most studies had relevant shortcomings. The proportion of respondents reporting that they had applied 'pure' placebos (for example, saline injection) during their professional life varied between 17% and 80% among physicians and between 51% and 100% among nurses, but it seems that the actual frequency of such use seems to be rare. The use of 'impure' or 'active' placebos (for example, antibiotics for viral infections) is likely to be much more frequent. However, it is impossible to make a reliable estimation because there is no agreement of what an impure placebo might be. Studies using qualitative methods or asking participants to judge case examples suggest that motivations and attitudes towards placebo use are complex and health care providers are often faced with a dilemma. CONCLUSIONS: Although the available evidence is incomplete and confusing at times there can be little doubt that the prevalence of placebo use outside of clinical trials is not negligible and that views and attitudes on placebos use differ considerably among individuals, both health care professionals and patients. Further research is needed to clarify these issues.

Bonus agreements of senior physicians in Switzerland - A qualitative interview study.

In Switzerland a legal prohibition of volume-based bonus agreements has been initiated which is expected to take force at the beginning of 2021. Bonus agreements for physicians pose a risk to unbiased indication, possibly leading to over-, under- and misuse of medical care. In order to investigate physicians' perceptions of bonus agreements and reflect on them from an ethical point of view, we conducted a qualitative interview study with Swiss senior physicians. The remuneration system is complex and diverse so that the interviewed physicians were not always able to explain in detail to which targets the variable components of their salary were linked. Study participants were aware of their ethical responsibility regarding non-biased indication and cost-effective medicine. All rejected volume-based bonus agreements. Target agreements should generally have a clear, comprehensible function and always contain a component related to the quality of care delivered. Critical attention should go beyond a narrow focus on volume-based bonus agreements to include other volume-oriented target agreements and reimbursement systems that have the potential to negatively affect patient care.

Use of placebo interventions among Swiss primary care providers.

BACKGROUND: Placebo interventions can have meaningful effects for patients. However, little is known about the circumstances of their use in clinical practice. We aimed to investigate to what extent and in which way Swiss primary care providers use placebo interventions. Furthermore we explored their ideas about the ethical and legal issues involved. METHODS: 599 questionnaires were sent to general practitioners (GPs) and paediatricians in private practice in the Canton of Zurich in Switzerland. To allow for subgroup analysis GPs in urban, suburban, and rural areas as well as paediatricians were selected in an even ratio. RESULTS: 233 questionnaires were completed (response rate 47%). 28% of participants reported that they never used placebo interventions. More participants used impure placebos therapeutically than pure placebos (57% versus 17%, McNemar's chi(2) = 78, p < 0.001). There is not one clear main reason for placebo prescription. Placebo use was communicated to patients mostly as being "a drug or a therapy" (64%). The most frequently chosen ethical premise was that they "can be used as long as the physician and the patient work together in partnership" (60% for pure and 75% for impure placebos, McNemar's chi(2) = 12, p < 0.001). A considerable number of participants (11-38%) were indecisive about statements regarding the ethical and legal legitimacy of using placebos. CONCLUSION: The data obtained from Swiss primary care providers reflect a broad variety of views about placebo interventions as well as a widespread uncertainty regarding their legitimacy. Primary care providers seem to preferentially use impure as compared to pure placebos in their daily practice. An intense debate is required on appropriate standards regarding the clinical use of placebo interventions among medical professionals.

A systematic review found no consistent difference in effect between more and less intensive placebo interventions.

OBJECTIVES: It has been suggested that some placebo interventions might be associated with larger clinical effects than others. In a systematic review, we investigated whether there is evidence from direct comparisons in randomized clinical trials including two or more placebo groups supporting this hypothesis. STUDY DESIGN AND SETTING: Eligible trials were identified through electronic database searches and citation tracking up to February 2013. Placebo interventions in a trial were categorized into a more intense and a less intense intervention based on complexity, invasiveness, or route of administration and time needed for application. RESULTS: Twelve studies with 1,059 patients receiving placebo met the eligibility criteria. Studies were highly heterogeneous regarding patients, interventions, outcomes, and risk of bias. Seven studies did not find any significant differences between the more intense and the less intense placebo intervention, four studies found differences for single outcomes, and one study consistently reported significantly larger effects of the more intense placebo. An explorative meta-analysis yielded a standardized mean difference -0.22 (95% confidence interval: -0.46, 0.02; P = 0.07; I(2) = 68%). CONCLUSION: In the studies included in this review, more intense placebos were not consistently associated with larger effects than less intense placebos.

