Compensating patients in trials: Perspectives from an ethical committee versus sponsor.

BACKGROUND: According to European clinical research legislation, no undue influence, including financial incentives, should be used to encourage participation in clinical trials. Financial compensation should be based on the inconvenience experienced by patients and is determined by the sponsor. OBJECTIVES: The objective of this study was to assess the adequacy of patients' financial compensation by obtaining an external ethical opinion compared to the actual compensation provided. METHODS: We randomly selected and reviewed 50 clinical drug trials, including 25 academic and 25 industry-sponsored studies. An external ethics group consisting of three members from French ethics committees, blinded to the actual compensation and the sponsor, retrospectively reviewed the study characteristics and assessed whether financial compensation was appropriate. Cohen's Kappa test measured agreement between actual compensation and the ethics group's opinion, and the McNemar test measured discrepancies. RESULTS: There was no agreement between the actual financial compensation and the ethics group's opinion (K = -.07; 95% CI = [-.16-.02]). More discrepancies were found in favour of financial compensation according to the ethics group than provided by sponsors (12 vs. 2, p = .016). The ethics group recommended financial compensation in 12 out of 50 studies (24%), which were studies with a higher number of additional visits (p = .004) and were more frequently sponsored by industry (p = .008). Sponsors only provided financial compensation in 2 out of 50 studies (4%). CONCLUSION: Patients are rarely compensated despite the perceived inconvenience. Both sponsors and ethics members struggle to determine the need for financial compensation, indicating a need for more precise recommendations for both parties.

Incidence of Asymptomatic and Symptomatic Influenza Among Healthcare Workers: A Multicenter Prospective Cohort Study.

BACKGROUND: Influenza is an important cause of viral hospital-acquired infection involving patients, healthcare workers (HCW), and visitors. The frequency of asymptomatic influenza among HCW with possible subsequent transmission is poorly described. The objective is to determine the cumulative incidence of asymptomatic, paucisymptomatic, and symptomatic influenza among HCW. METHOD: A multicenter prospective cohort study was done in 5 French university hospitals, including 289 HCW during the 2016-2017 influenza season. HCW had 3 physical examinations (time [T] 0, before epidemic onset; T.1, before epidemic peak; T.2, T.3, after epidemic peak). A blood sample was taken each time for influenza serology and a nasal swab was collected at T1 and T2 for influenza detection by polymerase chain reaction (PCR). Positive influenza was defined as either a positive influenza PCR, and/or virus-specific seroconversion against influenza A, the only circulating virus, with no vaccination record during follow-up. Symptoms were self-reported daily between T1 and T2. Cumulative incidence of influenza was stratified by clinical presentation per 100 HCW. RESULTS: Of the 289 HCW included, 278 (96%) completed the entire follow-up. Overall, 62 HCW had evidence of influenza of whom 46.8% were asymptomatic, 41.9% were paucisymptomatic, and 11.3% were symptomatic. Cumulative influenza incidence was 22.3% (95% confidence interval [CI]: 17.4%-27.2%). Cumulative incidence of asymptomatic influenza was 5.8% (95% CI: 3.3%-9.2%), 13.7% (95% CI: 9.9%-18.2%) for paucisymptomatic influenza, and 2.9% (95% CI: 1.3%-5.5%) for symptomatic influenza. CONCLUSIONS: Asymptomatic and paucisymptomatic influenza were frequent among HCW, representing 47% and 42% of the influenza burden, respectively. These findings highlight the importance of systematic implementation of infection control measures among HCW regardless of respiratory symptoms from preventing nosocomial transmission of influenza. CLINICAL TRIALS REGISTRATION: NCT02868658.

On-Demand Sildenafil as a Treatment for Raynaud Phenomenon: A Series of n-of-1 Trials.

