Good Clinical Research Practice Research Articles

Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents III: The 2023 Geneva revision.

The set of guidelines for good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents was developed following an international consensus conference in Copenhagen in 1996 (Viby-Mogensen et al., Acta Anaesthesiol Scand 1996, 40, 59-74); the guidelines were later revised and updated following the second consensus conference in Stockholm in 2005 (Fuchs-Buder et al., Acta Anaesthesiol Scand 2007, 51, 789-808). In view of new devices and further development of monitoring technologies that emerged since then, (e.g., electromyography, three-dimensional acceleromyography, kinemyography) as well as novel compounds (e.g., sugammadex) a review and update of these recommendations became necessary. The intent of these revised guidelines is to continue to help clinical researchers to conduct high-quality work and advance the field by enhancing the standards, consistency, and comparability of clinical studies. There is growing awareness of the importance of consensus-based reporting standards in clinical trials and observational studies. Such global initiatives are necessary in order to minimize heterogeneous and inadequate data reporting and to improve clarity and comparability between different studies and study cohorts. Variations in definitions of endpoints or outcome variables can introduce confusion and difficulties in interpretation of data, but more importantly, it may preclude building of an adequate body of evidence to achieve reliable conclusions and recommendations. Clinical research in neuromuscular pharmacology and physiology is no exception.

Validity and Tolerability of Awake Calibration of an Accelerometer Neuromuscular Monitor.

Validity and Tolerability of Awake Calibration of an Accelerometer Neuromuscular Monitor.

Development of the Sm14/GLA-SE Schistosomiasis Vaccine Candidate: An Open, Non-Placebo-Controlled, Standardized-Dose Immunization Phase Ib Clinical Trial Targeting Healthy Young Women.

We report the successful closure of Phase I clinical trials, comprising Phases Ia and Ib, of the vaccine candidate against human schistosomiasis: the Schistosoma mansoni 14 kDa fatty acid-binding protein (Sm14) + glucopyranosyl lipid A in squalene emulsion (GLA-SE). Shown here are the results of Phase Ib, an open, non-placebo-controlled, standardized-dose immunization trial involving 10 healthy 18–49-year-old women. Fifty micrograms of the Sm14 protein plus 10 µg GLA-SE per dose was given intramuscularly thrice at 30-day intervals. Participants were assessed clinically, biochemically, and immunologically for up to 120 days. In preambular experiments involving vaccinated pregnant female rabbits, we did not find any toxicological features in either the offspring or mothers, and the vaccine induced adaptive immunity in the animals. In women, no adverse events were observed, and vaccination induced high titers of anti-Sm14 serum IgG antibody production. Vaccination also elicited robust cytokine responses, with increased TNFα, IFNγ, and IL-2 profiles in all vaccinees on days 90 and 120. The completion of Phase I clinical trials, which were performed to the highest standards set by Good Clinical Research Practice (GCP) standards, and preclinical data in pregnant rabbits enabled the vaccine candidate to proceed to Phase II clinical trials in endemic areas.

The Proposed 5 Subgroups of Diabetes Have Less Clinical Utility Than Models Using Simple Clinical Features: An Evaluation in Randomised Trial Data

Background: Recent research using data-driven cluster analysis has proposed five subgroups of diabetes with different diabetes progression and complication risk. We aimed to compare the clinical utility of this subgroup-based approach with an alternative strategy using specific outcome models that use routine clinical features. Methods: We identified clusters in the ADOPT (n=4,351) trial cohort using the cluster analysis reported by Ahlqvist and colleagues (Lancet Diabetes Endocrinology 2018;6:361-69). Differences between clusters in glycaemic and renal progression were evaluated, and contrasted with stratification using routine measures (age at diagnosis and baseline renal function). We tested the performance of a strategy of selecting glucose lowering therapy using clusters with one using simple clinical features (sex, BMI, age at diagnosis, baseline HbA1c) in an independent trial cohort (RECORD (n=4,447)). Findings: Clusters identified in trial data were similar to those described in the original study. Clusters showed differences in glycaemic progression, but a model with age at diagnosis alone had similar predictive ability. We found differences in CKD incidence between clusters however baseline eGFR was a better predictor of time to CKD. Clusters differed in glycaemic response, with a particular benefit for cluster 3 (insulin-resistant) with thiazolidinediones and cluster 5 (older) with sulfonylureas. However simple clinical features outperformed clusters to select therapy for individual patients. Interpretation: Precision medicine in type 2 diabetes is likely to have most clinical utility if based on an approach of using specific continuous clinical measures to predict specific outcomes, rather than stratifying patients into subgroups. Funding Statement: This work was supported by the Medical Research Council (UK) (MR/N00633X/1). Data for both ADOPT and RECORD trials were accessed through the Clinical Trial Data Transparency Portal under approval from GSK (Proposal 930). ATH is a NIHR Senior Investigator and a Wellcome Trust Senior Investigator (098395/Z/12/Z). AGJ is supported by an NIHR Clinician Scientist award (CS-2015-15- 018). JMD, ATH and BMS are supported by the NIHR Exeter Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the MRC, the NIHR or the Wellcome Trust Declaration of Interests: WEH declares a grant from IQVIA. All other authors declare no competing interests. Ethics Approval Statement: Individual-level participant data from the ADOPT and RECORD trials were accessed through the Clinical Trial Data Transparency Portal, with study approval from GlaxoSmithKline (Proposal 930). Both trials were conducted according to Good Clinical (Research) Practice guidelines and the Declaration of Helsinki (1996).

