ª» π ß π Õ À ËÕß π π π ß π» «Ÿ π πÿ å Ÿª μ π ß π» «Ÿ π πÿ å

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1 ª» π ß π Õ À ËÕß π π π ß π» «Ÿ π πÿ å Ÿª μ π ß π» «Ÿ π πÿ å â«π ß π Õ À ÀÁ𠫪» Àâ â π π π ß π» «Ÿ π πÿ å Ÿª μ π ß π» «Ÿ π πÿ å æ ËÕ ªìπ π«ªø μ À⺟â Ëπ Õ π ß π» «Ÿ μ À ±å» «Ÿ âõ à ß Ÿ μâõß À ÿ æ ªìπ Ë Õ π Ÿ ªìπ ªμ μ π «Èß à«π à«àâ æ Õπÿ μ ß π» «Ÿ ªìπ ª Õ à ß ª æ Ëß Èπ ß Õ μ Õ π â ª»π È ß Õª» Àâ Ë«π ª» «π Ë ÿπ π æ.» π π À ºŸâª π ß π» «Ÿ π πÿ å ª π ß π» «Ÿ 1

2

3 2 π π À ºŸâª π ß π» «Ÿ π πÿ å ª π ß π» «Ÿ

4 2 Ÿª μ π Õß ß π» «Ÿ π πÿ å

5 π π æ ËÕ ß π» «Ÿ π πÿ å Ÿª μ π Õß ß π» «Ÿ π πÿ å Õß «ÿ π ß π Õ À «ß ÿ Ÿª μ π Õß ß π» «Ÿ π πÿ å 3

6 (CONTENTS) «ÿàßà (PURPOSE) 5 ß â ß Õß ß π (STRUCTURAL FORMAT) 5 Ÿª μ π Õß ß π» «Ÿ π πÿ å 6 Õ Õß ß π (DETAILS OF REPORT) 7 1. Õ π (Title/Cover Page) 7 2. ÿª àõ» (Study Synopsis) 9 3. (Table of Contents) àõ π» æ å (Abbreviations and Definitions of Terms) π (Introduction) «μ ÿª ß å (Objectives) âõ Ÿ Õߺ μ ±å (Product Information) ºπ» (Investigational Plan) º» Õ ª (Results and Discussion) ÿªº» (Conclusion) Õ Õâ ßÕ ß (References) ºπ«(Appendices) 38 πÿ (BIBLIOGRAPHY) 50 Ÿª μ π Õß ß π» «Ÿ π πÿ å Õ π (Title/Cover Page) ÿª àõ» (Study Synopsis) (Table of Contents) àõ π» æ å (Abbreviations and Definitio of Terms) π (Introduction) «μ ÿª ß å (Objectives) âõ Ÿ Õߺ μ ±å (Product Information) ºπ» (Investigational Plan) º» Õ ª (Results and Discussion) ÿªº» (Conclusion) Õ Õâ ßÕ ß (References) ºπ«(Appendices) 86 4 Ÿª μ π Õß ß π» «Ÿ π πÿ å

7 π π æ ËÕ ß π» «Ÿ π πÿ å GUIDANCE FOR PREPARATION OF THE IN VIVO BIOEQUIVALENCE STUDY REPORT π ß π Õ À Food and Drug Adminis «ÿàßà (PURPOSE) æ ËÕ Àâ ß π» «Ÿ Õߺ μ ±å π πÿ å Õߪ» ªìπ ªÕ à ß Ÿ μâõß π À μ π π π π μ π ß π Õ À Õß «ÿ ß â Õ çé π È Õ» À àß âõ Ÿ ß«Õߪ»μà ßÊ Õß The ASEAN Bioavailabilty/Bioequivalence (BA/BE) Taskforce æ ËÕ â ªìπ π«ß π ß πœ ºŸâ Ë «âõß ÿ ΩÉ â à ºŸâ Àâ ÿπ» «ºŸâ π π» ºŸâ º Õ ß πœ Õ Õß π π μ Õ π È Àâ â æõ «æ ËÕ Ë â ß πœ âõ à ß Ÿ μâõß â«π Ëß à«π à«àâ æ ß πœ Õß π ß π Õ À À ª Õ æ æ ËÕ Èπ πº μ ±å π π âõ à ß «Á«ªìπª πåμàõ ÿ ΩÉ ß â ß Õß ß π (STRUCTURAL FORMAT) ß π» «Ÿ œ ËμâÕß àß Õ Àâ Õß «ÿ æ æ ËÕ ªìπÀ πª Õ Èπ πμ À à (NG) «μ Ÿª μ π Õß ß π» ß π (Clinical Study Report) Õ Ëß Õ ÿ π ÈÕÀ Õ à ßπâÕ ßμàÕ ªπ È Ÿª μ π Õß ß π» «Ÿ π πÿ å 5

8 Ÿª Õß ß π» «Ÿ π πÿ å 1. Õ π (TITLE/COVER PAGE) 2. ÿª àõ» (STUDY SYNOPSIS) 3. (CONTENTS) 4. àõ π» æ å (ABBREVIATIONS AND DEFINITION OF TERMS) 5. π (INTRODUCTION) 6. «μ ÿª ß å (OBJECTIVES) 7. âõ Ÿ º μ ±å (PRODUCT INFORMATION) 8. ºπ» «(INVESTIGATIONAL PLAN) 9. º» Õ ª (RESULTS AND DISCUSSION) 10. ÿªº» (CONCLUSION) 11. Õ Õâ ßÕ ß (REFERENCES) 12. ºπ«(APPENDICES) 12.1 ß à ßß π» «Ë â Õπÿ μ Àπ ß Õ Õß «π πÿ å (Approval of the Institutional Review Board) 12.2 ß π ª πº «Àå (Validation Report) æ âõ âõ Ÿ μ (raw chromatograms) Õ à ßπâÕ 20% 12.3 ß π «Àå (Analytical Report) æ âõ âõ Ÿ μ (raw chromatograms) Õ à ßπâÕ 20% (Chromatogram) Õ à ßπâÕ 20% 12.4 ß π ª à«π âõ Ÿ À«à ß Õ μâπ (Comparative Dissolution Profile Report) 12.5 À π ß Õß μ π Õß π Ë» «ß π (Certificate of Clinical facility) ÀâÕßªØ μ Ëμ ««Àåº ß π (Clinical laboratory) μ ««Àå (Analytical laboratory) (if any) 6 Ÿª μ π Õß ß π» «Ÿ π πÿ å

9 Õ Õß ß π (DETAILS OF REPORT) π ÈÕÀ μà à«π Õß ß πœ «ª Õ â«õ ßμàÕ ªπ È 1. Õ π (TITLE/COVER PAGE) «π ÈÕÀ à πàπ ËßÀπâ π A4 ª Õ â«à» (study number), ËÕ μá Õß ËÕß Ë» (study title), ºŸâ π π» (investigators), π Ë», ºŸâ ß π (report written by), ºŸâ Àâ ÿπ» «(sponsorûs name), âõ Ÿ Õߺ μ ±å â à ËÕ (generic name) ËÕ â (brand name) Õß Ë Õ, Õâ ßÕ ß Ë â (reference drug), ÿàπ º μ (lot/batch number), «π ˺ μ (date of manufacture), «πà Õ ÿ(date of expiration), π Ë â (dosage strength) Ÿª ««Àâ Èß «À Õ À Èß Àâ âõß«à ß À Õ Àâæ âõ Õ À «π Ë â Õπÿ μ» à«ß ß π (clinical study date) à«ß ««Àå π Õ (analytical study date) «π «ËºŸâ«Õß ß π (report approved date) ßμ «Õ à ß πμ ß Ë 1 Ÿª μ π Õß ß π» «Ÿ π πÿ å 7

10 μ ß Ë 1:μ «Õ à ß Õ π (TITLE/COVER PAGE) ß π» «Ÿ œ Study Title: Protocol No. TPIC/BEP Comparative randomized, single dose, two-way crossover open-label study to determine the bioequivalence of acetaminophen formmulations, PARACETO 500 mg tablet and TYLENOL 500 mg tablet, after oral administration to healthy Thai volunteers. FINAL STUDY REPORT Principle Investigator: Dr. Deeda Jaroenkijakarn, Ph.D. Faculty of Biomedical Science, Central Bangkok University, Bangkok, THAILAND Clinical Investigator: Dr. Morthai Karndeemark, M.D. University Hospital, Central Bangkok University, Bangkok, THAILAND Clinical Laboratory Investigator: Dr. Tivavan Mankamnuan, Ph.D. University Hospital, Central Bangkok University, Bangkok, THAILAND Sponsor: THAI PHARMACEUTICAL INDUSTRIES COM. LTD (TPIC) Phaholyothin Road, Chatuchak, Bangkok 10900, THAILAND Analytical Investigator: Mr. Wijaya Lertkarnpean, M.S. Faculty of Biomedical Science, Central Bangkok University, Bangkok, THAILAND Pharmacokinetic and Statistic Investigator: Mr. Kamnuan Reungrojmaha, B.Pharm. Faculty of Biomedical Science, Central Bangkok University, Bangkok, THAILAND IRC/Ethical Approval Date: DD/MM/YYYY Clinical Study Date: DD/MM/YYYY - DD/MM/YYYY Analytical Study Date: DD/MM/YYYY - DD/MM/YYYY Approved Signatures: Principle Investigator:... Date.../.../... Clinical Investigator:... Date.../.../... Analytical Investigator:... Date.../.../... PK & Statistic Investigator:... Date.../.../... Other Investigator:... Date.../.../... 8 Ÿª μ π Õß ß π» «Ÿ π πÿ å

11 2. ÿª àõ» (STUDY SYNOPSIS) Àâ π Ÿª μ ß ËÕà π âßà π ÈÕÀ à π 3 Àπâ âõ Ÿ Õ à ßπâÕ ßμàÕ ªπ È sponsorûs name, product information (generic name, test and reference product), study title, protocol and study number, ethics, objectives, study design, administration, sampling, analytical method, pharmacokinetic parameters ßμ «Õ à ß πμ ß Ë 2 GENERIC NAME Acetaminophen TEST PRODUCT Paraceto REFERENCE PRODUCT Tylenol STUDY TITLE: INVESTIGATORS: PROTOCOL NUMBER STUDY NUMBER IRC/ ETHICS APPROVAL DATE OBJECTIVES: DOSAGE REGIMEN CLINICAL STUDY SITE STUDY SUBJECTS DEMOGRAPHIC DATA (N = 24) ADMISSION AND CONFINEMENT DRUG ADMINISTRATION μ ß Ë 2:μ «Õ à ß Ÿª ÿª àõ» (STUDY SYNOPSIS) SPONSORûs NAME: THAI PHARMACEUTICAL INDUSTRIES COM. LTD (TPIC) Comparative Randomized, Single Dose, Two-Way Crossover Open- Label Study to Determine the Bioequivalence of Acetaminophen from Paraceto 500 mg Tablet and Tylenol 500 mg Tablet, After Oral Administration to Healthy Thai Volunteers. Dr. Deeda Jaroenkijakarn, et al. TPIC/BEP TPIC/BES Central Bangkok University Ethic Committee, Thailand Approval Date DD/MM/YYYY To investigate the single dose bioequivalence of TPIC (Test Product, Paraceto Tablet) and McNeil (Reference Product, Tylenol Tablet) 500 mg acetaminophen per tablet in healthy adult Thai males after fasting conditions. Test Product: Single dose, 500 mg of Paraceto Tablet. Batch No. ####, Exp. Date MM/YY Refernce Product: Single dose, 500 mg of Tylenol Tablet. Batch No. ####, Exp. Date MM/YYYY CBU Hospital (Clinical Research Ward) 24 subjects plus 4 alternatives, selected randomly from healthy adult Thai male volunteers. Age = year; Height = cm; Weight kg Subjects were admitted the night before study drug administration, supervised for at least 10 overnight fasting and confined until collecting the 24-hr sample. Each subject randomly received an single dose of the assigned formulation, administered with 240 ml of water. Ÿª μ π Õß ß π» «Ÿ π πÿ å 9

