SAMPLE SIZE DETERMINATION

Type of Studies
• Qualitative

• Quantitative

Dr. R.M. Pandey

Professor & Head
Dept. of Biostatistics
A.I.I.M.S., New Delhi

rmpandey@yahoo.com 1 2

Two Questions Asked about

Quantitative Studies
• Exploratory
– Being done for the first time
– No idea/guess about the anticipated results
– Sample size is based on feasibility
the Study Results
• Validity or accuracy
– It is a function of conduct of study
• Reliability or reproducibility
– It is function of sample size

• Confirmatory
– To confirm or refute the limited evidence coming from • Validity is the priority in all scientific endeavours
existing small studies
– Sample size is computed using the anticipated results • Reliability is for the valid study result
based on prior studies, confidence level, and
precision/power.
• By increasing the sample size, results can not be made
more valid
3 4

Sample Size is an Issue at Two Stages

Sample Size Considerations
of the Study
1. Design stage: • In some studies no formal sample size is
How many subjects are necessary to estimate a calculated
parameter with a specified precision?

i.e., How many subjects I need to enroll in my study • Instead, the number of participants available
in order to get a precise/positive result? to the investigators during some period
determines the size
2. Interpretation stage:
Does the study has adequate precision/power for
the reported result

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1
 The Implications? The Implications?
If ‘n’ is too small…. If ‘n’ is too large….
• Even the most rigorously executed study may fail to
answer its research question • The study will be more difficult and costly than
necessary
• Study may fail to detect important effects or
associations or • Waste of resources

• May estimate those effects or associations too

imprecisely • May even lead to a loss in accuracy, as it is often
more difficult to maintain high data quality
• The word Pilot Study is frequently misused 7 8

Definition and Meaning of

Random Error
Commonly Used Terms
• Random Error • Sampling Variability
Describes the role of chance, particularly Subject-to-subject Differences
when the effects of explanatory or predictive
factors have already been taken into account • Can be controlled and reduced to
acceptably low level:
• Systematic Error Averaging
Describes deviations that are not a Increasing Sample Size
consequence of chance alone Repeating the Experiment

9 10

Approaches of Sample Size

Systematic Error (Bias) Determination
• Precision based
• Several factors (e.g. patient selection) might contribute to it – The degree to which variable has the same value when
measured several times. A measure of consistency. A
function of random error.
• These factors may not be amenable to measurement, but can
usually be removed or reduced by good design and conduct of
the experiment – Simply refers to the width of CI

• A strong bias can yield an estimate very far from the true – Large ‘n’ → Good Precision
value, even in the wrong direction
– Good Precision → Greater the Power at given ‘n’
• Increasing sample size is not a solution to reduce bias in the • Hypothesis based
study result
– Null hypothesis
– Alternate hypothesis
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2
 Prerequisites for Understanding
Precision α 1/SE Sample Size Determination
• Relative Precision (d) 1. Type of Variables (MUST)
p = 50% Categorical/ quantitative/ time to an event
d = 10% of 50% = 5%
Therefore, Range for p = 45% - 55% 2. Type of study designs (MUST)
– cross-sectional/ cohort / case-control/ experimental
• Absolute Precision (ε)
3. Summary measures (MUST)
p = 50% - Mean, SD, %, r, k,OR, RR, RD, etc
ε = 10% (i.e. 10 percentage points)
Therefore, Range for p = 40% - 60% 4. Type-I error, Type-II error, power, CI and hyp testing (MUST)

• Large n → Be er Precision → Less SE → Narrow CI 5. Standard Normal distribution (DESIRABLE)

13 14

Determined Sample Size for the

Three Ways to Determine Sample Size
Study: Is it a Rule?
‘n’ is not a rule 1. Formulae

Approximations to the exact distributions 2. Ready-made tables (for most common

situations)
Guesses about some parameters
3. Software’s
Based on prior small studies (Epi-Info, STATA, ‘n’ Query, nMaster, etc.)

