Data Monitoring Committee Members Research Articles

Training the Next Generation of Data Monitoring Committee Members: An Initiative of the HeartFailure Collaboratory.

Clinical trials are vital for assessing therapeutic interventions. The associated data monitoring committees (DMCs) safeguard patient interests and enhance trial integrity, thus promoting timely, reliable evaluations of those interventions. We face an urgent need to recruit and train new DMC members. The HeartFailure Collaboratory (HFC), a multidisciplinary public-private consortium of academics, trialists, patients, industry representatives, and government agencies, is working to improve the clinical trial ecosystem. The HFC aims to improve clinical trial efficiency and quality by standardizing concepts, and to help meet the demand for experienced individuals on DMCs by creating a standardized approach to training new members. This paper discusses the HFC's training workshop, and an apprenticeship model for new DMC members. It describes opportunities and challenges DMCs face, along with common myths and best practices learned through previous experiences, with an emphasis on data confidentiality and need for quality independent statistical reporting groups.

Subacromial spacers for adults with symptomatic, irreparable rotator cuff tears: the START:REACTS novel group sequential adaptive RCT

Background A balloon spacer is a relatively simple addition to an arthroscopic debridement procedure for irreparable rotator cuff tears. Objective To evaluate the clinical and cost-effectiveness of a subacromial balloon spacer for individuals undergoing arthroscopic debridement for irreparable rotator cuff tears. Design A multicentre participant-and assessor-blinded randomised controlled trial comparing arthroscopic debridement with the InSpace® (Stryker, Kalamazoo, MI, USA) balloon to arthroscopic debridement alone, using a novel adaptive design. Pretrial simulations informed stopping boundaries for two interim analyses, using outcome data from early and late time points. Setting A total of 24 NHS centres. Participants Adults with a symptomatic, irreparable rotator cuff tear for whom conservative management had been unsuccessful. Interventions Arthroscopic debridement of the subacromial space plus insertion of the InSpace balloon compared with arthroscopic debridement alone. Main outcome measures Oxford Shoulder Score at 12 months. Results A predefined stopping boundary was met at the first interim analysis. Recruitment stopped with 117 participants randomised. We obtained primary outcome data on 114 participants (97%). The mean Oxford Shoulder Score at 12 months was 34.3 in the debridement-only group (59 participants of 61 randomised) and 30.3 in the debridement with balloon group (55 participants of 56 randomised; mean difference: −4.2; 95% confidence interval −8.2 to −0.26; p = 0.037). There was no difference in safety events. In the cost-effectiveness analysis, debridement-only dominated with a probability of <1% that the device is cost-effective. Magnetic resonance imaging substudy To evaluate the function of the balloon, we developed a dynamic magnetic resonance imaging protocol to induce humeral movement by activating the deltoid. The pandemic restricted recruitment, so the sample size was small (n = 17). Statistical methodology study We applied the novel adaptive design approach to data from seven previous randomised controlled trials. The method would have been applicable to five of these trials and would have made substantial savings in time to recruitment, without compromising the main findings of the included trials. Interim analysis interpretation study We asked potential data monitoring committee members to review interim analysis reports presented using Bayesian and frequentist frameworks. They did not always follow the stopping rules and would benefit from additional information to support decision-making. Limitations The InSpace balloon could be beneficial in a different population although we are not aware of it being widely used for other purposes. As a result of the pandemic, we were not able to complete data collection for objective measures. Conclusions In this efficient adaptive trial, clinical and cost-effectiveness favoured the control treatment without the InSpace balloon. Therefore, we do not recommend this device for the treatment of irreparable rotator cuff tears. Future work There is an urgent need for high-quality research into interventions for people with irreparable rotator cuff tears as there is a lack of good evidence for all available treatment options at present. Trial registration This trial is registered as ISRCTN17825590. Funding This project (project reference 16/61/18) was funded by the Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council and National Institute for Health and Care Research (NIHR) partnership. The trial is co-sponsored by the University of Warwick and University Hospitals Coventry and Warwickshire NHS Trust. This study will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No 3. See the NIHR Journals Library website for further project information.

The challenges of data safety monitoring for a pragmatic study: Lessons from the ADAPTABLE study

Data monitoring committees (DMCs) play a critical role in protecting the safety of participants and integrity of clinical studies. While there are well-established DMC guidelines for traditional, randomized controlled trials, the clinical trial community is still in the search for best practices in data and safety monitoring in pragmatic clinical trials. ADAPTABLE was a large, open label, pragmatic, randomized controlled trial, harnessing real world data from multiple sources and studying the comparative effectiveness of the two most common dosages of aspirin in patients with atherosclerotic cardiovascular disease. Specific issues arose in ADAPTABLE such as data quality, information latency, and protocol adherence, and these issues were both expected and unexpected features of the pragmatic study design. These issues imposed great challenges to the DMC members who were tasked to make critical decisions during the study. This article summarizes the unique experience of the ADAPTABLE DMC, including the internal debates and concerns, the concerted efforts to accomplish its mission, and the special contribution of the patient representatives. We also offer recommendations on data and safety monitoring for future pragmatic trials.

