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The primary way in which the Statistical Directors oversee and influence the integrity of CIBMTR data analysis is in their role as members of the CIBMTR Working Committees. They guide the analytical assessment of data extracted from the large database that are relevant to the scientific question(s) of each ongoing study.

Statistics meetings are held weekly and attended by all CIBMTR MD Scientific Directors, CIBMTR PhD Statistical Directors, Coordinating Center Statistical Staff, and, in most cases, study PIs to discuss protocol design, selection of the study population, proper variables, and the approach to statistical analysis. The Statistical Directors are available to the members of their Working Committees for in-person or phone consultation, and they attend teleconferences of their assigned Working Committee leadership meetings. The CIBMTR Statistical Directors approve univariate analyses completed by the CIBMTR MS-level Statisticians and perform the

CIBMTR Manual of Operations Chapter 5: Statistical Resources

multivariate analyses for each study. CIBMTR Scientific Directors and assigned Statistical Directors work closely with study PIs during all phases of study development including final approval of the manuscript that is submitted to peer-reviewed journals for publication.

The Immunobiology Working Committee (Chapter 7) has a unique and independent mission. It addresses scientific questions about the association between genetic factors and successful transplantation outcomes. The committee’s studies include comparisons of clinical outcomes from different donor types (e.g. mismatched related versus unrelated donors).

5.3.2 Center-Specific Analysis

In 1986, the National Bone Marrow Donor Registry (managed by NMDP/Be The Match) was established. It is responsible for maintaining an unrelated donor registry for HCT. In 1990, the Transplants Amendment Act made reporting of center-specific outcomes for unrelated HCT mandatory in the US. This activity has been conducted by the NMDP/Be The Match since 1994 and includes risk-adjusted, one-year survival data on HCT using unrelated donors from all US centers. These analyses have included:

 Five-year interval increments;

 Presentation of results in groups according to number of transplants performed at the center;

 Presentation of 95% confidence intervals surrounding the observed survival such that smaller centers have larger confidence limits.

With the Stem Cell Therapeutic and Research Act of 2005 (Chapter 10), the requirement to report outcomes of HCT by transplant center was broadened to include all allogeneic (related and unrelated) HCTs in the US. As contractor for the SCTOD, the CIBMTR is responsible for this data collection. The CIBMTR, and the MCW PhD Biostatisticians (CIBMTR Statistical Directors) in particular, have collaborated closely with NMDP/Be The Match since 2003 in generating these center-specific outcomes reports for unrelated donor HCT for the HRSA.

The Stem Cell Therapeutic and Research Act substantially expanded the patient population in these analyses. At most centers, it doubled the percentage of included patients. Centers that do not perform unrelated donor HCTs were included in these analyses for the first time beginning in 2010. Some of the difficulties of performing the center-specific outcomes analyses include:

 Patient-donor heterogeneity;  Small sample sizes;

 Conveying data to non-statisticians;

 Achieving medical community acceptance;

 Possible unintended consequences (e.g., negative affect on center patient selection, misinterpretation by patients, payer misinterpretation, etc.).

In 2008, the CIBMTR began working towards providing center-specific survival reports for all allogeneic HCTs in the US. Guided by recommendations of a multidisciplinary group of consultants, the CIBMTR identified the following ideal features for future reports:

 Scientifically valid;  Equitable;

 Free from bias;

 Useful to centers for improving quality;  Informative to the public.

Center Outcomes Forums have been conducted by the CIBMTR biennially since 2008.

5.3.3 Public Website Display of Survival Data

As part of the SCTOD contract, the CIBMTR provides information about autologous as well as related and unrelated allogeneic transplants performed by US transplant centers. The reports provide a moving five year window of data:

• US Patient Survival Report (http://bloodcell.transplant.hrsa.gov/RESEARCH/Transplant _Data/US_Tx_Data/Survival_Data/survival.aspx). Published every few years, this report provides patient survival estimates by disease at the following time points after

transplant: 100 days, 1 year and 3 years. Survival estimates are also available by patient age, patient gender, patient race, and cell source.

o The window for these data includes five years of “accrual” into the cohort and three years of follow-up.

o Sample sizes for some categories are quite small, so statistically valid estimates of overall survival outcome cannot be calculated where there is not enough patient data available for analysis.

• US Transplant Data by Center Report (http://bloodcell.transplant.hrsa.gov/RESEARCH/ Transplant_Data/US_Tx_Data/Data_by_Center/center.aspx). Published annually, this report provides the number of bone marrow and cord blood transplants performed at a specific transplant center for various diseases and donor types over a five year time period.

• US Transplant Data by Disease Report (http://bloodcell.transplant.hrsa.gov/RESEARCH/ Transplant_Data/US_Tx_Data/Data_by_Disease/national.aspx). Published annually, this report provides the number of bone marrow and cord blood transplants reported for a specific disease over a five year time period. Data are also available by patient age, patient gender, patient race, cell source, and year the transplant was performed.

5.3.4 BMT CTN and RCI BMT

A CIBMTR Statistical Director plays a lead role in the activities of both the BMT CTN and RCI BMT, which comprise the CIBMTR Clinical Trials Support Program (Chapter 8). A PhD Statistician is assigned to each clinical trial and is responsible for the design and analysis of that trial, the sample size, power calculations, data analysis and interpretation. They provide this support throughout the course of the study. Designing HCT clinical trials that produce meaningful results requires that special consideration be given to sample size; eligibility criteria; multiple, competing outcomes; center effects (e.g., those affecting patient outcomes due to practices / approaches unique to center transplant teams); early stopping guidelines; and other issues. Adequate sample sizes are needed to detect meaningful differences in treatment strategies. Selecting eligibility criteria that control for the heterogeneity of the patient population while allowing for reasonable patient accrual is also essential. Using the CIBMTR Research Database, Coordinating Center personnel explore the effects of specific eligibility criteria on the potential

CIBMTR Manual of Operations Chapter 5: Statistical Resources

for enrollment in clinical trials. The Database is also used in trial design and when considering amendments to enhance accrual.

Assessing multiple, competing outcomes can be challenging, as they can also interfere with assessment of the primary endpoint of a trial. Center effects, which can confound statistical analyses, are particularly important when evaluating complex treatments like HCT, in which substantial differences in supportive care-related practice patterns among centers exist (e.g., prophylactic and preemptive therapy for infection, nutritional support, isolation practices). Study data is stratified by transplant center whenever feasible to minimize center effects on study results.

Detailed study design and analysis plans vary from the larger phase II-III trials (randomized or not) of the BMT CTN to the smaller phase I-II studies of the RCI BMT. In both cases, the CIBMTR Research Database provides fundamental data for use by the Statistical Directors in developing and designing these trials.

5.3.5 HSR

The CIBMTR HSR Program (Chapter 9) also benefits from the statistical expertise of the Coordinating Center in conducting HCT-related research.

Some representative examples of HCT-related studies that are accomplished through this unique initiative, in partnership with the Statistical Directors, are:

 Barriers to HCT access;  Practice patterns;

 Workforce issues;

 Patient care and outcomes;

 Quality of care;

 Economic and cost analyses;  International variation;