Robust Design and Analysis of Clinical Trials With Non-proportional Hazards: A Straw Man Guidance from a Cross-pharma Working Group

Background Historically, four divisions of the National Institute of Allergy and Infectious Diseases (NIAID) that manage clinical trials and oversee data and safety monitoring have operated fairly autonomously with respect to their approaches to Data and Safety Monitoring Board (DSMB) operations. We recognized the need for a revised policy on DSMB operations in an effort to encourage greater harmonization of procedures across the four divisions. Purpose The purpose of this article is to describe the considerations that motivated the development of the new policy, summarize current DSMB policies and ongoing harmonization efforts across the four divisions, and offer some recommendations for DSMB operations in the hope that other organizations may benefit from our experience. Methods From 2005 to 2009, a working group undertook a review of DSMB responsibilities, policies, and operations. We analyzed and summarized the final policy document that the working group produced, gathered data describing current DSMB activities, and developed a tabular, cross-sectional overview highlighting how divisions are harmonizing their DSMB operations. Results In 2010, there were 44 DSMBs in NIAID monitoring 169 protocols, and those DSMBs conducted 209 reviews of the protocols. Review and analysis of DSMB practices across the four divisions have led to recommendations for efficient and successful DSMB operations: adopt an inclusive approach, whereby the trial investigators assist in the process of forming and utilizing DSMBs; structures other than DSMBs can often provide many of the features of DSMBs but with greater flexibility in membership, access to interim data, and scheduling; the trial protocol should specify what safety and other concerns should trigger a DSMB review and what data should be included in prespecified reviews; present data in thoughtful and user-friendly ways that answer specific questions; allow sufficient time to plan for working with the DSMB. Limitations We recognize that NIAID’s specific circumstances and DSMB policy may not apply to the operation of DSMBs in every organization. Nevertheless, we believe that useful lessons can be learned from our experiences and efforts toward harmonization. Conclusions Homogeneity in DSMB operations and management has appeal as a matter of organizational policy and efficiency. Some limited flexibility, as long as it honors fundamental principles of independence, confidentiality of interim trial results, and clear lines of reporting and approval, may be appropriate on occasion. NIAID’s 2009 institute-level policy established a collective understanding of the important contribution that DSMBs make to the responsible conduct of clinical trials. Thinking will continue to evolve, leading to further policy refinements and the continued assurance of patient safety in our clinical trials.

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Achieving Consensus on Total Joint Replacement Trial Outcome Reporting Using the OMERACT Filter: Endorsement of the Final Core Domain Set for Total Hip and Total Knee Replacement Trials for Endstage Arthritis

The Journal of Rheumatology ◽

10.3899/jrheum.161113 ◽

2017 ◽

Vol 44 (11) ◽

pp. 1723-1726 ◽

Cited By ~ 23

Author(s):

Jasvinder A. Singh ◽

Michelle M. Dowsey ◽

Michael Dohm ◽

Susan M. Goodman ◽

Amye L. Leong ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Total Knee Replacement ◽

Knee Replacement ◽

Joint Replacement ◽

Working Group ◽

Total Joint Replacement ◽

Core Domain ◽

Total Knee ◽

Core Domain Set

Objective.Discussion and endorsement of the OMERACT total joint replacement (TJR) core domain set for total hip replacement (THR) and total knee replacement (TKR) for endstage arthritis; and next steps for selection of instruments.Methods.The OMERACT TJR working group met at the 2016 meeting at Whistler, British Columbia, Canada. We summarized the previous systematic reviews, the preliminary OMERACT TJR core domain set and results from previous surveys. We discussed preliminary core domains for TJR clinical trials, made modifications, and identified challenges with domain measurement.Results.Working group participants (n = 26) reviewed, clarified, and endorsed each of the inner and middle circle domains and added a range of motion domain to the research agenda. TJR were limited to THR and TKR but included all endstage hip and knee arthritis refractory to medical treatment. Participants overwhelmingly endorsed identification and evaluation of top instruments mapping to the core domains (100%) and use of subscales of validated multidimensional instruments to measure core domains for the TJR clinical trial core measurement set (92%).Conclusion.An OMERACT core domain set for hip/knee TJR trials has been defined and we are selecting instruments to develop the TJR clinical trial core measurement set to serve as a common foundation for harmonizing measures in TJR clinical trials.

