Experimental Design By Arun Kumar Mishra Iftm

A SEMINAR ON

EXPERIMENTAL DESIGN IN CLINICAL TRIALS

SUBMITTED TO Dr. S. AWASTHI DEPTT. OF MANAGEMENT IFTM, MORADABAD

SUBMITTED BY ARUN Kr. MISHRA M.PHARM IST SEM. IFTM MORADABAD 1

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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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FDA GUIDELINES FOR CLINICAL EVALUATION 3. Proper planning, design and clinical analysis of investigation of clinical pharmacology must be there to efficacy and safety 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. 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

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PRINCIPLES OF DESIGN AND DATA ANALYSIS:-2. 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. 6. CHOICE OF PATIENTS Age, sex, bodyweight, disease condition are necessraily to be considered while selecting patients. 9. ADEQUATE PRECISION More 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.

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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). 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 6

BLOCK OF 8 7

4

8

2

4

3

1

5

2

8

3

1

6

7

5

6

2B 4B 1A 6B 8B 5A 3A 7A

4

1

2

5

8

5

6

3

6

3

2

7

1

7

8

8

6

1

7

5

4

2

4

3

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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 SUBSET 1 1,5,6,7,9

NEW DRUG 2,3,4,8,10

SUBSET 2 11,13,15,1 12,14,16,1 7,18 9,20 SUBSET 3 22,24,27,2 21,23,25,2 8,29 6,30 SUBSET 4 31,33,36,3 32,34,35,3 8,39 7,40

P= Placebo N=New drug

From Table

4

5

6

7

1P 8N 4N 10 P 9P 5P 7N 2P 3N 6N

3 2 7 8 1 6 9 5 10 4

4 7 8 9 6 2 3 1 5 10

1 4 5 8 6 9 10 7 3 2 9

PLACEBO Exercise time Patient Pre Post 1 377 345 6 272 310 7 348 347 8 348 300 12 133 150 13 102 129 14 156 110 15 205 251 18 296 262 20 328 297 21 315 278 22 133 124 26 223 289 27 256 303 28 493 487 32 336 309 34 299 281 35 140 186 36 161 125 37 259 236 MEAN 259 s.d. 102

256 95

Post-Pre -32 38 -01 -48 17 27 -46 46 -34 -31 -37 -09 66 47 -06 -27 -18 46 -36 -23 -3.05 36.3

ACTIVE DRUG Exercise time Patient Pre Post 02 232 372 03 133 120 04 206 294 05 140 358 09 240 340 10 246 393 11 226 315 16 123 180 17 166 334 19 264 381 23 241 376 24 074 264 25 400 541 29 320 410 30 216 301 31 153 143 33 193 348 38 330 440 39 258 365 40 353 483

Post-Pre 140 -13 088 118 100 147 089 057 168 117 135 190 141 090 085 -010 155 110 107 130

226 083

107.2 51.5

333 106

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RESULT OF EXERCISE TEST COMPARING PLACEBO TO ACTIVE DRUG Qu.:- 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+S22/2)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 range11 t0.05/38

ANOVA for the Posttreatment Readings:H0; “No significance difference”

Source Between Groups Within Groups Total

d.f

SS

MS

1

59213

59213

38

383787

10099.7

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 experiment Eg. 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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C O N C.

High plasma conc. Due to pcd X not eliminated yet X Y

TIME

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Long washout Period provided C O N C.

CMAX

X

AUC

Y

tP TIME

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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 17

REFERENCES:-•

Bolton.S, “Pharmaceutical Statistics”,- 3rd edition, New York, Mrcel Dekker, P.P-384-442.

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

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

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