The Significance of Graphics in Early Phase Safety Reporting Kelly - PowerPoint PPT Presentation

Shaping the F uture o f Drug De ve lo pme nt The Significance of Graphics in Early Phase Safety Reporting Kelly Huang Nand Kishore Rawat 1

OVER ERVIEW VIEW 1. Goals in 1. Goals in Phase I Studies Phase I Studies 2. 2. Data Checking Data Checking 3. 3. Repor porting ing 4. 4. Exam Example Study ple Study 5. 5. Summar Summary 2 2 0 1 6 C Y T E L . P H U S E S D E F R E N C H T O W N , N J

“WHA HAT” T” ARE ARE THE GO THE GOALS IN PHASE I ALS IN PHASE I STUDIES? STUDIES? To assess the preliminar assess the preliminary saf y safety ty, t , tolera lerability bility, and , and pharmacokine pharmacokinetic pr tic prof ofile of ile of a drug a drug Estimate ho Estimat e how large a w large a dose can dose can be be giv given bef n before unacceptable t re unacceptable toxicity is xicity is experienced via perienced via dose escal dose escalation tion Resulting dose decisions help t sulting dose decisions help to mo move trial int trial into follo llowing phases ing phases Safety Saf ty is is assessed thr assessed through ECG, ugh ECG, vital signs, and vital signs, and lab lab measurements measurements  Tables and figures for data issue checking and reporting 3 2 0 1 6 C Y T E L . P H U S E S D E F R E N C H T O W N , N J

“HO “HOW” T ” TO A ACHIEVE GO HIEVE GOALS OF PHASE I ALS OF PHASE I STUDIES? STUDIES? Data Checking Data Checking Re Reporting 4 2 0 1 6 C Y T E L . P H U S E S D E F R E N C H T O W N , N J

“WHY” D “W DO W WE P PERFORM DATA CHECKING? CHECKING? Data checking Data checking is critical is critical  Make sure all necessary data is available for analysis  Small samples in early phase studies, so errors in data can have huge effect on analyses  Assumptions for models possibly not met if there are data errors 5 2 0 1 6 C Y T E L . P H U S E S D E F R E N C H T O W N , N J

“ HO HOW” DO WE PERF W” DO WE PERFORM ORM DATA CHECKING? CHECKING? Done at Done at the star the start of t of ever ery study req y study request uest Freq equency table f uency table for timepoints r timepoints  Checking for missing or extra timepoints against study flow chart Boxplo Bo xplots t ts to check f check for outlier r outliers  Use of macro  Identifies “farlow”, “farhigh”, “low”, and “high” values 6 2 0 1 6 C Y T E L . P H U S E S D E F R E N C H T O W N , N J

“WHY” DO WE REPORT? HY” DO WE REPORT? Dose escalation mee Dose escalation meetings ings  Decision on whether to continue dose escalation sequence according to protocol, change dose escalation sequence, or stop dosing CSR Creation CSR Creation  Section 12 7 2 0 1 6 C Y T E L . P H U S E S D E F R E N C H T O W N , N J

“WHA HAT” T” DO WE REPORT? DO WE REPORT? Freq equency table f uency table for v r values and lues and change change fr from baseline f om baseline for each parame r each parameter at r at Change (Mean +/- SE) from Baseline for <Drug> Summary for <Domain> Parameter each timepoint each timepoint <Domain> Parameter= Param 1 Part= Part x Panel= Panel x 2.5 Change from Baseline (Mean +/- SE) 0.0 Figures Figures f for change fr r change from baseline f om baseline for each parame r each parameter -2.5 -5.0 -7.5 T T T T T T i i i i i i m m m m m m e e e e e e p p p p p p o o o o o o i i i i i i n n n n n n t t t t t t 1 2 3 4 5 6 Time (Hours) Treatment Placebo Treatment 1 Treatment 2 § Placebo is pooled over periods 8 2 0 1 6 C Y T E L . P H U S E S D E F R E N C H T O W N , N J

EXAMPLE STUDY EXAMPLE STUD Phase I study f Phase I study for an r an acut acute e treatment of treatment of migraine with or without aura migraine with or without aura Study Objectiv Study Objective: Assess the preliminar e: Assess the preliminary saf y safety ty, t , tolerability and lerability and pharmacokine pharmacokinetic (PK) pr tic (PK) prof ofile of drug ile of drug af after single and r single and multiple dose multiple dose administrations administrations Study Design: Randomized, double-blind Study Design: Randomized, double-blind, placebo-contr , placebo-controlled dose study in lled dose study in health healthy male subjects y male subjects 9 2 0 1 6 C Y T E L . P H U S E S D E F R E N C H T O W N , N J

EXAMPLE STUD EXAMPLE STUDY: STUD STUDY Y DESIGN DESIGN Tw Two P Parts:  Part I: Single rising oral doses in up to five periods with minimum of 7-days washout period between treatments periods Panel Panel Period 1 riod 1 Period 2 eriod 2 Period 3 eriod 3 Period 4 eriod 4 Period 5 eriod 5 A 40 mg 100 mg 200 mg 400 mg 40 mg w/food  Part II: Four serial panels where subjects receive daily dose of drug for 10 consecutive days Panel Panel Dose Le Dose Level B 50 mg C 100 mg D 200 mg E 400 mg 10 2 0 1 6 C Y T E L . P H U S E S D E F R E N C H T O W N , N J

