Evaluating Missing Data in BA/ BE Trials – BioPharma Services

Refer to Part 1 and Part 2 of this topic series.

This blog is based off a poster presentation presented at the ASCPT 2024 annual meeting. To download a PDF version, click here.

Clinical studies are, albeit well-controlled, not immune to missing data, and it is crucial to retain statistical power as a few missing values can disrupt a study. It’s important to recognize that incomplete observations are also a major source of bias and the strategy employed to handle them might be a potential source of bias itself. Presently, there is no universal best approach to handle these problematic data in the Bioavailability/Bioequivalence (BA/BE) realm. 

To investigate the influence of including or excluding missing data on Bioavailability/Bioequivalence results, we conducted simulations incorporating varying degrees of missing individual Cmax values.

The Method

To observe the impact of missing data on the BE outcome, a “control group” which has a complete dataset and is sensitive to missing values was generated.

Python was utilized to generate 3 “control groups” mimicking 2-way crossover studies of 50 subjects with the same 16-TP sampling schedule from a master set of 280 subjects with intact data. All control studies showed Bioequivalence with ISCVs of up to 37%. Simulations with low to high rates of subjects missing Cmax were also created.

NCA and ANOVA were performed using WinNonlin® Phoenix 8.3. Scenarios failing FDA-defined Bioequivalence criteria were considered to critically impact BE results. Missing data and its effects on concentration-time curves were reviewed to address changes in Pharmacokinetic profiles.

Fig. 1) Flowchart of the simulation procedure GMRs comparison

The Results

A total of 33 simulations were generated.

In scenarios where subjects with missing Cmax values were included, the second-highest concentrations were treated as the new Cmax for Bioequivalence analysis. Notably, Bioequivalence was achieved even at 70% missing data rates.

When impacted subjects were excluded, similar remarks were observed up to 30% missing rate. However, beyond this point, Bioequivalence was not met due to a substantial reduction in sample size. (Fig. 2a)

This finding mirrors our prior works on missing TPs within Tmax range, emphasizing that the threshold for inequivalence is markedly lower when impacted subjects are excluded compared to when they are retained. Nevertheless, it’s crucial to acknowledge that significant alterations in Pharmacokinetic profiles in the latter approach can forfeit the study’s overall conclusion. (Fig. 2b)

Fig. 2a) GMRs of Cmax and AUCt summarized by missing rates

Fig. 2b) Concentration-time profiles and Key PK parameters by different missing rates—including impacted subjects (Dataset a, Treatment B)

Many believe data loss around the absorption peak to be sensitive to study outcome, but our simulations showed that bioequivalence remains unaffected unless a substantial amount of data is missing.

Although including subjects allows greater tolerance to missing data in bioavailability and bioequivalence, it is crucial to strike a fine balance between preserving study power and minimizing impact on Pharmacokinetic profiles. Statistical compliance must also involve addressing the significance of any notable change in Pharmacokinetic profiles, considering their impact on the study’s reliability and practical implications.

Why Choose BioPharma Services for Your Next Drug Development Project? 

Recognizing the complexities inherent in maintaining the integrity of data and statistical power of Phase 1 or Bioavailability/Bioequivalence clinical studies, the BioPharma Services team possesses the requisite expertise to assess and anticipate possible scenarios, thereby formulating a meticulous analysis plan to ensure the study results’ validity.

Engaging a partner such as BioPharma Services for your drug development process ensures that you are working with professionals who are well-versed in handling missing data and similar challenges. Drawing upon our expertise in pharmacokinetics and our thorough understanding of regulatory standards, we skillfully navigate clients through the complexities of drug development, ensuring strict adherence to expected safety and efficacy standards.

Find out why BioPharma might be the right partner for you! Learn more about BioPharma Services and the wide array of bioanalytical services we provide.

Written by: Thuy Van Nguyen, Pharmacokinetic Scientist.