Background: Treatment of Raynaud phenomenon (RP) with phosphodiesterase-5 inhibitors has shown moderate efficacy. Adverse effects decrease the risk-benefit profile of these drugs, and patients may not be willing to receive long-term treatment. On-demand single doses before or during exposure to cold may be a good alternative. Objective: To assess the efficacy and safety of on-demand sildenafil in RP. Design: Series of randomized, double-blind, n-of-1 trials. (ClinicalTrials.gov: NCT02050360). Setting: Outpatients at a French university hospital. Participants: Patients with primary or secondary RP. Intervention: Each trial consisted of a multiple crossover study in a single patient. Repeated blocks of 3 periods of on-demand treatment were evaluated: 1 week of placebo, 1 week of sildenafil at 40 mg per dose, and 1 week of sildenafil at 80 mg per dose, with a maximum of 2 doses daily. Measurements: Raynaud Condition Score (RCS) and frequency and daily duration of attacks. Skin blood flow in response to cooling also was assessed with laser speckle contrast imaging. Mixed-effects models were used and parameters were estimated in a Bayesian framework to determine individual and aggregated efficacy. Results: 38 patients completed 2 to 5 treatment blocks. On the basis of aggregated data, the probability that sildenafil at 40 mg or 80 mg was more effective than placebo was greater than 90% for all outcomes (except for RCS with sildenafil, 80 mg). However, the aggregated effect size was not clinically relevant. Yet, substantial heterogeneity in sildenafil's efficacy was observed among participants, with clinically relevant efficacy in some patients. Limitation: The response to sildenafil was substantially heterogeneous among patients. Conclusion: Despite a high probability that sildenafil is superior to placebo, substantial heterogeneity was observed in patient response and aggregated results did not show that on-demand sildenafil has clinically relevant efficacy. In this context, the use of n-of-1 trials may be an original and relevant approach in RP. Primary Funding Source: GIRCI (Groupement Interrégional de Recherche Clinique et d'Innovation) Auvergne Rhône-Alpes (academic funding) and Pfizer.

Population pharmacokinetics of micafungin in ICU patients with sepsis and mechanical ventilation.

OBJECTIVES: To identify the factors associated with the interindividual pharmacokinetic (PK) variability of micafungin and to evaluate the probability of reaching the previously determined PK/pharmacodynamic efficacy thresholds (AUC/MIC >5000 for non-parapsilosis Candida sp. and ≥285 for Candida parapsilosis) with the recommended 100 mg daily dose in ICU patients with sepsis and mechanical ventilation. METHODS: One hundred patients were included and 436 concentrations were available for PK analysis performed with NONMEM software. PTA was determined by Monte Carlo simulations. RESULTS: Micafungin obeyed a two-compartment model with first-order elimination from the central compartment. Mean parameter estimates (percentage interindividual variability) were 1.34 L/h (34%) for clearance (CL), 11.80 L (38%) and 7.68 L (39%) for central (Vc) and peripheral (Vp) distribution volumes, respectively, and 4.67 L/h (37%) for distribution clearance. CL, Vc and Vp increased by 14% when the albumin level was ≤25 g/L and CL decreased by 25% when SOFA score was ≥10. Body weight was related to CL, Vc and Vp by allometric models. PTA was ≥90% in Candida albicans and Candida glabrata infections, except when the MIC was ≥0.015 mg/L, and ranged between 0% and 40% for C. parapsilosis infections with MIC ≥0.5 mg/L. CONCLUSIONS: A possible increase in the dose should be evaluated for infections due to C. parapsilosis and for infections due to C. albicans and C. glabrata with MICs ≥0.015 mg/L.

Empirical Micafungin Treatment and Survival Without Invasive Fungal Infection in Adults With ICU-Acquired Sepsis, Candida Colonization, and Multiple Organ Failure: The EMPIRICUS Randomized Clinical Trial.