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CTIM-10. REPRODUCIBILITY OF CLINICAL TRIALS USING CMV-TARGETED DENDRITIC CELL VACCINES IN PATIENTS WITH GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noab196.202 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi51-vi51

Author(s):

Kristen Batich ◽

Duane Mitchell ◽

Patrick Healy ◽

James Herndon ◽

Gloria Broadwater ◽

...

Keyword(s):

Clinical Trials ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Cox Proportional Hazards ◽

Recurrent Glioblastoma ◽

Cox Proportional Hazards Model ◽

Total N ◽

Dc Vaccine ◽

Dc Vaccines

Abstract INTRODUCTION Vaccination with dendritic cells (DCs) fares poorly in primary and recurrent glioblastoma (GBM). Moreover, GBM vaccine trials are often underpowered due to limited sample size. METHODS To address these limitations, we conducted three sequential clinical trials utilizing Cytomegalovirus (CMV)-specific DC vaccines in patients with primary GBM. Autologous DCs were generated and electroporated with mRNA encoding for the CMV protein pp65. Serial vaccination was given throughout adjuvant temozolomide cycles, and 111Indium radiolabeling was implemented to assess migration efficiency of DC vaccines. Patients were followed for median overall survival (mOS) and OS. RESULTS Our initial study was the phase II ATTAC study (NCT00639639; total n=12) with 6 patients randomized to vaccine site preconditioning with tetanus-diphtheria (Td) toxoid. This led to an expanded cohort trial (ATTAC-GM; NCT00639639) of 11 patients receiving CMV DC vaccines containing granulocyte-macrophage colony-stimulating factor (GM-CSF). Follow-up data from ATTAC and ATTAC-GM revealed 5-year OS rates of 33.3% (mOS 38.3 months; CI95 17.5-undefined) and 36.4% (mOS 37.7 months; CI95 18.2-109.1), respectively. ATTAC additionally revealed a significant increase in DC migration to draining lymph nodes following Td preconditioning (P=0.049). Increased DC migration was associated with OS (Cox proportional hazards model, HR=0.820, P=0.023). Td-mediated increased migration has been recapitulated in our larger confirmatory trial ELEVATE (NCT02366728) of 43 patients randomized to preconditioning (Wilcoxon rank sum, Td n=24, unpulsed DC n=19; 24h, P=0.031 and 48h, P=0.0195). In ELEVATE, median follow-up of 42.2 months revealed significantly longer OS in patients randomized to Td (P=0.026). The 3-year OS for Td-treated patients in ELEVATE was 34% (CI95 19-63%) compared to 6% given unpulsed DCs (CI95 1-42%). CONCLUSION We report reproducibility of our findings across three sequential clinical trials using CMV pp65 DCs. Despite their small numbers, these successive trials demonstrate consistent survival outcomes, thus supporting the efficacy of CMV DC vaccine therapy in GBM.

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Proposals for revised IWG 2018 hematological response criteria in patients with MDS included in clinical trials

Blood ◽

10.1182/blood-2018-06-857102 ◽

2019 ◽

Vol 133 (10) ◽

pp. 1020-1030 ◽

Cited By ~ 19

Author(s):

U. Platzbecker ◽

P. Fenaux ◽

L. Adès ◽

A. Giagounidis ◽

V. Santini ◽

...