Data monitoring committee interim reports: We must get there soon!

Currently, too many Data Monitoring Committee Reports for interim review of trial progress are quite inadequate for Data Monitoring Committees to make informed decisions about risks and benefits. Immediate serious improvement is necessary for Data Monitoring Committees to meet their ethical, clinical, and scientific responsibility to trial participants, investigators, sponsors, and participating institutions. To achieve this critical goal, all parties involved in the Data Monitoring Committee process including sponsors, investigators, Data Monitoring Committee members, and the independent statistical reporting group need to have a better understanding of the structure, function, and needs of a Data Monitoring Committee and the content of a Data Monitoring Committee Report. Training modules through the Society for Clinical Trials are now available on their website to facilitate this.

Economic Evaluation for the US of Venetoclax Versus Allogeneic Hematopoietic Stem-Cell Transplantation for Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia with 17p Deletion

Background: Until the advent of targeted agents, the primary treatment for patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) with 17p deletion (del(17p)) was allogeneic hematopoietic stem cell transplantation (HSCT). Venetoclax is a targeted therapy that has been shown to effect significant progression free (PFS) and overall survival (OS) with an acceptable safety profile and the convenience of oral administration. HSCT is potentially curative but is associated with potential transplant-associated morbidity and mortality (incl. graft-versus-host disease) and relapse. Both treatments are expensive, HSCT largely up-front and venetoclax long term, with relative differences in cost of treatment and supportive care management. Considering these different efficacy, safety, and procedural profiles, we evaluated the cost-effectiveness and cost-utility of venetoclax versus HSCT in R/R CLL del(17p) from a US payer perspective.Methods: A life time horizon Markov model was constructed specifying 3 health states: PFS with embedded sub-states specifying whether patient is on or off therapy, progression, and death. Data sources to simulate the R/R CLL del(17p) patients included Stilgenbauer et al (Lancet Oncol 2016) for venetoclax and Schetelig et al (J Clin Oncol 2008) for HSCT. Kaplan-Meier PFS and OS curves were digitized, PFS and OS data extracted, and Weibull distributions fitted to these data for both venetoclax and HSCT. The wholesale acquisition cost of venetoclax was sourced from RedBook. Costs of the HSCT procedure, pre-conditioning treatment, and post-procedural side effects were estimated from published prediction equations and national private claims database. EQ-5D utility values were sourced from published literature. Disutility values for side effects were assumed same for both interventions. A discount rate of 3% was applied when survival exceeded one year. Following extrapolation to a life time horizon, the life years (LY) and quality adjusted LY (QALY) for each treatment were estimated, and the incremental LY and QALY gained with venetoclax over HSCT calculated. From the respective total treatment costs, cost differentials and the incremental cost effectiveness (ICER) and cost utility ratios (ICUR) were determined. Base case analyses were validated by probabilistic sensitivity analyses (PSA) of 2000 iterations.Results: Venetoclax prevailed in PFS over HSCT until ~190 weeks (3.7 years) when curves crossed and HSCT prevailed. Venetoclax prevailed in OS over HSCT over the full life time horizon. As shown in the Table, in the life time Markov model, compared to HSCT, venetoclax showed cost savings of -$360,995 (PSA: -$350,350) and incremental gains of 0.64 (PSA: 0.62) LY and 0.39 (PSA: 0.37) QALY. This yielded an ICER of savings of -$564,054 (PSA: -$565,080) per LY gained and an ICUR of savings of -$925,628 (PSA: -$946,891) per QALY gained.Conclusion: Against a life time horizon, venetoclax prevails in OS and for ~3.7 years in PFS over HSCT in the management of patients with R/R CLL del(17p). Yielding a cost saving by ~$565,000 if LYs gained are concerned but by ~$945,000 in the case of QALYs gained, it has the life time benefit of being clinically superior in combined OS and safety at markedly lower cost. While surviving HSCT-treated patients had improved outcomes with a slightly higher likelihood of subsequent PFS than venetoclax-treated patients, this marginal benefit is dominated by the significantly higher probability of OS for patients with venetoclax therapy. Venetoclax provides significantly greater life time clinicoeconomic value in the treatment of patients with R/R CLL del(17p) versus HSCT. [Display omitted] DisclosuresPersky:Genentech: Consultancy; MorphoSys: Other: Independent Data Monitoring Committee member ; Verastem: Consultancy; Spectrum Pharmaceuticals: Research Funding. Abraham:Janssen Oncology (Johnson & Johnson, LLC): Consultancy.