12 GENERIC NAME Acetaminophen TEST PRODUCT Paraceto REFERENCE PRODUCT Tylenol μ ß Ë 2:μ «Õ à ß Ÿª ÿª àõ» (STUDY SYNOPSIS) (μàõ) SPONSORûs NAME: THAI PHARMACEUTICAL INDUSTRIES COM. LTD (TPIC) STUDY PERIOD Screening: DD/MM/YYYY - DD/MM/YYYY Enrollment: DD/MM/YYYY - DD/MM/YYYY Period 1: DD/MM/YYYY DD/MM/YYYY Period 2: DD/MM/YYYY - DD/MM/YYYY WASHOUT PERIOD 7 days from the first period: DD/MM/YYYY - DD/MM/YYYY BLOOD SAMPLING SCHEDULE Thirteen blood samples were drawn at 0.00 (pre-dose sample) and 0.25, 0.5, 1.0, 2.5, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, 12.0, and 24.0 hours (post-dose). The total volume of blood draw did not exceeded 300 ml. BLOOD SAMPLING HANDLING The blood sample for acetaminophen were placed in lithium heparin tubes, centrifuged, and the separating plasma samples were immediately stored at -20 o C until analyzed. CLINICAL SAMPLE STORAGE CBU Hospital Lab. ANALYTICAL SITE CBU Hospital Lab. BIOANALYTICAL METHODOLOGY HPLC with UV detector, LLOQ = 50 ng/ml ANALYTE Plasma acetaminophen concentration SAFETY EVALUATION Both treatments were well tolerated. No clinically significant or serious ADR were observed SURROGATE PARAMETERS Drug plasma concentrations to indicate clinical activity. PRIMARY PHARMACOKINETIC PARAMETERS C max, AUC 0 t, and AUC 0 SECONDARY PHARMACOKINETIC PARAMETERS T max, (AUC 0 t /AUC 0 )%, t 1/2, and K e PK CONFIDENCE INTERVALS 90% confidence intervals for the log-transformed Test/Reference ratios of : C max ( ( ) % AUC 0 t ( ( ) % AUC 0 ( ( ) % CONCLUSION Point estimates and the 90% confidence intervals for the log-trans formed ratios (Test/Reference) for the C max, AUC 0 t, and AUC 0 were within the Therefore, the bioequivalence of TPIC (Paraceto Tablet) and McNeil (Tylenol Tablet) 500 mg acetaminophen per tablet, can be concluded. DATE OF REPORT DD/MM/YYYY Ÿª μ π Õß ß π» «Ÿ π πÿ å

13 3. (CONTENTS) «ª Õ â«àπâ Õß π ÈÕÀ Ë ÿ π ß πœ μà à«π æ ËÕ ««π âπ Õ «Õßμ ß Ÿª ø ˪ Ø π ß πœ Õß ºπ«(Appendix) â«4. àõ π» æ å (ABBREVIATIONS AND DEFINITION OF TERMS) «ª Õ â«àõ π Õß «ÈßÀπà««(measurement unit) Ë â π ß π» œ πõ π È π π ÈÕÀ Õß ß πœ ËÕª Ø ËμâÕß àõ ªìπ Èß «ß μá àõ Ë âõ Ÿà π«ß Á 5. π (INTRODUCTION) Àâ πõ à ß ÿ Àμÿº «ªìπ Õß» «ß π«ë Ë «âõß (Relevant literatures) âõ Ÿ Ë «μ «Ë â π» «π ÈÕÀ ßμàÕ ªπ È 5.1 «(Pharmacology) ª «μ Ë Õß ß ª ÿ μ ß æ Õß (Physicochemical properties) «ÕÕ ƒ Ï (pharmacology and mechanism of action) âõ àß â ß π Ë â (therapeutic indication and dosage) 5.2 π» μ å (Pharmacokinetics) ÿ π» μ å π Õß Ëß Õ ÿ «π À Ê Õ Ÿ (absorption) (distribution) Õ (metabolism) à ÕÕ à ß (excretion) «Èß à æ μõ å Ë ß π» μ å Ë ºŸâ ß π «â â«ë Ë «âõß» «Ÿ àπ C max, AUC, K e, t max, t 1/3 ªìπμâπ 5.3 Àμÿ å àæ ߪ ß å (Adverse events) Àâ ÿõ àæ ߪ ß å (adverse drug reactions) âõ ««ß âõàâ â Õ πμ Õ Ëπ (precautions, contraindications and drug interactions) æ Ë À Õ Õ πμ ÿπ ß /À Õæ àõ Ÿª μ π Õß ß π» «Ÿ π πÿ å 11

14 6. «μ ÿª ß å (OBJECTIVES) Àâ ÿ Õ Õß«μ ÿª ß å» Õ μ Õß «ª πå Ë «à â Õ â âõ «Ë ÿ «â π Protocol àπ ç æ ËÕ ª Õ μ ª Ÿ Õߺ μ ±å... º μ ±å μâπ... ËÕ Àâ π π Ÿª «πé ªìπμâπ 7. âõ Ÿ º μ ±å (PRODUCT INFORMATION) «Õ Ë ªìπ â«π Èß Õߺ μ ±å Õ (Test product) º μ ±å Õâ ßÕ ß (Reference product) Ë â π» π ÈÕÀ ßμàÕ ªπ È 7.1 âõ Ÿ Õߺ μ ±å Õ ËÕ ß â (Trade Name) π ÕÕ ƒ Ï (Active Ingredient) «ß Ÿª μ (Strength, and Dosage Form) Ë ÿàπ º μ (Batch Number) «π ˺ μ «π ËÀ Õ ÿ(manufacturing Date and Expiry Date) «Õ âõß Õß π º μ À Õ «Ÿ (Batch size compliance) âõ Ÿ π ÈÕ â ºŸâ Àâ ÿπ Õ Õß μ Èßμ º μ ±å (Product Formulation) âõ Ÿ π ÈÕ â ºŸâ Àâ ÿπ ÿ μ æ Õߺ μ ±å Á Ÿª (Finished Product Specifications) ËÕ ËÕ Ÿà ÕߺŸâº μ (Name and Address of Manufacturer) 7.2 âõ Ÿ Õߺ μ ±å Õâ ßÕ ß ËÕ ß â (Trade Name) π ÕÕ ƒ Ï (Active Ingredient) «ß Ÿª μ (Strength, and Dosage Form) Ë ÿàπ º μ (Batch Number) «π ˺ μ «π ËÀ Õ ÿ(manufacturing Date and Expiry Date) π (registration number) ËÕ ËÕ Ÿà ÕߺŸâº μ (Name and Address of Manufacturer) ËÕ ËÕ Ÿà ÕߺŸâπ â À ÕºŸâ π Àπà (Name and Address of Importer or Authorization Holder) 12 Ÿª μ π Õß ß π» «Ÿ π πÿ å

15 7.3 âõ Ÿ «à ß (Pharmaceutical Equivalence Data) ª / «ß Õß π ÕÕ ƒ Ï (Content of Active Ingredient / Potency) «Ë Õ Õßμ «(Uniformity of Dosage Units) âõ Ÿ π ÈÕ â ºŸâ Àâ ÿπ (can be provided from sponsor) ß «â ªìπ Õ π ºπ«7.4 âõ Ÿ ª Õßμ «(Comparison of Dissolution Profiles) Àâ ß âõ Ÿ º Õß Èß μ ß Ÿª ø Ë ª Õß º μ ±å Èß Õßμ πμ «ß Ë À À Õμ Ë Àπ «â π μ μ π àπ 0.1 M HCl /À Õ Õ ËπÊ μ «ªìπ Àâ ß «Àåº ª Ÿª π à«ß «Ë À π«æ μõ å Èß à difference factor (f1) similarity factor (f2) æ âõ ÿªº ª Àâ π â«7.5 Àπ ß Õ Õßæ âõ ßπ ÕߺŸâ Àâ ÿπ» æ ËÕ π π«à º μ ±å Õ À Õπ º μ ±å Ë º μ æ ËÕ Àπà π âõßμ (Letter with a signed statement from the applicant confirming that the test produc is the same as the one that is submitted for marketing authorization) À Õ μ âõ Õ ß π Ÿªμ ß ÿª ª À«à ߺ μ ±å Õ Õâ ßÕ ß ßμ ß Ë 3 Ÿª μ π Õß ß π» «Ÿ π πÿ å 13

16 μ ß Ë 3 : μ «Õ à ßμ ß ÿª ª âõ Ÿ º μ ±å Õ Õâ ßÕ ß Õ º μ ±å Õ º μ ±å Õâ ßÕ ß (Test product) (Reference product) ËÕº μ ±å (Product/Brand Name) ºŸâº μ (Manufacturer) ÿàπ º μ (Batch/Lot No.) «π ˺ μ (Manufacture Date) DD/MM/YYYY DD/MM/YYYY «π ËÀ Õ ÿ (Expiration Date) DD/MM/YYYY DD/MM/YYYY π «ß (Strength) ## mg ## mg π (Registration Number) N/A... Ÿª μ (Dosage Form) π ÿàπº μ Ë â π» «Ÿ... N/A (Bio-batch Size) «Ë Õ Õßμ «... N/A (Content Uniformity, mean, %CV) π Ë â (Dose Administered) ## mg x single dose ## mg x single dose «Àâ (Route of Administration) PO PO 14 Ÿª μ π Õß ß π» «Ÿ π πÿ å