Keyword(s):

Clinical Trials ◽

Myelodysplastic Syndromes ◽

Working Group ◽

Lower Risk ◽

Response Assessment ◽

Response To Treatment ◽

Response Criteria ◽

Patient Response ◽

Erythroid Response ◽

Clinical Responses

Abstract The heterogeneity of myelodysplastic syndromes (MDSs) has made evaluating patient response to treatment challenging. In 2006, the International Working Group (IWG) proposed a revision to previously published standardized response criteria (IWG 2000) for uniformly evaluating clinical responses in MDSs. These IWG 2006 criteria have been used prospectively in many clinical trials in MDSs, but proved challenging in several of them, especially for the evaluation of erythroid response. In this report, we provide rationale for modifications (IWG 2018) of these recommendations, mainly for “hematological improvement” criteria used for lower-risk MDSs, based on recent practical and reported experience in clinical trials. Most suggestions relate to erythroid response assessment, which are refined in an overall more stringent manner. Two major proposed changes are the differentiation between “procedures” and “criteria” for hematologic improvement–erythroid assessment and a new categorization of transfusion-burden subgroups.

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Clinical trials update: Highlights of the Scientific Sessions of Heart Failure 2001, a meeting of the Working Group on Heart Failure of the European Society of Cardiology. CONTAK-CD, CHRISTMAS, OPTIME-CHF

European Journal of Heart Failure ◽

10.1016/s1388-9842(01)00175-1 ◽

2001 ◽

Vol 3 (4) ◽

pp. 491-494 ◽

Cited By ~ 44

Author(s):

Simon Thackray ◽

Alison Coletta ◽

Peter Jones ◽

Anita Dunn ◽

Andrew L. Clark ◽

...

Keyword(s):

Heart Failure ◽

Clinical Trials ◽

European Society ◽

Working Group ◽

European Society Of Cardiology

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Acute severe paediatric asthma: study protocol for the development of a core outcome set, a Pediatric Emergency Networks (PERN) study

10.21203/rs.2.13017/v2 ◽

2019 ◽

Author(s):

Simon Craig ◽

Franz E Babl ◽

Stuart R Dalziel ◽

Charmaine Gray ◽

Colin Powell ◽

...

Keyword(s):

Clinical Trials ◽

Severe Asthma ◽

Working Group ◽

Core Outcome Set ◽

Asthma Severity ◽

Core Outcome ◽

Acute Severe Asthma ◽

Paediatric Asthma ◽

Future Studies ◽

Outcome Set

Abstract Background. Acute severe childhood asthma is an infrequent, but potentially life-threatening emergency presentation. There is a wide range of different approaches to this condition, with very little supporting evidence, leading to significant variation in practice. To improve knowledge in this area, there must first be consensus on how to conduct clinical trials, so that valid comparisons can be made between future studies. We have formed an international working group comprising paediatricians and emergency physicians from North America, Europe, Asia, the Middle East, Africa, South America, Central America, Australasia and the United Kingdom. Methods / design. A five-stage approach will be used: (1) A comprehensive list of outcomes relevant to stakeholders will be compiled through systematic reviews and qualitative interviews with patients, families, and clinicians; (2) A Delphi methodology will be applied to reduce the comprehensive list to a core outcome set; (3) We will review current clinical practice guidelines, existing clinical trials, and literature regarding bedside assessment of asthma severity. We will then identify practice differences in clinical assessment of asthma severity, and determine whether further prospective work is needed to achieve agreement on inclusion criteria for clinical trials on acute paediatric asthma in the emergency department setting; (4) A retrospective chart review in Australia and New Zealand will identify the incidence of serious clinical complications in children hospitalized with acute severe asthma, such as intubation, ICU admission, and death. Understanding the incidence of such outcomes will allow us to understand how common (and therefore how feasible) particular outcomes are in an asthma ED population; (5) Finally, a meeting of the PERN asthma working group will be held, with invitation of other clinicians interested in acute asthma research, and patients / families. The group will be asked to achieve consensus on a core set of outcomes and to make recommendations for the conduct of clinical trials on acute severe asthma. If this is not possible, the group will agree on a series of prioritized steps to achieve this aim. Discussion The development of an international consensus on core outcomes is an important first step towards the development of consensus guidelines and standardised protocols for RCTs in this population. This will enable us to better interpret and compare future studies, reduce risks of study heterogeneity and outcome reporting bias, and improve the evidence base for the management of this important condition.

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