Utilisation of academic nursing competence in Europe — A survey among members of the European Academy of Nursing Science

BackgroundIn line with national and international strategies in Europe, the number of nurses with a doctoral degree has increased. The European Academy of Nursing Science (EANS) has for 18years delivered a three-year doctoral summer school for nurses. Questions have been raised in terms of how academic nurses' competencies are used and in what positions. AimTo understand the progression of nurses' academic careers following completion of the EANS Summer School and to picture how research and academic skills of the nurses are being used for research and/or other fields in nursing. MethodsWe commenced a cross-sectional survey. Former EANS Summer School participants were invited to take part in the online survey with questions developed specifically for this study. The study conformed to the principle of good clinical research practice and was reviewed and approved by the EANS Board. ResultsOf 380 former participants, 308 were eligible for participating in the survey. A total of 140 (45%) responded. The respondents originated from 21 countries. Sixty-nine percent had their main position in universities or university colleges and 25% in healthcare organisations. More than 80% were involved in research, teaching and supervision, and 26% were involved in direct client/patients care while 71% reported doing postdoctoral research where descriptive research designs dominated. The research topics covered a large variety of aspects in clinical nursing, education, development and theory. ConclusionThe EANS Summer School is an example of an effort to improve nurses' academic competencies. The survey indicates that the competencies of academically trained nurses in Europe primarily are used in universities and educational institutions. However, a large proportion is working close to and in collaboration with clinical practice. Evidence of the legacy of having undergone the EANS Summer School includes using advanced research methods and collaboration with the international EANS network.

Changes in duration of action of rocuronium following decrease in hepatic blood flow during pneumoperitoneum for laparoscopic gynaecological surgery

BackgroundA moderate insufflation pressure and deep neuromuscular blockade (NMB) have been recommended in laparoscopic surgery in consideration of the possible reduction in splanchnic perfusion due to the CO2-pneumoperitoneum. Since the liver is the major organ for rocuronium metabolism, the question of whether NMB of rocuronium would change with the variation of liver perfusion during pneumoperitoneum during laparoscopic surgery merits investigation.MethodsIn this prospective study, a total of sixty female patients scheduled for either selective laparoscopic gynaecological surgery (group laparoscopy) or laparotomy for gynaecological surgery (group control) were analyzed. Rocuronium was administered with closed-loop feedback infusion system, which was also applied to monitor NMB complied with good clinical research practice (GCRP). The onset time, clinical duration, and recovery index were measured. Hepatic blood flow was assessed by laparoscopic intraoperative ultrasonography before insufflation/after entering the abdominal cavity (T1), 5 min after insufflation in the Trendelenburg position/5 min after skin incision (T2), 15 min after insufflation in the Trendelenburg position/15 min after skin incision (T3), 30 min after insufflation in the Trendelenburg position/30 min after skin incision (T4), and 5 min after deflation/before closing the abdomen (T5) in group laparoscopy/group control respectively. The relationship between the clinical duration of rocuronium and portal venous blood flow was analyzed using linear or quadratic regression.ResultThe clinical duration and RI of rocuronium were both prolonged significantly in group laparoscopy (36.8 ± 8.3 min; 12.8 ± 5.5 min) compared to group control (29.0 ± 5.8 min; 9.8 ± 4.0 min) (P < 0.0001; P = 0.018). A significant decrease was found in portal venous blood flow during the entire pneumoperitoneum period in group laparoscopy compared with group control (P < 0.0001). There was a significant correlation between the clinical duration of rocuronium and portal venous blood flow (Y = 51.800-0.043X + (1.86E-005) X2; r2 = 0.491; P < 0.0001).ConclusionRocuronium-induced NMB during laparoscopic gynaecological surgery might be prolonged due to the decrease in portal venous blood flow induced by CO2-pneumoperitoneum. Less rocuronium could be required to achieve a desirable NMB in laparoscopic gynaecological surgery.Trial registrationChiCTR. Registry number: ChiCTR-OPN-15007524. Date of registration: December 4, 2015.