Importance: Although frequently used in treating intensive care unit (ICU) patients with sepsis, empirical antifungal therapy, initiated for suspected fungal infection, has not been shown to improve outcome. Objective: To determine whether empirical micafungin reduces invasive fungal infection (IFI)-free survival at day 28. Design, Setting, and Participants: Multicenter double-blind placebo-controlled study of 260 nonneutropenic, nontransplanted, critically ill patients with ICU-acquired sepsis, multiple Candida colonization, multiple organ failure, exposed to broad-spectrum antibacterial agents, and enrolled between July 2012 and February 2015 in 19 French ICUs. Interventions: Empirical treatment with micafungin (100 mg, once daily, for 14 days) (n = 131) vs placebo (n = 129). Main Outcomes and Measures: The primary end point was survival without proven IFI 28 days after randomization. Key secondary end points included new proven fungal infections, survival at day 28 and day 90, organ failure, serum (1-3)-ß-D-glucan level evolution, and incidence of ventilator-associated bacterial pneumonia. Results: Among 260 patients (mean age 63 years; 91 [35%] women), 251 (128, micafungin group; 123, placebo group) were included in the modified intent-to-treat analysis. Median values were 8 for Sequential Organ Failure Assessment (SOFA) score, 3 for number of Candida-colonized sites, and 99 pg/mL for level of (1-3)-ß-D-glucan. On day 28, there were 82 (68%) patients in the micafungin group vs 79 (60.2%) in the placebo group who were alive and IFI free (hazard ratio [HR], 1.35 [95% CI, 0.87-2.08]). Results were similar among patients with a (1-3)-ß-D-glucan level of greater than 80 pg/mL (n = 175; HR, 1.41 [95% CI, 0.85-2.33]). Day-28 IFI-free survival in patients with a high SOFA score (>8) was not significantly different when compared between the micafungin vs placebo groups (HR, 1.69 [95% CI, 0.96-2.94]). Use of empirical micafungin decreased the rate of new invasive fungal infection in 4 of 128 patients (3%) in the micafungin group vs placebo (15/123 patients [12%]) (P = .008). Conclusions and Relevance: Among nonneutropenic critically ill patients with ICU-acquired sepsis, Candida species colonization at multiple sites, and multiple organ failure, empirical treatment with micafungin, compared with placebo, did not increase fungal infection-free survival at day 28. Trial Registration: clinicaltrials.gov Idenitfier: NCT01773876.

Improved informed consent documents for biomedical research do not increase patients' understanding but reduce enrolment: a study in real settings.

AIMS: The aim was to evaluate the comprehension of participants of an improved informed consent document (ICD). METHOD: This was a randomized controlled French multicentre study performed in real conditions. Participants were adult patients undergoing screening for enrolment in biomedical research studies, who agreed to answer a validated questionnaire evaluating objective and subjective comprehension scored from 0 (no comprehension) to 100 (excellent comprehension). Patients were provided either the original ICD or an ICD modified in terms of structure and readability. The primary end point was the score of objective comprehension. The secondary end-points were the enrolment rate in the clinical study and patient characteristics associated with the score of objective comprehension. RESULTS: Four hundred and eighty-one patients were included, 241 patients in the original ICD group and 240 patients in the modified ICD group. There was no difference between the two groups for the score of objective comprehension (original ICD 72.7 (95% CI 71.3, 74.1) vs. modified ICD 72.5 (95% CI 71.0, 74.0); P = 0.81). However, the rate of enrolment in the clinical study was lower in the group who received the modified ICD (64.4% (95% CI 58.3, 70.5)) than for the original ICD (73.0% (95% CI 67.4, 78.7)) (P = 0.042). Only female gender and high educational level were associated with a better objective comprehension. CONCLUSIONS: Improving ICDs had no effect on participants' understanding, whereas the rate of enrolment was lower in this group. In attempts at improving potential participants' understanding of clinical research information, efforts and future trials should focus on other ways to improve comprehension.

Comparison of nine blood tests and transient elastography for liver fibrosis in chronic hepatitis C: the ANRS HCEP-23 study.

BACKGROUND & AIMS: Blood tests and transient elastography (Fibroscan™) have been developed as alternatives to liver biopsy. This ANRS HCEP-23 study compared the diagnostic accuracy of nine blood tests and transient elastography (Fibroscan™) to assess liver fibrosis, vs. liver biopsy, in untreated patients with chronic hepatitis C (CHC). METHODS: This was a multicentre prospective independent study in 19 French University hospitals of consecutive adult patients having simultaneous liver biopsy, biochemical blood tests (performed in a centralized laboratory) and Fibroscan™. Two experienced pathologists independently reviewed the liver biopsies (mean length=25±8.4 mm). Performance was assessed using ROC curves corrected by Obuchowski's method. RESULTS: Fibroscan™ was not interpretable in 113 (22%) patients. In the 382 patients having both blood tests and interpretable Fibroscan™, Fibroscan™ performed similarly to the best blood tests for the diagnosis of significant fibrosis and cirrhosis. Obuchowski's measure showed Fibrometer® (0.86), Fibrotest® (0.84), Hepascore® (0.84), and interpretable Fibroscan™ (0.84) to be the most accurate tests. The combination of Fibrotest®, Fibrometer®, or Hepascore® with Fibroscan™ or Apri increases the percentage of well classified patients from 70-73% to 80-83% for significant fibrosis, but for cirrhosis a combination offers no improvement. For the 436 patients having all the blood tests, AUROC's ranged from 0.82 (Fibrometer®) to 0.75 (Hyaluronate) for significant fibrosis, and from 0.89 (Fibrometer® and Hepascore®) to 0.83 (FIB-4) for cirrhosis. CONCLUSIONS: Contrarily to blood tests, performance of Fibroscan™ was reduced due to uninterpretable results. Fibrotest®, interpretable Fibroscan™, Fibrometer®, and Hepascore® perform best and similarly for diagnosis of significant fibrosis and cirrhosis.