15 16

Inputs Required for Sample Size

Values of Z1-α/2 and Z 1-β
Determination
_________________________________________
Two sided test One sided test • Anticipated outcomes
Level (α) (Z1-α/2) (Z 1-α )
• Precision or hypothesized value
0.01 2.576 2.326 • Statistical errors: Alpha and Beta(Power=1- Beta)
0.05 1.960 1.645
0.10 1.645 1.282 • Power would be needed only for analytic studies
--------------------------------------------------------------------- (hypothesis based studies)
Power (1- β) Z 1-β
• Anticipated non response/drop outs
0.80 0.842
0.90 1.282 • Sampling design in observational studies
0.95 1.645
099 2.326 • Method of randomization in intervention studies
_____________________________________________________________
• Modified alpha value due to Multiplicity
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3
 Research Questions: Primary/ Anticipated Vs Observed Precision
Secondary and Power
1. What is the prevalence of a condition?. • Precision and power used for sample size
2. What is the average (Mean) of a characteristics? determination will never be the same as observed
3. What is the strength of correlation between two quantitative precision in the estimate and power of the study.
variables?
4. What is the agreement between methods?
• Reviewers often insist on reporting power of the
5. What are the diagnostic characteristics of a candidate test
with reference to a “Gold Standard”?. study for inconclusive results.
6. What is incidence of an outcome?.
7. What are the predictors of an outcome?
8. What are the risk factors associated with an outcome?
9. Evaluation of a candidate intervention against a control
19 20

Study Objective(s) I. Cross-Sectional Study

Situation 1 : One sample,
• Primary or Specific categorical
specified precision

• Secondary or General required information :

1. anticipated population prop. = p
2. type I error (5%)
• Sample size is computed for each of the 3. precision required on either side of the
primary objective, and the one giving larger proportion (=d)
sample size is taken as the study size.
Z2 1-α/2 p(1-p) 4 (p) (1-p)
n = --------------------- = --------------------
21 22
d2 d2

I. Cross-Sectional Study

Example : p = 20% (= 0.2)

α = 5% (i.e. confidence level= 95%)
d = 5% (i.e. between 15-20% )

Z2 1-α/2 p(1-p) 4 (0.2) (1-0.2)

n = --------------------- = -------------------- = 245.8

d2 (0.05) (0.05)

From table 1b :
for row = 0.05 & col = 0.2, n = 246
From EpiInfo : n = 235 23
Dr. R.M. Pandey; Evening Classes at AIIMS 24

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Situation 2: One sample,
Quantitative outcome
Example :
Specified precision
Suppose an estimate is desired of the average retail price of twenty
tablets of a commonly used tranquillizer. A random sample of retail
Required information : pharmacies is to be selected. The estimate is required to be within
10 paise of the true average price with 95% confidence. Based on
1. standard deviation ( =σ) a small pilot study, the SD = 85 paise. How many pharmacies
should be randomly selected?
2. precision required
3. Prob. of type I error
4(0.85) (0.85)
n= ----------------------------- = 277.56
(z21- α/2 σ2 )
( 0.10) (0.10)
n = --------------------
d2
25 26

Correlation Studies Example :

Situation I : one sample
two quantitative variables The expected correlation coefficient between serum carbon
one correlation coefficient monoxide and bone density is -0.2, how many smokers need
to be studied in order to be sure of finding the above
correlation with 95% confidence and 90% power.
Required information :
anticipated correlation coefficient (r) Given : r = 1-0.21 – 0.2
ignore the sign α = 0.05 (one tailed), β= 0.10

STEPS: C = 0.5 In [ 1+0.2)/ (1-0.2) ]

n = [(1.64 + 1.28)/ C]2 + 3 = 222
1. probability of two types of errors (α and β)
2. C= 0.5 In { (1+ r) / ((1- r)} See the table : n = 211

n = [ Z 1- α/2 + Z 1- β / C]2 + 3
27 28

Sample Size for Diagnostic Test Studies

Like prevalence studies

Two calculations:
(1) Number of cases required:
Based on anticipated Sensitivity
Precision
level of confidence
(2) Number of non-cases required
Based on Specificity
Precision
Level of Confidence

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 Odds and Probability
#with Disease
Probability of Disease =
# with and without Disease

