PHARMACOKINETIC STUDY DESIGN AND DATA HANDLING IN BIOEQUIVALANCE STUDIES FOR SOLID DOSAGE FORM , ABBREVIATED NEW DRUG APPLICATION (ANDA) , NDA , IND SUBMISSIONS
For both replicate and nonreplicate, in vivo pharmacokinetic bioequivalence BE studies, the following general approaches are recommended, recognizing that the elements can be adjusted for certain drug substances and drug products. Study conduct:
• The test or reference products can be administered with about 8 ounces (240 milliliters) of water to an appropriate number of subjects under fasting conditions, unless the study is a food-effect bioavailability BA and bioequivalence BE study.
• Generally, the highest marketed strength can be administered as a single unit. If warranted for analytical reasons, multiple units of the highest strength can be administered, providing the total single-dose remains within the labeled dose range.
• An adequate washout period (e.g., more than 5 half lives of the moieties to be measured) would separate each treatment.
• The lot numbers of both test and reference listed drug RLD products and the expiration date for the reference product would be stated. The drug content of the test product cannot differ from that of the reference listed product by more than 5 percent. The sponsor can include a statement of the composition of the test product and, if possible, a side-by-side comparison of the compositions of test and reference listed drug products. In accordance with CFR 320.38, samples of the test and reference listed product must be retained for 5 years.
• Before and during each study phase, FDA recommend that subjects
(1) be allowed water as desired except for 1 hour before and after drug administration,
(2) be provided standard meals no less than 4 hours after drug administration, and
(3) abstain from alcohol for 24 hours before each study period and until after the last sample from each period is collected.Sample collection and sampling times:
FDA recommend that under normal circumstances, blood, rather than urine or tissue, be used. In most cases, drug, or metabolites are measured in serum or plasma. However, in certain cases, whole blood may be more appropriate for analysis. FDA recommend that blood samples be drawn at appropriate times to describe the absorption, distribution, and elimination phases of the drug. For most drugs, FDA recommend that 12 to 18 samples, including a predose sample, be collected per subject per dose. This sampling can continue for at least three or more terminal half lives of the drug. The exact timing for sample collection depends on the
nature of the drug and the input from the administered dosage form. The sample collection can be spaced in such a way that the maximum concentration of the drug in the blood (Cmax) and terminal elimination rate constant (λz) can be estimated accurately. At least three to four samples can be obtained during the terminal log-linear phase to obtain an accurate estimate of λz from linear regression. FDA recommend that the actual clock time when samples are drawn as well as the elapsed time related to drug administration be recorded.
Subjects with predose plasma concentrations:
• If the predose concentration is ≤ 5 percent of Cmax value in that subject, the subject’s data without any adjustments can be included in all pharmacokinetic measurements and calculations. FDA recommend that if the predose value is > than 5 percent of Cmax, the subject be dropped from all BE study evaluations.
Data deletion due to vomiting:
• FDA recommend that data from subjects who experience emesis during the course of a BE study for immediate-release products be deleted from statistical analysis if vomiting occurs at or before 2 times median Tmax. In the case of modified-release products, the data from subjects who experience emesis any time during the labeled dosing interval can be deleted. The following pharmacokinetic information is recommended for submission:
• Plasma concentrations and time points
• Subject, period, sequence, treatment
• AUC0-t, AUC0-∞, Cmax, Tmax, λz , and t1/2
• Intersubject, intrasubject, and/or total variability, if available
• Cmin (concentration at the end of a dosing interval), Cav (average concentration during a dosing interval), degree of fluctuation [(Cmax-Cmin)/Cav], and swing [(Cmax-Cmin)/Cmin] if steady-state studies are employed
• Partial AUC, requested only as discussed in section III. A.9.a. In addition, FDA recommend that the following statistical information be provided for AUC0-t, AUC0-∞, and Cmax:
Geometric mean
• Arithmetic mean
• Ratio of means
• Confidence intervals
FDA also recommend that logarithmic transformation be provided for measures used for bioequivalence BE demonstration.