17 8. ºπ» (INVESTIGATIONAL PLAN) «ª Õ â«ëμâõß ß ßμàÕ ªπ È 8.1 Ÿª» ß π (Clinical Study Design) Ÿª» Àâ ÿ Õ π / Ÿª «Ë â Õ cross over À Õ parallel «ß washout period π«πõ ºŸâ â à (Number of subjects) ±å â ÕÕ À Õ âõ â ß«μàÕÕ (inclusion, exclusion, restriction) ±å ÕπÕ ÕÕ» (Removal or withdrawal of subject from Assessment) μ π Õß» (Standardization of study condition) «Àâ (Drug administration) ) Àâ æ âõ Õ À (fed) À Õ âõß«à ß (fasted) Àâ Èß «(single dose) À Õ ÀâÀ Èß (multiple does) «ª π ÿ æ ÕßÕ (Health verification) âõ Ÿ ß Õ Õ (Subject detail) π«πõ (Number of subjects) «π Ë» Period 1 Period 2 «Èß sequence Õß â Ë ß π «[ â ] ««Ë Á μ «Õ à ß Õ (Sampling protocol/ time) μ μ «Õ à ß Á sample preparation/ handling, storage) ª Õ Ë Á (Volume of blood collected) ΩÑ «ßÕ (Subject monitoring) «μ «ßÕÕ ßæ π ÿ (Genetic phenotyping) [ â ] 8.2 «Àâ æ ËÕ» (Study Treatments) π Ë â (Single or multiple) «ÿà Õ Ë â (Method of assigning subjects to treatment groups, Randomization) Õ ßμ ß randomization schedule æ ËÕ «π ª ªî (Blinding) ª πè Ë Àâ Ë (Water volume) Ÿª μ π Õß ß π» «Ÿ π πÿ å 15

18 8.3 π âõ Ÿ «ª Õ âõ Ÿ ß π ÕßÕ (Clinical and Safety Records) Õ àæ ߪ ß å (Drug related ADR) 8.4 æ μõ å ß π» μ å «Õ (Pharmacokinetic Parameters and Tests) Àâ ßπ π«(definitions and calculation) Õßæ μõ å ß π» μ å Ë «Ë «âõß ÈßÀ â à C max, T max, AUC 0-t, AUC 0-, t 1/2, etc. «ÿ ËÕ computer software æ âõ version Ë â π π«â«8 8.5 ««Àå ß μ (Statistical Analyses) ««Àå âõ Ÿ Ë ª ß à Õ (Log transformed) âõ Ÿ Ë à â ª ß Õ (Non-log transformed) «ª à «Ë Á μ «Õ à ß â (Sample time adjustments) à ૪ ««Àå«π å computer software æ âõ version Ë â π π«μ π Õ «à ß «Ÿ (Standards for bioequivalence) ÿ «π«90% CI ±å Õ Ë â «À à Power of test 8.6 ««Àå μ «Õ «Ÿ μâõß Õß««Àå (Assay Methodology and Validation) Õ ««Àå (Assay method description) «π «Ë Ë Èπ ÿ «Àå π μà à«ß (Start and stop date of each batch) æ âõ À Õ Ë â μ ««Àå (List of subjects being analyzed) «μ «Õ «Ÿ μâõß (Validation procedure) âõ Ÿ à æ μõ å Ë â à selectivity/specificity, accuracy, precision, recovery, stability, LOQ, LOD, linearity, etc. 8.7 ª π ÿ æ Õß âõ Ÿ (Data Quality Assurance) 16 Ÿª μ π Õß ß π» «Ÿ π πÿ å

19 9. º» Õ ª (RESULTS AND DISCUSSION) μ ß Ë º» ß π (Clinical Study Results) ߪ ÕßÕ (Demographic characteristics of the subjects) Õ ß â ªìπ 2 Õ À ªìπ» crossover Àâ ß Õ ßμ «Õ à ß πμ ß Ë 4 μà â ªìπ parallel Õ Èß Õß æ» À ÈÕ μ Á «μ ß ß âõ Ÿ æ Ë ßμ ß Ë 5 Õ Õß ß π (Details of clinical activity) Ë ß π ß à ß «Ë Àπ «â (Deviation from protocol) ßμ ß Ë 6 [ â ] âõ Ÿ â / æ Õ ÕŒÕ å/ Ÿ ÿà Ë (Results of drug/alcohol/smoking usage) ª «μ º μ ««π ß æ å (medical history and medical examination) â à æ (vital sign) º Õ «π ßÀâÕßªØ μ (diagnostic laboratory test) ÕßÕ μ ß Ë ß πõ àæ ߪ ß å (adverse reaction) Ë º μ ±å Õ º μ ±å Õâ ßÕ ß Ëæ π À«à ß» ßμ «Õ à ß π μ ß Ë º ÿª Õß μ «Õ «Ÿ μâõß Õß««Àå (Summary of validation and analytical results) ÀâÕ º» «Ëæ ß ª «ß π Ÿªμ ß ÿªº ß 9.3 º «Àå ß π» μ å (Pharmacokinetic Analysis) ªìπ à«π Ë «Ë ÿ âõ Ÿ π à«ππ È ßμâÕß Õ Ë â«π Ÿ μâõß âπ μ «Õ æ ËÕ ª π «à π ß «Ÿ Õߺ μ ±å âõ à ß ««Á«μâÕß âõ Ÿ Ë â«àå ß π» μ å â «Õ Õ à ßπâÕ ßμàÕ ªπ È âõ Ÿ ß Ëμ «æ πõ μà π Ë «μà ßÊ ËÕ â º μ ±å Õ (μ ß Ë 10) º μ ±å Õâ ßÕ ß (μ ß Ë 11) «Èß ß à Ë π Õ Ë «μà ß Ê À ß â º μ ±å Õ º μ ±å Õâ ßÕ ß (Mean Drug Concentration VS. Time Curve for Test and Reference Product) æ ß «æ π å À«à ß Ë Ë «μà ßÊ (Mean plasma concentration-time profile) ËÕ plot à ª μ (linear plot, Ÿª Ë 1) ËÕ Ÿ ª ß ªìπ Ÿª Õ (semi-logarithmic plot, Ÿª Ë 2) Ÿª μ π Õß ß π» «Ÿ π πÿ å 17

20 æ ß «æ π å À«à ß Ë «μà ßÊ ÕßÕ μà π (Individual subject plasma concentration-time profile) ( Ÿª Ë 3-5) μâõß ß ÿ π Èß linear semi-logarithmic plot æ μõ å ß π» μ åõ μà π ËÕ â º μ ±å Õ º μ ±å Õâ ßÕ ß (Individual Pharmacokinetic Parameters for Test and Reference Product) (μ ß Ë 12) à«π ª Õßæ μõ å ß π» μ å (C max, T max, AUC 0-t, AUC 0- ) Õ μà π À«à ߺ μ ±å Õ º μ ±å Õâ ßÕ ß (Individual Ratio of Test and Reference Product for Pharmacokinetic Parameters) (μ ß Ë 13-15) 8 18 Ÿª μ π Õß ß π» «Ÿ π πÿ å

21 μ ß Ë 4: μ «Õ à ß âõ Ÿ ª ÕßÕ Ë â à» cross over (Demographic data and date of the clinical study of individual subjects) Subject Sequence Sex Age (yr) Weight (Kg) Height (m) BMI Period 1 Date (DD/MM/YYYY) Period 2 Date (DD/MM/YYYY) 1 RT F /10/ /10/ TR M /10/ /10/ Mean SD CV% Minimum Median Maximum N Ÿª μ π Õß ß π» «Ÿ π πÿ å 19

22 μ ß Ë 5: μ «Õ à ß âõ Ÿ ª ÕßÕ Ë â à ª À«à ß ÿà Ë â º μ ±å Õ Õâ ßÕ ß ªìπ» ËÕ π ÿà πà Õ Ÿà π π (parallel study) ÿ à Õß (Treatment Group) º μ ±å Õâ ßÕ ß (Reference product), N = º μ ±å Õ (Test product), N = Õ ÿ (ªï) Mean _ SD Range ÿà Õ ÿ (ªï) < 18 N (%) N (%) N (%) N (%) N (%) N (%) > 65 N (%) N (%) æ» Male N (%) N (%) Female N (%) N (%) ÈÕ μ ( À Asian N (%) N (%) ÈÕ μ ) Black N (%) N (%) Caucasian N (%) N (%) Hispanic N (%) N (%) Other N (%) N (%) + + BMI Mean _ SD Range æ μõ åõ ËπÊ ( â ) Ÿª μ π Õß ß π» «Ÿ π πÿ å

23 μ ß Ë 6: μ «Õ à ß ß Õ Õß «Á μ «Õ à ß Õ Ë Ë ß π Ë Àπ «â (Sampling time point protocol deviations). Subject number Time point (hr) Scheduled time Actual sampling time Deviations Hours Minutes Early/Late Reason for deviation Period Late Difficulty in finding vein Period Late Subject came late Ÿª μ π Õß ß π» «Ÿ π πÿ å 21

24 μ ß Ë 7.1: μ «Õ à ß ß Õ º μ «ßÀâÕßªØ μ π ÕßÕ μà π (List of individual clinical laboratory examinations). Pre-study Laboratory value Subject Number Lab. Parameter Normal Range Units Vital Signs Pulse beats/min Blood pressure / <90 sys/dia mm Hg 115/ Respiratory rate 8-14 rate/min Body temperature ÌC Blood chemistry Serum creatinine mg/dl Blood sugar mg/dl Urea nitrogen mg/dl Uric acid mg/dl Sodium meq/l Potassium meq/l Cholesterol mg/dl Triglyceride mg/dl Total protein g/dl Albumin g/dl Bilirubin (total) mg/dl Bilirubin (direct) mg/dl ALT (SGPT) 4-36 IU/L AST (SGOT) IU/L GGT 0-50 IU/L Serum amylase IU/L Alkaline phosphatase IU/L Ÿª μ π Õß ß π» «Ÿ π πÿ å

25 μ ß Ë 7.2: μ «Õ à ß ß Õ º μ «ßÀâÕßªØ μ π ÕßÕ μà π (List of individual clinical laboratory examinations. (continued)) Lab. Parameter Normal Range Units Pre-study Laboratory value Subject Number Hematology... Hemoglobin g/dl Hematocrit (M), (F) % RBC count million/mm Platelet count cells/mm Wbc count (total) 4,000-11,000 cells/mm 3 6, Neutrophils % Lymphocytes % Monocytes % Eosinophil % Blood group - A/B/AB/O B Urine analysis Appearance Clear, colorless-pale Pale yellow - yellow ph Specific gravity Protein Absent - Absent Glucose/Sugar Absent - Absent Bilirubin Absent - Absent Ketones Negative - Negative Blood Absent - Absent Leukocytes < 2-4 cells/ L μ Ÿª μ π Õß ß π» «Ÿ π πÿ å 23