Impact of the DRG-based reimbursement system on patient care and professional practise: perspectives of Swiss hospital physicians.

QUESTIONS UNDER STUDY: The reimbursement system SwissDRG sets incentives for hospitals and providers to treat patients in a cost-efficient way. Arising conflicts between the commitment to the patient's well-being and the economic interests of the hospital can lead to an impairment of quality and equity of health care. We developed and used a monitoring tool to evaluate ethically relevant aspects related to DRGs by surveying physicians. METHODS: We surveyed a random sample of physicians working in Swiss hospitals, exploring potentially positive and negative effects of DRGs on patient care. RESULTS: A total of 382 physicians completed the questionnaire (response rate 47%). More than 90% judged quality of health care "very good" or "rather good", and 83% were satisfied with their job. The majority of physicians gave more consideration to economic issues in their clinical practise than they would have liked and had experienced various forms of over- and under-provision over the past six months. Overall, physicians considered patient-orientation deteriorating since the introduction of DRGs with no gains in efficiency. Professional principles could not be applied in all instances. CONCLUSIONS: Two years after the introduction of SwissDRG the quality of patient care and the job satisfaction is rated as good by most physicians. However, quality of care could be seriously compromised if more economic pressure is put on physicians in the future. Careful monitoring is needed to ensure that the needed focus on cost-containment and sustainability does not come at the expense of the high performance of the Swiss health care system.

Metamizole-associated adverse events: a systematic review and meta-analysis.

BACKGROUND: Metamizole is used to treat pain in many parts of the world. Information on the safety profile of metamizole is scarce; no conclusive summary of the literature exists. OBJECTIVE: To determine whether metamizole is clinically safe compared to placebo and other analgesics. METHODS: We searched CENTRAL, MEDLINE, EMBASE, CINAHL, and several clinical trial registries. We screened the reference lists of included trials and previous systematic reviews. We included randomized controlled trials that compared the effects of metamizole, administered to adults in any form and for any indication, to other analgesics or to placebo. Two authors extracted data regarding trial design and size, indications for pain medication, patient characteristics, treatment regimens, and methodological characteristics. Adverse events (AEs), serious adverse events (SAEs), and dropouts were assessed. We conducted separate meta-analyses for each metamizole comparator, using standard inverse-variance random effects meta-analysis to pool the estimates across trials, reported as risk ratios (RRs). We calculated the DerSimonian and Laird variance estimate T2 to measure heterogeneity between trials. The pre-specified primary end point was any AE during the trial period. RESULTS: Of the 696 potentially eligible trials, 79 trials including almost 4000 patients with short-term metamizole use of less than two weeks met our inclusion criteria. Fewer AEs were reported for metamizole compared to opioids, RR = 0.79 (confidence interval 0.79 to 0.96). We found no differences between metamizole and placebo, paracetamol and NSAIDs. Only a few SAEs were reported, with no difference between metamizole and other analgesics. No agranulocytosis or deaths were reported. Our results were limited by the mediocre overall quality of the reports. CONCLUSION: For short-term use in the hospital setting, metamizole seems to be a safe choice when compared to other widely used analgesics. High-quality, adequately sized trials assessing the intermediate- and long-term safety of metamizole are needed.

Assessing the impact of DRGs on patient care and professional practice in Switzerland (IDoC) - a potential model for monitoring and evaluating healthcare reform.

QUESTIONS UNDER STUDY: The starting point of the interdisciplinary project "Assessing the impact of diagnosis related groups (DRGs) on patient care and professional practice" (IDoC) was the lack of a systematic ethical assessment for the introduction of cost containment measures in healthcare. Our aim was to contribute to the methodological and empirical basis of such an assessment. METHODS: Five sub-groups conducted separate but related research within the fields of biomedical ethics, law, nursing sciences and health services, applying a number of complementary methodological approaches. The individual research projects were framed within an overall ethical matrix. Workshops and bilateral meetings were held to identify and elaborate joint research themes. RESULTS: Four common, ethically relevant themes emerged in the results of the studies across sub-groups: (1.) the quality and safety of patient care, (2.) the state of professional practice of physicians and nurses, (3.) changes in incentives structure, (4.) vulnerable groups and access to healthcare services. Furthermore, much-needed data for future comparative research has been collected and some early insights into the potential impact of DRGs are outlined. CONCLUSIONS: Based on the joint results we developed preliminary recommendations related to conceptual analysis, methodological refinement, monitoring and implementation.