Effectiveness of a multifaceted intervention to improve interpersonal skills of physicians in medical consultations (EPECREM): protocol for a randomised controlled trial.

INTRODUCTION: Interpersonal skills, encompassing communication and empathy, are key components of effective medical consultations. Although many organisations have implemented structured training programmes, limited evidence exists on their effectiveness in improving physician interpersonal skills. This study aims to evaluate the effectiveness of a standardised, multifaceted, interpersonal skills development programme for hospital physicians. METHODS AND ANALYSIS: This study is a prospective, randomised (with a 1:1 allocation ratio), controlled, open-label, two parallel arm, superiority trial conducted at a single university hospital. Physicians will be randomised to receive either a multifaceted training programme or no intervention. The experimental intervention combines two 4-hour training sessions, dissemination of interactive educational materials, review of video-recorded consultations and individual feedback. The primary outcome measure is the overall 4-Habits Coding Scheme score assessed by two independent raters blinded to the study arm, based on video-recorded consultations, before and after intervention. The secondary outcomes include patient satisfaction, therapeutic alliance, physician self-actualisation and the length of medical consultation. ETHICS AND DISSEMINATION: The study protocol was approved on 21 October 2020 by the CECIC Rhône-Alpes Auvergne, Clermont-Ferrand, France (IRB 5891). All participants will provide written informed consent. Efforts will be made to release the primary results within 6 to 9 months of study completion, regardless of whether they confirm or deny the research hypothesis. TRIAL REGISTRATION NUMBER: NCT04703816.

Continuous assessment of volunteers' satisfaction in clinical research through simplified questionnaires.

OBJECTIVES: In our clinical research center, a 27 multiple-choice and 3 verbatim questions satisfaction questionnaire has been used since 2008 in order to assess the satisfaction of the volunteers participating in our studies. In this work, we aimed at reducing the number of questions of this cumbersome questionnaire while exploring the same dimensions. MATERIALS AND METHODS: We used k-mean and hierarchical clustering to determine which questions provided the same information or, on the contrary, which questions were able to discriminate a satisfied volunteer from an unsatisfied volunteer. RESULTS: We were able to reduce our satisfaction questionnaire from 30 questions to 6 closed-ended and 2 open-ended questions, which will allow to save volunteers time while increasing their participation rate. CONCLUSION: This questionnaire could be used in other structures practicing clinical research, as part of their quality process.

Informed consent document improvement does not increase patients' comprehension in biomedical research.

AIMS: International guidelines on ethics in biomedical research require that the informed consent of all enrolled participants is obtained. A written document describing the research, the informed consent (IC) document, must be given to all participants by the investigator. Most IC documents are long, containing much information. The aim of the present study was to determine whether the modification of the IC document by a working group or systematic improvement in its lexicosyntactic readability can improve comprehension of the written information given to patients participating in biomedical research. METHODS: One hundred and fifty-nine patients were randomized to read one of the three versions of the IC document: unchanged document, document modified using systematic improvement of lexicosyntactic readability and document modified by a working group. RESULTS: Neither the improvement in the lexicosyntactic readability, nor the intervention of the working group significantly improved the score of objective comprehension for the subjects included in this study: it was 66.6 (95% confidence interval 64.0, 69.2) for the control group, 68.8 (66.2, 71.4) for the group with the document improved for lexicosyntactic readability and 69.2 (66.0, 72.4) for the group who read the document improved by the working group (P= 0.38). CONCLUSIONS: We failed to show that improving IC document comprehension through a lexicosyntactic approach or by a working group leads to better comprehension.