A Phase II Intergroup Trial of PET-Directed Therapy for Limited Stage Diffuse Large B-Cell Lymphoma (DLBCL): SWOG Study S1001 (NCT01359592)

A Phase II Intergroup Trial of PET-Directed Therapy for Limited Stage Diffuse Large B-Cell Lymphoma (DLBCL): SWOG Study S1001 (NCT01359592)

Economic Evaluation for the US of Ibrutinib Versus Allogeneic Hematopoietic Stem-Cell Transplantation for Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia with 17p Deletion

Background: Prior to targeted therapies, allogeneic hematopoietic stem cell transplantation (HSCT) was the primary therapy for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) with 17p deletion (del(17p)). Treatment options now include oral ibrutinib, which produces significant progression free (PFS) and overall survival (OS) with acceptable safety and the convenience of being non-invasive. Complete remission is unlikely and ibrutinib is not considered curative. HSCT has curative potential, but is associated with high upfront cost, potential transplant-related morbidity and mortality (incl. graft-versus-host disease) and potential relapse. Both treatments are expensive with relative differences in cost of treatment and supportive care management. Considering these different profiles, we performed cost-effectiveness and cost-utility analyses of ibrutinib versus HSCT in R/R CLL del(17p) from a US payer perspective.Methods: Three-year and life time horizon Markov models were constructed specifying 3 health states: PFS with embedded sub-states specifying whether patient (pt) is on or off therapy, progression, and death. Data sources to simulate the R/R CLL del(17p) pts included O'Brien et al (Lancet Oncol 2016) for ibrutinib and Schetelig et al (J Clin Oncol 2008) for HSCT. Kaplan-Meier PFS and OS curves were digitized, PFS and OS data extracted, and Weibull distributions fitted for both ibrutinib and HSCT. Cost of ibrutinib was sourced from RedBook. Costs of HSCT procedure, pre-conditioning treatment, and post-procedural side effects were estimated from published prediction equations and national claims database. EQ-5D utilities were sourced from published literature; side effect disutilities were assumed same for both interventions. A discount rate of 3% was applied when survival exceeded one year. Following extrapolation to the 3-year and life time horizons, the life years (LY) and quality adjusted LY (QALY) for each treatment were estimated, and the incremental LY and QALY gained with ibrutinib over HSCT calculated. Total treatment costs, cost differentials, and the incremental cost effectiveness (ICER) and cost utility ratios (ICUR) were determined. Base case analyses were validated by probabilistic sensitivity analyses (PSA).Results: Ibrutinib prevailed in PFS and OS over HSCT over the 3-year horizon, when curves crossed and HSCT prevailed in PFS and OS over the life time horizon, hence the separate analyses. In the 3-year Markov model, compared to HSCT, ibrutinib showed cost savings of $48,642 (PSA: $48,678), incremental gains of 0.23 (PSA: 0.22) LY and 0.20 (PSA: 0.19) QALY, yielding an ICER of savings of -$211,487 (PSA: -$221,246) per LY gained and an ICUR of savings of -$243,210 (PSA: -$256,200) per QALY gained (Table). In contrast, in the life time Markov model, ibrutinib showed an incremental cost of $25,802 (PSA: $23,317), incremental gains of 0.12 (PSA: 0.09) LY and 0.13 (PSA: 0.11) QALY, yielding an ICER of $215,016 (PSA: $259,077) per LY gained and an ICUR of $198,476 (PSA: $211,972) per QALY gained.Conclusion: Against a 3-year time horizon, ibrutinib prevails in OS and PFS over HSCT in the management of patients with R/R CLL del(17p). As it is also cost saving, it has the 3-year benefit of being clinically superior in combined efficacy and safety at lower cost; but without curative potential. Against a life time horizon, ibrutinib still prevails in OS and PFS over HSCT but less so, is no longer cost saving as treatment costs continue, and attains cost effectiveness at a willingness-to-pay threshold of ~$260,000. This is due to survival curves crossing at ~160 weeks for PFS and ~140 weeks for OS, indicating lower PFS and OS probabilities for HSTC-treated patients over the first ~3 years. In contrast to their lower survival probabilities over that time period, surviving HSCT-treated patients had a higher likelihood of subsequent PFS and OS than ibrutinib-treated patients, indicating a potential curative effect in some patients. While the long-term curative potential of HSCT merits clinical consideration for young and fit patients, the lower survival probability in the first three years of treatment should be noted and may be relevant for elderly and less fit patients. Ibrutinib provides significantly greater clinicoeconomic value over the first three years of treatment in patients with R/R CLL del(17p) versus HSCT while the benefit declines beyond 3 years. [Display omitted] DisclosuresPersky:Genentech: Consultancy; MorphoSys: Other: Independent Data Monitoring Committee member ; Verastem: Consultancy; Spectrum Pharmaceuticals: Research Funding. Abraham:Janssen Oncology (Johnson & Johnson, LLC): Consultancy.

