E-Newsletter - October 2018
Message from the Group Statistician


Alliance statistics and Data Center:
on the cutting edge of statistical, methodological research

Since its formation in 2014, the Alliance Statistics and Data Center (SDC) has provided statistical, data management, and IT collaboration and support for all Alliance National Clinical Trials Network (NCTN) coordinated treatment and NCI Community Oncology Research Program (NCORP) trials, including more than150 trials where patient follow-up is continuing or that are in manuscript preparation. Currently, the Alliance database contains records for more than 150,000 patients enrolled on to 891 Alliance and legacy group-led clinical trials spanning the period 1955 to present. SDC staff continue to be on the cutting edge of statistical and methodological research, publishing extensively on novel statistical and bioinformatics methods, analyses and software, and providing statistical support and leadership on publications which leverage individual patient data from multiple Alliance studies.

Here’s a glimpse into two such research endeavors that have directly stemmed from data from Alliance studies.

Collection and reporting of adverse events are integral and important part of clinical trials to ensure patient safety, according to Jennifer Le-Rademacher, PhD, Lead Statistician for Alliance Symptom Intervention, Cancer in the Elderly, and Cancer Prevention Committees. In addition to the type and severity of an adverse event, regulatory agencies (NCI and FDA) require that the investigators report whether not the adverse event is attributable to the drug under investigation. The determination of an adverse event’s relatedness to an investigational drug is commonly known as adverse event attribution and is categorized as “not related”, “unlikely related”, “possibly related”, “probably related”, and “definitely related” to study treatment. Using data from nine completed multi-center randomized double-blind placebo-controlled clinical trials conducted by the Alliance, the Cancer Prevention Network and by Mayo Clinic, we found that 50 percent of adverse events reported for patients on the placebo arm were deemed related (including possibly, probably, and definitely related) to the investigational drug although they did not receive the active agent.[1, 2]  We further found that a very high proportion of adverse events reported as related to an investigational drug were classified as possibly related and that clinician-reported attribution overestimated the rate of adverse events related to an investigational agent. Fatigue, nausea, vomiting, diarrhea, constipation, and neurosensory symptoms were the most common adverse events that clinicians over-reported as related to an investigational drug. [1-3] These findings are consistent across all trials in settings including treatment, cancer prevention, and symptom intervention.[2] Based on these results, we recommended that the collection of adverse event attribution in randomized double-blind placebo-controlled trials be eliminated.  In these trials, the excess toxicity caused by the investigational drug can be reliably determined by comparing the toxicity rates between the investigational arm and the placebo arm. Even in randomized double-blind trials comparing a new therapy (or a new combination) to the standard of care, additional toxicity from the new therapy can also be estimated by comparing the investigational arm to the standard of care arm, much like in placebo-controlled trials. Therefore, adverse event attribution can also be eliminated in this setting.  This recommendation is now part of a consensus statement to improve attribution of adverse events from a working group consisting of researchers from MD Anderson Cancer Center and Mayo Clinic along with regulatory stakeholders from the NCI, the FDA and European Medicines Agency. [3, submitted manuscript]

Event-free survival (EFS) is often used as an endpoint in AML clinical trials, according to Jun (Vivien) Yin, PhD, Faculty Statistician for Alliance Leukemia Committee and Immuno-oncology Working Group. However, EFS-based endpoints are controversial due to the lack of a consistent definition for the timing of complete remission (CR), and consideration of hematopoietic cell transplantation (HCT). We examined the robustness of EFS by using alternative definitions through pooled analyses using data from five completed Alliance trials. We found that the results were similar both with and without censoring at HCT administration. Overall study conclusions on treatment effect were unaffected in randomized trials. However, EFS estimates differed considerably based on the timing of CR used to define induction failure in a single arm trial. The magnitude of difference was large enough in most cases (observed range: 14% to >100%) to lead to incorrect conclusions about efficacy in a single arm trial if the trial definition was not consistent with the definition used for the historical control. [4, 5] We next performed a formal surrogacy analysis of EFS for OS in untreated AML. Despite of a strong correlation between treatment effects observed using EFS and OS on the trial level, a lack of patient-level correlation was observed between individual patient EFS and OS times. We concluded that it remains debatable whether EFS represents a clinical benefit in itself for patient with untreated AML. [6]

I hope you enjoyed reading these little snippets of research led by Alliance SDC members. The Alliance SDC remains committed to leading and collaborating on high quality research and looks forward to the exciting new horizons the years ahead will bring.

Have a wonderful fall season!

Sumithra J. Mandrekar
Alliance Group Statistician


  1. Hillman SL, Mandrekar SJ, Bot B, et al. Evaluation of the Value of Attribution in the Interpretation of Adverse Event Data: A North Central Cancer Treatment Group and American College of Surgeons Oncology Group Investigation.  J Clin Oncol 2010; 28: 3002 – 3007.
  2. Le-Rademacher J, Hillman SL, Meyers J, et al: Statistical controversies in clinical research: Value of adverse events relatedness to study treatment: analyses of data from randomized double-blind placebo-controlled clinical trials. Ann Oncol 28:1183-1190, 2017.
  3. George GC, Barata P, Campbell A, Chen A, Chuk M, Cortes J, Hyman D, Jones J, Karagiannis T, Klaar S, Kluetz P, Le-Rademacher J, LoRusso P, Mandrekar SJ, Merino D, Minasian L, Mitchell S, Montez S, O’Connor D, Petit S, Silk E, Sloan JA, Stewart M, Takimoto C, Wong G, Yap TA, Cleeland CS, Hong DS. Improving Attribution of Adverse Events in Oncology Clinical Trials. Manuscript submitted Sep 2018.
  4. Yin, J., Laplant, B. R., Uy, G. L., Marcucci, G., Blum, W., Larson, R. A., Stone, R. M., & Mandrekar, S. (2016). Impact of the Timing of Complete Remission and Transplantation on Estimates of Event-Free Survival in Acute Myeloid Leukemia. Blood, 128(22), 214.
  5. Yin, J., Laplant, B. R., Uy, G. L., Marcucci, G., Blum, W., Larson, R. A., Stone, R. M., & Mandrekar, S. Impact of the Timing of Complete Remission and Transplantation on Estimates of Event-Free Survival in Acute Myeloid Leukemia. Manuscript submitted Sep 2018.
  6. Yin, J., Uy, G. L., Laplant, B. R., Storrick, E., Marcucci, G., Fernandez, H.F., Sun, Z., Litzow, M.R., Othus, M., Appelbaum, F.R., Larson, R. A., Stone, R. M., & Mandrekar, S. Event-Free Survival As a Surrogate Endpoint for Overall Survival Previously Untreated Acute Myeloid Leukemia: an Individual Patient-level Analysis of Multiple Randomized Trials (Alliance A151614). Abstract accepted for ASH 2019.



For other articles in this issue of the Alliance E-News newsletter, see below.