Patient safety in dialysis access: education and research.

Today, a growing activity to improve patient safety in all domains of medicine is reality. This chapter deals with patient safety research in general, but is also about strategies to implement this evidence in the daily clinical work treating patients on dialysis. Good clinical research practice has been well established for some years. In the domain of dialysis access, further basic, clinical, epidemiological and health service research will be important to further improve patient safety as a whole.

Projects not initiated by investigators

Some investigators on receiving queries from Institutional Ethics Committee (IEC), either leave the queries unanswered or withdraw their studies. The present study was conducted to assess the queries raised by two IECs after reviewing studies that were not initiated and to identify reasons for the same. Clinical Trials Registry-India (CTRI) website was checked to review approval status of these studies at other sites. A retrospective analysis of studies (submitted between January 2006 and December 2011) not initiated by investigators on receiving queries from IECs were identified. The nature of of these studies: whether sponsored (pharmaceutical industry (pharma)/government/investigator initiated), single-centre/multi-centric, and queries raised were analyzed. Status of multi-centric trials; not initiated at our site was checked at CTRI. Data was analyzed using descriptive statistics. A total of 219/2075 (11%) studies were not initiated. The proportions in pharma sponsored, investigator initiated, and government sponsored were 33%. 7.4%, and 8%, respectively. Out of a total of 1676 queries, the maximum queries were related to ethics (42%) and the least were administrative (7%). The largest proportion of queries in the pharma studies was ethical (47%), whereas majority were scientific queries (45.5%) for the investigator initiated studies. Twenty-one of the 94 multi-centric studies not initiated at our site were found registered at the CTRI and were ongoing or completed at 2-55 sites. Inability of investigators to defend studies due to lack of good clinical research practice (GCP) and research methodology training or unwillingness of sponsors to comply with local IEC requirements could be potential reasons for studies remaining uninitiated. Continued GCP training of investigators and IEC members and development of uniform ethical review standards across IECs are strongly recommended.

C1-4: Preparing for FDA Bioresearch Monitoring (BIMO) and Good Clinical Research Practice (GCP) Inspections: Fundamentals for KP Clinical Trial Sites

Background/Aims With over 300 FDA-regulated clinical trials currently open at Kaiser Permanente Northern California (KPNC), the need for a quality-based systems approach for managing clinical trials and preparing for FDA audit of these trials is paramount. Over the past five years, the FDA’s Division of Bioresearch Monitoring (BIMO) has conducted, on average, 325 to 350 inspections of medical device clinical trials each year. In 2011, FDA issued warning letters to Sponsors, IRBs, and Clinical Investigators, citing numerous GCP violations involving pharmaceutical trials. Non-compliance findings ran the gamut; from violations related to required regulatory submissions to deviations from written procedures, and failures to maintain study documents. This presentation will: (1) discuss the triggers and types of FDA audit and the procedures necessary to prepare KP investigators and sites for a successful audit, and (2) discuss the approaches to ensure GCP and audit-readiness at all times. A case study of a routine BIMO audit of a KPNC study site participating in an investigational device trial will be presented.