The patient's perspective of placebo use in daily practice: a qualitative study.

QUESTIONS UNDER STUDY: The use of placebo outside of randomised controlled trials raises ethical and legal issues. So far, patients' perspectives have been considered only in quantitative studies. These studies did not distinguish between pure placebos (no pharmacological effect) and impure placebos (pharmacological ingredient, but no disease-specific effect). The aim of our study was to explore patients' conceptualisation, experiences and attitudes regarding the use of placebos in daily clinical practice. METHODS: Qualitative study with a convenience sample of 12 patients and semistructured interviews. The interviews were digitally recorded; full transcripts were obtained. The information was analysed in accordance with the qualitative content analysis method. RESULTS: The definition of placebo given by the participants mostly matched the common understanding of a pure placebo. Most participants supposed that placebos were mainly effective in diseases in which psychological influences play an important role. Furthermore, most participants believed that placebos themselves mainly worked via psychological effects. The acceptance of a hypothetical earlier use of a placebo depended on the success of the therapy. CONCLUSION: Patients were not aware of the differences between pure and impure placebos. Even regarding pure placebos, patients were more open than many physicians would expect. Trust between the patient and the general practitioner is an important element of the acceptance of a placebo. Appropriate communication could further increase the acceptance. Further research is needed to adapt the information given to the patient about possible placebo therapy.

Use of placebos and nonspecific and complementary treatments by German physicians--rationale and development of a questionnaire for a nationwide survey.

BACKGROUND: We are performing a nationwide survey in a random sample of German general practitioners (GPs), orthopedists, and internists on the use of placebos and nonspecific as well as complementary treatments and their association with basic professional attitudes. In this article we explain the theoretical considerations behind the study approach and the development of the questionnaire. METHODS: Based on a systematic review of published surveys, own surveys on the topic, and on theoretical considerations we developed a preliminary version of a 4-page questionnaire that was tested for feasibility in a convenience sample of 80 participants of a general medical education event. We also performed cognitive interviews with 8 physicians to investigate whether the questions were understood adequately. RESULTS: The questions on typical placebos and complementary treatments were well understood and easy to answer for participants. Discussions about the phrasing of questions on nonspecific treatments during interview reflected the vagueness of this concept; but this did not seem to create major problems when answering the related questions. The original questions regarding basic professional attitudes partly were not understood in the manner intended. The relevant questions were modified but the interviews suggest that these issues are difficult to grasp in a quantitative survey. CONCLUSION: Our testing procedures suggest that our questionnaire is well-suited to investigate our questions with some limitations regarding the issue of basic professional attitudes.

Differential effectiveness of placebo treatments: a systematic review of migraine prophylaxis.

IMPORTANCE: When analyzing results of randomized clinical trials, the treatment with the greatest specific effect compared with its placebo control is considered to be the most effective one. Although systematic variations of improvements in placebo control groups would have important implications for the interpretation of placebo-controlled trials, the knowledge base on the subject is weak. OBJECTIVE: To investigate whether different types of placebo treatments are associated with different responses using the studies of migraine prophylaxis for this analysis. DESIGN, SETTING, AND PARTICIPANTS: We searched relevant sources through February 2012 and contacted the authors to identify randomized clinical trials on the prophylaxis of migraine with an observation period of at least 8 weeks after randomization that compared an experimental treatment with a placebo control group. We calculated pooled random-effects estimates according to the type of placebo for the proportions of treatment response. We performed meta-regression analyses to identify sources of heterogeneity. In a network meta-analysis, direct and indirect comparisons within and across trials were combined. Additional analyses were performed for continuous outcomes. EXPOSURE: Active migraine treatment and the placebo control conditions. MAIN OUTCOMES AND MEASURES: Proportion of treatment responders, defined as having an attack frequency reduction of at least 50%. Other available outcomes in order of preference included a reduction of 50% or greater in migraine days, the number of headache days, or headache score or a significant improvement as assessed by the patients or their physicians. RESULTS: Of the 102 eligible trials, 23 could not be included in the meta-analyses owing to insufficient data. Sham acupuncture (proportion of responders, 0.38 [95% CI, 0.30-0.47]) and sham surgery (0.58 [0.37-0.77]) were associated with a more pronounced reduction of migraine frequency than oral pharmacological placebos (0.22 [0.17-0.28]) and were the only significant predictors of response in placebo groups in multivariable analyses (P = .005 and P = .001, respectively). Network meta-analysis confirmed that more patients reported response in sham acupuncture groups than in oral pharmacological placebo groups (odds ratio, 1.88 [95% CI, 1.30-2.72]). Corresponding analyses for continuous outcomes showed similar findings. CONCLUSIONS AND RELEVANCE: Sham acupuncture and sham surgery are associated with higher responder ratios than oral pharmacological placebos. Clinicians who treat patients with migraine should be aware that a relevant part of the overall effect they observe in practice might be due to nonspecific effects and that the size of such effects might differ between treatment modalities.