# with Disease
Odds of disease =
# without Disease
II. Sample size calculation for Unmatched Case-
control studies

31 32

OR: Disease Case-control study : Precision based

D+ D- total
E+ a (60) b (40) (a+b) = (100) Information required
Exposure 1. exposure rate in cases
E- c (20) d (80) (c+d) = (100) 2. exposure rate in controls
3. odds ratio (at least two of the above must be specified, third one can
total (a+c) (b+d) N=a+b+c+d be determined)
80 120 =200 4. probability of type – I error

Odds of disease among exposed = a/b = 60/40 = 1.5 Z2 1- α/2 [1/ {P1 ( 1- P1 ) + 1/ {P2 ( 1- P2)]
Odds of disease among non-exposed = c/d = 20/80 = 0.25 n = -------------------------------------------------------
(log (1-d)) 2
Odds ratio = (a/b)/ (c/d) = 6.0 relationship between P1, P2 and OR
P1 = OR.P 2
RR: -----------------------

Risk of disease among exposed = a/(a+b) = 60/100 = 0.6 OR.P 2 + (1-P 2))
Risk of disease among non-exposed = c/c+d) = 20/100 = 0.2
PI = exposure rate in cases
P2 = exposure rate in controls
Relative risk = a/ (a+b)
------- = 0.6/0.2 = 3.0
c/ (c+d)
33 34

Example:
What sample size would be needed in each of the two groups for a case-
control study to be 95% confident of estimating the population odds
ratio to within 25% of the true value which is believed to be in the
vicinity of 2.0 and the exposure rate among control is estimated to be
0.30.

Given : 5% , d = 0.25, OR = 2.0, P2= 0.3

2 * 0.3
P = --------------------------------- = 0.46
2 * 0.3 + 1- 0.3
n = (1.96) 2 [1/ {(0.46 ) (0.54) ) + 1/ (0.3) (1 – 0.7)]
------------------------------------------------------------------------------------------------
(log (1- 0.25) 2
= 407. 91

See table 9g : intersection OR = 2 & P2= 0.3, n = 408

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 III. Cohort Studies Example:
Suppose an outcome is present in 20% of the unexposed group of the cohort
study, how large a sample would be needed in each of the exposed and
information required :
unexposed groups to estimate the RR within 10% of the true value, which is
believed to be approx 1.75, with 95% confidence.
1. any two out of P1, P2 and RR (P1/ P2 )
Given : P2 = 0.20, RR = 1.75 , α = 5%, d = 0.10
2. confidence level
Since RR = P1 / P2 , therefore P1 = RR * P2 =0.35
3. Precision
( 1.96) + ( 1 - 0.35)/ 0.35} + ( 1- P2) / P2)]
2

n= --------------------------------------------------------------
Z2 1- α/2 [( 1 - P1) / P1 )]2 + ( 1 - P2) / P2)] (log (1-d) 2
n= ------------------------------------------------------------
(log (1-d) 2 = 2026.95 = ~ 2026 in each group

see table 11 e :
Intersection of RR = 1.75 & P2 = 0.20, n = 2027

37 38

IV. Sample size calculation for

experimental studies

39 40

Design: PARRALEL TRIAL Factorial Design

Int. B

R N Yes
A Event Int. A
o Actually just like a parallel design
N No n n 2n
D Intervention A Yes No
O Yes n n 2n
M
Eligible Consent
I 2n 2n 4n
Patients
subjects obtained Z A no, B no
A Intervention B Yes No
T
I A no, B yes
4n
O eligible
N A yes, B no

Similar groups of individuals from same source population are allocated A yes, B yes
at random to receive or not to receive an intervention,
then observed for occurrence of outcome(s).
41 42

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 Incomplete Factorial Design Two Sequence, Two period Crossover Design
Eg.: For treatment of depression; if unethical to do R Period
A
nothing: N
I II
D Sequence 1 Test W Control
O
A
• A – Desipramine Patients
M
I S
H
• B – Congnitive therapy Z
A O
• C – Combination of A & B T
I Control
U
Sequence 2 T Test
O
N

A no, B yes
3n All interventions are administered to all subjects at different times
eligible A yes, B no
Sample Size Requirement: One fourth of the parallel group
Data Analysis:

