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Experimental Design by Arun Kumar Mishra Iftm

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    A SEMINAR ON

    EXPERIMENTAL DESIGN INCLINICAL TRIALS

    SUBMITTED TODr. S. AWASTHIDEPTT. OF MANAGEMENTIFTM, MORADABAD

    SUBMITTED BYARUN Kr. MISHRAM.PHARM IST SEM.IFTM MORADABAD

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    WHAT IS CLINICAL TRIALS ?

    Clinical trials are performed to find out efficacy, safety, bioavalibility and bioequivalance studies in animals. Dataoutcome of experimentation is statistically treated.

    INTRODUCTION

    Clinical trials are to be done under proper control, adequate proper control group(placebo and active) and preplanned

    design of experimentation must be there.

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    GENERAL GUIDE LINES

    Objective of clinical study must be clear Documentation of every step is essential Suitable number of patients must be available Control group considerations Avoid the bias

    FDA GUIDELINES FOR CLINICAL EVALUATION

    3. Proper planning, design and clinical analysis of investigation

    of clinical pharmacology must be there to efficacy andsafety parameters.

    4. Protocols must be framed including criteria for subjects how patients are to be selected and important parameters.

    3. Planning removes the inprocess problems.

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    PRINCIPLES OF DESIGN AND DATAANALYSIS:--

    2. SIMPLICITY AND SYMMETRYAs simplicity is available in design, lesser restriction, lesser the expense and less time consumption will be there.It must be having equal no. of patients, equal no. of visits

    per patients, balance order of administration.

    6. CHOICE OF PATIENTSAge, sex, bodyweight, disease condition are necessraily to

    be considered while selecting patients.

    9. ADEQUATE PRECISIONMore the no. of patients more precise results but ethics andexpense are to be considered.Blocking boost up the precision.

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    4. INTENT TO TREATThe drug given should improve the diseases status. Whendiscontinuation of medication, in proper withdrawal of

    blood samples, irregular dose frequency- efficacy is notconsidered(such patient are not considered).

    6 RANDOMIZATIONRandomly selection of data is randomization.

    Mean outcome of two test must be similar.Eg. 48 patients are to be randomly selected?From block of 8, up to 6 th column

    OR From block of 6, up to 8 th columnA = odd no., B= even no.Eg. 3 rd column of 8 th block is selected,2,4,1,6,8,5,3,7then random assignment is BBABBAAA

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    3427 A65

    4573 A76

    1685 A13

    8718 B82

    7236 B51

    6361 A34

    5854 B28

    2142 B47

    BLOCK OF 8

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    PARELLEL DESIGN

    Two or more drug are considered Every patient is given a single drug Drug is given to randomly assigned patients Objective To test in increase in exercise time after giving

    placebo and drug to angina patients

    Eg. 40 patients to be selected, odd no. for placebo and evenfor new drug.Sol. The selection may be done from block of 10 fromcolumn 4 to 7

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    32,34,35,37,40

    31,33,36,38,39

    SUBSET 4

    21,23,25,26,30

    22,24,27,28,29

    SUBSET 3

    12,14,16,19,20

    11,13,15,17,18

    SUBSET 2

    2,3,4,8,101,5,6,7,9SUBSET 1

    NEWDRUG

    PLACEBO

    21046 N

    35103 N7152 P

    10397 N

    9265 P

    6619 P

    89810 P

    5874 N

    4728 N1431 P

    7654

    P= Placebo N=New drug

    From Table

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    PLACEBO ACTIVE DRUGExercise time Exercise time

    Patient Pre Post Post-Pre Patient Pre Post Post-Pre1 377 345 -32 02 232 372 1406 272 310 38 03 133 120 -13

    7 348 347 -01 04 206 294 0888 348 300 -48 05 140 358 11812 133 150 17 09 240 340 10013 102 129 27 10 246 393 14714 156 110 -46 11 226 315 08915 205 251 46 16 123 180 05718 296 262 -34 17 166 334 168

    20 328 297 -31 19 264 381 11721 315 278 -37 23 241 376 13522 133 124 -09 24 074 264 19026 223 289 66 25 400 541 14127 256 303 47 29 320 410 09028 493 487 -06 30 216 301 08532 336 309 -27 31 153 143 -01034 299 281 -18 33 193 348 15535 140 186 46 38 330 440 11036 161 125 -36 39 258 365 10737 259 236 -23 40 353 483 130

    MEAN 259 256 -3.05 226 333 107.2

    s.d. 102 95 36.3 083 106 51.5

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    RESULT OF EXERCISE TEST COMPARING PLACEBO TOACTIVE DRUGQu.:- Is there a significant difference between active and placebo.

    Hypothesis There is no significant difference between two treatmentin pre of placebo and active drug

    Sp = (S 12+S 22/2) 1/2

    = [(102) 2+(83) 2/2] 1/2 = 93

    t = X 1-X 2 / Sd.(1/N 1+1/N 2)1/2

    = 259-226 / 93 (0.1) 1/2 = 1.12

    t0.05/38 = 2.03

    INTERPRETATION - Cal. Value of t=1.12 which falls under range t 0.05/38

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    ANOVA for the Posttreatment Readings:-

    H0; No significance difference

    44300039Total

    10099.738378738WithinGroups

    59213592131BetweenGroups

    MSSSd.f Source

    F1,38 =5.86

    F tabulated=4.10

    Interpretation:- Rejection of Null Hypothesis

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    CROSS OVER DESIGN & BIOAVLABILITY STUDIES

    In crossover half of the subjects are randomly chosen to take either

    One or other of two formulations on experimental occasion andRemaining formulation on second occasion.A sufficient time is given to washout drug so that all of drug iseliminated before second dose administration.

    It is a type of Latin square. No. of treatment is equal to no. of patients Order of treatment is included in experimentEg. Patient 1 st and 2 nd . 1 st is given treatment firstly by A then after Wash period B.And in other case 2 nd is given treatment B then after wash period A.That is 2 X 2 Latin square.

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    AB2

    BA1

    SECONDFIRSTPATIENT

    2 X 2 Table

    CBAD4

    BADC3

    ADCB2

    DCBA1

    4th 3rd 2nd 1st SUB.

    4 X 4 Table

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    CO

    NC.

    TIME

    High plasma conc.Due to pcd X noteliminated yet

    XY

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    CO

    NC.

    TIME

    AUC

    CMAX

    tP

    YX

    Long washout

    Period provided

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    ADVANTAGE AND DISADVANTAGE OF CROSSOVER DESIGN

    Random comparison of two treatment is done

    A ----> B & B ----> A Intrasubject variability is considered Crossover is economical and less time is consumed Smaller chances of variation

    Data missing imposes a great problem Possibility of interaction of the drug Residual effect Extra time for the wash period In acute diseases patient may be cured up so much improved after

    first treatment that the different state of illness is treated in 2 nd doseof crossover

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    REFERENCES:-- Bolton.S, Pharmaceutical Statistics ,- 3 rd edition,

    New York, Mrcel Dekker, P.P-384-442.

    Remington, The Science & Practical of Pharmacy Volume 1 st , P.P-146-147.

    Lachman.L& Liberman The Theory & Practical of Industrial Pharmacy 2nd P.P-276-279.

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