Rounding off of confidence interval values:
• FDA recommend that confidence interval (CI) values not be rounded off; therefore, to pass a CI limit of 80 to125, the value would be at least 80.00 and not more than 125.00.
For both replicate and nonreplicate, in vivo pharmacokinetic bioequivalence BE studies, the following general approaches are recommended, recognizing that the elements can be adjusted for certain drug substances and drug products. Study conduct:
• The test or reference products can be administered with about 8 ounces (240 milliliters) of water to an appropriate number of subjects under fasting conditions, unless the study is a food-effect bioavailability BA and bioequivalence BE study.
• Generally, the highest marketed strength can be administered as a single unit. If warranted for analytical reasons, multiple units of the highest strength can be administered, providing the total single-dose remains within the labeled dose range.
• An adequate washout period (e.g., more than 5 half lives of the moieties to be measured) would separate each treatment.
• The lot numbers of both test and reference listed drug RLD products and the expiration date for the reference product would be stated. The drug content of the test product cannot differ from that of the reference listed product by more than 5 percent. The sponsor can include a statement of the composition of the test product and, if possible, a side-by-side comparison of the compositions of test and reference listed drug products. In accordance with CFR 320.38, samples of the test and reference listed product must be retained for 5 years.
• Before and during each study phase, FDA recommend that subjects
(1) be allowed water as desired except for 1 hour before and after drug administration,
(2) be provided standard meals no less than 4 hours after drug administration, and
(3) abstain from alcohol for 24 hours before each study period and until after the last sample from each period is collected.Sample collection and sampling times:
FDA recommend that under normal circumstances, blood, rather than urine or tissue, be used. In most cases, drug, or metabolites are measured in serum or plasma. However, in certain cases, whole blood may be more appropriate for analysis. FDA recommend that blood samples be drawn at appropriate times to describe the absorption, distribution, and elimination phases of the drug. For most drugs, FDA recommend that 12 to 18 samples, including a predose sample, be collected per subject per dose. This sampling can continue for at least three or more terminal half lives of the drug. The exact timing for sample collection depends on the
nature of the drug and the input from the administered dosage form. The sample collection can be spaced in such a way that the maximum concentration of the drug in the blood (Cmax) and terminal elimination rate constant (λz) can be estimated accurately. At least three to four samples can be obtained during the terminal log-linear phase to obtain an accurate estimate of λz from linear regression. FDA recommend that the actual clock time when samples are drawn as well as the elapsed time related to drug administration be recorded.
Subjects with predose plasma concentrations:
• If the predose concentration is ≤ 5 percent of Cmax value in that subject, the subject’s data without any adjustments can be included in all pharmacokinetic measurements and calculations. FDA recommend that if the predose value is > than 5 percent of Cmax, the subject be dropped from all BE study evaluations.
Data deletion due to vomiting:
• FDA recommend that data from subjects who experience emesis during the course of a BE study for immediate-release products be deleted from statistical analysis if vomiting occurs at or before 2 times median Tmax. In the case of modified-release products, the data from subjects who experience emesis any time during the labeled dosing interval can be deleted. The following pharmacokinetic information is recommended for submission:
• Plasma concentrations and time points
• Subject, period, sequence, treatment
• AUC0-t, AUC0-∞, Cmax, Tmax, λz , and t1/2
• Intersubject, intrasubject, and/or total variability, if available
• Cmin (concentration at the end of a dosing interval), Cav (average concentration during a dosing interval), degree of fluctuation [(Cmax-Cmin)/Cav], and swing [(Cmax-Cmin)/Cmin] if steady-state studies are employed
• Partial AUC, requested only as discussed in section III. A.9.a. In addition, FDA recommend that the following statistical information be provided for AUC0-t, AUC0-∞, and Cmax:
Geometric mean
• Arithmetic mean
• Ratio of means
• Confidence intervals
FDA also recommend that logarithmic transformation be provided for measures used for bioequivalence BE demonstration.
Rounding off of confidence interval values:
• FDA recommend that confidence interval (CI) values not be rounded off; therefore, to pass a CI limit of 80 to125, the value would be at least 80.00 and not more than 125.00.
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