Summary of US Food and Drug Administration Chimeric Antigen Receptor (CAR) T-Cell Biologics License Application Approvals From a Statistical Perspective.

The approval of tisagenlecleucel and axicabtagene ciloleucel in 2017 marked a milestone in the development of oncology therapies. Since 2017, the breakthrough in treatment or even cure of previously intractable diseases represented by this new class of cancer treatments has continued with subsequent chimeric antigen receptor T (CAR T)-cell approvals. To date, the US Food and Drug Administration has approved five autologous CAR T-cell products for seven indications.

IL-10 Signaling Elicited by Nivolumab-Induced Activation of the MAP Kinase Pathway Does Not Fully Contribute to Nivolumab-Modulated Heterogeneous T Cell Responses.

Immune checkpoint inhibitor (ICI) therapy has revolutionized anti-cancer treatment for many late-stage cancer patients. However, ICI therapy has thus far demonstrated limited efficacy for most patients, and it remains unclear why this is so. Interleukin 10 (IL-10) is a cytokine that has been recognized as a central player in cancer biology with its ability to inhibit anti-tumor T cell responses.

Exploring the Potential Use of a PBMC-Based Functional Assay to Identify Predictive Biomarkers for Anti-PD-1 Immunotherapy.

The absence of reliable, robust, and non-invasive biomarkers for anti- Programmed cell death protein 1 (PD-1) immunotherapy is an urgent unmet medical need for the treatment of cancer patients. No predictive biomarkers have been established based on the direct assessment of T cell functions, the primary mechanism of action of anti-PD-1 therapy. In this study, we established a model system to test T cell functions modulated by Nivolumab using anti-CD3 monoclonal antibody (mAb)-stimulated peripheral blood mononuclear cells (PBMCs), and characterized T cell functions primarily based on the knowledge gained from retrospective observations of patients treated with anti-PD-1 immunotherapy.

Graphical Analyses in the Regulatory Evaluation of Gene Therapy Applications.

The Center for Biologics Evaluation and Research (CBER) at the US Food and Drug Administration (FDA) regulates gene therapies, among other products. The approval of four gene therapy products since 2017 represents a significant milestone for a new class of treatments with the potential to treat or cure diseases, particularly rare diseases, that were previously considered incurable. Several factors have contributed to the recent rapid development of gene therapies including advances in genetics to facilitate target-detection, advances in vectors, and regulatory incentives such as breakthrough therapy designation, priority review and market exclusivity.

BRAF and MEK inhibitors differentially affect nivolumab-induced T cell activation by modulating the TCR and AKT signaling pathways.

Immune checkpoint inhibitors (ICIs) such as the anti-PD-1 antibody Nivolumab, achieve remarkable clinical efficacy in patients with late stage cancers. However, only a small subset of patients benefit from this therapy. Numerous clinical trials are underway testing whether combining ICIs with other anti-cancer therapies can increase this response rate.

FDA Approval Summary: Axicabtagene Ciloleucel for Relapsed or Refractory Large B-cell Lymphoma.

In October 2017, the FDA granted regular approval to axicabtagene ciloleucel, a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, for treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. Efficacy was based on complete remission (CR) rate and duration of response (DOR) in 101 adult patients with relapsed or refractory large B-cell lymphoma (median 3 prior systemic regimens) treated on a single-arm trial. Patients received a single infusion of axicabtagene ciloleucel, preceded by lymphodepleting chemotherapy with cyclophosphamide and fludarabine.

FDA Approval Summary: Tisagenlecleucel for Treatment of Patients with Relapsed or Refractory B-cell Precursor Acute Lymphoblastic Leukemia.

Tisagenlecleucel (Kymriah; Novartis Pharmaceuticals) is a CD19-directed genetically modified autologous T-cell immunotherapy. On August 30, 2017, the FDA approved tisagenlecleucel for treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory in second or later relapse. Approval was based on the complete remission (CR) rate, durability of CR, and minimal residual disease (MRD) <0.

CBER's Experience With Adaptive Design Clinical Trials.

There is considerable interest among pharmaceutical and other medical product developers in adaptive clinical trials, in which knowledge learned during the course of a trial affects ongoing conduct or analysis of the trial. When the FDA released a draft Guidance document on adaptive design clinical trials in early 2010, expectations were high that it would lead to an increase in regulatory submissions involving adaptive design features, particularly for confirmatory trials. A 6-year (2008-2013) retrospective survey was performed within the Center for Biologics Evaluation and Research (CBER) at the FDA to gather information regarding the submission and evaluation of adaptive design trial proposals.

Validity and power considerations on hypothesis testing under minimization.

Minimization, a dynamic allocation method, is gaining popularity especially in cancer clinical trials. Aiming to achieve balance on all important prognostic factors simultaneously, this procedure can lead to a substantial reduction in covariate imbalance compared with conventional randomization in small clinical trials. While minimization has generated enthusiasm, some controversy exists over the proper analysis of such a trial.

Missing data handling methods in medical device clinical trials.

One of the major problems in the analysis of clinical trials is missing data caused by patients dropping out before study completion. The issue of missing data can result in biased treatment comparisons and can impact the interpretation of study results. Since the missing data mechanism is unknown and unverifiable in most situations, regulatory agencies often request various sensitivity analyses for handling missing data to evaluate the robustness of study results.

Mixed noninferiority margin and statistical tests in active controlled trials.

In an active controlled noninferiority trial without a placebo arm, one of the major considerations is the selection of the noninferiority margin. Although the ICH E10 guideline provides general principles for the selection of appropriate noninferiority margins, there are no established rules or gold standards for the selection of noninferiority margins in active control trials. Hung et al.