Sugammadex Dosing in Bariatric Patients

We read with interest the article by Llauradó et al .1focusing on the efficiency of ideal body weight–adjusted sugammadex dosing in patients undergoing bariatric surgery. The authors report a high incidence of slow responders and outliers leading to a potential risk of recurarization; they consider ideal body weight–adjusted dosing of sugammadex as unsafe. However, we feel that a significant lack of clarity in both design and methods makes it difficult to draw any conclusion from that study.First, patients in the deep-block group had a posttetanic count (PTC) ⩽ 2, thus including also those with no response to PTC. According to the good clinical research practice for pharmacodynamic studies of neuromuscular blocking agents, deep block is defined as no response to train-of-four stimulation but at least one response to the 15 PTC stimulations.2This definition is used because PTC1 is the deepest neuromuscular block that can be precisely defined; as soon as no response to PTC is detectable, neuromuscular block can no longer be quantified. Indeed, it may be close to return of the first PTC response, but it may also be much more intense, with no return to the first PTC answer for a long period. This heterogeneous group of neuromuscular blockade with no response to PTC is summarized as intense blockade.2Although the recommended dose of sugammadex to antagonize moderate or deep block is 2 and 4 mg/kg, respectively, only a few studies focused on sugammadex dosing for intense neuromuscular block, i.e. , when no response to PTC can be detected.3,4They proposed a dose between 8 and 16 mg/kg depending on the elapsed time interval between rocuronium injection and start of reversal. In the present study, however, these patients were also treated with 4 mg/kg ideal body weight sugammadex. Thus, independently of whether sugammadex dosing is based on real or ideal body weight, it was significantly underdosed in patients with no response to PTC. This may have contributed to the “outliers” observed by Llauradó et al . Second, all patients in the present study had either a PTC ⩽ 2 or a train-of-four count ≥ 2. Not 1 of the 120 patients included in this observational study has a neuromuscular block level in between, that is, corresponding to 3–15 PTC or a train-of-four count of 1. This is at least surprising and let suppose an active control rather than a real observation. Third, induction of anesthesia was not standardized; some patients received succinylcholine, whereas others did not. This, however, does not facilitate the interpretation of the results. How can the authors exclude that some of the patients in their study were “slow responders” or “outliers” because of impaired plasmacholinesterase activity leading to slow succinylcholine metabolism rather than a delayed response to sugammadex-induced reversal? Fourth, there may be a bias in the patient’s group assignment. According to the authors, the level of neuromuscular block at the end of surgery determined whether the patients were assigned to deep or moderate block group. However, the total dose of rocuronium was identical in both groups, and surgical time was slightly longer in the deep-block group. Thus, despite the same dose of rocuronium and somewhat longer surgical procedure, 43 patients had a profound block, whereas the remaining 77 patients had a shorter duration but only a moderate neuromuscular block. Interindividual variability to neuromuscular blocking agents is large and the group assignment let suppose that patients more “resistant” to rocuronium were assigned to the moderate group, whereas patients more “sensitive” to rocuronium were assigned to the deep group. Finally, if the train-of-four ratio did not reach 0.9 within 2 or 3 min, respectively, a second dose of sugammadex was given. This, however, did not allow to draw any conclusions on either the risk of recurarization or the time course of an ideal body weight–adjusted sugammadex dosing.Denis Schmartz, M.D.,*Philippe Guerci, M.D., Thomas Fuchs-Buder, M.D., Ph.D.*CHU de Nancy, Hôpital Brabois Adultes, Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu, France. d.schmartz@chu-nancy.fr

Rocuronium for rapid sequence induction in morbidly obese patients

Rocuronium for rapid sequence induction in morbidly obese patients

Train-of-Four monitoring: overestimation

Train-of-Four monitoring: overestimation

A primer for clinical researchers in the emergency department: Part I: Ethical and regulatory background

Research is an important part of emergency medicine and provides the scientific underpinning for optimal patient care. Although increasing numbers of emergency physicians participate in research activities, formal research training is currently neither part of emergency physician training in Australia nor easily available for clinicians interested in clinical research. In a two-part series, which is targeted at part-time clinical researchers in the ED, we set out and explain the key elements for conducting high-quality and ethical research. In Part I, we describe important underlying ethical principles for research in humans and explain key regulatory processes and documents pertaining to good clinical research practice in Australia. The ethics of research in children as a particularly vulnerable group will also be addressed. Part II will address important elements of research science and conduct.

Advancing evidence in preterm neonatal medicine.

Few interventions and treatments for premature infants have undergone the rigors of a randomized controlled trial (RCT), the cornerstone of evidence-based healthcare. Multiple barriers in establishing a quality evidence base for the care of preterm infants are examined including the systematic exclusion of children from drug trials, vulnerability of the infants, burden to families of the consent process for RCTs, and the lack of standard measurements and subgroup definitions that impede systematic reviews. Delays in getting evidence into practice are highlighted, including clinician knowledge of existing evidence, attitudes about the evidence, and behavior. Landmark trials are used as examples. Finally, a call for the research community to develop guidance on good clinical research practice for preterm infants is offered that will allow the synthesis of the totality of evidence.