EXAMPLE STUD EXAMPLE STUDY: DATA CHECKING ECG CHECKING ECG Obs EGTPT COUNT 1 DAY10 2 HR 32 2 DAY10 24 HR 32 3 DAY10 PREDOSE 32 4 DAY3 2 HR 32 5 DAY3 PREDOSE 32 6 DAY5 2 HR 32 7 DAY5 PREDOSE 32 8 DAY1 1 HR 40 9 DAY1 30 MIN 40 10 DAY1 4 HR 40 11 DAY1 2 HR 72 12 DAY1 24 HR 72 13 DAY1 PREDOSE REPEAT 1 72 14 DAY1 PREDOSE REPEAT 2 72 15 DAY1 PREDOSE REPEAT 3 72 2 0 1 6 C Y T E L . P H U S E S D E F R E N C H T O W N , N J 11

EXAMPLE STUD EXAMPLE STUDY: DATA CHECKING ECG CHECKING ECG 519 Obs Statistics Value N_Obs 500 1 FARHIGH 500.00 1 0 2 FARHIGH 519.00 1 0 3 HIGH 440.00 1 0 440 438 (Max) 401 (Q3) 388 (Median) 376 (Q1) 347 (Min) FARHIGH values are values > 3*IQR + Q3, where IQR = Q3 – Q1 12 2 0 1 6 C Y T E L . P H U S E S D E F R E N C H T O W N , N J

EXAMPLE STUD EXAMPLE STUDY: DATA CHECKING ECG CHECKING ECG Obs Statistics Value N_Obs 584 & 586 1 FARHIGH 584.000 1 2 FARHIGH 586.000 1 3 HIGH 466.000 3 4 HIGH 468.000 1 5 HIGH 472.000 1 466, 468, 472, 6 HIGH 474.000 1 474, 478, 486 7 HIGH 478.000 1 464 (Max) 8 HIGH 486.000 1 414 (Q3) 398 (Median) 380 (Q1) 330 (Min) 13 2 0 1 6 C Y T E L . P H U S E S D E F R E N C H T O W N , N J

EXAMPLE STUD EXAMPLE STUDY: DATA CHECKING CHECKING ECG ECG outlier outliers identif identified b ied by bo boxplo xplots ts ecg_ ecg_pa parm an_ an_num vt_nu vt_num PRSDTLTM PRSDTLTM date date val value clien ent comm t commen ent There were 2 unscheduled ECGs at 11:11 and 11:13 with QT of QT 21 7 DAY1 2 HR 2012-08-07T11:10 584 410 and 422. There was an unscheduled ECG at 9:19 with QT 414. QT 38 7 DAY10 24 HR 2012-09-14T09:17 586 For all of these, the protocol specifies that the average of the measurements will represent the QT value. QTCF 21 7 DAY1 2 HR 2012-08-07T11:10 500 There was an unscheduled ECG at 9:19 with QTC Intv 377 msec There were 2 unscheduled ECGs at 11:11 and 11:13 with QTC QTCF 38 7 DAY10 24 HR 2012-09-14T09:17 519 Intv 386 and 364 msec. There were 2 unscheduled ECGs at 11:11 and 11:13 with QTC Intv 386 and 364 msec. 14 2 0 1 6 C Y T E L . P H U S E S D E F R E N C H T O W N , N J

EXAMPLE STUD EXAMPLE STUDY: DATA CHECKING V CHECKING VS SEMI-RECUMBENT STANDING Obs Statistics Value N_Obs 174 1 FARHIGH 174.00 1 2 FARLOW 62.00 1 3 HIGH 146.00 1 4 HIGH 147.00 4 5 HIGH 148.00 3 6 HIGH 149.00 2 145 146 7 HIGH 150.00 4 8 HIGH 151.00 4 9 HIGH 152.00 1 127 127 10 HIGH 153.00 3 120 120 11 HIGH 154.00 1 115 114 12 HIGH 155.00 1 13 HIGH 157.00 1 14 HIGH 158.00 1 97 15 LOW 92 1 95 62 FARLOW values are values < Q1 - 3*IQR, where IQR = Q3 – Q1 15 2 0 1 6 C Y T E L . P H U S E S D E F R E N C H T O W N , N J

EXAMPLE STUDY: DATA CHECKING EXAMPLE STUD CHECKING VS and LB VS and LB outliers identif outliers identified b ied by bo boxplo xplots ts domain domai param param an_ n_num vt_nu t_num bp_ p_ps pst prs rsdtl dtltm date ate val alue unit unit VS DIABP 3 5 Standing DAY1 24 HR 2012-07-25T09:06 114 mmHg VS DIABP 5 4 Standing DAY1 1 HR 2012-07-17T10:21 38 mmHg VS SYSBP 1 2 Semi- DAY1 PREDOSE REPEAT 2012-06-19T08:27 174 mmHg recum 1 VS SYSBP 5 4 Standing DAY1 1 HR 2012-07-17T10:21 62 mmHg LB Eosinophils 6 4 DAY1 PREDOSE 2012-07-16T09:25 1.53 10[9]/L Sponsor d onsor decision t sion to n not e t exclude ude a any LB Alanine 35 7 DAY10 24 HR 2012-09-14T09:10 1.319 microkat/ Aminotransferase L 16 2 0 1 6 C Y T E L C O N F I D E N T I A L . I N T E R N A L U S E O N L Y .

EXAMPLE STUD EXAMPLE STUDY: ELEMENT ELEMENTS OF OF REPORT REPORT 1. 1. ECG tables ECG tables 2. 2. ECG f ECG figures gures 3. 3. Vital Signs tables Vital Signs tables 4. 4. Vital Signs f Vital Signs figures gures 5. 5. Lab tables Lab tables 6. 6. Lab f Lab figures gures 17 2 0 1 6 C Y T E L . P H U S E S D E F R E N C H T O W N , N J