Justifying the lack of incurred sample reproducibility in a study Perspective
specific to each laboratory but can also provide use- able data. One must however take into account that these samples were repeated because of a doubt on the initial result. Therefore, as with the analytical repeats, the use of the nonanalytical repeat data to dem- onstrate that an assay is reproducible must be done carefully and accompanied by a rationale. The evaluation of the repeat analysis in order to
show the reproducibility of the assay is illustrated in Figure 2 below.
The obtained PK data in the study Following the EMA recommendation, in the absence of ISRs, the PK data obtained in the study should be compared with the PK data available in-house or in the literature. Of course, this element of the justification is easier applied for bioequivalence studies. When possible, as a first attempt, the study princi- ,
pal PK parameters data such as mean Cmax, AUC 0-inf Tmax
available from the monograph of the reference prod- uct or from a paper published by a regulatory agency like the FDA, EMA or MHRA. If PK data is not available from such references, comparison can also be made with published PK data from other sources. In this case, an exhaustive literature review is performed
and T1/2 are compared with the published data
administration of a drug when the maximum plasma concentration is reached.
Key terms Cmax
AUC0-inf
/Tmax: Maximum observed concentration/Time after : Area under the concentration time curve from
time zero to infinity calculated as AUC0-t + Clast/Kel. T1/2
: Apparent elimination half-life calculated as: ln 2/Kel.
90% geometric confidence interval: Confidence intervals provide an ‘estimate interval’, that is, a range of values around the point estimate within which the true value can be expected to fall. For example, for a ratio (or point estimate) and 90% CI equal to 92% (85% to 115%), the 90% confidence interval provides a range, in this case 85% to 115%, within which we are 90% confident that the true population proportion would have a point estimate of 92%.
Intra subject coefficient of variation: Differences in the plasma levels of a given drug in the same subject when given on different occasions.
in order to obtain the most relevant PK data, in other words, from clinical studies using the same refer- ence product (similar formulation) administered in the same conditions (single or multiple doses, fasted or fed state, etc.) to a comparable study population. Finally, when no data are available from literature, PK data from an in-house study, using or not the same
Repeats in the project?
No
Yes
Runs rejected for causes other than the calibration curve not meeting acceptance criteria?
• Disregarded repeats? • Investigational or PK repeats? • Analytical repeats?
No
Yes
Build an ISR table and assess reproducibility
Build an ISR table and assess reproducibility
The justification will have to rely on the other response elements
Figure 2. Summary of the repeat analysis evaluation process. ISR: Incurred sample reanalysis; PK: Pharmacokinetic.
future science group
www.future-science.com 225
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92 |
Page 93 |
Page 94 |
Page 95 |
Page 96 |
Page 97 |
Page 98 |
Page 99 |
Page 100 |
Page 101 |
Page 102 |
Page 103 |
Page 104 |
Page 105 |
Page 106 |
Page 107 |
Page 108 |
Page 109 |
Page 110 |
Page 111 |
Page 112 |
Page 113 |
Page 114 |
Page 115 |
Page 116 |
Page 117 |
Page 118 |
Page 119 |
Page 120 |
Page 121 |
Page 122 |
Page 123 |
Page 124 |
Page 125 |
Page 126 |
Page 127 |
Page 128 |
Page 129 |
Page 130 |
Page 131 |
Page 132 |
Page 133 |
Page 134 |
Page 135 |
Page 136 |
Page 137 |
Page 138 |
Page 139 |
Page 140 |
Page 141 |
Page 142 |
Page 143 |
Page 144 |
Page 145 |
Page 146 |
Page 147 |
Page 148 |
Page 149 |
Page 150 |
Page 151 |
Page 152 |
Page 153 |
Page 154