Nitrous oxide-oxygen mixture during care of bedsores and painful ulcers in the elderly: a randomized, crossover, open-label pilot study.

Bedsore and ulcer care can often be painful and no standardized analgesic method exists today for pain relief during treatment in adults and the elderly. To evaluate the analgesic efficacy of a nitrous oxide-oxygen mixture vs. morphine during painful bedsore and ulcer care in adult and elderly patients, we conducted a randomized, crossover, multicenter, prospective, open-label, pilot study. Thirty-four inpatients, aged 53-96 years (median 84 years), were recruited in Grenoble University Hospital, Annecy Hospital and Chambéry Hospital, France, from January to June 2001. Each of the 34 patients received morphine (M), nitrous oxide-oxygen mixture (E), or morphine+nitrous oxide-oxygen mixture (ME) during painful care in a crossover protocol. Treatments were changed every two days and the study duration was six days. Analgesia was evaluated before and after each care session using a behavioral scale to evaluate pain in noncommunicating adults (ECPA), a visual analog scale (VAS), a global hetero-evaluation scale (GHES), and the DOLOPLUS-2 scale. There was a significant overall difference (P<0.01) among the three treatments. On the ECPA, the average difference after and before care was +5.2+/-8.6 (M), -0.3+/-8 (E), and -0.6+/-7.4 (ME), respectively. There was a significant difference between M and E, and M and ME (each P<0.01). No difference was found between E and ME (P=0.97). There were similar significant differences in the GHES and DOLOPLUS-2 scales (all tests P<0.01). Post hoc comparisons showed a significant difference (P<0.01) between M and E, and between M and ME without any additional effect for M+E. No differences were found with regard to safety or tolerability. This pilot study demonstrates the superiority of nitrous oxide-oxygen mixture over morphine for analgesia. This experience suggests that this mixture has ease of use, rapid effect, and limited contraindications when used during painful bedsore and ulcer care in elderly patients. Furthermore, it is well accepted by these patients and by nursing staff.

[Developing patient information sheets in general practice. Proposal for a methodology]. / Elaboration de fiches d'information pour les patients en médecine générale. Proposition d'une méthodologie.

BACKGROUND: Health information is patients' wish and right. For general practitioners, it is a duty, a legal obligation and a pre-requisite in any preventive approach. Written information must complete oral information since it improves health care quality. However, in general practice, there are no patient documents which are scientifically valid, understandable and efficient in terms of communication. OBJECTIVE: To develop a method for creating patient information sheets and to experiment its feasibility through the development of 125 sheets focused on the most common clinical conditions in general practice. METHOD: Research and literature review pour the development of specifications, and creation of 125 sheets following these specifications. RESULTS: The specifications developed consist of the 10 following steps: selection of the topic and the objectives, literature review, selection of the sections, drafting, validation of the scientific contents, assessment among patients, validation of the layout, selection of the media, delivery to patients and update. Following these specifications, we developed 125 information sheets. Each of these was reviewed by several physicians and assessed with R. Flesh readability test (the established acceptable threshold value was 40). The 30 sheets associated with the lowest scores were selected and reviewed to improve their overall readability. CONCLUSION: Even though some difficulties cannot be avoided when developing patient information sheets, each physician or physician association can create its own documents following the proposed specifications and thus deliver a customized message.

Improvement of the comprehension of written information given to healthy volunteers in biomedical research: a single-blind randomized controlled study.

Writing an informed consent form (ICF) for biomedical research is a difficult task. We conducted a multicenter single-blind randomized controlled trial to identify whether a working group or the systematic improvement in lexico-syntactic readability or an association of the two could increase the comprehension of the written information given to healthy volunteers enrolled in biomedical research. Participants were randomized to read one of four versions of the ICF: unchanged ICF (A), ICF with systematic lexico-syntactic readability improvement (B), ICF modified by a working group (C), and ICF modified by the working group followed by systematic lexico-syntactic improvement (D). The primary end-point was the objective comprehension score at day 0 for each study group. The scores of objective comprehension at day 0 were statistically different between the four study groups (anovaP = 0.020). The pairwise analysis showed an improvement in the working group vs. the unchanged group (P = 0.003), and a tendency to improvement in the group who read the ICF modified using lexico-syntactic readability and in the group who read the ICF modified using the two methods (P = 0.020 and 0.027 respectively). We conducted a two-way anova to identify some characteristics of the population which could explain this score. There was a significant interaction between the type of informed consent document (ICD) and the gender. Improving the ICD in phase I biomedical research leads to better comprehension, whether the method used is systematic lexico-syntactic improvement or a review by a working group. The improvement is specifically observed in men compared with women. Conversely, while both methods diverge in their effect on lexico-syntactic readability, their association is not mandatory. We suggest that in all phase I clinical trials, the ICF be improved by either method.

