Use of biological assignment in hematopoietic stem cell transplantation clinical trials.
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.


OBJECTIVE
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.


CONCLUSIONS
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.
Logan
Brent
B
Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI, USA. blogan@mcw.edu
Leifer
Eric
E
Bredeson
Chris
C
Horowitz
Mary
M
Ewell
Marian
M
Carter
Shelly
S
Geller
Nancy
N
D005240:Feasibility Studies; D006680:HLA Antigens; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006650:Histocompatibility Testing; D006801:Humans; D009101:Multiple Myeloma / Q000276:immunology / Q000628:therapy; D018579:Patient Selection; D011897:Random Allocation; D016032:Randomized Controlled Trials as Topic; D015983:Selection Bias; D014182:Transplantation, Autologous; D014184:Transplantation, Homologous
D006680:HLA Antigens