scholarly journals Data and Safety Monitoring Board and the Ratio Decidendi of the Trial

2015 ◽  
Vol 15 (2) ◽  
pp. 1-26 ◽  
Author(s):  
Roger Stanev ◽  
Keyword(s):  
Safety Monitoring ◽  
Safety Monitoring Board ◽  
Ratio Decidendi

scholarly journals Data and Safety Monitoring Board evaluation and management of a renal adverse event signal in TOPCAT

2016 ◽  
Vol 19 (4) ◽  
pp. 457-465 ◽  
Author(s):  
Michael R. Bristow ◽  
Kavita Sharma ◽  
Susan F. Assmann ◽  
Stuart Linas ◽  
Bernard J. Gersh ◽  
...  
Keyword(s):  
Adverse Event ◽  
Safety Monitoring ◽  
Safety Monitoring Board ◽  
Renal Adverse Event ◽  
Adverse Event Signal

scholarly journals The data and safety monitoring board in sponsored pediatric clinical trials: practical applications

2015 ◽  
Vol 4 (1) ◽  
pp. 57
Author(s):  
Pramod M. Lad ◽  
Rebecca Dahl
Keyword(s):  
Clinical Trials ◽  
Los Angeles ◽  
Phase I ◽  
Drug Application ◽  
Safety Monitoring ◽  
Stopping Rules ◽  
Practical Applications ◽  
Time Of Application ◽  
Safety Monitoring Board ◽  
Institutional Review

The Data and Safety Monitoring Board (DSMB) monitors the progress of clinical trials for safety and implements stopping rules as needed. Although NIH and FDA guidelines recommend the use of a DSMB for phase I, II, and III pediatric clinical trials, the manner in which the DSMB is constituted has received little attention. In this study we reviewed the Institutional Review Board (IRB) applications submitted between 2008 and 2012 at our institution (Children’s Hospital Los Angeles) for phase I, II and III studies which were multi-site, sponsored and performed under a sponsor’s Investigation New Drug Application (IND) for the type of data and safety monitoring that was being used. Our results indicate that approximately two-third of the studies used an independent DSMB, 10% utilized a sponsor’s DSMB and the remaining studies (25%) did not utilize a DSMB and relied instead on safety monitoring by the Principal Investigator (PI) and the medical monitor/director. This pattern was observed across all study phases and for blinded as well as unblinded studies. Our result suggests that a Data and Safety Monitoring Plan (DSMP), although required by the IRB, is rarely submitted by the sponsor at the time of application. Instead the DSMP is submitted to the IRB by the PI on IRB supplied templates. IRB review of these completed templates were critical to ensuring DSMB related compliance. Additionally, a significant percent of sponsored clinical trials used the PI or an individual designated as medical director/monitor, rather than constituting a DSMB.

The Data and Safety Monitoring Board and Acquired immune deficiency syndrome (AIDS) clinical trials

1995 ◽  
Vol 16 (6) ◽  
pp. 408-421 ◽  
Author(s):  
David L. DeMets ◽  
Thomas R. Fleming ◽  
Richard J. Whitley ◽  
James F. Childress ◽  
Susan S. Ellenberg ◽  
...  
Keyword(s):  
Immune Deficiency ◽  
Clinical Trials ◽  
Safety Monitoring ◽  
Immune Deficiency Syndrome ◽  
Acquired Immune Deficiency Syndrome ◽  
Deficiency Syndrome ◽  
Safety Monitoring Board ◽  
Aids Clinical Trials ◽  
Acquired Immune Deficiency

BTK and/or PLCG2 Mutations in Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Ibrutinib: Characteristics and Outcomes at the Time of Progression

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3050-3050 ◽  
Author(s):  
Paul J. Hampel ◽  
Timothy G. Call ◽  
Sara J. Achenbach ◽  
Kari G Rabe ◽  
Wei Ding ◽  
...  
Keyword(s):  
Median Time ◽  
Research Funding ◽  
Resistance Mutation ◽  
Safety Monitoring ◽  
Data Safety Monitoring Board ◽  
Data Safety ◽  
Safety Monitoring Board ◽  
Progression Of Disease ◽  
Richter’S Transformation ◽  
Richter's Transformation

