Ethical aspects of clinical trials: the attitudes of participants in two non-cancer trials

OBJECTIVES: To investigate attitudes to clinical trials in non-cancer trial participants. DESIGN: Questionnaires at entry, during, and after participation in a clinical study. SETTING: Participants in: (i) ROC: a clinical study comparing systemic interferon-alpha-2A treatment vs. prednisolone enemas in ulcerative colitis; and (ii) MRCRUC: a clinical study investigating low-field magnetic resonance imaging as a new modality for the evaluation of patients with inflammatory bowel disease. SUBJECTS: Thirty-two patients in ROC and 47 patients in MRCRUC. OUTCOME MEASURES: Attitudes towards different aspects of clinical research. RESULTS: The majority found scientific testing of clinical methods necessary, having positive attitudes towards both participation by themselves and others. The creation of a personal moral problem by denying participation was rejected by a large majority, and still both personal and altruistic motives for participation were highly rated. An important motive for accepting inclusion was the expectation of being 'a special patient' during the trial. The presence of research ethics committees controlling clinical research had a significant positive impact on decisions to participate, and drawing lots and blinding were found problematic by only a minority. Patients valued their satisfaction with participation in the trials highly, and would almost all accept a request to participate in future trials. The most important reason for this was a feeling of receiving better care and information than expected outside a trial setting, primarily determined by the patients seeing only one physician during the trials. A pronounced wish to obtain follow-up information was expressed. CONCLUSION: Attitudes towards medical research are positive with both altruistic and nonaltruistic motives for participation. Expectations of being treated as 'a special patient' in the trial were important in accepting to participate. Seeing the same physician at control visits was an important factor for satisfaction with participation.     

Clinical trials and public trust: the geographical shift to the Asia‐Pacific region

Multiple issues surrounding the publication of clinical trials and the conduct of clinical trials, especially those that are industry‐sponsored, have raised doubts regarding the integrity of their results, and of the integrity of the medical profession. An appreciation of the historical and economic changes in the relationship between physicians and industry is crucial to the understanding of these issues. Increasingly, as healthcare professionals and centers in the Asia‐Pacific region become involved in corporate‐funded multi‐center drug trials, these ethical issues similarly come into play. It is imperative for medical leaders to take actions ensuring rights of subjects participating in these clinical trials, and to ensure the integrity of physicians and authors of clinical trials from this region of the world.     

Translation of clinical trials into clinical practice

The results of well-conducted clinical trials should be translated into practice but there is good evidence that this is not happening. There are a number of reasons for this - ignorance of doctors and patients, uncertainty as to the applicability of trials to individual patients, indolence and inefficiency on the part of practitioners, and financial considerations. More attention needs to be paid to correct all these factors.     

Attitudes towards clinical research amongst participants and nonparticipants

OBJECTIVES: To investigate attitudes to clinical research amongst cancer trial participants and nonparticipants, and to compare results with those from previous studies amongst participants in noncancer trials. DESIGN: Trial participating respondents were given three questionnaires during the clinical trials. Respondents amongst patients declining randomization answered a single questionnaire. SETTING: Participants and nonparticipants in randomized clinical cancer trials. SUBJECTS: Forty-one participants and 47 nonparticipants in cancer trials. RESULTS: Altruistic motives of physicians to conduct medical research were highly rated. Attitudes towards clinical research were positive in all groups, with nonparticipant respondents being the least positive. Eight to nine tenths found scientific testing necessary before general health service implementation. Trial participants were, as compared with nonparticipating respondents, more positive towards both participation of self and others. Both personal and altruistic motives for participation were highly rated. Primary reasons for nonparticipation were fear of 'the unknown' and/or unease with randomization. Only a minority felt a moral problem created by declining trial participation. Respondents amongst noncancer participants were more satisfied with the information given than both cancer participants and cancer nonparticipants. Negative experiences in cancer participants generally dealt with frustration related to seeing too many physicians at check-up appointments. CONCLUSION: Attitudes towards clinical research are generally positive even in cancer nonparticipants. Both personal and altruistic motives for participation were highly rated. A fear of 'the unknown' and resentments towards randomization were primary reasons to renounce participation. Seeing too many physicians at check-up appointments seems to be an important factor for negative experiences in cancer trial participants.     

