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Use of biological assignment in hematopoietic stem cell transplantation clinical trials. Clin Trials 2008;5(6):607-16 PMID: 19029209 PMCID: PMC2671015

Pubmed ID



BACKGROUND: When comparing treatments for a specific illness, it is sometimes impractical or impossible to conduct a randomized clinical trial (RCT). Biological assignment trials are one alternative design. In hematopoietic stem cell transplantation (HCT) trials, a human leukocyte antigen (HLA)-matched sibling donor is considered optimal, but such donors are available for only 20-30% of otherwise eligible patients. Rather than randomizing only those with a matched sibling donor, in a recent multiple myeloma trial, the type of HCT each patient received was biologically based, i.e., chosen according to whether or not the patient had a matched sibling donor.

PURPOSE: This article describes the design and implementation of biological assignment trials as well as their advantages and disadvantages.

METHODS: We focus on several aspects of such trials, including efficiency of trial duration, ethical issues, and potential sources of bias. Statistical issues are considered including sample size calculations, monitoring for biased enrollment, and adjustments for imbalances in patient characteristics. A multiple myeloma trial is used as an illustration.

RESULTS: Although they often require a larger sample size, biological assignment trials can provide substantial efficiency in terms of study duration over randomized trials when accrual to a randomized trial would be slow. Determination of sample size requires consideration of the anticipated proportion of patients with a biologically favored (HLA-matched sibling) donor. An add-on randomization of patients without a matched sibling donor may alleviate ethical concerns about applicability of study results to all patients regardless of whether the biological assignment groups differ with respect to outcome.

LIMITATIONS: Prognostic factor imbalance and enrollment bias can occur in a biological assignment trial. Statistical adjustment for potential imbalance in prognostic factors is important, as is monitoring center accrual for enrollment bias and performing an appropriate intention-to-treat analysis.

CONCLUSIONS: A biological assignment trial can be a reasonable way to compare treatments which are biologically based, such as HLA-matched sibling transplants, when the gold-standard randomized trial design is impractical or impossible. Implementing such a trial requires careful consideration of the ethical issues and potential biases.

Author List

Logan B, Leifer E, Bredeson C, Horowitz M, Ewell M, Carter S, Geller N


Mary M. Horowitz MD, MS Center Director, Professor in the Medicine department at Medical College of Wisconsin
Brent R. Logan PhD Director, Professor in the Institute for Health and Equity department at Medical College of Wisconsin


2-s2.0-61449562164   16 Citations

MESH terms used to index this publication - Major topics in bold

Feasibility Studies
HLA Antigens
Hematopoietic Stem Cell Transplantation
Histocompatibility Testing
Multiple Myeloma
Patient Selection
Random Allocation
Randomized Controlled Trials as Topic
Selection Bias
Transplantation, Autologous
Transplantation, Homologous
jenkins-FCD Prod-299 9ef562391eceb2b8f95265c767fbba1ce5a52fd6