Characteristics and Outcomes of Patients with Double-Protein Expression in Limited Stage Diffuse Large B-Cell Lymphoma (DLBCL): Analysis of SWOG Study S1001 (NCT01359592)

Characteristics and Outcomes of Patients with Double-Protein Expression in Limited Stage Diffuse Large B-Cell Lymphoma (DLBCL): Analysis of SWOG Study S1001 (NCT01359592)

Results from a Phase 1/2 Study of INCB050465, a Highly Selective and Highly Potent PI3Kδ Inhibitor, in Patients with Relapsed or Refractory B-Cell Malignancies (CITADEL-101)

Results from a Phase 1/2 Study of INCB050465, a Highly Selective and Highly Potent PI3Kδ Inhibitor, in Patients with Relapsed or Refractory B-Cell Malignancies (CITADEL-101)

Phase II/1b Trial of Ibrutinib Plus Prednisone and Rituximab Induction Followed By Venetoclax Plus Ibrutinib Maintenance in Newly Diagnosed High-Risk Chronic Lymphocytic Leukemia

Introduction: Therapy options for chronic lymphocytic leukemia (CLL) are rapidly changing with the approval of ibrutinib, an irreversible Bruton's tyrosine kinase inhibitor, and venetoclax, a Bcl2 inhibitor. In the RESONATE studies, ibrutinib showed significant improvements in overall response rates (ORR), progression-free-survival (PFS), and overall survival (OS). Nonetheless, complete response (CR) rates were only about 4%.During the first few weeks of treatment, ibrutinib will mobilize CLL cells from tissue sites into peripheral blood. Rituximab, a chimeric monoclonal CD20 antibody, when used with ibrutinib, has shown to immediately clear CLL from the blood with durable responses but with CR's of only 8%.Venetoclax is approved for relapsed or refractory CLL with 17p deletion. In a phase 2 study, at a median follow-up of 12.1 months, the ORR was ~79%, but with only 16% CR's. Amongst the 45 patients of whom minimal residual disease (MRD) was assessed, 24 were negative for MRD.In vitro studies have shown that nurse-like cells (NLCs) will protect CLL cells against spontaneous apoptosis by producing chemokines and interleukins such as SDF1, suggestive of a mechanism of ibrutinib resistance. SDF1 was shown to bind to its receptor CXCR4 located on CLL cells and activate a signal transduction pathway that would reduce spontaneous apoptosis. Dexamethasone was found to decrease NLC viability. This suggests that a combined therapy of ibrutinib plus steroids along with rituximab and venetoclax may be necessary to achieve deeper CR's in high-risk CLL.In addition, CLL with overexpression of exosome miR-155 is associated with a poor response to chemoimmunotherapy. In prior preclinical studies, exosome miR-150 and miR-155 have been shown to increase with BCR activation via α-IgM stimulation. We hope that via next generation microRNA sequencing from our patients' CLL plasma cells we will observe a decrease in the levels of exosome miR-150 and miR-155 in response to inhibition of BCR-pathway by ibrutinib as seen in preclinical studies.Methods: Patients with newly diagnosed high-risk CLL per FISH studies will be enrolled. Ibrutinib will be administered orally 420 mg daily, rituximab will be dosed at 375 mg/m2 intravenously on days 1, 8, 15, 22 of cycle 1 and on day 1 for cycle 2-6. Prednisone will be administered as 10 mg one week on, one week off per cycle. Each cycle will last 28 days. After 6 cycles, if patients have MRD, venetoclax will be added in on a weekly schedule with weekly ramp up from 20mg to 50mg, 100mg, and 200mg for a total duration of 6 months plus ibrutinib at 420mg as maintenance until disease progression or drug intolerance. There is the option to reintroduce venetoclax, prednisone, or rituximab if patients progress during maintenance.Results: The primary objectives of this study are to evaluate safety and MRD negative CR rates based on IWG-CLL criteria. For the evaluation of safety, the proportions of the 29 subjects with any adverse events, each specific adverse event, and study-related adverse events will be reported along with the 95% confidence intervals. The proportion of the 29 subjects who demonstrate a MRD negative CR will be reported along with the 95% confidence interval. A sample size of 29 will produce a two-sided 95% confidence interval with a width≤ 0.380.In addition, Kaplan-Meier method will be performed to evaluate time to first MRD negativity (TTMN), time to first relapse (TTFR), PFS and OS, respectively. Based on the Kaplan-Meier curve, the median time to TTMN, TTFR, PFS and OS, respectively, will be reported along with the 95% confidence interval if it exists. Correlation coefficients will be derived to describe the relationship between continuous endpoints and Kendall's tau will be derived to describe the relationship between categorical endpoints.There is no planned interim analysis for the CR rate. However, at any time point if an excessive number of adverse events are observed, the study will be terminated.Conclusion: In this Phase IB/II clinical trial, we seek to observe prolonged response rates of ibrutinib via inhibiting NLC's by adding prednisone. Also, we anticipate that rituximab will further amplify the CR's. For maintenance therapy, we hope that by combining venetoclax with ibrutinib in high-risk CLL patients who were unable to achieve negative MRD's, we will be able to induce deeper remissions. [Display omitted] DisclosuresPersky:Genentech: Consultancy; MorphoSys: Other: Independent Data Monitoring Committee member ; Verastem: Consultancy; Spectrum Pharmaceuticals: Research Funding.

A joint industry-sponsored data monitoring committee model for observational, retrospective drug safety studies in the real-world setting.

