Estimation of the dose proportionality and bioavailability of a drug in TD delivery system
A Case study of Pharmaceutical programming in Preparing CRFs to Tables, Listings and Graphs analysing data of a Single-centre, Randomized, Single-Dose, Open-label, 4-way Cross over study
A leading international pharmaceutical company involved in manufacturing of drugs.
The Challenges
A pharmaceutical company approached Guires to develop integrated SAP (that includes a detailed description of all patient population, and statistical analyses to be carried out on the data collected during the clinical investigation), for the integrated summary of safety (ISS) and integrated summary of Efficacy (ISE), based on the research objective and requirement analyses. The requirements were to produce Tables, Listing and Graphs (TLGs) for Phase IIa based on pre-defined objectives and hypothesis (i.e., in this case, bioavailability and dose proportionality endpoints). Besides, the client also requested Guires to validate the TLG through an independent review of programming code by a statistical programmer, different from the one who generate original programs. Finally, to produce a clinical statistical report (CSR) in conjunction with the preparation of a full clinical report
Our Strategy
The study was Phase 1, open-label, randomised, single-dose, cross-over study to estimate the dose proportionality and bioavailability in TD delivery system relative to comparator immediate-release tablet formulation in adult healthy volunteers. The study statistician worked closely with the client to get an in-depth insight on clinical trial and the study, trial planning, the way it has been conducted and reported, and about regulatory requirements involved with it. The statistician also worked with in-house medical experts to refine the objectives and identified variables that were required from the client’s end. This includeds type of design and comparison, randomization and blinding method, definition and measurement of primary and secondary indicators, test hypothesis, definition of analysis set, plan for efficacy and safety evaluation and statistical analysis, principles for the analysis of primary indicators and expected method of analysis, and finally generalized principles and methods for explanator trials. The datasheet was shared to us that contained participant information including their demographic, clinical parameters including their body mass index, medical history, physical examination, electrocardiogram (ECG), routine laboratory tests (blood chemistry, haematology, and urinalysis. Prior to database lock, we cross-checked for any mismatches with the data shared and the objectives /endpoints.
The draft of statistical analysis plan (SAP) and TLF and other necessary documents as final protocol, incorporating all amendments and summaries, the SAP template used to create the SAP and investigator brochure was handed over to the medical writer. The role of the medical writer was to perform functional QC in terms of content, reliability and format. We ensured that the medical writer provided comments on TLFs prior to database lock. Once the SAP was finalized, medical writer drafted CSR without the inclusion of actual results and circulated the shell for co-author’s review. Conflicting comments were resolved successfully. After database lock, final TLFs were run and handed over to medical writer which included a) final SAP including any amendments b) Interim analysis findings and c) Approved TLFs in a prescribed format.
Our Outcomes and Impact
An appropriate analysis was carried out, such as descriptive statistics, linear regression analysis with log-transformed data to examine the relationship of dose and AUCs and identify dose linearity. To identify effects due to participant, period and treatment, a cross-over analysis of variance (ANOVA)using log-transformed dose-adjusted AUC and Cmax. Using the pooled residual error and associated degrees of freedom from the ANOVA, the power to detect a 20% difference between treatment means for an alpha level of 0.05 (2-tailed) was calculated. Our medical writer experienced in handling pharmacokinetics came up with a clinical study report accompanied by tables, listing and figures (TLFs) displaying all study data and results with required appendices compliant with International Conference on Harmonization (ICH) E3 (Structure and Content of Clinical Study Reports) guidelines. Our writer ensured to follow standard American Medical Association (AMA) punctuation rules. The report was prepared with a description of the findings of the statistical analyse for the clinical investigation and confirm that the analyses were conducted per the statistical analysis plan. Deviations from the statistical analysis plan or additional unplanned analyses are fully described in the statistical report.
Lessons Learned
- During the analyses, it is mandatory to check study objectives, efficacy parameters and safety parameters were consistent with the protocol. If any changes, the justifications should be described.
- The statistician must understand how the TLFs correspond to the study objectives and endpoints.
- It is the responsibility of the medical writer to refer and state World Health Organization Drug Dictionary WHO DD and Medical Dictionary for Regulatory Activities (MedDRA) to clarify the definitions.
