General considerations for clinical data management of antineoplastic drugs / 中国临床药理学与治疗学

With the enormous resources having been invested in oncology drugs development in China in recent years, the Center for Drug Evaluation (CDE) of National Medical Products Administration has been issuing a number of technical guidelines to further standardize the requirements on implementation and registration of domestic oncology clinical trials. As data is the cornerstone of clinical trials, data integrity and quality will directly decide the outcome of clinical studies. Given the specific characteristics of oncology therapeutic clinical trials, and combined with the clinical data standards established by the Clinical Data Interchange Standards Consortium (CDISC) and the issued industrial guidelines, this article introduces the general considerations of clinical data management for oncology clinical trials, with the aim of emphasizing normative data collection and timely data monitoring to ensure the data quality and reliability of results of the study. This article discusses the impact of complex study design on CRF, design CRF according to CDASH, develop DVP scientifically, rolling submissions and data cut-off.

Optimization of clinical dosing schedule to manage neutropenia: learnings from semi-mechanistic modeling simulation approach.

Neutropenia is a common side-effect of oncology drugs. We aimed to study the impact of exposure and dosing schedule on neutropenia to guide selection of dosing schedules that minimize neutropenia potential while maintaining the desired minimum concentration (Cmin) required for target engagement. Dose, frequency and PK parameters were chosen for five hypothetical drugs of various half-lives to (1) achieve same exposure with continuous dosing and evaluate impact of 4 intermittent dosing schedules; and (2) achieve same nadir for continuous and intermittent dosing and evaluate impact on % time above Cmin, a surrogate assumed to indicate target engagement. Absolute neutrophil count (ANC) profiles were simulated using Friberg model, a widely used semi-mechanistic myelosuppression model, assuming drug concentration directly reduce the proliferation rate of stem cells and progenitor cells in proliferation compartment. The correlations between different PK measures and neutropenia metrics were explored. In (1), when the same daily dose was used, intermittent schedules offered better management of ANC nadir. The reduced average drug exposure with intermittent dosing led to lower% time above Cmin. In (2), when the dose was adjusted to achieve the same nadir, drugs with moderate half-life (8-48 h) showed similar % time above Cmin regardless of schedule, while continuous dosing was better for a short half-life (4 h). Area under the concentration curve (AUC) was highly correlated with neutropenia. In summary, continuous dosing, with the dose selected correctly, is most effective to maintain % time above Cmin while providing similar tolerability as intermittent dosing with a higher dose. But dose interruptions could be required to manage individual toxicities. Intermittent schedules, on the other hand, allow recovery of ANC, enabling more orderly schedules.