A yes, B yes • Different from Parralel group design

43 • Have to see period effect, period * treatment interaction 44

Cross-Over Designs
Incomplete Cross-Over Designs
Event
Event
Int. B
Int. A No Event Event
No Event
Int. A
No Event
Consenting
Wash-out
Randomization
Eligible
Consenting Randomization
Event Event Eligible

Int. B Int. A
Event Event
No Event No Event
Placebo Int. A

No Event No Event

45 46

Effect: Effect:
Superiority Trials Equivalence Trials
• Goal: Show that the effect of one treatment on a certain • Goal: Show effects of two treatments on a certain endpoint differ by
endpoint is superior to that of another treatment no more than a pre-specified amount

• Examples:
Placebo-controlled efficacy trials
Trials to show one active treatment is superior to another
active therapy with respect to a certain endpoint – e.g.
greater effect on lowering LDL cholesterol, better symptom
control in asthma
• Example:
Show that 2 different formulations of the same active compound
have equivalence pharmakokietics (required for approval of generic
drugs)
Demonstrate lot-to-lot consistency of vaccine manufacturing
process by showing equivalent immunogenicity of the first few
manufactured of vaccine (required for vaccine approval)

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 Effect: Confidence Interval Approach to Superiority
Non-Inferiority Trials Superiority Shown

• Goal: Show effect of a new treatment on a certain endpoint is

no worse than that of an existing treatment by more than a Superiority Not Shown
pre-specified amount

Superiority Shown
• Example:
Superiority Not Shown
Establish efficacy of a new investigational treatment by
showing non-inferiority compared to a treatment known to be
efficacious -δ 0 δ
Show that one approved drug is no less efficacious than Treatment Difference
another, while having certain other advantages such as less
frequent dosing or better tolerability Control better New drug better
49 50

Confidence Interval Approach to Superiority Confidence Interval Approach to Equivalence

Superiority Shown
Equivalence Shown
δ Effect Size 95% CI
10 15 11, 19
10 30 9, 51 Superiority Not Shown
Equivalence Not Shown
10 5 2, 8

Are two drugs equivalent?

Superiority Not Shown Equivalence Shown

-δ 0 δ -δ 0 δ
Treatment Difference Treatment Difference

Control better New drug better Control better New drug better
51 52

Confidence Interval Approach to Equivalence Confidence Interval Approach to Non-Inferiority

Equivalence Shown NI Shown

δ Effect Size 95% CI
10 15 11, 19
10 30 9, 51
Equivalence Not Shown NI Not Shown
10 5 2, 8

Equivalence Shown Superiority

-δ 0 δ -δ 0
Treatment Difference Treatment Difference

Control better New drug better Control better New drug better
53 54

9
 Confidence Interval Approach to Non-Inferiority Sample Size Calculation for
δ Effect Size 95% CI Experimental Studies
NI Shown
-10 -15 -19, -11
-10 - 30 -51, -9
1. Continuous outcome
-10 - 5 -11, 1
NI Not Shown
2. Binary outcome (yes/no)
Superiority
3. Equivalence of two interventions
-δ 0
Treatment Difference 4. Cross over study design
Control better New drug better
55
5. Time to an event 56

Nutritionists wish to study the effect of lowering sodium in diet on systolic

1. Continuous Outcome Variable blood pressure (SBP). During a pilot study it was observed that the
standard deviation of SBP in community with a low sodium diet = 11.3
Inputs required : mm Hg while in that with high sodium diet it was 13.0 mm hg. If α= 0.05
and β = 0.10, how many persons from each community should be studied
(a) mean of the outcome variable in group 1 = M1
(b) mean of the outcome variable in group 2 = M2 if one wants to detect 3.0 mm Hg difference in SBP in the two
(c ) SD of the outcome variable in group 1 = σ1 communities.
(d) SD of the outcome variable in group 2 = σ2
(e) probability of two types of errors Solution : . [Z 1- α/2 + Z 1- β]2
n = (σ12 + σ22 ) -------------------------------------
E = 3.0, SD=12,
n = (σ12 + σ22 ) . [Z 1- α/2 + Z 1- β]
2 (M1 - M2)2
----------------- E/SD = 0.25
(M - M 2) 2
1 . [1.96 + 1.282]2
n = {(11.3)2 + (13.0)}2 ) ------------------------------------- = 347
(3.0)2