PurposeTo share better practice in establishing data monitoring committees (DMCs) for observational, retrospective safety studies with joint‐industry sponsorship.MethodsA DMC model was created to monitor data from an observational, retrospective, post‐authorization safety study investigating risk of medullary thyroid cancer in patients treated with long‐acting glucagon‐like peptide‐1 receptor agonists (LA GLP‐1RAs) (NCT01511393). Sponsors reviewed regulatory guidelines, best practice and sponsors' standard operation procedures on DMCs. Discussions were held within the four‐member consortium, assessing applicability to observational, retrospective, real‐world studies. A DMC charter was drafted based on a sponsor‐proposed, adapted DMC model. Thereafter, a kick‐off meeting between sponsors and DMC members was held to receive DMC input and finalize the charter.ResultsDue to this study's observational, retrospective nature, assuring participant safety – central for traditional explanatory clinical trial models – was not applicable to our DMC model. The overall strategy and key indication for our real‐world model included preserving study integrity and credibility. Therefore, DMC member independence and their contribution of expert knowledge were essential. To ensure between‐sponsor data confidentiality, all study committees/corporations and sponsors, besides the DMC, received blinded data only (adapted to refer to data blinding that revealed the specific marketed LA GLP‐1RA/sponsor). Communication and blinding/unblinding of these data were facilitated by the contract research organization, which also provided crucial operational oversight.ConclusionsTo our knowledge, we have established the first DMC model for joint industry‐sponsored, observational, retrospective safety studies. This model could serve as a precedent for others performing similar post‐marketing, joint industry‐sponsored pharmacovigilance activities.

791P - Impact of pembrolizumab (pembro) versus paclitaxel on health-related quality of life (HRQoL) in patients with advanced gastric or gastroesophageal junction (GEJ) cancer that has progressed after first-line chemotherapy (KEYNOTE-061)

791P - Impact of pembrolizumab (pembro) versus paclitaxel on health-related quality of life (HRQoL) in patients with advanced gastric or gastroesophageal junction (GEJ) cancer that has progressed after first-line chemotherapy (KEYNOTE-061)

"You have to keep your nerve on a DMC." Challenges for Data Monitoring Committees in neonatal intensive care trials: Qualitative accounts from the BRACELET Study.

BackgroundData Monitoring Committees (DMCs) are essential to the good conduct of many trials. Typically they comprise a small expert group which monitors safety, efficacy, progress and early outcome data as trials recruit. DMCs can recommend protocol revisions and early stopping of a trial. As DMC meetings usually consider unblinded interim data confidentially, their deliberations are seldom exposed to research scrutiny. Although there have been some case studies from trials from mixed specialties which offer insights into some of the common issues faced by DMCs, we have, however, little empirical information about the challenges faced within specific clinical settings.MethodsIn-depth interviews with participants in the BRACELET Study on death and bereavement in neonatal intensive care trials produced qualitative accounts of experiences and views of a subgroup of 18 DMC members. These interviews explored views of DMC members in relation to the clinical context of neonatal intensive care and the conduct of neonatal intensive care trials.ResultsInterviewees felt that an understanding of both the neonatal intensive care setting and population was crucial in a DMC. They considered the neonatal intensive care research population especially vulnerable, and that outcomes that included both death and severe disability raised particular challenges rarely faced in other settings. In exploring these key outcomes they were mindful of the need to meet high scientific standards and the needs of babies in the trials and their families. DMC members discussed particular difficulties around the composite outcome of death and severe disability, especially when mortality data were available long before data on longer term disability. While statistical stopping guidance is helpful, DMC members described decisions about stopping, revising or continuing a trial being informed by a wider set of considerations and discussions than a pre-set p value. These included potentially competing needs of current trial participants and future patients, and reflections on the nature of benefit and harm. Given their cognisance of the potential impact and consequences of the decisions made by DMCs in this setting of life, death, and disability, interviewees commonly used the imagery of bravery, and described DMCs either holding or losing their nerve.ConclusionsDMCs for trials in other fields may also face difficult ethical trade-offs in monitoring composite outcomes. The experience from this sample of DMC members suggest that for neonatal intensive care trials there are some very specific challenges seldom faced elsewhere. The vulnerability of the population, and the different timescales for essential data becoming available to inform decisions, presented particular challenges. We suggest that it is important to consider the challenges raised in other settings to better understand the complex work of these committees and to prepare future generations of DMC members.