Placebo interventions, placebo effects and clinical practice.

This article reviews the role of placebo interventions and placebo effects in clinical practice. We first describe the relevance of different perspectives among scientists, physicians and patients on what is considered a placebo intervention in clinical practice. We then summarize how placebo effects have been investigated in randomized controlled trials under the questionable premise that such effects are produced by placebo interventions. We further discuss why a shift of focus from the placebo intervention to the overall therapeutic context is necessary and what research methods can be used for the clinical investigation of the relevance of context effects. In the last part of the manuscript, we discuss why placebo or context effects are seen as positive in clinical practice when they are associated with active treatments, while placebo interventions pose major ethical and professional problems and have to be avoided.

Placebo interventions in practice: a questionnaire survey on the attitudes of patients and physicians.

BACKGROUND: Few studies have investigated whether patients and physicians differ in their attitudes regarding placebo interventions in medical practice. AIM: To compare the proportions of patients and physicians who would accept therapies that do not work through specific pharmacological or physiological action but by enhancing self-healing capacities and by exploiting contextual factors. DESIGN OF STUDY: Survey of a random sample of GPs and patients consecutively attending in primary care practices. SETTING: Four hundred and seventy-seven patients and 300 GPs from primary care practices of the Canton Zurich of Switzerland were approached. METHOD: Two questionnaires on responders' attitudes regarding non-specific therapies. RESULTS: The response rates were 87% for patients and 79% for GPs. Eighty-seven per cent of patients and 97% of GPs thought that physical complaints can get better by believing in the effectiveness of the therapy. Overall there was more support for placebo interventions among patients than among GPs, yet 90% of the physicians admitted to actively proposing treatments intended to take advantage of non-specific effects. Seventy per cent of the patients wanted to be explicitly informed when receiving a non-specific intervention, whereas physicians thought this was the case for only 33% of their patients. Fifty-four per cent of patients would be disappointed when learning they had unknowingly been treated with pure placebo ('sugar pill'), while only 44% would feel that way after treatment with impure placebo (for example, herbal medicine). CONCLUSION: GPs rather underestimate the openness of their patients to non-specific therapies. However, patients want to be appropriately informed. Developing specific professional standards could help physicians to harness the 'power of the placebo', while remaining authentic and credible.

Validity of original studies in health technology assessment reports: significance of standardized assessment and reporting.

OBJECTIVES: As health technology assessments (HTA) may have considerable impact on health-care decisions, it is essential to guarantee the expected quality of these assessments. Variations in the methods used or lack of transparency can affect the important role of HTA reports. METHODS: In our study, we analyzed the methods used in two corresponding HTA reports to assess the validity of two key papers, which were included in both reports. Also the discussions and the final conclusions of both reports were compared. RESULTS: The authors of the two HTA reports used different instruments to assess the validity of the original studies. A minor problem is differences that were found in the assessments of identical validity aspects of the included studies and in the information provided in the HTA reports. A more serious problem was found in both HTA reports which identified the weakness of the key papers and expressed these limitations in the discussions (read mainly by scientists) but not in the conclusions (read mainly by policy-makers). CONCLUSIONS: The results of this study may be important for any institution that prepares recommendations for policy-makers. In the case of HTA reports, no new checklists are necessary as the checklist offered by the INAHTA contains the needed information. It may be necessary, however, to consider an "intramural quality board," which helps the member organizations guarantee both the transparency of the original studies included in HTA reports and the transparency of the HTA report itself.