[Readability and information density in biomedical research]. / Lisibilité et densité d'information en recherche biomédicale.

OBJECTIVE: This study was performed in order to compare the lexicosyntactic readability, and the information density in the informed consent forms used in biomedical research, in comparison with standard scientific texts dedicated to the general population. In addition, we studied whether there is a correlation between information readability and density. METHODS: Fifteen informed consent forms, 6 articles from "Sciences et Avenir" and 6 articles from "Sciences et Vie Junior" were analyzed. The lexicosyntactic readability was calculated using the Flesh score, and the information density using the number of information bits related to the number of words. RESULTS: The lexicosyntactic readability was lower in the informed consent forms (25, 17-32) compared with "Sciences et Avenir" (32, 29-38), but even higher in "Sciences et Vie Junior" (42, 38-57). Conversely, the information density was similar in "Sciences et Vie Junior" (0.24, [0.21-0.27]) and the informed consent forms (0.24, [0.22-0.26]), but higher in "Sciences et Avenir" (0.32, [0.26-0.38]). CONCLUSION: Informed consent forms are less readable, but paradoxically less dense than scientific papers dedicated to the general population. There is no correlation between density and readability.

French adaptation and preliminary validation of a questionnaire to evaluate understanding of informed consent documents in phase I biomedical research.

The content of informed consent documents (ICD) is a crucial element in the process of providing information to participants in biomedical research. Clear comprehension of the information, i.e. the ability to understand its meaning and its consequences, is of utmost importance. The objective of this study was to describe the different steps in the French adaptation and preliminary validation of the Qualité de Compréhension des Formulaires d'information et de consentement (QCFic) questionnaire (http://www.lyon.inserm.fr/cic-grenoble) based on the American Quality of Informed Consent (QuIC) questionnaire. Adaptation and preliminary validation of the QuIC for use in France was composed of five principal steps: translation, scientific validation, lexical validation, edition of gold-standard answers and a pilot study. Each stage was conducted by independent groups of experts, under the coordination of the study board. Thirteen questions were added and one was suppressed. Two steps were required for the scientific validation and for lexical validation, 21 modifications were proposed. Relative to gold-standard answers, the three experts gave the same answer for 24 questions and for nine other questions, two of the three gave identical answers, which were validated by the study board. Results of a pilot study showed a global QCFic score of 88.99 (84.13-90.92) and no specific commentary was made about the content of the questions, so no more modification needed to be made. A preliminary validated French questionnaire, the QCFic, is now available to evaluate the quality of an informed consent document in phase I clinical trials. It is quick and easy to use.

[Evolution of the satisfaction of subjects enrolled in clinical studies]. / Evolution de la satisfaction des usagers du CIC de Grenoble.

Within the context of a quality initiative for a clinical research unit, participants' opinions relative to participation conditions allows the identification and quantification of certain dysfunctions in the unit or more widely of the site. An initial satisfaction survey of users of the Grenoble Clinical Research Center showed that the management of volunteers by a staff dedicated to, and in an environment adapted to, clinical research protocols is associated with elevated participant satisfaction. Corrective action has been taken relative to points of dissatisfaction. We conducted a second participant survey from June 1st, 2004, to May 31st, 2005, to measure the impact of our corrective actions. Eighty five percent of the persons contacted responded, and 90.4% of completed questionnaires were valid. The global satisfaction level on a scale of ten was 8.53 +/- 1.16 in 2005 (n = 292) versus 8.61 +/- 1.16 in 2004 (n = 144) (Not Significant = NS). Scores for each dimension of care (comprising 1-6 questions each) were not statistically different between the two years. An improvement was noted for the frequency of physician visits, the communication of results, and the explication of aftercare. On the other hand, there was a moderate decline of the satisfaction score relative to concern for personal needs, the swiftness of check in at arrival and the unit's peace and quiet. Globally, the participation of a subject in clinical research in the context of a Clinical Research Center is associated with a high satisfaction score. Nevertheless, the practice of annual satisfaction surveys permits the sensitisation of staff to certain specifics points, and to observe the effect of corrective action. It serves as an important element in the context of a quality initiative.