Data Monitoring Committees: Current issues

Maintaining confidentiality of emerging data and ensuring the independence of Data Monitoring Committees are best practices of considerable importance to the ability of these committees to achieve their mission of safeguarding the interests of study participants and enhancing the integrity and credibility of clinical trials. Even with the wide recognition of these principles, there are circumstances where confidentiality issues remain challenging, controversial or inconsistently addressed. First, consider settings where a clinical trial's interim data could provide the evidence regulatory authorities require for decisions about marketing approval, yet where such a trial would be continued post-approval to provide more definitive evidence about principal safety and/or efficacy outcomes. In such settings, data informative about the longer term objectives of the trial should remain confidential until pre-specified criteria for trial completion have been met. Second, for those other than Data Monitoring Committee members, access to safety and efficacy outcomes during trial conduct, even when presented as data pooled across treatment arms, should be on a limited "need to know" basis relating to the ability to carry out ethical or scientific responsibilities in the conduct of the trial. Third, Data Monitoring Committee members should have access to unblinded efficacy and safety data throughout the trial to enable timely and informed judgments about risks and benefits. Fourth, it should be recognized that a mediator potentially could be useful in rare settings where the Data Monitoring Committee would have serious ethical or scientific concerns about the sponsor's dissemination or lack of dissemination of information. Data Monitoring Committee Contract Agreements, Indemnification Agreements and Charters should be developed in a manner to protect Data Monitoring Committee members and their independence, in order to enhance the Data Monitoring Committee's ability to effectively address their mission.

How to construct an optimal interim report: What the data monitoring committee does and doesn't need to know.

Data monitoring committees for randomized clinical trials have the responsibility of safeguarding interests of trial participants. To do so, the data monitoring committee must receive reports on safety and efficacy to assess risk/benefit and on trial conduct to ensure that the study can achieve its goals. This article outlines the key components of reports to the data monitoring committee and the important role of the unblinded statistician in preparing those reports. Most data monitoring committee meetings include open and closed sessions. For each session, there is a report of interim results. The open session is attended by the sponsor and lead investigators, including the statistician(s) responsible for the trial design. These investigators are blinded to the interim treatment comparisons. The closed session is attended by the data monitoring committee members and by the statistician(s) who prepared the closed report. These individuals are unblinded to interim treatment comparisons and therefore are not involved in study design changes. The optimal content of data monitoring committee reports and qualifications of the unblinded statistician(s) are discussed. Open reports should include responses to data monitoring committee recommendations, a synopsis of the protocol, a review of the protocol history and amendments, and information on enrollment, baseline characteristics, completeness of follow-up, and data quality. The open report is also a vehicle through which the sponsor and investigators should inform the data monitoring committee of relevant external information. Data in the open report are pooled over the treatment groups. The open report should not include data summaries by treatment group. The closed report should include a written summary with references to key tables and figures and methods used to prepare them. Tables and figures should summarize baseline characteristics, follow-up completeness, treatment adherence, and major safety and efficacy outcomes by treatment group. Text summaries should accompany the tables and figures. The data monitoring committee monitoring history (e.g. treatment differences at previous meetings) should be summarized. The unblinded statistician preparing the closed report should be familiar with the protocol and data collection plan and be capable of customizing the report to the current stage of the trial. This includes anticipating questions that may arise during the data monitoring committee review and pro-actively including data summaries to address these questions. There is considerable variation in the quality of open and closed data monitoring committee reports. Open and closed data monitoring committee reports should be concise, up to date, and informative. To achieve this, unblinded statisticians responsible for preparing closed data monitoring committee reports should be familiar with the statistical methods, the trial protocol, and the data collection plan. They should be capable of anticipating questions from the data monitoring committee and responding to requests for additional analyses.

Medical Comorbidities Assessed By CIRS Negatively Impact Survival in the Era of Targeted Therapies in CLL: A Multicenter Retrospective Analysis