INTRODUCTION Mutations in BTK and PLCG2 have been reported to occur in ~80% of CLL patients (pts) who have progression of disease on ibrutinib therapy (Woyach, JCO 2017; Ahn, Blood 2017). These mutations are described as appearing months before actual relapse and thus considered as a potential predictive biomarker for future relapse (Quinquenel, Blood 2019). However, the outcomes of these pts after disease progression are not well described. In this study, we seek to investigate time to next therapy and overall survival (OS) following progression among CLL pts on ibrutinib therapy with and without these resistance mutations. METHODS Between 10/2012 and 6/2019, we identified 34 pts in the Mayo Clinic clinical CLL resource who progressed while receiving ibrutinib therapy and also had testing for BTK and PLCG2 mutation performed as part of routine clinical practice at either NeoGenomics Laboratories or The Ohio State University. OS was calculated from time of ibrutinib progression to last known alive or death date; OS was plotted using Kaplan Meier methods and was compared using the log-rank test between various groups (e.g., mutation positive vs negative; CLL progression vs Richter's). Cumulative incidence of time to next treatment in those who had a treatment after progression was adjusted for the competing risk of death. RESULTS Of 34 pts who progressed while receiving ibrutinib, 26 pts experienced CLL progression and 8 pts had Richter's transformation; baseline characteristics in Table 1A. The presence of a BTK or PLCG2 mutation was found in 20/34 (59%) pts (specific mutations in Table 1B). BTK mutation alone was present in 9 pts, 7 pts had PLCG2 mutation alone, and 4 pts had both mutations. Median time between a positive test and start of next therapy was 4 months (range 1-19 months) and did not vary between BTK vs PLCG2 mutations. Among the 26 pts with CLL progression, 18 (69%) pts had a mutation present: BTK alone (n=8), PLCG2 alone (n=6), both (n=4). Therapy following progression on ibrutinib in these pts was as follows: venetoclax (n=16; 11 pts who continued ibrutinib in combination), idelalisib (n=4), investigational treatments (n=2), continued ibrutinib alone (n=2), dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab; n=1), and unknown (n=1). Twelve of the 26 pts with CLL progression on ibrutinib, including 8 pts with a prior resistance mutation detected, had subsequent progression of disease on the aforementioned next line therapy. Treatment of these patients consisted of the following: restarted ibrutinib in addition to current treatment of venetoclax (n=5), venetoclax (n=2), pembrolizumab (n=2; 1 pt with continued ibrutinib), obinutuzumab with continued ibrutinib (n=1), gemcitabine and vinorelbine with continued ibrutinib (n=1), and no further treatment (n=1). Among the 8 pts with Richter's transformation as the initial progression event on ibrutinib after mutation testing, 1 pt had a BTK mutation and 1 pt had a PLCG2 mutation. Treatments following progression on ibrutinib included multi-agent chemoimmunotherapy (n=3; 2 pts received rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone [R-CHOP] with continued ibrutinib and 1 pt received doxorubicin, bleomycin, vinblastine, dacarbazine [ABVD] alone), pembrolizumab (n=3; 1 pt in combination with continued ibrutinib), venetoclax in combination with continued ibrutinib (n=1), and venetoclax and obinutuzumab (n=1). The median time to next treatment (second line of treatment beyond ibrutinib) for the 31 pts who started another therapy following progression on ibrutinib was 16.7 months (95% CI 9.6-NE; Figure 1A) and was not significantly different for pts with or without a resistance mutation (p=0.57). Median OS for all 26 pts with CLL progression was 28.7 month and there was no difference according to presence or absence of a resistance mutation (median 28.7 months vs 18.2 months, p=0.53; Figure 1B). The 8 pts with Richter's transformation had a median OS of 7.1 months (95% CI 2.0-NE). CONCLUSION Approximately 60% of pts tested in this progression cohort had a BTK or PLCG2 mutation at time of or preceding progression on ibrutinib therapy. OS and time to next therapy did not differ statistically between pts with mutated vs non-mutated clones; however, caution should be applied with the conclusions given the limited sample size. Disclosures Ding: DTRM Biopharma: Research Funding; Merck: Research Funding. Kenderian:Novartis: Patents & Royalties, Research Funding; Tolero: Research Funding; Humanigen: Other: Scientific advisory board , Patents & Royalties, Research Funding; Lentigen: Research Funding; Morphosys: Research Funding; Kite/Gilead: Research Funding. Kay:MorphoSys: Other: Data Safety Monitoring Board; Infinity Pharmaceuticals: Other: DSMB; Celgene: Other: Data Safety Monitoring Board; Agios: Other: DSMB. Parikh:Ascentage Pharma: Research Funding; Genentech: Honoraria; Janssen: Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; AbbVie: Honoraria, Research Funding; Acerta Pharma: Research Funding.

