ファーマコビジランスプラン解説書 - jpma.or.jp

1 19 7 . E. DM .. 1. _____ 1. _____ 1. _____ 1. E2E _____ 2. _____ 2. _____ 3. _____ 3. _____ 4. _____ 4. _____ 4. 2. _____ 5. _____ 5. _____ 5. Effect measure _____ 5. _____ 6. cross-sectional study _____ 7. _____ 7. _____ 7. _____ 7. _____ 8. _____ 8. _____ 8. _____ 8. _____ 9. cohort study _____ 9. _____ 9. _____ 9. _____ 9. _____ 10. _____ 10. _____ 10. _____11. _____11. _____ 13. case-control study _____ 14. _____ 14. _____ 14. _____ 14. _____ 15. _____ 15. _____ 15. _____ 15. _____ 15. _____ 16. nested case-control study _____ 16. case-cohort study _____ 17. case-crossover study _____ 18. _____ 19. 3. _____ 22. _____ 22. _____ 23. _____ 23. _____ 23. selection bias _____ 23. information bias assessment bias __ 23.

2 _____ 24. _____ 24. _____ 24. _____ 27. _____ 28. _____ 28. _____ 28. _____ 28. 4. _____ 29. 5. _____ 30. Appendix 1 _____ 32. Appendix 2 2 2 _____ 34. Appendix 3 Balancing Score Propensity Score _____ 38. Appendix 4 _____ 43. Appendix 5 _____ 46. Appendix 6 _____ 49. 1.. Post Marketing Surveillance PMS .. pharmacovigilance .. ICH International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use . 2004 11 E2E 3 Step4 . 2005 9 Step5 .. RAD-AR 1989 5 .. 1996 . 2002 5 PMS 2003 7 . PMS PMS PMS . 2004 10 .. 2001 3 .. 1.. 2003 3 DM .. 2004 .. 1988 CSM Committee on the Safety of Medicines ABPI the Association of the British Pharmaceutical Industry RCGP the Royal College of General Practitioners BMA British Medical Association PMS.

3 MCA Medicines Control Agency . 1994 SAMM Guideline Guidelines for company-sponsored safety assessment of marketed medicines 1999 EU EMEA European Medicines Agency . Pharmacovigilance Guideline . SAMM guideline FDA 2005 3 Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment . ICPE Guidelines for good pharmacoepidemiology practices GPP 2004 8 . E2E . 2005 9 16 0916001 0916001 . ICH E2E GPSP .. E2E . pharmacovigilance .. Safety Specification Pharmacovigilance Plan .. GPMSP Good Post Marketing Surveillance Practice . 2005 4 1 . 2. GPMSP GVP Good Vigilance Practice . GPSP Good Post-marketing Study Practice .. ICH E2E .. 9 4 1 . 15 30 .. ICH E2E .. 6 .. ICH E2E .. 9. 3 27 34 95% . 1 3000 .. 3.. 2 E2E.

4 3 .. 3 .. 2 .. Appendix Appendix .. 4. 2.. ICH. E2E Pharmacovigilance plan PvP Safety Specification .. EMEA .. ( ) .. Effect measure .. Appendix 1 .. 5.. prevalence: .. incidence: .. 1) . 2) .. 6.. cross-sectional study .. cross-sectional study .. 7.. 9 3 27 34 . 95% 1 3,000 .. log(1 p ). n= n r p . log(1 r ). 95% . r = , p = . log(1 ) n= 2995 3000. log(1 ) 8. 3,000 .. cohort study .. 1949 Framingham .. 9.. LOCF Last observation carried forward .. 10.. p . p= . Clopper-Pearson 95% .. p0 p .. p p0= = .. 5 .. 5 . 3500 . 11. = . Schlesselman . 2. 1 1 p (1 p ) . n= Z 1 / 2 1 + U (1 U ) + Z 1 pR(1 Rp) + . [ p (1 R)]2 K k . Kp + pR. U =. K +1. n p R . Z1-x x K .. Clopper-Pearson 95% . 95% . 100 200 300 400 500 600 700 800 900 1000 2000 12.

5 = .. 200 400 600 800 1000 1200 1500 2000 3500 p= . R= = .. K. 1 3500 2 7000 3 10500 4 14000 5 17500 6 21000 3500. 7 24500 8 28000 9 31500 10 35000 30 105000 50 175000 .. Kaplan-Meier . 13.. Kaplan-Meier Log-rank Cox . Cox .. Appendix 3 . case-control study .. case-control study .. 14.. n 1/ .. 1 . 1 + / n n K . K .. 1 1 2 . 1 . 5 .. 2. 1 1 p (1 p ) . n= Z 1 / 2 1 + U (1 U ) + Z 1 V (1 V ) + . p (1 V ) 2 K K . 15. p R pR. U = K+ V =. K +1 1 + p ( R 1) 1 + p ( R 1). n p R Z1-x . x K .. Appendix 4 .. concordant pair discordant pair .. 1 1 1 1 1 . K 1 K N K .. 1 1 McNemar 1 K . Mantel-Haenszel . N K .. conditional risk ratio .. nested case-control study .. Synthetic Case-control Study .. 16.. nested .. 1 .. (a) (c) (e).