Introduction: The majority of patients with chronic lymphocytic leukemia (CLL) present with comorbidities, commensurate with the median age at diagnosis of 71 years. The Cumulative Illness Rating Scale (CIRS) is a widely used index which has been incorporated into clinical research in CLL. CIRS consists of 14 categories related to different body systems and scores the severity of each condition from 0-4. We have previously reported in a single-center study that CIRS predicted outcomes in patients with CLL treated with chemo-immunotherapy (CIT). However, to date it is not yet known how comorbidities impact outcomes in the era of novel agents. We tested a hypothesis that CIRS and severe organ dysfunction would retain prognostic significance.Methods: We conducted a retrospective analysis of patients with CLL who underwent treatment at three academic medical centers between 2000 and 2016. CIRS score was calculated as in Salvi et al, 2008. Overall survival (OS) and progression-free survival (PFS) were assessed by Cox proportional hazards models adjusting for performance status (PS), age group, and chemotherapy regimen. Survival analysis in patients treated with ibrutinib was adjusted for age, PS, Rai stage, del17p and prior treatment. In addition, the impact of severe organ dysfunction (CIRS-3+, i.e. CIRS score ≥3 in single organ system) was assessed.Results: Median age in patients receiving CIT was 65 years (N=233). The most common comorbidities were hypertension, endocrine (e.g. diabetes mellitus) and vascular (e.g. deep vein thrombosis). Fludarabine-Rituximab (N=61), Fludarabine-Cyclophosphamide-Rituximab (N=67), Rituximab-Cyclophosphamide-Vincristine-Prednisone (N=35), Bendamustine-Rituximab (N=38) and chlorambucil (N=47) were the most commonly used regimens. 79.5% of treatments were administered in a frontline setting. Average total CIRS was 6.6 and 47% had CIRS-3+. Median OS among all patients receiving CIT was 112 months (95% CI: 105 - 128 months). CIRS≥7 and CIRS3+ were associated with inferior OS compared to patients without significant comorbidities (87, 92 and 129 months, respectively, p<0.05). In multivariate analysis, OS and PFS both decreased with each increase in total CIRS by one point (HR=1.09; p=0.006 and HR=1.05; p = 0.02), while CIRS-3+ was associated with inferior OS among patients treated with CIT (HR=1.50, p=0.01).In patients treated with ibrutinib the median age was 71 years (N=83), which was significantly older than in the CIT cohort (p<0.001). The most common comorbidities were musculoskeletal (e.g., osteoarthritis), and gastrointestinal (e.g., acid reflux). Median follow up was 12 months (range, 1-39 months). Contrary to patients receiving CIT, 86% of patients had relapsed/refractory disease, with a median of 2 prior treatments (range 0-6). 35% had received prior fludarabine and 54% had received an alkylating agent. Average CIRS was 8.6 and 67% had CIRS-3+. Patients treated with ibrutinib who required dose reductions had higher CIRS (mean score 11.6 vs 7.6; p<0.0003). CIRS-3+ was also associated with dose reduction (RR=4.6, p=0.01). In multivariable analysis, time to treatment failure, defined as ibrutinib discontinuation due to either disease progression or intolerable side effects, shortened with each increase in total CIRS score by one point (HR=1.23; p<0.001). CIRS-3+ was similarly associated with increased risk of treatment failure in multivariable analysis (HR=3.80; p=0.02). In univariate analysis comparing low vs high CIRS (CIRS <7 vs CIRS≥7), median time to treatment failure was 37 vs 23 months (p=0.01; Fig. 1A). OS at 24 months was 100% vs 79% (p=0.02; Fig 1B).Conclusion: In this multicenter retrospective analysis we show that CIRS has prognostic significance in patients with CLL treated with either CIT or ibrutinib, where increased comorbidities correlate with shortened progression-free and overall survival. CIRS appears to carry prognostic value in both upfront and relapsed settings, including patients whose disease can be salvaged with ibrutinib. Larger prospective studies of patients with lymphoid malignancies who have comorbidities are necessary to better define the prognostic value of CIRS in the era of targeted agents and determine the optimal approach to therapy of such patients. [Display omitted] DisclosuresPersky:Genentech: Consultancy; MorphoSys: Other: Independent Data Monitoring Committee member ; Verastem: Consultancy; Spectrum Pharmaceuticals: Research Funding.

Recommendations for data monitoring committees from the Clinical Trials Transformation Initiative.

Background/aimsUse of data monitoring committees to oversee clinical trials was first proposed nearly 50 years ago. Since then, data monitoring committee use in clinical trials has increased and evolved. Nonetheless, there are no well-defined criteria for determining the need for a data monitoring committee, and considerable variability exists in data monitoring committee composition and conduct. To understand and describe the role and function of data monitoring committees, and establish best practices for data monitoring committee trial oversight, the Clinical Trials Transformation Initiative—a public–private partnership to improve clinical trials—launched a multi-stakeholder project.MethodsThe data monitoring committee project team included 16 individuals charged with (1) clarifying the purpose of data monitoring committees, (2) identifying best practices for independent data monitoring committee conduct, (3) describing effective communication practices, and (4) developing strategies for training data monitoring committee members. Evidence gathering included a survey, a series of focus group discussions, and a 2-day expert meeting aimed at achieving consensus opinions that form the foundation of our data monitoring committee recommendations.ResultsWe define the role of the data monitoring committee as an advisor to the research sponsor on whether to continue, modify, or terminate a trial based on periodic assessment of trial data. Data monitoring committees should remain independent from the sponsor and be composed of members with no relevant conflicts of interest. Representation on a data monitoring committee generally should include at least one clinician with expertise in the therapeutic area being studied, a biostatistician, and a designated chairperson who has experience with clinical trials and data monitoring. Data monitoring committee meetings are held periodically to evaluate the unmasked data from ongoing trials, but the content and conduct of meetings may vary depending on specific goals or topics for deliberation. To guide data monitoring committee conduct and communication plans, a charter consistent with the protocol’s research design and statistical analysis plan should be developed and agreed upon by the sponsor and the data monitoring committee prior to patient enrollment. We recommend concise and flexible charters that explain roles, responsibilities, operational issues, and how data monitoring committee recommendations are generated and communicated. The demand for data monitoring committee members appears to exceed the current pool of qualified individuals. To prepare a new generation of trained data monitoring committee members, we encourage a combination of didactic educational programs, practical experience, and skill development through apprenticeships and mentoring by experienced data monitoring committee members.ConclusionOur recommendations address data monitoring committee use, conduct, communication practices, and member preparation and training. Furthermore recommendations form the foundation for ongoing efforts to improve clinical trial oversight and enhance the safety and integrity of clinical research. These recommendations serve as a call to action for implementation of best practices that benefit study participants, study sponsors, and society.