26 μ ß Ë 8.1: μ «Õ à ß ÿª âõ Ÿ Õ àæ ߪ ß å Ëæ πõ À«à ß â º μ ±å Õ (TEST PRODUCT, T) Subject AE Dosing (D/T) Onset (D/T) Resolution (D/T) AE Duration Severity Outcome Relationship 01 Flatulence 7/10/07 / /10/07 / /10/07 / h 30 min Mild Spontaneous Possible 02 Diarrhea 7/10/07 / /10/07 / /10/07 / min Mild Spontaneous Possible 04 Headache 7/10/07 / /10/07 / /10/07 / h Moderate Spontaneous Probable 20 Diarrhea 7/10/07 / /10/07 / /10/07 / min Mild Spontaneous Possible μ ß Ë 8.2: μ «Õ à ß ÿª âõ Ÿ Õ àæ ߪ ß å Ëæ πõ À«à ß â º μ ±å Õâ ßÕ ß (REFERENCE PRODUCT, R) Subject AE Dosing (D/T) Onset (D/T) Resolution (D/T) AE Duration Severity Outcome Relationship 03 GI upset 28/10/2007 / /10/2007 / /10/2007 / h Mild Spontaneous Probable 09 Drowsiness 28/10/2007/ /10/2007 / /10/2007 / h Mild Spontaneous Possible 18 Headache 28/10/2007/ /10/2007 / /10/2007 / h 30 min Mild Spontaneous Probable 22 Diarrhea 28/10/2007 / /10/2007/ /10/2007/ min Mild Spontaneous Probable Ÿª μ π Õß ß π» «Ÿ π πÿ å

27 μ ß Ë 9: μ «Õ à ß ÿªº μ «Õ «Ÿ μâõß Õß««Àå Information Requested Data Analyte (drug) Provide the name(s) of the analyte(s) Internal standard (IS) Identify the internal standard used Method description Brief description of extraction method; analytical method Lower limit of quantitation LLOQ/LOQ, units Average recovery of drug (%) % Average recovery of internal standard (%) % Standard curve concentrations (units/ml) Standard curve range and appropriate conc. units Regression analysis Regression Model and weighting factor QC concentrations (units/ml) List all the concentrations used QC Intraday precision range (%) Range or per QC QC Intraday accuracy range (%) Range or per QC QC Interday precision range (%) Range or per QC QC Interday accuracy range (%) Range or per QC Freeze-thaw stability (cycles) # cycles Long-term stability (days) 17 ÌC (or other) Short-term stability (hrs) room temperature Post-preparative stability e.g. autosampler room temperature stability (hrs) Stock-solution stability (days) 4 ÌC Selectivity No interfering peaks noted in blank plasma samples Ÿª μ π Õß ß π» «Ÿ π πÿ å 25

28 μ ß Ë 10: μ «Õ à ߺ âõ Ÿ π Õ ÕßÕ μà π Ë «μà ßÊ (h) À ß â º μ ±å Õ (TEST PRODUCT, T) Subject S P Drug plasma concentration (ng/ml) for test product [T] at time (h) RT BLQ 2 TR Mean SD CV% Minimum Maximum N S = sequence of drug treatment, P = period of drug treatment, BLQ = below limit of quantification. Any concentration below LLOQ was record as BLQ except at time 0. Zero is used in the calculation of area under the curve (AUC) for times preceding the first observed concentration and in the calculation of summary statistics. 26 Ÿª μ π Õß ß π» «Ÿ π πÿ å

29 μ ß Ë 11: μ «Õ à ߺ âõ Ÿ π Õ ÕßÕ μà π Ë «μà ßÊ (h) À ß â º μ ±å Õâ ßÕ ß (REFERENCE PRODUCT, R) Subject S P Drug plasma concentration (ng/ml) for reference product [R] at time (h) RT BLQ 2 TR 2 BLQ Mean SD CV% Minimum Maximum N S = sequence of drug treatment, P = period of drug treatment, BLQ = below limit of quantification. Any concentration below LLOQ was record as BLQ except at time 0. Zero is used in the calculation of area under the curve (AUC) for times preceding the first observed concentration and in the calculation of summary statistics. Ÿª μ π Õß ß π» «Ÿ π πÿ å 27

30 Ÿª Ë 1 μ «Õ à ß ø ß «æ π å À«à ß Ë Ë «μà ßÊ πõ ËÕ â º μ ±å Õ Õâ ßÕ ß ËÕ â à ª μ (Linear plot of mean drug concentrations versus time in study subjects (N =24)) Ÿª Ë 2 μ «Õ à ß ø ß «æ π å À«à ß Ë Ë «μà ßÊ πõ ËÕ â º μ ±å Õ º μ ±å Õâ ßÕ ß ËÕ â à Ë Ÿ ª ß ªìπ Õ (Semi-logarithmic plot of mean drug concentrations versus time in study subjects (N =24)) 28 Ÿª μ π Õß ß π» «Ÿ π πÿ å

31 Ÿª Ë 3 ø ß «æ π å À«à ß Ë «μà ßÊ πõ μà (Individual Subject Profile or Spaghetti Plot) ËÕ â º μ ±å Õ (T) Ÿª Ë 4 ø ß «æ π å À«à ß Ë «μà ßÊ πõ μà (Individual Subject Profile or Spaghetti Plot) ËÕ â º μ ±å Õâ ßÕ ß (R) Ÿª μ π Õß ß π» «Ÿ π πÿ å 29

32 Ÿª Ë 5 μ «Õ à ß ø ß «æ π å À«à ß Ë «μà ßÊ πõ μà π ËÕ â º μ ±å Õ (T) Õâ ßÕ ß(R) ËÕ â à ª μ ( æ π) ËÕ â à Ë Ÿ ª ß ªìπ Õ ( æ à ß) 30 Ÿª μ π Õß ß π» «Ÿ π πÿ å

33 μ ß Ë 12: μ «Õ à ß ßæ μõ å ß π» μ åõ μà π ËÕ â º μ ±å Õ (TEST PRODUCT, T) º μ ±å Õâ ßÕ ß (REFERENCE PRODUCT, R) AUC 0-t AUC 0- T Subject Sequence max (h) C max (ng/ml) (ng.h/ml) (ng.h/ml) AUC 0-t /AUC 0- Half-life (h) Kel (h -1 ) Formulation Formulation Formulation Formulation Formulation Formulation Formulation T R T R T R T R T R T R T R 1 RT TR Mean SD CV% Minimum Maximum N Ÿª μ π Õß ß π» «Ÿ π πÿ å 31

34 μ ß Ë 13: μ «Õ à ߺ «Àå à«πæ μõ å C max ÕßÕ μà π ËÕ â º μ ±å Õ (TEST PRODUCT, T) º μ ±å Õâ ßÕ ß (REFERENCE PRODUCT, R) C max (ng/ml) Subject Test (T) Reference (R) Ratio (T/R) Untransformed Transformed Untransformed Transformed Untransformed Transformed data data (ln) data data (ln) data data (ln) Mean SD % CV Min Max N Ÿª μ π Õß ß π» «Ÿ π πÿ å

35 μ ß Ë 14: μ «Õ à ߺ «Àå à«πæ μõ å AUC 0-t ÕßÕ μà π ËÕ â º μ ±å Õ (TEST PRODUCT, T) º μ ±å Õâ ßÕ ß (REFERENCE PRODUCT, R) AUC 0- t (ng.h/ml) Subject Test (T) Reference (R) Ratio (T/R) Untransformed Transformed Untransformed Transformed Untransformed Transformed data data (ln) data data (ln) data data (ln) Mean SD % CV Min Max N Ÿª μ π Õß ß π» «Ÿ π πÿ å 33

36 μ ß Ë 15: μ «Õ à ߺ «Àå à«πæ μõ å AUC 0- ÕßÕ μà π ËÕ â º μ ±å Õ (TEST PRODUCT, T) º μ ±å Õâ ßÕ ß (REFERENCE PRODUCT, R ) AUC 0- (ng.h/ml) Subject Test (T) Reference (R) Ratio (T/R) Untransformed Transformed Untransformed Transformed Untransformed Transformed data data (ln) data data (ln) data data (ln) Mean SD % CV Min Max N Ÿª μ π Õß ß π» «Ÿ π πÿ å

37 9.4 º «Àå ß μ (Statistical Analyses) Àâ ߺ μ âõæ ß μ Ë â (Statistical considerations) º ÿª «Àå à æ μõ å ß π» μ å Ë π ß μ â à T max, C max, AUC 0-t, AUC 0-, extrapolated AUC, t 1/2, % K el (μ ß Ë 16) μ ß Ë 16 : μ «Õ à ß ß à æ μõ å ß π» μ å Ë º «Àå ß μ Product/Statistics 8 T max (h) C max * (ng/ml) AUC 0-t * (ng.h/ml) AUC 0- * (ng.h/ml) %ext. AUC Formulation T Mean CV (%) N Formulation R Mean CV (%) N Ratio of least square mean T/R (%) % Confidence Intervals (T/R) Lower Limit: Upper Limit: Power (%) Intra-subject CV (%) * Log-transformed parameters, the antilog of the mean (i.e. the geometric mean) is reported 8 t 1/2 (h) K el (1/h) Ÿª μ π Õß ß π» «Ÿ π πÿ å 35

38 º «ÀåÕ æ subject, sequence, period treatment (formulation) π Ÿªμ ß ßº «Àå «ª ª «π (ANOVA Table) (μ ß Ë 17) º ª à Ë Õß ß π» μ å «least squares (μ ß Ë 18) μ ß Ë 17 : μ «Õ à ßμ ߺ «Àå «ª ª «π (ANOVA Table) Õßæ μõ å ß π» μ å C max, AUC 0-t, AUC 0-8 Sources C max (Ln transformed data) D.F. SS MS F p-values Subject (Sequence) Sequence Period Treatment (Formulation) Error Total Sources AUC0-t (Ln transformed data) Subject (Sequence) Sequence Period Treatment (Formulation) Error Total Sources AUC 0- (Ln transformed data) 8 Subject (Sequence) Sequence Period Treatment (Formulation) Error Total Ÿª μ π Õß ß π» «Ÿ π πÿ å

39 ߺ ª π à à«ß Ààß «ËÕ Ëπ (90% confidence interval) À à à«π æ μõ å ß π» μ å Ë â π ª π «à ß «Ÿ Õ C max AUC Èß Ë â âõ Ÿ ËÕ ª ß âõ Ÿ ªìπ Õ (logarithmic) (μ ß Ë 18) μ ß Ë 18 : μ «Õ à ß ßº ª à Ë ÕßÕ μ à«π (Ratio of Log-transformed Least Square Mean) à«ß Ààß «ËÕ Ëπ (90% confidence interval) Õß à æ μõ å ß π» μ å Ë â π ª π «à ß «Ÿ Parameter Ratio of Least Square Mean 90% C.I. Ln C max Ln AUC 0-t Ln AUC ÿªº» (CONCLUSION) Àâ ÿª æ Ë Ë «âõß ß «à ß «Ÿ Õߺ μ ±å Õ º μ ±å Õâ ßÕ ß «Èß ª º «Àå ß μ Ëπ Ÿà âõ ÿª ß à «π È â«11. Õ Õâ ßÕ ß (REFERENCES) Õ Õ ß â π Harvard System À Õ Vancouver System À Õ Õ ËπÊ Ë ªìπ μ π Ë Õß Õâ ßÕ ßÕ à ß π «ªìπ «πμ Õ Èß ß π æ ËÕ à«π âπà Õ Õâ ßÕ ß π ˺Ÿâª πμâõß Õ Ë Ë «âõß æ Ë μ μ ßÕ à ß Õâ ßÕ ß Õß Èß Harvard System c]t Vancouver System Õ â ßμàÕ ªπ È Ÿª μ π Õß ß π» «Ÿ π πÿ å 37

