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It has been well established that randomized clinical trials have poor external validity, resulting in findings that may not apply to relevant—or target—populations. When the trial is sampled from the target population, generalizability methods have been proposed to address the applicability of trial findings to target populations. When the trial sample and target populations are distinct, transportability methods may be applied for this purpose. However, generalizability and transportability studies present challenges, particularly around the strength of their conclusions. We review and summarize state-of-the-art methods for translating trial findings to target populations. We additionally provide a novel step-by-step guide to address these challenges, illustrating principles through a published case study. When conducted with rigor, generalizability and transportability studies can play an integral role in regulatory decisions by providing key real-world evidence.

Plerixafor, a CXCR4 receptor antagonist, reduces the binding and chemotaxis of hematopoietic stem cells to the bone marrow stroma, resulting in predictable peak of cluster of differentiation 34+(CD34+) cells in the peripheral blood (PB) approximately 10 h after its administration. We developed a model that could predict the CD34+harvest volume on the first day of apheresis (AP-CD34+) based on PB-CD34+counts immediately prior to commencing apheresis in pediatric population. In all, data from 45 pediatric patients from the MOZAIC study who received either granulocyte colony-stimulating factor (G-CSF) alone or G-CSF plus plerixafor were included. The modeling of the data exhibited a strong and highly predictive linear relationship between the counts of PB-CD34+cells on the first day of apheresis and AP-CD34+cells collected on the same day. It is predicted that there are approximately 13 new collected CD34+cells for 100 new circulating CD34+cells before apheresis. Our predictive algorithm can be used to quantify the minimal count of PB-CD34+cells that enables to collect at least 2 × 106or 5 × 106AP-CD34+cells/kg with sufficient assurance (probability = 0.90) and can guide the use of plerixafor in patients at higher perceived risk for mobilization failure. Trial registration of MOZAIC study: ClinicalTrials.gov, NCT01288573; EudraCT, 2010-019340-40.

We propose a test of comparison of treatment groups adjusted based on information brought by a baseline covariate in a randomized clinical trial for which the main efficacy endpoint is a binary or a categorical criterion. This test is linked to the statistical information notions of Kullback-Leibler information and I-projection and leads to a test statistic that must be compared to the chi-square distribution with the same degrees of freedom as the Pearson chi-square test. With some simulations, the nonasymptotic properties of this test have been investigated: it is shown that in some cases the power of this adjusted test is superior to the Pearson chi-square test whereas the type I error is less sensitive to the large baseline empirical differences of the prognostic covariate.

We propose a test of comparison of treatment groups adjusted based on information brought by a baseline covariate in a randomized clinical trial for which the main efficacy endpoint is a binary or a categorical criterion. This test is linked to the statistical information notions of Kullback-Leibler information and I-projection and leads to a lest statistic that must be compared to the chi-square distribution with the same degrees of freedom as the Pearson chi-square test. With some simulations, the nonasymptotic properties of this test have been investigated: it is shown that in some cases the power of this adjusted test is superior to the Pearson chi-square test whereas the type I error is less sensitive to the large baseline empirical differences of the prognostic covariate.

Background and Purpose:Combined perfusion and oxygen metabolism PET imaging is highly predictive of spontaneous outcome after middle cerebral artery (MCA) stroke, independent of clinical scores, but whether the assessment of perfusion alone by SPECT provides similar information remains unclear. We have assessed the prognostic value of 99mTc-HMPAO-SPECT at the acute stage of stroke. Methods:Twenty-seven first-ever nonhemorrhagic MCA territory stroke patients were prospectively studied 4–20 h (mean: 12 h) after onset with 99mTc-HMPAO-SPECT. None was part of a therapeutic trial or received thrombolysis. Neurological deficits were quantified at admission and 2 months later with Orgogozo’s MCA scale. SPECT images were visually classified by 3 independent observers into one of three patterns, as follows: pattern I = marked and extensive tracer hypofixation; pattern II = moderate and/or focal hypofixation with or without combined hyperfixation, and pattern III = normal or increased uptake without hypofixation. In addition to this visual analysis, we also calculated a voxel-based ‘hypoperfusion score’, an index of severity × extent of hypofixation according to Mountz’s method. Results:There was a good intra- and interobserver agreement. After consensus, 9, 14 and 4 patients were classified in patterns I, II and III, respectively. These patterns had a significant predictive value for raw outcome but not for percentage recovery (p = 0.008 and p = 0.127, respectively). Thus, all patients in pattern III had a good outcome, while most (but not all) patients in pattern I had a poor or intermediate outcome; pattern II patients were more evenly distributed among outcomes. Hypoperfusion scores were highly significantly positively correlated with both 2-month outcomes and percentage recoveries, even after controlling the predictive value of day 0 MCA scores by partial correlations. Comments:We found that SPECT had a significant added predictive value even when compared to admission neurological scores. Although less accurate than PET, 99mTc-HMPAO-SPECT may help to predict spontaneous individual neurological evolution, especially whenever perfusion images are normal or show an increased tracer uptake without associated hypofixation.

Background:Isatuximab (Isa) is a CD38 monoclonal antibody with multiple modes of action for killing tumor cells through direct tumor targeting and immune cell engagement (Moreno, Clin Cancer Res, 2019). The addition of Isa to pomalidomide (P) and dexamethasone (d) was associated with a significant and clinically meaningful benefit in progression-free survival (PFS) in heavily pre-treated patients with relapsed/refractory multiple myeloma (RRMM) (ICARIA-MM, NCT02514668) (Attal, Lancet, 2019). Isa, in combination with Pd, is approved in the United States, the European Union, Canada, Australia, Switzerland, and Japan for the treatment of adult patients with RRMM who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.

Thai: Sanofi: Current Employment. Gaudel-Dedieu:Sanofi: Current Employment. Cerou:Sanofi: Current Employment. Sebastien:Sanofi: Current Employment. van de Velde:Sanofi: Current Employment, Current equity holder in publicly-traded company. Semiond:Sanofi: Current Employment. Veyrat-Follet:Sanofi: Current Employment.

Background:Isatuximab (Isa) is an anti-CD38 monoclonal antibody with multiple modes of action for killing tumor cells through direct tumor targeting and immune cell engagement. Exposure-Response (E-R) analysis and disease modelling of tumor burden were performed to evaluate the relationship between Isa exposure and efficacy outcomes. This analysis also supports the Isatuximab dosing regimen selection/confirmation when administered in combination in relapsed/refractory multiple myeloma (RRMM) patients.

Rachedi: Sanofi: Employment. Koiwai:Sanofi: Employment. Gaudel-Dedieu:Sanofi: Employment. Sebastien:Sanofi: Employment. Thai:Sanofi: Employment. El-Cheikh:Sanofi: Employment. Brillac:Sanofi: Employment. Fau:Sanofi: Employment. Nguyen:Sanofi: Employment. Liu:Sanofi: Employment. Campana:Sanofi: Employment. van de Velde:Sanofi: Employment. Semiond:Sanofi: Employment.