Impact of French 'Comités de Protection des Personnes' on the readability of informed consent documents (ICD) in biomedical research: more information, but not better information.

Information is the keystone to the participation of subjects in biomedical research. Clear comprehension of the informed consent documents (ICDs) is primordial and a necessary requirement is that they are readable. While submission of a protocol to a French 'Comités de Protection des Personnes' (CPP) is a mandatory step with regard to the French legislation on biomedical research, no published data are available concerning its influence on ICDs readability. The aim of our study was to determine the impact of French CPP on the readability of ICDs, using lexico-syntactic readability indexes and ICDs from four clinical research centres and one clinical research unit. Twenty-five ICDs were analysed. The Flesch score was not modified after CPP review, while the Cordial score was significantly lower [from 4 (1-14) to 1 (1-13), P = 0.014]. The information was longer and more complex following CPP review. No protocol characteristics had any impact on the variation before and after review for either the Flesch or the Cordial indexes, nor on the number of syllables per word. Changes in the total number of words before and after review varied considerably between study centre, supporting heterogeneity of CPP review. Since August 2004, French CPP have to study the intelligibility of ICDs in addition to the scientific and ethic aspects of a research. We show that their current reviews do not increase the readability, while increasing the length of ICDs.

[Satisfaction of subjects enrolled in clinical studies]. / Evaluation de la satisfaction des participants a une recherche biomédicale.

OBJECTIVE: The Grenoble clinical research centre carried out a prospective satisfaction survey of subjects taking part in clinical studies undertaken in its buildings. MATERIALS AND METHODS: A questionnaire adapted from Grenoble teaching hospital's inpatient satisfaction survey was sent to 198 subjects. It comprised 24 items pooled in categories on which were calculated average scores. The participation rate of the survey was 82.6%. On the whole, 94.4% of the questioned subjects would accept to take part in a new study if we requested them, and 72.2% were satisfied or very satisfied with their stay; 24% had no opinion. The mean overall satisfaction score was 8.6 (95% confidence interval: 7.6-9.6) out of 10. CONCLUSION: This investigation shows that the assumption of responsibility of the subjects by specific personnel and in an adapted place, within the framework of clinical protocol of research, is associated with a high satisfaction of the subjects. However, we still have to improve the transmission of the clinical study results to the patients.

Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers.

The new anticoagulants dabigatran and rivaroxaban can be responsible for haemorrhagic complications. As for any anticoagulant, bleeding management is challenging. We aimed to test the effect of all putative haemostatic agents on the anticoagulant activity of these new drugs using thrombin generation tests. In an ex vivo study, 10 healthy white male subjects were randomised to receive rivaroxaban (20 mg) or dabigatran (150 mg) in one oral administration. After a two weeks washout period, they received the other anticoagulant. Venous blood samples were collected just before drug administration (H0) and 2 hours thereafter. Reversal of anticoagulation was tested in vitro using prothrombin complex concentrate (PCC), rFVIIa or FEIBA® at various concentrations. Rivaroxaban affects quantitative and kinetic parameters, including the endogenous thrombin potential (ETP-AUC and more pronouncedly the thrombin peak), the lag-time and time to peak. PCC strongly corrected ETP-AUC, whereas rFVIIa only modified the kinetic parameters. FEIBA corrected all parameters. Dabigatran specially affects the kinetics of thrombin generation with prolonged lag-time and time to peak. Although PCC increased ETP-AUC, only rFVIIa and FEIBA corrected the altered lag-time. For both anticoagulants, lower doses of FEIBA, corresponding to a quarter to half the dose usually used, have potential reversal profile of interest. In conclusion, some non-specific reversal agents appear to be able to reverse the anticoagulant activity of rivaroxaban or dabigatran. However, clinical evaluation is needed regarding haemorrhagic situations, and a meticulous risk-benefit evaluation regarding their use in this context is required.