a Randomized, Double-Blinded, Placebo Controlled Study of IVIG Vs. IVIG with High Dose Methylprednisolone in Rapidly Augmenting Platelet Counts in Childhood ITP

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 868-868
Author(s):  
Manuel Carcao ◽  
Mariana Silva ◽  
Michele David ◽  
Robert J. Klaassen ◽  
MacGregor Steele ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Research Funding ◽  
Safety Monitoring ◽  
Data Safety Monitoring Board ◽  
Blood Type ◽  
Data Safety ◽  
Platelet Counts ◽  
Safety Monitoring Board ◽  
Life Threatening ◽  
Double Blinded

Abstract The combination of intravenous (IV) methylprednisolone (IVMP) and IV immune globulin (IVIG) is often used in children with immune thrombocytopenia (ITP) to rapidly increase platelet counts (PCs) to a safe hemostatic level. However, there are no controlled data to support the use of combination therapy over IVIG alone in children with severe thrombocytopenia [PC <20 x109/L] and/or life-threatening bleeding. We conducted a randomized, double-blinded, placebo controlled, multicenter, prospective study to evaluate 2 regimens: IVMP (Solu-Medrol®, UpJohn) 30 mg/kg (max. 1 gram) over 1 hour (h) followed by IVIG 1 g/kg (Gammunex 10%, Bayer) given at a rapid infusion rate (over a maximum of 3 h), vs IV placebo over 1 h followed by IVIG 1 g/kg in children with primary ITP. The goal was to evaluate the rapidity of the PC increment and associated adverse events with both regimens. Eligible patients were children [ages: 1 to 17 years (y)] with acute (defined at the time of study initiation as <6 months (mo.) since diagnosis) or chronic primary ITP (>6 mo.), with PCs <20x109/L in whom it was decided to treat with IVIG. Exclusion criteria included: previous splenectomy, life/organ threatening hemorrhage, renal disease, diabetes, hypertension, sepsis, fever >38.5°C, disseminated intravascular coagulation, pregnancy or a previous documented lack of response to IVIG. Baseline studies included: a complete blood count (CBC), a reticulocyte count, Coombs test and renal and liver function tests. CBCs were repeated at the end of the IVIG infusion, at 8±1h, 24±2h, 72±4h, day 7±2 day (d) and day 21±3d following the start of the placebo/IVMP. The primary outcome measure was the PC increment over the first 24 h following the administration of therapy; the main secondary outcome measures were the attainment of a PC of ≥20x109/L and ≥50x109/L at times + 8, +24 and +72h. Sample size was estimated based on the assumption that patients treated with placebo + IVIG would attain a mean PC at +24h of 30x109/L vs. 50x109/L for those treated with IVMP + IVIG. For 80% power to show a difference in PC of 20x109/L (at +24h)with an a of 0.025 (two-sided) and a b of 0.2, 32 patients were required. Patients were stratified by block randomization according to type of ITP (acute vs. chronic) and according to center. The trial was registered in ClinicalTrials.gov. (NCT00376077). Thirty two patients were enrolled (ages: median 8 y; min. 1.2 y; max: 17.5 y; 22 male: 10 female; 16 acute: 16 chronic; 11 were blood type O; 14 blood type A and 7 blood type B). Fourteen patients were randomized to IVMP+IVIG while 18 were randomized to placebo+IVIG. Randomization was not equal as 1 patient was randomized and then immediately declined to participate and another patient was incorrectly assigned; both were assigned to the placebo group. PCs for the 2 groups of patients at the different time points are shown in table 1. The difference in PC was statistically significant at the 24 hr time point (p<0.0001). At this time the proportion of patients achieving a PC of ≥50x109/L was 77% in the IVMP+IVIG vs 50% in the placebo+IVIG. No patient experienced a severe bleed or an unexpected severe adverse event during the study. There was a statistically significant drop in mean Hb post-treatment among all patients (baseline 133.3 (13.6) g/L to 121.6 (14.2) g/L at time +8h) but there was no difference between O and non-O blood type patients or between treatment groups. This study showed that PCs increased rapidly following administration of IVIG with or without IVMP such that by 8h post initiation of therapy 55% (17/31) of all patients had achieved a PC ≥20x109/L. The mean PC was significantly different between the groups at time +24h. Our findings provide level 1 evidence to support the use of combination therapy (IVMP+IVIG) in life threatening situations where it is deemed to important to attain as rapidly as possible a hemostatic platelet count. Table 1 Table 1. Disclosures Blanchette: Shire: Consultancy, Other: Member of a Data Safety Monitoring Board, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; CSL-Behring: Research Funding; Octapharna: Other: Member of a Data Safety Monitoring Board; Biogen Idec: Research Funding; Bayer Healthcare: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau.