Research governance: current knowledge among clinical researchers

To characterise the understanding of good clinical research practice (GCRP) among clinical researchers. Survey of all staff within the largest clinical research group (Critical Care and Neurosciences) of a non-government research institute affiliated with a major children's hospital, between 1 April and 31 May 2007. Staff's role and research activity; knowledge of relevant guidelines and translation into practice; GCRP training; and experience of research audits. 122 of 154 research staff (79%) responded and were divided into three categories: clinicians (45%); research students/junior researchers (32%); and researchers (23%). While 60% of researchers reported they had read (at least in part) the two key Australian documents (the National statement on ethical conduct in human research and the Australian code for the responsible conduct of research), only 36% of clinicians and 30% of students/junior researchers stated they had done so. GCRP, such as obtaining consent and document storage, was only partially understood. 13% of all respondents had experienced a research project audit and 10% had undertaken formal GCRP training. Reasons given for the lack of GCRP training included insufficient resources, no training provided, and no time. 79% of staff felt that research auditing was important and 74% would like more education in GCRP. Many clinical researchers are unaware of all the responsibilities involved in GCRP. A formal mandatory training program and GCRP auditing would be likely to improve practice.

Good Clinical Research Practice guidelines and PK‐PD modelling without twitch stabilisation

Acta Anaesthesiologica ScandinavicaVolume 52, Issue 4 p. 577-578 Letters to the Editor Good Clinical Research Practice guidelines and PK-PD modelling without twitch stabilisation D. J. Eleveld, D. J. EleveldSearch for more papers by this authorJ. H. Proost, J. H. ProostSearch for more papers by this authorA. De Haes, A. De HaesSearch for more papers by this authorJ. M. K. H. Wierda, J. M. K. H. WierdaSearch for more papers by this author D. J. Eleveld, D. J. EleveldSearch for more papers by this authorJ. H. Proost, J. H. ProostSearch for more papers by this authorA. De Haes, A. De HaesSearch for more papers by this authorJ. M. K. H. Wierda, J. M. K. H. WierdaSearch for more papers by this author First published: 13 March 2008 https://doi.org/10.1111/j.1399-6576.2007.01577.xCitations: 1 Address:Dr Douglas EleveldResearch Group for Experimental Anesthesiology and Clinical PharmacologyPO Box 30001Groningen 9700RBThe Netherlandse-mail: d.j.eleveld@anest.umcg.nl Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume52, Issue4April 2008Pages 577-578 RelatedInformation

Good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents II: the Stockholm revision

The set of guidelines for good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents, which was developed following an international consensus conference in Copenhagen, has been revised and updated following the second consensus conference in Stockholm in 2005. It is hoped that these guidelines will continue to help researchers in the field and assist the pharmaceutical industry and equipment manufacturers in enhancing the standards of the studies they sponsor.

Percutaneous tracheostomy in obese patients

Percutaneous tracheostomy in obese patients

Inhalation Induction of Anesthesia with 8% Sevoflurane in Pediatric Ambulatory Surgery: Conditions for Nasotracheal Intubation and the Effects of Dexamethasone on Postoperative Nausea and Vomiting

Backgrounds: In this study, we assessed nasotracheal intubation conditions following an inhalation induction using 8% sevoflurane and nitrous oxide with fentanyl and evaluated the effect of 0.1 mg/kg dexamethasone on postoperative nausea and vomiting (PONV) in pediatric ambulatory patients. Methods: Forty-two pediatric patients requiring nasotracheal intubation were scheduled for ambulatory procedures. Anesthesia was induced with sevoflurane 8% in a nitrous oxide and oxygen mixture, and after an end-expiratory concentration of sevoflurane of at least 4.5% had been reached, the trachea was intubated. Intubating conditions were graded as excellent, good, poor or impossible according to Good Clinical Research Practice criteria, and the incidence of adverse events during induction were also noted. Patients were randomly allocated to receive normal saline (control group, n = 20) or dexamethasone 0.1 mg/kg (dexamethasone group, n= 22) after the induction of anesthesia. Results: Nasotracheal intubation was accomplished successfully in 100% of the patients and clinically acceptable intubating conditions were obtained in 38 patients (25 excellent and 13 good). There were no significant differences between the two groups in age, sex, and operation time. In the 0 to 6 hour postoperative period, the incidences of PONV were 15% and 9% in the control and dexamethasone groups respectively, but this was not significantly different. Conclusions: Induction with sevoflurane in nitrous oxide and oxygen provided ideal conditions for nasotracheal intubation. Intraoperative dexamethasone did not significantly reduce PONV after inhalation induction and maintenance with sevoflurane during the first 6 hour postoperative period in pediatric patients.

The molecular biologist against infectious disease: Infectious diseases, in both the developing and the developed world, still pose considerable challenges to biomedical research. But science alone is clearly not sufficient to overcome the burden of disease in the world

The molecular biologist against infectious disease: Infectious diseases, in both the developing and the developed world, still pose considerable challenges to biomedical research. But science alone is clearly not sufficient to overcome the burden of disease in the world