kumarnaidu
★    

Mumbai, India,
2019-04-26 10:31

Posting: # 20242
Views: 442
 

 In-vitro microbial kill rate study [Study As­sess­ment]

Hi,

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In OGD (Draft Guidance on Dexamethasone; Tobramycin), it is states that 90% confidence interval for test/reference ratios of average kill rate for each time points should be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.
Parameter                                      RefGeoLSM  TestGeoLSM  Ratio   Lower  Upper
1=Escherichia coli ATCC 8739                      99.78       99.80   100.02   99.96 100.09
2=Pseudomonas aeruginosa ATCC 9027                99.96       99.96   100.00   99.99 100.02
3=Klebsiella pneumonia ATCC 700603                45.10       49.53   109.82   96.55 124.91
4=Staphylococcus aureus ATCC 6538                 99.98       99.98   100.00   99.99 100.01
5=Haemophilus influenzae ATCC 10211 (June 2018)  100.00      100.00   100.00  100.00 100.00
5=Haemophilus influenzae ATCC 10211 (Dec 2018)   100.00      100.00   100.00  100.00 100.00
6=Aspergillus brasiliensis ATCC 16404             10.03       12.23   121.96   90.67 164.05
7=Morganella morganii ATCC 49993                  98.69       98.49    99.80   99.26 100.34
8=Actinobacillus pleuropneumoniae ATCC 43803      99.43       98.91    99.48   99.09  99.88
9=Candida albicans ATCC 10231                     13.68       11.71    85.62   59.54 123.11
10=Acinetobacter calcoaceticus ATCC 51432         55.96       51.17    91.43   78.42 106.59
11=Staphylococcus epidermidis ATCC 35984          67.41       63.31    93.91   80.79 109.15
12=Proteus mirabilis ATCC 29906                   97.58       97.72   100.15   99.67 100.63
13=Enterobacter aerogenes ATCC 15038              99.97       99.98   100.01  100.00 100.02
14=Proteus vulgaris ATCC 13315                    99.17       98.84    99.67   99.44  99.90
15=Neisseria sicca ATCC 29256                     99.99       99.99   100.00  100.00 100.00
16=Moraxella lacunata ATCC 11748                 100.00      100.00   100.00  100.00 100.00
17=Streptococcus pneumoniae ATCC 49619            99.99       99.93    99.94   99.88 100.00


Kindly give your opinion on the following:
  • Is it reasonable to claim bio equivalence on the GMR values rather than 90% CI.
  • Two out of three which are outside criteria are anti-fungal, can these be ignored and justified based on the results obtained only. That is not applying the 90% CI criteria.
  • Is there any widening criteria for such type of product?
Your inputs will be highly appreciated.


Edit: Category changed; see also this post #1. Guidance linked. [Helmut]

Kumar Naidu
ElMaestro
★★★

Denmark,
2019-04-26 11:07

@ kumarnaidu
Posting: # 20243
Views: 390
 

 In-vitro microbial kill rate study

Hi KumarNaidu,


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...
Best regards,
ElMaestro
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