Submitting Advanced Bioanalytical Test Methods for Regulatory Approval - - BioPharm International

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Submitting Advanced Bioanalytical Test Methods for Regulatory Approval


BioPharm International


Demonstrating Non-inferiority


Figure 2. Graphical Illustration of Non-Inferiority Results for Candidate Test vs EP/USP Sterility Test
A faster and technologically advanced method for sterility testing was validated and compared to the compendial EP/USP sterility test. The non-inferiority comparison at the 95% confidence level (p=0.05) was chosen with a pre-specified delta of –10% versus the compendial (current) method. A non-inferiority test with a delta of –10% was justified. Non-inferiority, equivalence, and superiority are all acceptable outcomes, and the increased testing frequency of daily (n=7 per week) for the new sterility versus twice weekly (n=2 per week) for the EP/USP Sterility test significantly increases the likelihood of detecting organisms with the new method. The statistical results are given in Figure 1, and a graphical presentation of the 95% confidence interval is shown in Figure 2. The 95% confidence level in Figure 2 includes 0 (no difference) and lies entirely to the right of the pre-specified delta of –10%. The comparison results indicate that the candidate method is not inferior to the EP/USP sterility test method.

Demonstrating Superiority


Figure 3. Results for the Superiority Test: New Method (7x per Week) vs. EP/USP Sterility (2x per Week)
When the relative testing frequency of our example under non-inferiority of n=7 (new method) versus n=2 (EP/USP method) for the compendial method is integrated in our comparison studies, the superiority of the new method could be demonstrated. A summary of the statistical results (at 95% confidence) using the data from Figure 1 is given in Figure 3. Superiority at the 95% confidence level could be demonstrated because the new method's 95% confidence interval (0.9997 – 1.0000) for the positive-to-fail probability (0.9999) lies entirely to the right of the 95% confidence interval (0.9205 – 0.9665) of the compendial method's positive-to-fail probability (0.9472). Therefore, the likelihood of observing potential microbial growth is significantly increased when the sampling frequency is integrated.

Given the results when different testing frequencies were considered, we could have easily demonstrated the superiority of the new method versus non-inferiority with a difficult-to-justify, pre-specified delta. At the end, the superiority test was passed with a much greater relative margin than the non-inferiority test. This is a good example why we should always first consider an upfront comparison study to select and defend our strategy in regulatory submission.


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