40 The Harvard System YOU, C.H., LEE, K.Y., CHEY, W.Y., MENGUY, R. (1980) Electrogastrographic study of patients with unexplained nausea, bloating and vomiting, Gastroenterology 79, pp Royal College of General Practitioners (1998). The primary health care team. [Online]. Available from: URL: [Accessed August ]. The Vancouver System You CH, Lee KY, Chey WY, Menguy R. Electrogastrographic study of patients with unexplained nausea, bloating and vomiting. Gastroenterology 1980; 79: Royal College of General Practitioners. The primary health care team. [Online] [cited 1999 Aug 22]; [10 screens]. Available from: URL: /rcf0021.htm [Accessed August ]. 12. ºπ«(APPENDICES) 12.1 ß à ßß π» «Ë â Õπÿ μ /À Õ Àπ ß Õ Õß «π πÿ å (Approval of the Institutional Review Board) «Õ ª Õ æ â à Àπ ß ÕÕπÿ μ Õß ß à ßœ ÕßÀπà«ß π Ë Õ π àπ π ß π Õ À - ( â ) Àπ ß Õ Õß «π πÿ å Õß πà ÕÀπà«ß π (Approval of the Institutional Review Board) ß à ß «(Study Protocol) ß «π Õ (Informed Consent Form) Õ ÕßÕ À ËÕ â (Diet Listing) Õ Õß Ë ß π ß à ßœ (Protocol Deviation Listing) [ â ] Õ Àμÿ å àæ ߪ ß å (List of Adverse Events) Õ Õ ß âà μ «Õ à ß àπ Ë ß π μ ß Ë 19 [ â ] Case report form 38 Ÿª μ π Õß ß π» «Ÿ π πÿ å

41 μ ß Ë 19 : μ «Õ à ß ß Õ Àμÿ å àæ ߪ ß å Ëæ À«à ß» «Ÿ Body System / Reported AE Incidence by Treatment Groups Adverse Event Body as a whole Dizziness º μ ±å Õ (Test product) N (%) º μ ±å Õâ ßÕ ß (Reference product) N (%) Etc. N (%) N (%) Cardiovascular Hypotension N (%) N (%) Etc. N (%) N (%) Gastrointestinal Constipation N (%) N (%) Etc. N (%) N (%) Other organ system N (%) N (%) Total N (%) N (%) 12.2 ß π ª πº «Àå (Validation Report) æ âõ âõ Ÿ μ (raw chromatograms) Õ à ßπâÕ 20% Õ π Ÿª ß π Ë ËÕºŸâ º Õ «Àå Õ Õß Õß «ª Õ â«âõ Ÿ º «Àå ßμàÕ ªπ È «Ÿ μâõß àπ Õß «ËμË ÿ Ë«ª â (LLOQ) (μ ß Ë 20) «Ÿ μâõß àπ Õß «Ë «â âπμà ßÊ Èß Ë π«π «π μà ß π (within-day and between-day) (μ ß Ë 21) «æ π å ß âπμ ß (linearity) À«à ß response «â âπ Õß Ë μà ßÊ â regression equation ( Ÿª Ë 6) ÿ weighing factor ( â â) À % recovery Õß (μ ß Ë 22), internal standard ˺à π «π æ à «æ ß Õß««Àå (Selectivity) Ÿª μ π Õß ß π» «Ÿ π πÿ å 39

42 «ßμ «Õß πæ à ËÕ Ÿà π À«à ß «Àå â à freeze-thaw stability (μ ß Ë 23), short-term stability (μ ß Ë 24), long-term stability (μ ß Ë 25), postpreparation stability (μ ß Ë 24) stock-solution stability (μ ß Ë 27), ªìπμâπ À «âõõ ËπÊ μ «À àπ dilution integrity, matrix effect, anticoagulant effect, etc. μ ß Ë 20 : μ «Õ à ß Within-batch and between-batch precision and accuracy of LLOQ (25 ng/ml) of drug analysis. Within-batch Between-batch Sample number Measured value % Accuracy Day Measured value % Accuracy Mean Mean SD SD %CV %CV Data expressed as mean of 5 determinations. 40 Ÿª μ π Õß ß π» «Ÿ π πÿ å

43 μ ß Ë 21 : μ «Õ à ß Within-batch and between- batch precision and accuracy of drug analysis at three different concentrations i.e. low (LC), medium (MC) and high (HC). Sample/ Batch Within-batch precision Between-batch precision LC MC HC Sample LC MC HC Mean Mean SD SD % CV % CV Sample/ Batch Within-batch accuracy LC MC HC Measured % Measured % Measured % value Accuracy value Accuracy value Accuracy Mean SD % CV Sample/ Batch Between-batch accuracy LC MC HC Measured % Measured % Measured % value Accuracy value Accuracy value Accuracy Mean SD % CV Ÿª μ π Õß ß π» «Ÿ π πÿ å 41

44 CONCENTRATION (ng/ml) SLOPE INTERCEPT R 2 Nominal , , , Concentration Back calculated , , , concentration % Nominal Ÿª Ë 6 μ «Õ à ß âπ ø μ π Õß «Àå «ªìπ âπμ ß Õß âπ ø μ π Õß «Àå πμ «Õ à ß Õ 42 Ÿª μ π Õß ß π» «Ÿ π πÿ å

45 μ ß Ë 22 : μ «Õ à ß À % recovery Õß internal standard πμ «Õ à ß Õ ËÕºà π àõπ𠪫ÀåÀ ª Assay no. Peak Response LQC MQC HQC Un-extracted Extracted Un-extracted Extracted Un-extracted Extracted Mean SD %CV % Recovery μ ß Ë 23 : μ «Õ à ß «ßμ «Õß πμ «Õ à ß Õ ËÕºà π Á freeze-thaw 3 cycles Low QC (ng/ml) High QC (ng/ml) Assay No 0 cycle 3 cycle 0 cycle 3 cycle Mean SD %CV % Change Ÿª μ π Õß ß π» «Ÿ π πÿ å 43

46 μ ß Ë 24 : μ «Õ à ß «ßμ «Õß πμ «Õ à ß Õ ËÕπ «â ËÕÿ À Ÿ ÀâÕß ªìπ «μà ßÊ àõπ (Short Term Stability) LQC HQC (ng/ml) (ng/ml) No. 0 hr 3 hr * 6 hr * 0 hr 3 hr * 6 hr * Mean SD CV % Change * «Ë â Èπ «Ë «à μ «Õ à ß Õ Õ Ÿà ËÕÿ À Ÿ ÀâÕßπ π à π «à μ «Àå Á μ ß Ë 25 : μ «Õ à ß «ßμ «Õß πμ «Õ à ß Õ ËÕ Á «â ËÕÿ À Ÿ -80 ÌC À Õ Õÿ À Ÿ Õ Ëπ Ë â Á μ «Õ à ß Õ Day after storage * Low QC (ng/ml) Mean concentration (ng/ml) High QC (ng/ml) % Deviation Mean concentration % Deviation (ng/ml) * «Ë â «Õ ÿ «μ Èß μà Ë Á μ «Õ à ß Õ Õ π Ëß «Àåμ «Õ à ß ÿ â Èπ ÿ 44 Ÿª μ π Õß ß π» «Ÿ π πÿ å

47 μ ß Ë 26 : μ «Õ à ß «ßμ «Õß À ß μ Èß «â π ËÕß μ «Õ à ßÕ μ π μ (Postpreparative Stability) LQC (ng/ml) HQC (ng/ml) No. 0 hr 6 hr * 12 hr * 0 hr 6 hr * 12 hr * Mean SD CV % Change * «Ë â Èπ «Ë «à â π «Àåμ «Õ à ß π μà batch size μ ß Ë 27 : μ «Õ à ß «ßμ «Õß μ π Õßμ «Internal Standard Ë Á «â Ë Õÿ À Ÿ... o C Day after storage * Stock of Analyte (ng/ml) at... ÌC Mean concentration (ng/ml) Stock of IS (ng/ml) at... ÌC * «Ë â «Õ ÿ «Ë «à Á μ ππ Èπ «â % Deviation Mean concentration % Deviation (ng/ml) Ÿª μ π Õß ß π» «Ÿ π πÿ å 45

48 μ ß Ë 28: μ «Õ à ß ª π «Ë ß Õß««Àå μ «Õ à ß «ÿ ÿ æ (QC) Ë â À«à ß «Àåμ «Õ à ß «Ÿ Run Subject LQC (75 ng/ml) MQC (2400 ng/ml) HQC (4800 ng/ml) No. No. Cal conc. % RD Cal conc. % RD Cal conc. % RD , * Mean SD Accuracy (%RD) Precision (%CV) * Value outside acceptance limit. 46 Ÿª μ π Õß ß π» «Ÿ π πÿ å

49 μ ß Ë 29 : μ «Õ à ß ÿªº ª π «Ë ß Õß««Àå ËÕª π ø μ π (Standard Curve) μ «Õ à ß «ÿ ÿ æ (QC) Ë â À«à ß «Àåμ «Õ à ß «Ÿ * Summary of the Experimental Parameters and Results of the Valldation of a High performance Liquid Chromatographic Method for the Determlnation of Sertraline in Human Plasma EXPERIMENTAL PARAMETERS VALIDATION Analyte Sertraline Paroxeline Biological Matrix Plasma Plasma Detection (m/z) Retention Time (minute) Analytical Range (ng/ml) Minlmum Quantiflable (ng/ml) Within Batch Accuracy (%) Between Batch Accuracy (%) Within Batch Precision (%CV) Between Batch Precision (%CV) % Recovery LQC MQC-55.7 MQC HQC % Stability (Mean) Freeze/thaw lll Bench Top (5.25 Hours) In-injector (23.95 Hours) Stock Solution (18 Days) LongTerm (17 Days) (-70 ÌC) LongTerm (17 Days) (-20 ÌC) Dilution Integrity 2 Times Dilution Accuracy (%) Precision (% CV) Times Dilution Accuracy (%) Precision (%CV) Matrix Effect Accuracy (%) Precision (% CV) Ruggedness Within Batch Accuracy (%) Within BatchPrecision Z%CV) Effect of anticoagulant ACPD Accuracy (%) Precision (%CV) EDTA Accuracy (%) Precision (%CV) Ÿª μ π Õß ß π» «Ÿ π πÿ å 47