Therefore, a minimum of 347 persons from each community would be required

to be included in the study.
57 58

Non Parametric Two Group

Wilcoxon Mann Whitney U - Test
Assumptions
• The observations are independent.
• The variable under study is continuous or ordinal.
Formula
Z  Z 
2
 /2
n
12c 1  c  p " 0.5 
2
Where
p“ = Probability that a score from X is larger than a
score from Y is larger than ½.
c = 1/(1+k) where k = allocation ratio

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 Example
We consider an example concerning a clinical trial for
evaluation of the effect of a test drug with some 2. Binary Outcome Variable
continuous clinical endpoint. Suppose that, based on
historical data, it is estimated that p” = 0.67. What is This is the most straight forward method to compare
the sample size required for detection of a clinically two proportions .
meaningful improvement with 80% power and alpha 5%?
Besides Z 1- α/2 and Z 1- β the other two inputs required :
Solution (a) Anticipated X – year event rate in group 1 = P1
Probability that a score from X is larger than a score (b) Anticipated X – year event rate in group 2 = P2
from Y is larger than ½ : 0.67
Allocation Ratio : 1.1
[Z 1- α/2 . √2 P(1-P) + Z 1- β . √{ P1(1-P1) + P2 (1-P2)}] 2
Alpha error (%) : 5 n = -----------------------------------------------
Power (%) : 80 (P1 - P2 ) 2

1 or 2 sided test : 2
Where , P = (P1 + P2 ) / 2

Number needed (n) : 90

61 62

Suppose The cure rate on a standard treatment is 60%. The new

treatment would be considered superior if it offers at least 20 % more over
60%. What is the minimum number of patients required in each group to
determine whether this is significant at 5% level if we wish to have 80%
chance of detecting the difference if it is real?

Solution :
Given : P1 = 0.6 , P2 = 0.8
P = (0.6 + 0.8) / 2= 0.7
α= 0.10 , β = 0.20,
Therefore;
[1.96 √2( 0.7) (1-0.7) + 0.842 √{( 0.6) (1-0.6)+ (0.8) (1-0.8)}]2
n = -------------------------------------------------------------------------------
(0.6 -0.8)]2
= 82

Therefore, at least 82 patients per group will be needed to be sure that a difference of
20%, if exists, could be detected with 80% confidence.

Using Table 7e: n = 82 per group

|P2-P1|=0.2 , (1-P2)=0.2 since it is smallest of P1,
(1-P1), P2, (1-P2)

63 64

3. Equivalence of Two Interventions Example:

When the standard therapy is invasive, expensive or toxic and the We wish to have probability of 80% for establishing
experimental therapy is conservative, one may be interested in showing equivalence.
that the experimental therapy is equivalent in efficacy to the control Underlying 5 year survival rate in 2 groups is 80%.
therapy, rather than necessarily superior. The threshold for equivalence is 10%

2*(0.8)(0.2) [ 1.645 + 0.84 ] 2

In this situation the null hypothesis may specify that the difference in
n = --------------------------------------------
success rate of the control therapy (Pc) and standard therapy (Ps) by up
(0.1)2
to d amount will be considered equivalent.

2P(1-P) [Z 1- α + Z 1- β] 2 n = 198 subjects per group

n = --------------------------
(d)2

here, Pc = Ps = P

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 Paired Dichotomous Response Paired Dichotomous Response
• In this case, the number of paired observations, Np, • An alternative approximate formula for Np is
may be estimated by:

Np=[Zα√f + Zβ√f-d2]2/d2 Np=[Zα + Zβ]2f/ d2

where d = difference in the proportion of successes

(d = pi-pc) and f is the proportion of participants
whose response is discordant

67 68

Paired Dichotomous Response Paired Dichotomous Response

• Example • Using the latter sample size formula for a two-
– Consider an eye study where on eye is treated for sided 5% significance level and 90% power, the
loss of visual acuity by a new laser procedure and number of pairs Np is estimated as 132 since;
the other eye is treated by a standard therapy