Randomized clinical trials of osteoarthritis: a review

Aim: The objective of this study was to review published randomized clinical trials (RCTs) of osteoarthritis (OA) in three time periods to determine the characteristics of RCTs and the types of outcome measures used and whether any changes have occurred. Methods: We identified RCTs assessing clinical efficacy of treatments for osteoarthritis published in English in 1987/1988, 1997/1998 and 2001/2002, using MEDLINE. RCTs were then assessed for baseline disease characteristics, treatment type and outcome measures utilized. We classified outcome measures into 10 broad subgroups. Results: The number of RCTs increased with each time period (31 in 1987/1988; 36 in 1997/1998; 91 in 2001/2002). The majority of RCTs were of knee, hip or both (94% in 1987/1988, 69% in 1997/1998, 71% in 2001/2002). The median duration of RCTs for all three time periods was ≤ 3 months. In 1987/1988, nonsteroidal anit‐inflammatory drugs (NSAIDs) accounted for 65% of RCTs. In 1997/1998, NSAID/COX‐2 trials accounted for 41.7%, with glucosamine (14%) and hyaluronan (11%). In 2001/2002, 28% of RCTs were related to NSAID/COX‐2 inhibitors and 25% to complementary therapies. The median number of participants was unchanged over the three time periods. The median number of outcome measures used at all three time periods was four (range 1–8). The most commonly used outcome measures were: (i) symptoms (pain, stiffness); (ii) function; (iii) global assessment (patient, physician); and (iv) composite scores (such as Western Ontario and McMaster [WOMAC] Osteoarthritis index) in order of use. There has been significant increase in use of function and composite score as outcome measures. Conclusion: There has been a recent increase in both the number and variety of therapeutic interventions for OA. This study shows that currently a wide variety of outcome measures are used. This reinforces the importance of using standardized responder criteria, such as the OMERACT‐OARSI set of responder criteria, which incorporate pain, function and patient's global assessment.     

Enhancing the validity and utility of randomized clinical trials in addictions treatment research: I. Treatment implementation and research design

PURPOSE: This paper is the first in a series that examines methods for improving the validity and utility of randomized clinical trials (RCTs) in addictions treatment research. The specific foci of this article are treatment implementation and research design. SCOPE: We begin by considering the conditions under which the RCT provides an appropriate design choice. Sections that follow discuss methodological issues with respect to RCT structure and collaborative arrangements; treatment specification, delivery and cost; experimental design; and randomization/blinding procedures. We emphasize the importance of advance planning; treatment integrity and discriminability; treatment standardization; staff training and supervision; client compliance; maintenance of between-group equivalence across study conditions; and inclusion of appropriate comparison groups in study designs. CONCLUSIONS: Investigators are encouraged to maximize the internal validity of RCTs, but also to consider methods for enhancing external validity. The utility of addictions RCTs for advancing theory and improving clinical practice can be enhanced by investigating underlying mechanisms of action.     

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.     

Ethical analysis of vulnerabilities in cluster randomized trials involving people living with dementia in long-term care homes

Cluster randomized trials (CRT) of non-pharmacological interventions are an important means of improving the quality of care and quality of life of people living with dementia (PLWD) in long-term care (LTC) homes. PLWD in LTC homes are, however, vulnerable in manifold ways. Therefore, researchers require guidance to ensure that the rights and welfare of PLWD are protected in the course of this valuable research. In this article, we introduce a framework for identifying vulnerabilities in randomized trials and apply it to three CRTs involving PLWD in LTC homes. CRTs may render PLWD in LTC homes vulnerable to three autonomy wrongs: inadequately informed consent, inadequately voluntary consent, and invasions of privacy; two welfare wrongs: risks of therapeutic procedure exceed potential benefits, and excessive risk of non-therapeutic procedures; and one justice wrong: unjust impact of research activities on care. We then discuss appropriate, feasible additional protections that can be implemented to mitigate vulnerability while preserving the scientific validity of the CRT. Corresponding additional protections that can be feasibly implemented include capacity assessments, substitute decision-makers, assent, insulation from LTC home employees during the consent process, patient advocates, utilizing LTC home employees for data collection, stakeholder engagement, additional supervision during study procedures, using caregivers to complete questionnaires by proxy, and gatekeeper permission. Reassuringly, many of these additional protections promote, rather than imperil, the scientific validity of these trials.     

Setting up a respiratory trials unit

Clinical trials are essential in advancing our knowledge and treatment of patients with respiratory disease. Conducting well-designed clinical studies which accurately and reliably answer important clinical questions is challenging. The expertise required to deliver such studies is increasingly concentrated in clinical trials units. This article will describe some of the challenges associated with clinical studies and the methods and personnel involved in a clinical trials unit.     

The importance of randomized clinical trials and evidence-based medicine: A clinician's perspective

Clinical evaluation of therapies for patient care has evolved during the twentieth century from a variety of scientific methods. As a result of medical, political, and economic changes that occurred in the 1990s, randomized clinical trials and evidence-based methods are presently in the forefront of the physician's thinking in the decision-making process for therapeutic interventions. A new standard of patient care has emerged during this process. This report provides a clinician's viewpoint of the importance and interpretation of evidence-based methods and suggests a strategy when such evidence does not exist.     