50 12.3 ß πº «Àå (Analytical Report) Ëß âõ Ÿ àπ μ Èß ÿ (Complete chromatogram of analytical run) Õ à ßπâÕ 20% º «Àåμ «Õ à ß Õ ÕßÕ ( Ÿª Ë 7) μâõß ß chromatograms Ë â Õ π Èπ ÿ μ «Õ à ß Èß Period 1 Period 2 «ß μ Õß standard curve QC sample Ë â «Àå π«π «π À Õ Èß «(batch/run) π μ «Õ à ß ÈßÀ ÕßÕ π Èπ Ÿª Ë 7 μ «Õ à ß μ Õß «Àå π Õ ÕßÕ Ë «2 Ë«ßÀ ß â Õ 12.4 ß π ª à«π âõ Ÿ À«à ß Õ μâπ (Comparative Dissolution Profile Report) Õ μ ß ÿªº «Àå ª Õß º μ ±å Õ Õâ ßÕ ß ßμ «Õ à ß π μ ß Ë À π ß Õß μ π Õß π Ë» «ß π (Certificate of clinical facility) ÀâÕßªØ μ Ëμ ««Àåº ß π (Clinical laboratory) μ ««Àå (Analytical laboratory) [ â ] 48 Ÿª μ π Õß ß π» «Ÿ π πÿ å

51 μ ß Ë 29 : μ «Õ à ß ÿªº «Àå ª Õߺ μ ±å Õ Õâ ßÕ ß Dissolution Conditions Apparatus: Speed of Rotation: Medium: Volume: Temperature: Firmûs Proposed Specifications Dissolution Testing Site (Name, Address) Study Testing Product ID \ Batch No. Ref No. Date (Test-Manufacture Date) (Reference - Expiration Date) Dosage No. of Strength Dosage & Form Units Study Test Product mg 12 Mean Report Tablet Range #: Capsule %CV Study Reference Product mg 12 Mean Report Tablet Range #: Capsule %CV Collection Times (minutes or hours) Study Report Location Provide dissolution data for all strengths (test and reference). Ÿª μ π Õß ß π» «Ÿ π πÿ å 49

52 πÿ (BIBLIOGRAPHY) De Muth JE. BASIC STATISTICS AND PHARMACEUTICAL STATISTICAL APPLICATIONS. Boca Raton: Chapman & Hall/CRC, 2006, 714 pp. Niazi SK. HANDBOOK OF BIOEQUIVALENCE TESTING. New York: Informa Healthcare USA, Inc., 2007, 569 pp. Shargel L, Kanfer I. GENERIC DRUG PRODUCT DEVELOPMENT. New York: Macel Dekker Inc., 2005, 381 pp. Õ ÕßÀπà«ß π Ë Ë «âõß EUROPEAN AGENCY FOR THE EVALUATION OF MEDICINAL PRODUCTS Guideline on the Investigation of Bioequivalence. 2010, 27 pp. Draft Guideline on the Evaluation of Bioanalytical assay. 2009, 17 pp. Questions and Answers on the Bioavailability and Bioequivalence Guideline. 2006, 5 pp. INTERNATIONAL CONFERENCE ON HARMONIZATION (ICH) E 3 Structure and Content of Clinical Study Reports. 1996, 48 pp. E 8 General Considerations for Clinical Trials, 1998, 14 pp. E 9 Statistical Principles for Clinical Trials. 1998, 37 pp. NATIONAL DRUG REGULATORY AGENCIES Thailand-FDA. Guidelines for the Conduct of Bioavailability and Bioequivalence Studies. 2009, 26 pp. US-FDA. Guidance for Industry: Statistical Approaches to Establishing Bioequivalence. 2001, 45 pp. US-FDA. Guidance for Industry: Bioanalytical Method Validation. 2001, 22 pp. US-FDA. Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations. 2003, 23 pp. US-FDA. Reviewer Guidance: Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review. 2005,79 pp. US-FDA. Guidance for Reviewer Staff and Industry: Good Review Management Principles and Practices for PDUFA Products. 2005, 32 pp. US-FDA. Manual of Policies and Procedures: Good Review Practices. 2006, 4 pp. Health Canada. Draft Guidance Document: Conduct and Analysis of Comparative Bioavailability Studies. 2009, 45 pp. Health Canada. Draft Guidance Document: Comparative Bioavailability Standards: Formulations Used for Systemic Effects. 2009, 8 pp. WORLD HEALTH ORGANIZATION Handbook for good clinical research practice (GCP): Guidance for implementation. 2005, 125 pp. Expert Committee on Specifications for Pharmaceutical Preparations: Fortieth Report. Technical Report Series 937, 2006, 461 pp. Annex 7: Presentation of Bioequivalence Trial Information. 2010, 19 pp. 50 Ÿª μ π Õß ß π» «Ÿ π πÿ å

53 Ÿª μ π Õß ß π» «Ÿ π πÿ å STANDARD FORMAT OF THE IN VIVO BIOEQUIVALENCE STUDY REPORT Õß «ÿ π ß π Õ À «ß ÿ Ÿª μ π Õß ß π» «Ÿ π πÿ å 51

54 52 Ÿª μ π Õß ß π» «Ÿ π πÿ å

55 Ÿª μ π Õß ß π» «Ÿ π πÿ å 1. Õ π (TITLE/COVER PAGE) 1.1 ËÕ ß π (Study Title) 1.2 ËÕ ËÕ ŸàºŸâ Àâ π πÿπ (Name and Address of Sponsor) 1.3 ËÕºŸâ º Õ ß» ËÕ Ÿà Õß π Ë» (Name, Person in Charge and Address of Institution) 1.4 ËÕ ËÕ Ÿà ÕߺŸâ À (Name and Address of Principal Investigator) 1.5 ËÕ æ åà ÕºŸâ ß π (Name of Medical/Clinical Investigator) 1.6 ËÕ ËÕ Ÿà ÕߺŸâ º Õ À â πàâõߪø μ ß π (Name, Person in Charge and Address of Clinical Laboratory) 1.7 ËÕ ËÕ Ÿà ÕߺŸâ º Õ À â πàâõߪø μ «Àå (Name, Person in Charge and Address of Analytical Laboratory) 1.8 ËÕ ËÕ Ÿà ÕߺŸâ º Õ À â π âõ Ÿ «Àå ß π» μ å ß μ (Name, Person in Charge and Address for Data Management, Pharmacokinetics and Statistical Analysis) 1.9 ËÕ ËÕ Ÿà ÕߺŸâ à «πõ Ëπ Ê (Name and Address of Other Investigator(s) and Study Personnel) 1.10 «π «Ë Ë ÿμ» ß π «Àå (Start and End Date of Clini cal and Analytical Study) 1.11 ßπ æ âõ «π Ë ÕߺŸâ» «(Signature and Date of Investigator(s)) ºŸâ π ß π ß æ å (Medical Writer) ºŸâ â π ª π ÿ æ (QA Manager) (if Applicable) 2. ÿª àõ» (STUDY SYNOPSIS) 3. (TABLE OF CONTENTS) 4. àõ π» æ å (ABBREVIATIONS AND DEFINITION OF TERMS) Ÿª μ π Õß ß π» «Ÿ π πÿ å 53

56 5. π (INTRODUCTION) «(Pharmacology) 5.2 π» μ å (Pharmacokinetics) 5.3 Àμÿ å àæ ߪ ß å (Adverse Events) 6. «μ ÿª ß å (OBJECTIVES) 7. âõ Ÿ º μ ±å (PRODUCT INFORMATION) 7.1 º μ ±å Õ (Test Product Information) Trade Name Active Ingredient, Strength, and Dosage Form Batch Number, Manufacturing Date and Expiry Date Batch Size Compliance (can be provided by sponsor) Product Formulation (can be provided by sponsor) Finished Product Specifications (can be provided by sponsor) Name and Address of Manufacturer 7.2 º μ ±å Õâ ßÕ ß (Reference Product Information) Trade Name Active Ingredient, Strength, and Dosage Form Batch Number, Manufacturing Date and Expiry Date Name and Address of Manufacturer Name and Address of Importer or Authorization Holder 7.3 âõ Ÿ «à π ß (Pharmaceutical Equivalence Data) Comparing Content of Active Ingredient / Potency Uniformity of Dosage Units 7.4 âõ Ÿ ª (Comparison of Dissolution Profile) (can be provided by sponsor) 7.5 Àπ ß Õ Õßæ âõ ßπ ºŸâ πõ ß π«à Õ Sponsor æ ËÕ π π«à º μ ±å Õ À Õπ º μ ±å Ë º μ æ ËÕ Àπà π âõßμ 8. ºπ» (INVESTIGATIONAL PLAN) 8.1 Ÿª» ß π (Clinical Study Design) Study Design (crossover, parallel) Fasted, Fed Inclusion, Exclusion, Restriction Ÿª μ π Õß ß π» «Ÿ π πÿ å

57 Standardization of Study Condition Drug Administration Removal of Subject from Assessment Health Screening Subject Detail, Number of Subjects, Deviation Sampling Protocol/Time, Sample Preparation/Handling, Storage, Deviation Volume of Blood Collected Subject Monitoring Genetic Phenotyping (if applicable) 8.2 «Àâ æ ËÕ» (Study Treatments) Selection of Doses - Single, Multiple Identity of Investigational Products, Dosing Randomization Blinding Washout period Water intake volume 8.3 π âõ Ÿ «ª Õ âõ Ÿ ß π ÕßÕ (Clinical and Safety Records) Adverse Event Drug related Adverse Drug Reaction 8.4 æ μõ å ß π» μ å «Õ (Pharmacokinetic Parameters and Tests) Definitions and Calculation 8.5 «Àå ß μ (Statistical Analyses) Log Transformed Data Analysis (AUC, C max ) Sampling Time Adjustments T max, T 1/2 Acceptance Criteria for Bioequivalence ANOVA presentation Power 8.6 ««Àå μ «Õ «Ÿ μâõß Õß««Àå (Assay Methodology and Validation) Assay Method Description Method of Detection Validation Procedure and Summary Results Ÿª μ π Õß ß π» «Ÿ π πÿ å 55

58 Specificity Accuracy Precision Recovery Stability LOQ Linearity 8.7 ª π ÿ æ Õß âõ Ÿ (Data Quality Assurance) 9. º» Õ ª (RESULTS AND DISCUSSION) 9.1 º» ß π (Clinical Study Results) Demographic Characteristics of the Subjects. Details of Clinical Activity. Deviation from Protocol, if any. Results of Drug/Alcohol/Smoking Usage, Medical History and Medical Examination, vital sign and diagnostic laboratory test of subjects. Adverse event/reaction reports for test product and reference product. 9.2 º ÿª «Àå (Summary of Analytical Results) 9.3 «Àå ß π» μ å (Pharmacokinetic Analyses) Drug levels at each sampling time, descriptive statistics Table of individual subject pharmacokinetic parameters, descriptive statistics Figure of mean plasma or urine concentration-time profile Figure of individual subject plasma or urine concentration-time profile 9.4 «Àå ß μ (Statistical Analyses) Statistical considerations Time points selected for K el, t 1/2 Summary statistics of pharmacokinetic parameters: T max, C max, AUC 0-t, AUC 0-, % AUC extrapolated, K el, t 1/2 Summary of statistical significance for C max and AUC (based on log-transformed data calculated as 90% CI of test/reference Geometric Means) and for T max (based on non-transformed data calculated as p value) Similar calculation for urine data: Ae and dae/dt (Ae corresponds to AUC, (dae/dt) max corresponds to C max ). Ÿª μ π Õß ß π» «Ÿ π πÿ å

