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EXPERIMENTAL DESIGN IN CLINICAL TRIALS

Presented byARUN Kr. MISHRALecturerPharmacy College AzamgarhUP INDIA 223223

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WHAT IS CLINICAL TRIALS ?

Clinical trials are performed to find out efficacy, safety, bioavalibility and bioequivalance studies in animals. Data outcome 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

1. Proper planning, design and clinical analysis of investigation of clinical pharmacology must be there to efficacy and safety parameters.

2. 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 DATA ANALYSIS:--1. SIMPLICITY AND SYMMETRY

As 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.

2. CHOICE OF PATIENTSAge, sex, bodyweight, disease condition are necessraily to be considered while selecting patients.

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

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4. INTENT TO TREAT The drug given should improve the diseases status. When discontinuation of medication, in proper withdrawal of blood samples, irregular dose frequency- efficacy is not considered(such patient are not considered).5 RANDOMIZATION Randomly 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 6th column

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

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7 4 2 B 4 1 2

8 2 4 B 5 8 5

4 3 1 A 6 3 6

1 5 6 B 3 2 7

2 8 8 B 1 7 8

3 1 5 A 8 6 1

6 7 3 A 7 5 4

5 6 7 A 2 4 3

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 even for new drug. Sol. The selection may be done from block of 10 from column 4 to 7

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PLACEBO NEW DRUG

SUBSET 1 1,5,6,7,9 2,3,4,8,10

SUBSET 2 11,13,15,17,18

12,14,16,19,20

SUBSET 3 22,24,27,28,29

21,23,25,26,30

SUBSET 4 31,33,36,38,39

32,34,35,37,40

4 5 6 71 P 3 4 1

8 N 2 7 4

4 N 7 8 5

10 P 8 9 8

9 P 1 6 6

5 P 6 2 9

7 N 9 3 10

2 P 5 1 7

3 N 10 5 3

6 N 4 10 2P= PlaceboN=New drug

From Table

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PLACEBO ACTIVE DRUG Exercise time Exercise timePatient Pre Post Post-Pre Patient Pre Post Post-Pre1 377 345 -32 02 232 372 1406 272 310 38 03 133 120 -137 348 347 -01 04 206 294 0888 348 300 -48 05 140 358 11812 133 150 17 09 240 340 10013 102 129 27 10 246 393 147 14 156 110 -46 11 226 315 089 15 205 251 46 16 123 180 05718 296 262 -34 17 166 334 16820 328 297 -31 19 264 381 11721 315 278 -37 23 241 376 13522 133 124 -09 24 074 264 190 26 223 289 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 39 258 365 107 37 259 236 -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 TO ACTIVE DRUGQu.:- Is there a significant difference between active and placebo.Hypothesis – There is no significant difference between two treatment in pre of placebo and active drug

Sp = (S12+S2

2/2)1/2

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

t = X1-X2 / Sd.(1/N1+1/N2)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 t0.05/38

Hence there is no significant difference and hypothesis is accepted.

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ANOVA for the Posttreatment Readings:-

H0; “No significance difference”

Source d.f SS MS

BetweenGroups

1 59213 59213

Within Groups

38 383787 10099.7

Total 39 443000

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 and Remaining formulation on second occasion.A sufficient time is given to washout drug so that all of drug is eliminated 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 1st and 2nd . 1st is given treatment firstly by A then after Wash period B.And in other case 2nd is given treatment B then after wash period A.That is 2 X 2 Latin square.

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PATIENT FIRST SECOND

1 A B

2 B A

2 X 2 Table

SUB. 1st 2nd 3rd 4th

1 A B C D

2 B C D A

3 C D A B

4 D A B C

4 X 4 Table

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CONC.

TIME

High plasma conc. Due to pcd X not eliminated yet

XY

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CONC.

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 2nd dose of crossover

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REFERENCES:--1. Bolton.S, “Pharmaceutical Statistics”,- 3rd edition,

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

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

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

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