Something wrong in US FDA guidance?

From: "Kyun-Seop Bae" ksbae@kma.org Subject: [NMusers] Something wrong in US FDA guidance? Date: Fri, 19 Nov 2004 17:06:50 +0900 Dear all, I am asked to process an example data set in the US FDA "Guidance for industry: Topical Dermatologic Corticosteroids in vivo Bioequivalence" ( http://www.fda.gov/cder/guidance/old098fn.pdf) using NONMEM. In the gudiance, there is some data at page 28, and its results at page 29. But, there exists quite difference between my result using NONMEM and that of the guidance. Guidance NONMEM ED50 1.89 1.13 +/- 0.568 Emax -48.80 -39.7 +/- 8.63 Of course, the confidence intervals embrace the values of guidance. But, I think it's quite different, and different enough to lead different action. As the consequence of the analysis, they determined the doses(here, it is duration, coded as TIME in my control file) to be tested are 1.0, 2.0, and 4.0 (for use in the pivotal study, adding half and double of the ED50). But, if we think NONMEM is better, the 'to be tested dose' should be 0.5, 1.0, and 2.0. There is some points to consider, like in the guidance they did not use NONMEM but 'P-Pharm'(I don't know much about this software), And, curiously they seemed to use naive-pooling method, even though they said that P-Pharm is population PK-PD data modeling software. I tried also various error, eta, and covariance models, and even naive-pooling method useing NONMEM. But all the results are very similar to the above NONMEM result. For your convenience, I have included the NONMEM control code, data, and some graphics. Please, take a look and if you think my result is correct, give me some explanations to make others(non-NONMEM users) understand. Sincerely, Kyun-Seop Bae MD PhD Department of Clinical Pharmacology & Clinical Research Center Asan Medical Center 388-1 Pungnap-dong Songpa-gu, Seoul 138-736, Korea Tel: +82-2-3010-5901 Fax: +82-2-3010-5509 Email: ksbae@amc.seoul.kr ========================================== [Control File] $PROBLEM Skin PD $INPUT ID TIME DV MDV $DATA Steroid.CSV IGNORE=# $PRED EMAX = THETA(1)*EXP(ETA(1)) EC50 = THETA(2)*EXP(ETA(2)) IPRE = 0 - EMAX * TIME / (EC50 + TIME) Y = IPRE + EPS(1) $THETA (0, 55) (0, 2.5) $OMEGA 0.2 0.2 $SIGMA 100 $ESTIMATION MAXEVAL=9999 PRINT=5 METHOD=ZERO POSTHOC $COVARIANCE [Data File] #Subject,Dose Duration(hr),AUEC,MDV 1,0.25,-1.23,0 1,0.5,-7.39,0 1,0.75,-1.48,0 1,1,-3.8,0 1,1.5,-0.23,0 1,2,5.77,0 1,4,-4.74,0 1,6,-1.53,0 2,0.25,-0.02,0 2,0.5,-5.13,0 2,0.75,-8.92,0 2,1,-24.56,0 2,1.5,-19.21,0 2,2,-1.8,0 2,4,-43.07,0 2,6,-41.56,0 3,0.25,-13.87,0 3,0.5,-15.03,0 3,0.75,-18.39,0 3,1,-16.25,0 3,1.5,-15.44,0 3,2,-23.74,0 3,4,-24.8,0 3,6,-21.79,0 4,0.25,-27.27,0 4,0.5,-3.71,0 4,0.75,-43.82,0 4,1,-44.39,0 4,1.5,-77.04,0 4,2,-66.8,0 4,4,-62.96,0 4,6,-71.6,0 5,0.25,-10.65,0 5,0.5,7.72,0 5,0.75,-23.42,0 5,1,-20.37,0 5,1.5,-19.95,0 5,2,-32,0 5,4,-32.81,0 5,6,-61.51,0 6,0.25,-10.41,0 6,0.5,-5.94,0 6,0.75,-2.29,0 6,1,-8.92,0 6,1.5,-20.64,0 6,2,-19.52,0 6,4,-8.52,0 6,6,-19.01,0 7,0.25,4.2,0 7,0.5,-12.31,0 7,0.75,1.34,0 7,1,-18.84,0 7,1.5,-42.7,0 7,2,-37.29,0 7,4,-45.46,0 7,6,-37.24,0 8,0.25,-11.95,0 8,0.5,7.45,0 8,0.75,5.95,0 8,1,8.78,0 8,1.5,1.26,0 8,2,-48.83,0 8,4,-71.77,0 8,6,-8.14,0 9,0.25,-12.36,0 9,0.5,12.95,0 9,0.75,1.88,0 9,1,-43.35,0 9,1.5,-20.97,0 9,2,-39.79,0 9,4,-57.55,0 9,6,-34.18,0 10,0.25,1.15,0 10,0.5,-39.45,0 10,0.75,-40.68,0 10,1,-16.19,0 10,1.5,6.87,0 10,2,10.75,0 10,4,-37.64,0 10,6,-35.01,0 11,0.25,-30.03,0 11,0.5,-39.56,0 11,0.75,-61.06,0 11,1,-43.58,0 11,1.5,-40.73,0 11,2,-62.01,0 11,4,-27.82,0 11,6,-33.6,0 12,0.25,-7.25,0 12,0.5,14.73,0 12,0.75,-21.09,0 12,1,10.81,0 12,1.5,0.51,0 12,2,-10.51,0 12,4,-14.89,0 12,6,16.14,0 _____ ================================ Kyun-Seop Bae MD PhD Clinical Research Center, Asan Medical Center Pungnap-dong Songpa-gu Seoul, 138-736, Republic of Korea Tel: +82-2-3010-5901 Fax: +82-2-3010-5509 Email: ksbae@kma.org