59 Intra-subject variability Power of study Assessment of sequence, period and treatment effects TABLE - Analysis of Variance, Geometric least-squares means for each pharmacokinetic parameters. TABLE - Calculation of 90% confidence interval for the ratio of pharmacokinetic parameters under consideration in logarithmic transformation 10. ÿªº» (CONCLUSIONS) 11. Õ Õâ ßÕ ß (REFERENCES) 12. ºπ«(APPENDICES) 12.1 ß à ßß π» «Ë â Õπÿ μ Àπ ß Õ Õß «π πÿ å (Approval of the Institutional Review Board) Letter of approval from Drug Regulatory Authority (if applicable) Study protocol and its amendments together with Institutional Review Board/Ethical Committee approvals Informed Consent Form Protocol Deviation Listing Adverse Event Listing Finished Product (FP) Specification and Certificate of Analysis (CoA) 12.2 ß π μ «Õ «Ÿ μâõß Õß««Àå (Validation Report) æ âõ âõ Ÿ μ (raw chromatograms) Õ à ßπâÕ 20% 12.3 ß π «Àå (Analytical Report) æ âõ âõ Ÿ μ (raw chromatograms) Õ à ßπâÕ 20% 12.4 ß π ª à«π âõ Ÿ À«à ß Õ μâπ (Comparative Dissolution Profile Report) 12.5 À π ß Õß μ π Õß π Ë» «ß π (Certificate of Clinical facility) ÀâÕßªØ μ Ëμ ««Àåº ß π (Clinical laboratory) μ ««Àå (Analytical laboratory) (if any) Ÿª μ π Õß ß π» «Ÿ π πÿ å 57

60 Study Title: 1. Õ π (Title/Cover Page) Protocol No..../ Principal Investigator: Name:... Affiliation/Institution Name: Clinical Investigator: Name:... Affiliation/Institution Name: Clinical Laboratory Investigator: Name:... Affiliation/Institution Name: FINAL STUDY REPORT Sponsor: Name:... Address: Analytical Investigator: Name:... Affiliation/Institution Name: Pharmacokinetic and Statistic Investigator: Name:... Affiliation/Institution Name: FDA/IRC approval protocol date: DD/MM/YYYY Clinical Study date: DD/MM/YYYY - DD/MM/YYYY Analytical Study date: DD/MM/YYYY - DD/MM/YYYY Report Approved Signatures: Principal Investigator: Date / / Clinical Investigator: Date / / Analytical Investigator: Date / / PK & Statistic Investigator: Date / / Other Investigator: Date / / 58 Ÿª μ π Õß ß π» «Ÿ π πÿ å

61 GENERIC NAME... TEST PRODUCT... REFERENCE PRODUCT... STUDY TITLE: INVESTIGATORS: DISSOLUTION INVESTIGATORS: 2. ÿª àõ» (STUDY SYNOPSIS) SPONSORS NAME: PROTOCOL NUMBER... STUDY NUMBER... ETHICS AND APPROVAL DATE OBJECTIVES: DOSAGE REGIMEN CLINICAL STUDY SITE ANALYTICAL STUDY SITE... STUDY SUBJECTS DEMOGRAPHIC DATA ADMISSION AND... CONFINEMENT... DRUG ADMINISTRATION Ÿª μ π Õß ß π» «Ÿ π πÿ å 59

62 2. ÿª àõ» (STUDY SYNOPSIS) (CONTINUED) GENERIC NAME... TEST PRODUCT... REFERENCE PRODUCT... SPONSORS NAME: STUDY PERIOD: Screening... Enrollment:... Period 1:... Period 2:... WASHOUT PERIOD BLOOD SAMPLING SCHEDULE BLOOD SAMPLING HANDLING ANALYTICAL SITE... BIOANALYTICAL METHODOLOGY TOLERANCE/ SUBJECTS... WITHDRAWAL / ADR... SURROGATE PARAMETERS PRIMARY PHARMACOKINETIC... PARAMETERS... ANALYTE... SECONDARY PHARMACOKINETIC... PARAMETERS CONFIDENCE INTERVALS CONCLUSION DATE OF REPORT Ÿª μ π Õß ß π» «Ÿ π πÿ å

63 3. (CONTENTS) Àπâ Ë 1. Õ π (Title Page) ## 2. ÿª àõ» (Study Synopsis) ## 3. (Table of Contents) ## 4. àõ π» æ å (Abbreviations and Definitions of Terms) ## 5. π (Introduction) ## 6. «μ ÿª ß å (Objectives) ## 7. âõ Ÿ Õߺ μ ±å (Product Information) ## 8. ºπ» (Investigational Plan) ## 9. º» Õ ª (Results and Discussion) ## 10. ÿªº» (Conclusion) ## 11. Õ Õâ ßÕ ß (References) ## 12. ºπ«(Appendices) ## Ÿª μ π Õß ß π» «Ÿ π πÿ å 61

64 4. àõ π» æ å (ABBREVIATIONS AND DEFINITIONS OF TERMS) A...:... B...:... C...:... D...:... E...:... F...:......:......:......:......:......:......:......:......:......:......:......:......:... Z...: Ÿª μ π Õß ß π» «Ÿ π πÿ å

65 5. π (INTRODUCTION) 5.1 «(Pharmacology) 5.2 π» μ å (Pharmacokinetics) 5.3 Àμÿ å àæ ߪ ß å (Adverse events) Ÿª μ π Õß ß π» «Ÿ π πÿ å 63

66 6. «μ ÿª ß å (OBJECTIVES) 7. âõ Ÿ Õߺ μ ±å (PRODUCT INFORMATION) 7.1 âõ Ÿ Õß Õߺ μ ±å Õ (Test Product Information) Trade Name Active Ingredient, Strength, and Dosage Form Batch Number, Manufacturing Date and Expiry Date Batch Size Compliance (can be directly provided by Sponsor) Finished Product Specifications (can be directly provided by Sponsor) Name and Address of Manufacturer 7.2 âõ Ÿ Õß Õߺ μ ±å Õâ ßÕ ß (Reference Product Information) Trade Name Active Ingredient, Strength, and Dosage Form Batch Number, Manufacturing Date and Expiry Date Name and Address of Manufacturer Name and Address of Importer or Authorization Holder 7.3 âõ Ÿ «à ß (Pharmaceutical Equivalence Data) Comparing Content of Active Ingredient / Potency Uniformity of Dosage Units 7.4 âõ Ÿ ª ºπ Õßμ «(Comparison of Dissolution Profiles) âõ Ÿ π ÈÕ â ºŸâ Àâ ÿπ (can be from sponsor) 7.5 Àπ ß Õ Õßæ âõ ßπ ÕߺŸâ Àâ ÿπ» æ ËÕ π π«à º μ ±å Õ À Õπº μ ±å Ë º μ æ ËÕ Àπà π âõßμ (Letter with a signed statement from the applicant confirming that the test product is the same as the one that is submitted for marketing authorization) 64 Ÿª μ π Õß ß π» «Ÿ π πÿ å

67 μ ß Ë ##: ª âõ Ÿ (Comparison of Dissolution Profile) π 0.1 M HCl % API Dissolved (mean + SD) Time (min) º μ ±å Õ º μ ±å Õ (Test product, T) (Test product, T) lr-t l lr-t l f1 = {[Σ t=1 n R t - T t ]/[ Σ t=1 n R t ]} 100 =... f2 = 50 log {[1+(1/n) Σ t=1 n ( R t -T t ) 2 ] } =... Ÿª Ë ##: μ «Õ à ß ª âõ Ÿ (Comparison of Dissolution Profile) π 0.1 M HCl ÿª ª âõ Ÿ º μ ±å Èß Õßμ... Ÿª μ π Õß ß π» «Ÿ π πÿ å 65

68 μ ß Ë ## : ÿª ª âõ Ÿ º μ ±å Õ Õâ ßÕ ß Õ º μ ±å Õ º μ ±å Õâ ßÕ ß (Test product) (Reference product) ËÕº μ ±å (Product/Brand Name) ºŸâº μ (Manufacturer) ÿàπ º μ (Batch/Lot No.) «π ˺ μ (Manufacture Date) DD/MM/YYYY DD/MM/YYYY «π ËÀ Õ ÿ(expiration Date) DD/MM/YYYY DD/MM/YYYY π «ß (Strength) ## mg ## mg π (Registration Number) N/A... Ÿª μ (Dosage Form) π ÿàπº μ Ë â π» «Ÿ (Bio-batch Size) ª Õßμ «(Content of Active Ingredients/ Potency, mean, %CV) «Ë Õ Õßμ «(Content Uniformity, mean, %CV) π Ë â (Dose Administered) ## mg x single dose ## mg x single dose «Àâ (Route of Administration) PO PO 66 Ÿª μ π Õß ß π» «Ÿ π πÿ å

69 8. ºπ» (INVESTIGATIONAL PLAN) 8.1 Ÿª» ß π (Clinical Study Design) 8.2 «Àâ æ ËÕ» (Study Treatments) 8.3 π âõ Ÿ «ª Õ âõ Ÿ ß π ÕßÕ (Clinical and Safety Records) 8.4 æ μõ å ß π» μ å «Õ (Pharmacokinetic Parameters and Tests). 8.5 «Àå ß μ (Statistical Analyses) Ÿª μ π Õß ß π» «Ÿ π πÿ å 67

70 8.6 ««Àå μ «Õ «Ÿ μâõß Õß««Àå (Assay Methodology and Validation) 8.7 ª π ÿ æ Õß âõ Ÿ (Data Quality Assurance) 68 Ÿª μ π Õß ß π» «Ÿ π πÿ å

71 BE Reviewer Guidance_v º» Õ ª (RESULTS AND DISCUSSION) 9.1 º» ß π (Clinical Study Results) Ÿª μ π Õß ß π» «Ÿ π πÿ å 69

72 BE Reviewer Guidance_v3.0 μ ß Ë ##: âõ Ÿ ß ª ÕßÕ Ë â à» cross over (Demographic data and date of the clinical study of individual subjects) Subject Sequence Sex Age (yr) Weight (Kg) Height (m) BMI Period 1 Date (DD/MM/YYYY) Period 2 Date (DD/MM/YYYY) Mean SD CV% Minimum Median Maximum N Ÿª μ π Õß ß π» «Ÿ π πÿ å