6 (a) (g) . (b) (c) (f) .. case-cohort study .. 17.. (a) (c) (e) . (a) (g) .. case-crossover study .. 1 .. 4 .. PROBE . PROBE (Prospective, Randomized, Open-labeled, Blinded-Endpoint) .. 18.. PROBE 1992 . Blood Press. 1992 Aug;1(2):113-9. 2 .. MEGA Study Lancet. 2006 Sep 30;368(9542):1155-63.. GPSP GVP .. 3 .. 1 prospective retrospective . 2 cross sectional longitudinal . 3 experimental observational . (1) .. 19.. (2) .. Time to event .. (3) .. Book .. MR EDC Electric Data Capture visit .. 20.. time to event .. EMEA .. confounding by indication .. 21. 2006 .. Appendix 3 .. Pharmacovigilance plan PvP . 3.. * .. * .. 22.. selection bias .. self-selection bias . healthy worker's effect losses to follow up . Neyman's bias Berkson's bias.

7 Diagnostic bias Appendix 5 . information bias assessment bias .. 23. differential misclassification . non-differential misclassification .. diagnostic bias recall bias . interviewer bias .. publication bias .. p= . p= Simes, 1987 .. FDA .. 1/2 . 1. 24.. 25 75 100 18 72 90 7 3 10.. 50 50 100 8 32 40 42 18 60.. 10 IPE1 IPE1 .. IPE0 . IPE1 IPE0 .. 10 IPC .. 25.. IPE 0 = IPC.. IPE 0 IPC.. F IPCF . IPCF IPC . IPE0 F . 2 . F .. F .. F . F . Directed Acyclic Graph DAG . 26. DAG .. 3 .. F .. CMH Cochran-Mantel-Haenszel . 27.. Effect Modification .. E2E .. 16 12 28 .. 15 57 . 15 58 . 15 59 . 16 12 24 .. 28. 4.. ICH E2E .. Risk management .. ICH E2E Risk Management . GPSP .. 2004 4 .. 29. 5.. 1. Elandt-Johnson, R. C. (1975).

8 Definition of rates: some remarks on their use and misuse, American Journal of Epidemiology, 102, 267-271. 2. Greenland, S., Robins, J. M., Pearl, J. (1999). Confounding and collapsibility in causal inference, Statistical Science, 14, 29-46. 3. Last, J. M. (1995). A Dictionary of Epidemiology (3rd Ed.). Oxford University Press. 4. Last, J. M. ( ) (2000). 3 41-43, . 5. Jenicek, M. ( ) (1998).. 6. Maclure, M. (1991) The case-crossover design: a method for studying transient effects on the risk of acute events. American Journal of Epidemiology, 133(2): 144-153. 7. Rothman, K. J., Greenland, S. (1998). Modern epidemiology. 2nd ed. Lippincott Williams & Wilkins. 8. Nicholas P. J. (2004). Statistics for Epidemiology.

9 Chapman & Hall / CRC. 9. Rose, G., Barker, D. J. P. ( ) (1992).. 10. Rothman, K. J. (1986). Modern Epidemiology. Little, Brown and Company. 11. Woodward . (1999). Epidemiology study design and data analysis second edition. Chapman &. Hall/CRC. P410-412. 12. (1996).. 13. , (1991). 6 . 4 (in , , ).. 14. , , , , , (2002).. 15.. (2004). in . , .. 16. (2004).. 17. (1995). 16 (in , , . ).. 18. 1992 40 173-184 . 19. 1993 22 493-513 . 20. 1994 42 83-101 . 21. (2004). 55 .. 30. 22. , , (1996). SAS .. 23. (2002).. 24. ( 2001/06). 100 40 .. 25. (2001). (in RAD-AR . , ).. 26. , (2004).. 31. Appendix 1 . 1. Cohort .. 2. Closed Cohort .. 3. Open Cohort .. 4. Population at Risk .. 5.. 6.. Prevalence Incidence . Prevalence.

10 32. Incidence Proportion Incidence Rate .. 4 1 . (a) (d) 2 . 2 4 . 1 .. 1,000 100,000 . 4 +1+ + . 2 1 1 .. 1 . Relative Risk (Absolute risk).. 33. Odds ratio . A . pA B pB B . A . pA pB pA 1 pB. Odds Ratio = = . 1 p A 1 pB 1 p A pB.. Attributable risk .. E2E .. 4 .. attributable fraction Population Attributable Risk) Population Attributable Fraction) .. 1% 20 .. Appendix 2 . Appendix 2 2 2 . 2 2 .. 34. 2 2 .. n11 n12 n1+. n21 n22 n2+. n+1 n+ 2 n+ +. 2 2 .. P11 P12 P1+. P21 P22 P2+. P+1 P+ 2 P+ + (= 1).. : n + + . : n +1 , n + 2 . : n1+ , n 2+ .. 1. Risk Difference Risk Ratio .. n11. IP1 =. n1+. n21. IP0 =. n2 +. 95% .. n11 n21. RD = IP1 IP0 = . n1+ n2+. n11 n n n V (RD ) = V . n n + V 21 = 11 3 12 + 213 22. n1+ n2 + n1+ n2 +.