Independent academic Data Monitoring Committees for clinical trials in cardiovascular and cardiometabolic diseases

Data Monitoring Committees (DMCs) play a crucial role in the conducting of clinical trials to ensure the safety of study participants and to maintain a trial's scientific integrity. Generally accepted standards exist for DMC composition and operational conduct. However, some relevant issues are not specifically addressed in current guidance documents, resulting in uncertainties regarding optimal approaches for communication between the DMC, steering committee, and sponsors, release of information, and liability protection for DMC members. The Heart Failure Association (HFA) of the European Society of Cardiology (ESC), in collaboration with the Clinical Trials Unit of the European Heart Agency (EHA) of the ESC convened a meeting of international experts in DMCs for cardiovascular and cardiometabolic clinical trials to identify specific issues and develop steps to resolve challenges faced by DMCs.The main recommendations from the meeting relate to methodological consistency, independence, managing conflicts of interest, liability protection, and training of future DMC members. This paper summarizes the key outcomes from this expert meeting, and describes the core set of activities that might be further developed and ultimately implemented by the ESC, HFA, and other interested ESC constituent bodies. The HFA will continue to work with stakeholders in cardiovascular and cardiometabolic clinical research to promote these goals.

Data monitoring committees: Promoting best practices to address emerging challenges.

Data monitoring committees are responsible for safeguarding the interests of study participants and assuring the integrity and credibility of clinical trials. The independence of data monitoring committees from sponsors and investigators is essential in achieving this mission. Creative approaches are needed to address ongoing and emerging challenges that potentially threaten data monitoring committees' independence and effectiveness. An expert panel of representatives from academia, industry and government sponsors, and regulatory agencies discussed these challenges and proposed best practices and operating principles for effective functioning of contemporary data monitoring committees. Prospective data monitoring committee members need better training. Options could include didactic instruction as well as apprenticeships to provide real-world experience. Data monitoring committee members should be protected against legal liability arising from their service. While avoiding breaches in confidentiality of interim data remains a high priority, data monitoring committees should have access to unblinded efficacy and safety data throughout the trial to enable informed judgments about risks and benefits. Because overly rigid procedures can compromise their independence, data monitoring committees should have the flexibility necessary to best fulfill their responsibilities. Data monitoring committee charters should articulate principles that guide the data monitoring committee process rather than list a rigid set of requirements. Data monitoring committees should develop their recommendations by consensus rather than through voting processes. The format for the meetings of the data monitoring committee should maintain the committee's independence and clearly establish the leadership of the data monitoring committee chair. The independent statistical group at the Statistical Data Analysis Center should have sufficient depth of knowledge about the study at hand and experience with trials in general to ensure that the data monitoring committee has access to timely, reliable, and readily interpretable insights about emerging evidence in the clinical trial. Contracts engaging data monitoring committee members for industry-sponsored trials should have language customized to the unique responsibilities of data monitoring committee members rather than use language appropriate to consultants for product development. Regulatory scientists would benefit from experiencing data monitoring committee service that does not conflict with their regulatory responsibilities.

Understanding the functions and operations of data monitoring committees: Survey and focus group findings.

The use of data monitoring committees in the conduct of clinical trials has increased and evolved, but there is a lack of published information on when data monitoring committees are needed and utilized, the acceptable range of data monitoring committee practices, and appropriate qualifications of data monitoring committee members. To gain a better understanding of data monitoring committee operations and areas for improvement, the Clinical Trials Transformation Initiative conducted a survey and set of focus groups. A total of 143 respondents completed the online survey: 76 data monitoring committee members, 52 sponsors involved with organization of data monitoring committees, and 15 statistical data analysis center representatives. There were 42 focus group participants, including data monitoring committee members; patients and/or patient advocate data monitoring committee members; institutional review board and US Food and Drug Administration representatives; industry, government, and non-profit sponsors; and statistical data analysis center representatives. Participants indicated that the primary responsibility of a data monitoring committee is to be an independent advisory body representing the interests of trial participants by assessing the risk and benefit ratio in ongoing trials. They noted that data monitoring committees must have access to unmasked data in order to perform this role. No clear consensus emerged regarding specific criteria for requiring a data monitoring committee for a given trial, and some participants felt data monitoring committees may be overused. Respondents offered suggestions for the data monitoring committee charter and communications with sponsors, institutional review boards, and regulators. Overall, data monitoring committee members reported that they are able to function independently and their recommendations are almost always accepted by the sponsor. Participants indicated that there are no standards or guidelines pertaining to qualifications of data monitoring committee members. Furthermore, only 8% (6/72) of data monitoring committee member survey respondents received any formal training, and 94% (68/72) were not aware of any training programs. Findings from the survey and focus groups provide a better understanding of contemporary data monitoring committee operations and insights regarding challenges and best practices. Overall, it was clear that increased training will be needed to prepare the next generation of qualified data monitoring committee members to meet the growing demand. These findings can be used by Clinical Trials Transformation Initiative and others to develop recommendations and tools to improve data monitoring committee operations and the overall quality of trial oversight.