Posting: # 20242
We have carried out MKR (micro kill rate) study with clinical endpoints based on FDA guidance June 2016, and kill rate were measured at 5min, 10min, 15min, 60min and 120min.
In OGD (Draft Guidance on Dexamethasone; Tobramycin), it is states that 90% confidence interval for test/reference ratios of average kill rate for each time points should be calculated but they do not define any equivalence limit criteria.
In protocol it was specified that descriptive statistics is to be provided for all organisms at all sampling times. The primary evaluation, on which the 90% confidence intervals were calculated, for each organism, was 120 minutes (i.e. maximum time point) and equivalent limit was set as 80% to 125%.
The two one-sided test procedure was used to determine the 90% confidence interval for the test/reference ratios of average kill rate for 120 min.
When we evaluated results, out of 17 organisms, 14 organisms fall well within 80% to 125% limit. The three organisms which are not within the limits are Aspergillus brasiliensis, Candida albicans and Acinetobacter calcoaceticus
On other hand GMR (Geometric Mean Ratio) of all organism falls well within 80% to 125% limit at 60 min and at 120 min. Refer below table for results.
Summary statistics at 120 minutes.
Kindly give your opinion on the following:
Edit: Category changed; see also this post #1. Guidance linked. [Helmut]
Posting: # 20243
this is a failed trial, and there is little reason to submit in the present form, it will most likely be rejected.
However, you do have data strongly indicating that your product is not bioinequivalent. I think your problem is very likely a lack of power for the fungi.
It is probably this sentence that got you into trouble: "The in vitro microbial kill rate study should be conducted by using at least 12 replicates for each kill rate study of each organism." I guess you never really went into the "at least" part
You need to send a quick controlled correspondence to FDA and argue that it is lack of power that is your problem (not lack of BE, you just failed to show BE at your current sample size), and try to convince them that a repeat trial on some or all of the organisms with increased sample size is necessary and justified (you will need to discuss type I errors and more, rather than focusing only on bacteriology and mycology). Await their response and do exactly what they tell you.
Good luck. Please post here what you decide to do and what the outcome is.
I could be wrong, but...