Enhancing the validity and utility of randomized clinical trials in addictions treatment research: II. Participant samples and assessment

PURPOSE: This paper is the second in a series that describes strategies for optimizing the validity and utility of randomized clinical trials (RCTs) in addictions treatment research. Whereas the first paper focused on treatment implementation and research design, here we address issues pertaining to participant samples and assessment methods. SCOPE: With respect to participant samples, sections focus on the definition of study populations; informed consent; sample size and statistical power; recruitment and enrollment; sample retention; and participant tracking systems. Assessment topics include eligibility screening and baseline assessment; treatment-related variables; outcome measures; the frequency of follow-up evaluation; and assessment process. A final section highlights the importance of pilot testing. CONCLUSIONS: Sample recruitment and retention strategies are needed that safeguard both internal and external validity. Daily estimation assessment procedures are recommended because of their versatility for creating a range of outcome measures. Assessment batteries should include measures that permit the investigation of treatment processes and mechanisms of action.     

Off-label use of recombinant factor VIIa for treatment of haemorrhage: results from randomized clinical trials

Background  Recombinant factor VIIa (rFVIIa) is used for haemophilic patients with inhibitors against coagulation factor VIII or IX, but there is also an off-label use of rFVIIa for patients with massive bleeding. The aim of the present study was to review the randomized clinical trials (RCT) for evidence of such an approach.
Methods  In October 2007, a review of RCT involving rFVIIa for non-haemophilic indications was performed. The effect of rFVIIa on blood loss and transfusion requirements was recorded.
Results  Seventeen RCTs were identified concerning different bleeding conditions, for example, secondary to surgery, infection and stem cell transplantation. Three pilot studies reported a significant reduction in transfusion requirements and/or blood loss in the rFVIIa-treated groups, but these have not been confirmed in large randomized trials. No difference in thromboembolic complications between rFVIIa and placebotreated patients were found, except for a study in patients with intracranial haemorrhage. In the intracranial haemorrhage study, 16 out of 16 arterial thrombotic events and 19 out of 21 combined arterial and venous thromboembolic events were found in the rFVIIa-treated patients.
Conclusion  There is little evidence to support routine use of rFVIIa for patients with massive bleeding based on the results of the randomized trials performed. In patients with a normal haemostatic system, administration of rFVIIa may be associated with an increased risk of thromboembolic events.     

Enhancing the validity and utility of randomized clinical trials in addictions treatment research: III. Data processing and statistical analysis

PURPOSE: This is the third paper in a series that reviews strategies for optimizing the validity and utility of randomized clinical trials (RCTs) in addictions treatment research. Whereas the two previous papers focused on design and implementation, here we address issues pertaining to data processing and statistical analysis. SCOPE: Recommendations for enhancing data quality and utility are offered in sections on data coding and entry; and data format, structure and management. We discuss the need for preliminary data analyses that examine statistical power; patterns of attrition; between-group equivalence; and treatment integrity and discriminability. We discuss tests of treatment efficacy, as well as ancillary analyses aimed at explicating treatment processes. CONCLUSIONS: Safeguards are necessary to protect data quality, and advance planning is needed to ensure that data formats are compatible with statistical objectives. In addition to treatment efficacy, statistical analyses should evaluate study internal and external validity, and investigate the change mechanisms that underlie treatment effects.     

Effects of orlistat on blood pressure: a systematic review and meta-analysis of 27 randomized controlled clinical trials

Obesity and high blood pressure (BP) are strongly related and weight loss is mightily associated with a significant BP decrease. The aim of the present meta-analysis was to evaluate and quantify the BP decrease associated with orlistat use in randomized controlled trials. The search included PubMed-Medline, Scopus, Web of Science and Google Scholar databases by up to June 05, 2017, to identify randomized controlled trials investigating the impact of orlistat on blood pressure. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference and 95% confidence interval as summary statistics. Meta-regression and leave-one-out sensitivity analyses were performed to assess the modifiers of treatment response. Our meta-analysis included 27 randomized controlled clinical trials which comprehended overall 8150 subjects (4419 in the orlistat group and 3731 in the control one). We observed a statistically significant decreasing effect of orlistat on both systolic BP (?1.15 mmHg [?2.11, ?0.19]) and diastolic BP (?1.07 mmHg [?1.69, ?0.45]), regardless of its dosage. Significant associations were found between changes in systolic BP and diastolic BP with treatment duration but not with corresponding baseline BP values. In conclusion, Orlistat use contributes weight loss associated decrease in BP in overweight and obese subjects.     