73 BE Reviewer Guidance_v3.0 μ ß Ë ##: List of individual clinical laboratory examinations Pre-study Laboratory value Subject Number Lab. Parameter Normal Range Units Vital Signs Pulse beats/min Blood pressure / <90 sys/dia mm Hg Respiratory rate 8-14 rate/min Body temperature ÌC Blood chemistry Serum creatinine mg/dl Blood sugar mg/dl Urea nitrogen mg/dl Uric acid mg/dl Sodium meq/l Potassium meq/l Cholesterol mg/dl Triglyceride mg/dl Total protein g/dl Albumin g/dl Bilirubin (total) mg/dl Bilirubin (direct) mg/dl ALT (SGPT) 4-36 IU/L AST (SGOT) IU/L GGT 0-50 IU/L Serum amylase IU/L Alkaline phosphatase IU/L Ÿª μ π Õß ß π» «Ÿ π πÿ å 71

74 BE Reviewer Guidance_v3.0 μ ß Ë ##: List of individual clinical laboratory examinations. (continued) Lab. Parameter Normal Range Units Hematology Hemoglobin g/dl Hematocrit (M), (F) % RBC count million/mm Platelet count cells/mm Wbc count (total) 4,000-11,000 cells/mm Neutrophils % Lymphocytes % Monocytes % Eosinophil % Blood group - A/B/AB/O Urine analysis Appearance Clear, colorless-pale yellow -... ph Specific gravity Protein Absent Glucose/Sugar Absent Bilirubin Absent Ketones Negative Blood Absent Leukocytes < 2-4 cells/ L µ Pre-study Laboratory value Subject Number Ÿª μ π Õß ß π» «Ÿ π πÿ å

75 BE Reviewer Guidance_v3.0 μ ß Ë ##: Sampling time point protocol deviations Subject number Time point (hr) Scheduled time Actual sampling time Deviations Hours Minutes Early/Late Reason for deviation Period hh/mm hh/mm Period Ÿª μ π Õß ß π» «Ÿ π πÿ å 73

76 BE Reviewer Guidance_v3.0 μ ß Ë ##: Adverse evennt report for test and referrence product Reletionship Subject No. AE Dosing (D/T) Onset (D/T) Resolution (D/T) AE Duration Severity 1 Outcome 2 to Drug 4 Test Product DD/MM/YY- DD/MM/YY DD/MM/YY,hh/mm DD/MM/YY,hh/mm DD/MM/YY,hh/mm hh/mm Reference Product DD/MM/YY- DD/MM/YY DD/MM/YY,hh/mm DD/MM/YY,hh/mm DD/MM/YY,hh/mm hh/mm Severity should describe either as severe, moderate, or mild. 2Outcome should describe either as severe, moderate, or mild. 3Medication should describe either as test or reference product. 4Relationship should describe either as probable, possible, or unrelated. 74 Ÿª μ π Õß ß π» «Ÿ π πÿ å

77 BE Reviewer Guidance_v º ÿª Õß μ «Õ «Ÿ μâõß Õß««Àå º «Àå (Summary of validation and analytical results) μ ß Ë ##: ÿªº μ «Õ «Ÿ μâõß Õß««Àå Information Requested Data Analyte Provide the name(s) of the analyte(s) Internal standard (IS) Identify the internal standard used Method description Brief description of extraction method; analytical method Limit of quantitation LOQ, units Average recovery of drug (%) % Average recovery of IS (%) % Standard curve concentrations (units/ml) Standard curve range and appropriate conc. units QC concentrations (units/ml) List all the concentrations used QC Intraday precision range (%) Range or per QC QC Intraday accuracy range (%) Range or per QC QC Interday precision range (%) Range or per QC QC Interday accuracy range (%) Range or per QC Freeze-thaw stability (cycles) # cycles Long-term stability (days) ÌC (or other) Short-term stability (hrs) room temperature Post-preparative stability e.g. autosampler room temperature stability (hrs) Stock-solution stability (days) ÌC Selectivity No interfering peaks noted in blank plasma samples Ÿª μ π Õß ß π» «Ÿ π πÿ å 75

78 BE Reviewer Guidance_v º «Àå ß π» μ å (Pharmacokinetic Analysis) Ÿª μ π Õß ß π» «Ÿ π πÿ å

79 BE Reviewer Guidance_v3.0 μ ß Ë ##: âõ Ÿ π Õ ÕßÕ μà Ë «μà ßÊ (h) À ß â º μ ±å (PRODUCT, TEST OR REFERENCE) Subject S P Drug plasma concentration (ng/ml) for product at time (h) Mean SD CV% Minimum Maximum N S = sequence of drug treatment, P = period of drug treatment, BLQ = below limit of quantification. Any concentration below LLOQ was record as BLQ except at time 0. Zero is used in the calculation of area under the curve (AUC) for times preceding the first observed concentration and in the calculation of summary statistics. Ÿª μ π Õß ß π» «Ÿ π πÿ å 77

80 BE Reviewer Guidance_v3.0 μ ß Ë ##: æ μõ å ß π» μ åõ μà ËÕ â º μ ±å Õ (TEST PRODUCT, T) º μ ±å Õâ ßÕ ß (REFERENCE PRODUCT, R) Subject Sequence AUC 0-t AUC 0- T max (h) C max (ng/ml) (ng.h/ml) (ng.h/ml) AUC 0-t /AUC 0- Half-life (h) Kel (h -1 ) Formulation Formulation Formulation Formulation Formulation Formulation Formulation T R T R T R T R T R T R T R Mean SD CV% Minimum Maximum N Ÿª μ π Õß ß π» «Ÿ π πÿ å

81 BE Reviewer Guidance_v3.0 μ ß Ë ##: º «Àå à«πæ μõ å C max, AUC 0-t AUC 0-, ÕßÕ μà ËÕ â º μ ±å Õ (TEST PRODUCT, T) º μ ±å Õâ ßÕ ß (REFERENCE PRODUCT, R) 8 æ μõ å AUC 0-t À Õ AUC 0- Subject Test (T) Reference (R) Ratio (T/R) Untransformed Transformed Untransformed Transformed Untransformed Transformed data data (ln) data data (ln) data data (ln) Mean SD % CV Min Max N Ÿª μ π Õß ß π» «Ÿ π πÿ å 79

82 BE Reviewer Guidance_v3.0 Ÿª Ë ## ø ß «æ π å À«à ß Ë Ë «μà ßÊ πõ ËÕ â º μ ±å Õ º μ ±å Õâ ßÕ ß ËÕ â à ª μ (Linear plot of mean drug concentrations versus time in study subjects (N =24)) Ÿª Ë ## ø ß «æ π å À«à ß Ë Ë «μà ßÊ πõ ËÕ â º μ ±å Õ º μ ±å Õâ ßÕ ß ËÕ â à Ë Ÿ ª ß ªìπ Õ (Semi - logarithmic plot of mean drug concentrations versus time in study subjects (N =24)) 80 Ÿª μ π Õß ß π» «Ÿ π πÿ å

83 BE Reviewer Guidance_v3.0 Ÿª Ë ## ø ß «æ π å À«à ß Ë «μà ßÊ πõ μà (Individual Subject Profile or Spaghetti Plot) ËÕ â º μ ±å Õâ ßÕ ß (T) Ÿª Ë ## ø ß «æ π å À«à ß Ë «μà ßÊ πõ μà (Individual Subject Profile or Spaghetti Plot) ËÕ â º μ ±å Õâ ßÕ ß (R) Ÿª μ π Õß ß π» «Ÿ π πÿ å 81

84 BE Reviewer Guidance_v3.0 Ÿª Ë ## ø ß «æ π å À«à ß Ë «μà ßÊ πõ μà ËÕ â º μ ±å Õ (T) º μ ±å Õâ ßÕ ß (R) 9.4 º «Àå ß μ (Statistical Analyses) Ÿª μ π Õß ß π» «Ÿ π πÿ å

85 BE Reviewer Guidance_v3.0 μ ß Ë ## : ß à æ μõ å ß π» μ å Ë º «Àå ß μ Product/Statistics T max (h) C max * (ng/ml) AUC 0-t * (ng.h/ml) AUC 0- * (ng.h/ml) %ext. AUC K el (1/h) Formulation T Mean CV (%) N Formulation R Mean CV (%) N Ratio of least square mean T/R (%) % Confidence Intervals (T/R) Lower Limit: Upper Limit: Power (%) * Log-transformed parameters, the antilog of the mean (i.e. the geometric mean) is reported 8 t 1/2 (h) Ÿª μ π Õß ß π» «Ÿ π πÿ å 83

86 BE Reviewer Guidance_v3.0 μ ß Ë ## : º «Àå «ª ª «π (ANOVA Table) Õßæ μõ å ß π» μ å C max, AUC 0-t, AUC 0-8 Sources C max (Ln transformed data) D.F. SS MS F p-values Subject (Sequence) Sequence Period Treatment (Formulation) Error Total Sources AUC 0-t (Ln transformed data) Subject (Sequence) Sequence Period Treatment (Formulation) Error Total Sources AUC 0- (Ln transformed data) 8 Subject (Sequence) Sequence Period Treatment (Formulation) Error Total Ÿª μ π Õß ß π» «Ÿ π πÿ å

87 BE Reviewer Guidance_v3.0 μ ß Ë ## : μ «Õ à ß ßº ª à Ë ÕßÕ μ à«π (Ratio of Log-transformed Least Square Mean) à«ß Ààß «ËÕ Ëπ (90% confidence interval) Õß à æ μõ å ß π» μ å Ë â π ª π «à π ß «Ÿ Parameter Ratio of Least Square Mean 90% C.I. Ln C max Ln AUC 0-t Ln AUC ÿªº» (CONCLUSION) Õ Õâ ßÕ ß (REFERENCES) Ÿª μ π Õß ß π» «Ÿ π πÿ å 85

88 BE Reviewer Guidance_v ºπ«(APPENDICES) 12.1 ß à ßß π» «Ë â Õπÿ μ /À Õ Àπ ß Õ Õß «π πÿ å (Approval of the Institutional Review Board) ß π ª πº «Àå (Validation Report) Ëß «âõ Ÿ (raw data) Õß μ (Chromatogram) Õ à ßπâÕ 20% º «Àå πõ ÈßÀ μ Ë â À«à ß μ «Õ «Ÿ μâõß Õß««Àå μ «Õ à ß «ÿ (Method Validation and QC) ªìπμâπ ß πº «Àå (Analytical Report) Ëß âõ Ÿ àπ μ Èß ÿ (Complete chromatogram of analytical run) Õ à ßπâÕ 20% º «Àåμ «Õ à ß Õ ÕßÕ Ÿª μ π Õß ß π» «Ÿ π πÿ å

89 BE Reviewer Guidance_v ß π ª à«π âõ Ÿ À«à ß Õ μâπ (Comparative Dissolution Profile Report) À π ß Õß Õß π Ë» «ß π (Certificate of Clinical facility) ÀâÕßªØ μ Ëμ ««Àåº ß π μ ««Àå (Clinical laboratory and Analytical laboratory) [ â ] Ÿª μ π Õß ß π» «Ÿ π πÿ å 87

90 BE Reviewer Guidance_v æ æå Ë : ßæ æå π ß πæ æÿ» π Ààß μ π«πæ æå 500 à æ.» Ÿª μ π Õß ß π» «Ÿ π πÿ å

91