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Fundamental Principles of Clinical Trials
Published in Demissie Alemayehu, Birol Emir, Michael Gaffney, Interface between Regulation and Statistics in Drug Development, 2020
Demissie Alemayehu, Birol Emir, Michael Gaffney
To ensure that the safety of study participants is protected and that the trial achieves the desired outcome, the sponsor should seek input from all applicable stakeholders, including patient advocates, key opinion leaders, and drug regulatory bodies. In addition, reference should be made to relevant guidance documents issued by regulatory agencies, especially when considering nontraditional trial designs or novel analytical approaches. In certain situations, it may also be essential to establish Data Monitoring Committees (DMCs) with a mandate to periodically assess the safety and scientific validity and integrity of clinical trials, or to make appropriate recommendations for changes in trial design or duration (Ellenberg et al. 2002; US FDA 2006).
Considerations and Bayesian Applications in Pharmaceutical Development for Rare Diseases
Published in Mani Lakshminarayanan, Fanni Natanegara, Bayesian Applications in Pharmaceutical Development, 2019
With limited subjects’ availability and sometimes a more complicated trial design, holding trial conduct to a rigorous standard25 is critical for small sample size trials, where achieving a high level of accuracy is essential. First and most important component in trial conduct is to maximize data quality. This goal requires obtaining accurate and precise measurements of key variables through the implementation of standardized data collection processes. The overarching goal is to minimize bias in data ascertainment and reduce the measurement errors of key variables in order to increase the precision of estimates. Other aspects that may aid trial conduct are training and monitoring. Use of a well-organized data monitoring committee (DMC)26,27 to implement interim analyses can enhance trial conduct and efficiency. Moreover, central training of clinic personnel on data acquisition and data entry and clinical monitoring and auditing of data collection can reduce measurement errors and variabilities.
Methods and Procedures
Published in Richard A. Jonas, Jane W. Newburger, Joseph J. Volpe, John W. Kirklin, Brain Injury and Pediatric Cardiac Surgery, 2019
Jane W. Newburger, Wypij David
The Safety and Data Monitoring Committee was comprised of eight members, each of whom is eminent in one of the specific areas at issue in the study: Pediatric Cardiology, Cardiovascular Surgery, Cardiac Anesthesia, Neurology, Developmental Psychology, and Biostatistics. Members of the Safety and Data Monitoring Committee included Julien I.E. Hoffman, M.D. (Chair); John W. Kirklin, M.D.; Barry M. Lester, Ph.D.; Robert J. Levine, M.D.; Eli M. Mizrahi, M.D.; Joseph G. Reves, M.D.; George W. Williams, Ph.D.; and Joel I. Verter, Ph.D. The function of the Safety and Data Monitoring Committee was to advise the National Heart, Lung, and Blood Institute, the Executive Committee, and the Coordinating Center on (1) final study design and protocol prior to the beginning of data collection, (2) problems with protocol implementation, (3) frequency of occurrence of adverse effects of perfusion techniques, (4) withdrawals and losses to follow-up, (5) data interpretation and ethical issues, and (6) recommendations arising from the study. The Safety and Data Monitoring Committee met initially during the Planning Phase to review the final protocol, Manual of Operations, and data forms. Thereafter, the Committee met at intervals no longer than 6 months. Members reviewed whether patient accrual was progressing as projected, the incidence of adverse effects in the two treatment groups, and results of preliminary data analyses.
New insights into ErbB3 function and therapeutic targeting in cancer
Published in Expert Review of Anticancer Therapy, 2020
Umbreen Hafeez, Adam C Parslow, Hui K Gan, Andrew M Scott
MM-111 a bispecific fusion protein consisting of two human single chain variable fragments (scFv) antibodies linked by modified human serum albumin and targeted against ErbB2 and ErbB3. It inhibits NRG activated ErbB3 signaling in ErbB2 amplified tumors by preventing the formation of ErbB2/ErbB3 heterodimers (Figure 4). In a randomized phase II trial (NCT01774581) in patients with ErbB2 expressing advanced gastroesophageal cancers, the addition of MM-111 to paclitaxel and trastuzumab resulted in significantly worse OS and PFS. Median PFS in experimental arm (paclitaxel + trastuzumab + MM111) was 9.6 weeks vs 23.3 weeks in control arm (paclitaxel + trastuzumab). Median OS was 32.1 weeks in MM111 arm vs. 56.1 weeks in the control arm. The Data Monitoring Committee closed this trial early. Toxicities reported with this bispecific antibody in combination arms were gastrointestinal side effects, anemia, renal impairment, chest pain, and stomatitis [100]. Given this disappointing result, all further studies of MM-111 were ceased, and the company has ceased further development of MM-111.
Ultra-shortwave diathermy - a new purported treatment for management of patients with COVID-19
Published in Physiotherapy Theory and Practice, 2020
Homer Peng-Ming Yu, Alice YM Jones, E Dean, E- Liisa Laakso
A well-designed case series with consenting adults using rigorous standardization of methods and outcome measures would assist in establishing the safety, feasibility, tolerability, and indicators of effectiveness of the intervention. Case studies are necessary to identify risks and potentially beneficial dosing parameters, prior to embarking on pilot-randomized controlled trials. If case studies and pilot studies suggest that USWD has some benefit, a control group of patients matched for disease severity, age, and gender must be included as part of an adequately powered and rigorously controlled randomized clinical trial to compare any purported outcome advantage, prior to implementation in people with COVID-19. A data monitoring committee should meet regularly to evaluate safety data to determine suitability to continue with the study, or the need to close the study. Before further reliable evidence is established, it is recommended that the very recently published clinical practice guideline for the management of COVID-19 by physiotherapists be adopted as these recommendations are based on the best available relevant evidence.
Ethical Considerations for Unblinding a Participant’s Assignment to Interpret a Resolved Adverse Event
Published in The American Journal of Bioethics, 2018
Benjamin S. Wilfond, Christian Morales, Liza-Marie Johnson, Holly A. Taylor
The investigator requested that the Data Monitoring Committee allow the investigator and the participant to be unblinded, such that investigator could better determine the possibility that the adverse event was related to the study drug or a natural progression of her disease. If it turned out she had only ever been on the placebo treatment, then the patient would know that this was from her lupus, and there would be less concern that other participants would be at risk. An ethics consult was requested by the DMC to consider whether the participant’s assignment in the original research study ought to be disclosed, and the impact of that on the study. The ethics consultant also was asked to address whether this adverse event necessitated breaking the blind altogether and stopping the study, and if not, how this possibly study-related event should be communicated to current and future research participants in the study, given that it indicated an uncertain but possibly significant research-related risk. ▪