Chromium supplementation in overweight and obesity: a systematic review and meta‐analysis of randomized clinical trials

The increased prevalence of obesity has made the use of dietary supplements as weight reducing agents highly popular, but their efficacy has not been proven. One such supplement is chromium. The purpose of this review was to evaluate the evidence for or against the efficacy of chromium supplementation in overweight and obese individuals. Electronic searches were conducted in Medline, Embase, Amed and The Cochrane Library. The bibliographies of located articles were also searched. No age, gender or language restrictions were imposed. The reporting quality of identified randomized clinical trials (RCTs) was assessed using a methodological checklist adapted from the Consolidated Standard of Reporting Trials Statement and Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. Thirty‐nine trials were identified and 20 were included. There were variations in reporting quality of included studies. A meta‐analysis of 11 studies showed a statistically significant difference in weight loss favouring chromium over placebo (mean difference (MD): ?0.50 kg; 95% confidence interval (CI): ?0.97, ?0.03). There was a high statistical heterogeneity. Adverse events included watery stools, vertigo, headaches and urticaria. The evidence from available RCTs shows that chromium supplementation generates statistically significant reductions in body weight. The magnitude of the effect is small, and the clinical relevance is uncertain. Future trials should last at least 16 weeks and greater uniformity in the measuring and assessment tools for body composition is recommended.     

Planning of clinical trials

This article focuses on steps of planning clinical trials most relevant to the question the clinician asks and how this question is properly transformed in a design and a protocol. All steps are important for the data quality or the validity of the results. A clinical trial is an experiment aimed at testing an hypothesis regarding the efficacy of a given intervention on an event, symptom or impaired quality of life in patients with a defined condition and a particular profile. As such, it should meet the fundamentals of scientific discovery that guarantee causality between the observed difference and the intervention. All the planning components are thought according to these fundamentals.     

Asthma research and randomized controlled trials: a remarkable phenomenon

Background. Time trends in the number of publications of randomized controlled trials (RCTs) in asthma research have never been evaluated. Methods. A PubMed database scan was made to identify publications in asthma research per year since 1990 until 1 January 2010, using the term ‘asthma’. The total number of publications was ascertained, as was the number when restricting the search strategy to RCTs only. Results. The total number of publications in asthma research increased from 2240 per year in 1990 to 5601 per year in 2009. The number of publications of RCTs in asthma research was 198 per year in 1990 and 233 per year in 2009. Discussion. The remarkable phenomenon of an almost unchanged number of publications of RCTs in asthma research per year in the period 1990-2009 may be explained by criticism to RCTs in asthma research. Conclusion. Despite an increase in total publications of asthma research, time trends in the number of publications of RCTs in asthma research per year show an almost unchanged number in the period 1990-2009. Evidence-based medicine within the field of asthma still faces many challenges.     

The effect of renal denervation on resistant hypertension: Meta-analysis of randomized controlled clinical trials

Background: This meta-analysis was conducted to evaluate the efficiency of renal denervation (RDN) on resistant hypertension. Methods: PubMed, EMBASE, and the Cochrane Central database were searched for eligible randomized controlled clinical trials (RCTs). Changes from the baseline of the office blood pressure and the 24-h ambulatory blood pressure were extracted. Results: Nine RCTs were included. RDN reduced the mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) by ?8.23 mm Hg (95%CI: ?16.86, 0.39) and ?3.77 mm Hg (95%CI: ?7.21, ?0.32), respectively, compared with the control. In the population with a baseline SBP more than 170 mm Hg, the RDN reduced SBP by ?17.77 mm Hg (95%CI: ?33.73, ?1.82) and DBP by ?7.51 mm Hg (95%CI: ?12.58, ?2.44). In the subgroup with no medication adjustment, the RDN reduced SBP by ?15.56 mm Hg (95%CI: ?26.33, ?4.80) and DBP by ?6.89 mm Hg (95%CI: ?9.99, ?3.79). The proportion of patients with SBP decrease of 10 mm Hg or more and the controlled office BP were not different between two groups. RDN reduced 24-h mean SBP and DBP by ?3.34 mm Hg (95%CI: ?5.30, ?1.38) and ?1.56 mm Hg (95%CI: ?2.71, ?0.41), respectively. The SBPs in the subgroups with higher baseline SBP and with no medication adjustment were significantly decreased after the HTN-3 was omitted. Conclusion: Radiofrequency RDN in a randomized manner did not have superiority compared with medical treatment at 6-month follow-up in general population. Current evidence provides insufficient evidence to support the use of such RDN strategy in the treatment of resistant hypertension. The result could not be used to extrapolate other strategies’ effect.     

Issues in extrapolating from clinical trials to clinical practice and outcomes

Extrapolation of clinical trial results to clinical practice requires consideration of whether the trial patients were representative of clinical practice, whether the trial therapy studied was optimal, whether the sample size was adequate, and the impact of adjunctive treatments.
In thrombolytic trials in particular, regional variations in attitudes to coronary angiography may have affected outcomes. Clinical trial results need to be interpreted in the light of the cost effectiveness of the application.
The assessment of clinical outcomes depends on interplay between the structure and process of care, patient factors and chance. Large standardised databases are necessary to assess clinical practice and outcomes.