scholarly journals Patient Reported Financial Toxicity in Acute Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4796-4796 ◽  
Author(s):  
Thomas G. Knight ◽  
Myra Robinson ◽  
Michael R. Grunwald ◽  
Lauren M. Bohannon ◽  
Erin Blackwell ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Safety Monitoring ◽  
Data Safety Monitoring Board ◽  
Financial Toxicity ◽  
Advisory Committees ◽  
Data Safety ◽  
Safety Monitoring Board ◽  
Data Safety Monitoring

Abstract Background: Financial Toxicity (FT) is increasingly recognized as a major contributor to morbidity and mortality in a variety of cancers. Treatment of acute leukemia is associated with heavy healthcare utilization and high costs. The purpose of this study was to define rates, risk factors, and mortality implications for FT in patients with acute leukemia using patient reported data. Methods: All patients seen at the Levine Cancer Institute, a tertiary hospital-based leukemia practice, were surveyed prior to each visit over a six-month period. All patients were aged ≥18 years and were diagnosed with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). The survey consisted of the PROMIS Global-10 measure and two questions from the COST measure. FT was defined as scoring 4 or less (maximum: 10) in agreement with the COST questions: "I know that I have enough money in savings, retirement, or assets to cover the costs of my treatment" and "I am satisfied with my current financial situation." Demographic data and disease characteristics were abstracted from the medical record. Model selection was carried out using logistic regression to identify factors impacting the incidence of financial toxicity. Correlation of numerical financial toxicity scores with PROMIS scores and with mortality data was assessed using linear regression. Results: Of the 106 patients, 58 (54%) met the definition of exhibiting FT. The factors associated with incidence of FT included: age, race, and insurance type. The odds of FT in those patients <65 years of age were 2.7 times the odds of FT in those ≥65, adjusting for race, insurance, and time since first treatment (95% CI: 0.884 - 8.438, p = .081). The odds of FT in African American patients were 4.3 times the odds of FT in Caucasian patients, adjusting for age, insurance, and time since first treatment (CI: 0.408 - 44.824, p = .150). The odds of FT in patients with Medicaid insurance were 14.2 times the odds of FT in patients with commercial insurance, adjusting for age, race, and time since first treatment (CI: 1.658 - 121.862, p = .106). Gender, distance from the hospital, type of acute leukemia, history of blood/marrow transplant, and history of relapsed disease were not found to be significant. There was a significant correlation for both the PROMIS global physical (p < .001) and mental (p < .001) scores with the FT score. Lower FT score (higher degree of FT) was associated with lower mental and physical scores. There was no statistically significant difference in survival between patients with FT scores >4 compared to patients with FT scores <=4; however, there was a trend toward decreased survival in those with lower FT scores (Figures 1 and 2). Conclusions: Patients with acute leukemia represent an extremely vulnerable population for financial toxicity with rates of distress even higher than other reported malignancies. Urgent interventions are indicated in this population. Disclosures Grunwald: Medtronic: Equity Ownership; Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Research Funding; Janssen: Research Funding; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Avalos:Juno: Membership on an entity's Board of Directors or advisory committees. Symanowski:Five Prime Therapeutics: Other: Data Safety Monitoring Board ; Boston Biomedical: Other: Data Safety Monitoring Board ; Eli Lily & Co: Other: Data Safety Monitoring Board; Immatics: Other: Data Safety Monitoring Board.

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