Np = (1.96+1.282)2(0.5)/(0.40-.20)2
– The failure rate on the control, pc is estimated to
be 0.40 and the new procedure is projected to =262 x 0.5 = 132
reduce the failure rate to 0.20

if the discordant rate is 0.8, then 210 pair of

– The discordant rate f is assumed to be 0.50
eyes will be needed

69 70

Two Sequence, Two period Crossover Design 5. Comparison Two Survival curves
– Equal Allocation
Period
Assumption
R I II
A
N
• The hazards for the two groups are merely assumed
to be proportional.
D Sequence 1 Test W Control
O
M
A
Patients I S
Z
A
H  
2 E
T O 2   1   2 
I
O
U W h e re ,
N Sequence 2 Control T Test   
2

 H  
2
R  1  Z
 
Z  1 
 
1
  
E   
Sample Size Requirement: One fourth of the parallel group H R  1 
2

Data Analysis: Different from Parallel group design n  m  ( N / 2 ); H R =

1n  2 
1n  1 
Have to see  1 : P ro p o rtio n o f s u r v iv a l in tr e a tm e n t in g ro u p

period effect, & period * treatment interaction  2 : P ro p o rtio n o f s u rv iv a l in c o n tro l in g ro u p

 : S i g n i f i c a n c e le v e l
71 1 - : P ow er 72

12
Example
A trial is planned involving patients with bedsores. It is postulated
that ultrasound treatment will have the healing time of such sores
and a double-blind trail is proposed using ultrasound and a placebo
4. Cross-over Studies
being a non-functioning ultrasound machine. The investigator would
like a power of 90% and a two sided at 5%. The proportion healed
without treatment at 21 days is approximately 0.70 and with the
treatment, 0.80. How many patients should be recruited to the
study? σ2d (Z 1- α/2 + Z 1- β ) 2
n = ----------------------------------------------------
Solution 2 σ2
Proportion of survival in the first group : 0.8
Proportion of survival in the second group : 0.7 Where σ2d = variance of difference score
Hazard ratio : 1.6
Alpha error (%) : 5
(response on treatment 1
Power (%) : 90 - response on treatment -2)
1 or 2 sided test :2
δ = anticipated treatment benefit
Number needed for the first group : 396
Number needed for the Second group : 396

73 74

Suppose we want to study the effect of postmenopausal hormones (PMH) on the

level of DBP. Women in group 1 will get PMH pills in period 1 ( 4 weeks) and
. design discussed , where we randomized the subjects to either PMG
placebo pills in period 2 ( 4 weeks) and PMH pills in period 2. There will be 2
weeks wash out period between each 4 week active treatment period. Women
will have their DBP measured at the end of each active treatment period based
on mean of three readings at a single visit. If we anticipate 2mm Hg treatment
benefit and the within subject variance of the difference in mean DBP between
the two periods is estimated to be 31 and we require 80 % power, 5% level of
An alternative design for such a study will be the parallel group
or placebo and measured their DBP at baseline and at the end of 4
weeks of follow up, and base the measure of efficacy for an individual
patient on DBP follow up – DBP at base line. The sample size for such
an study will be calculated as :
n = sample size per group = 2 σ2d (Z 1- α/2 + Z 1- β ) 2
----------------------------------------------

significance, then how many women need to be enrolled ? (δ2 )

We have, σ2d = 31, α = 0.05, power = 80% δ = 2 = 4 x sample size per group for a cross over study
Therefore,
= 4 x (30.4) = 122 subjects per group or 244 subjects overall

σ2d (Z 1- α/2 + Z 1- β ) 2 31.(1.96 + 0.84) 2

n = ------------------------------------- = -------------------------
2δ2 2(4)
= 30.4

Thus we need to enroll 31 women per group, i.e., 62 subjects overall to achieve
80% power using this design

75 76

EQUIVALANCE EQUIVALANCE
Two-Sample Parallel Design: Means
Two-Sample Parallel Design: Means
Example: Clinical trial for evaluation of the effect of a test drug on cholesterol
The sample size needed to achieve the desired power of 1 – β is given by in patients with coronary heart disease (CHD).
A pharmaceutical company is interested in conducting a clinical trail to compare
two cholesterol lowering agents for treatment of patients with CHD through a
n1  kn2 parallel design. The primary efficacy parameter is the LDL.
For the establishment of equivalence, suppose the true mean difference is 1%
( z  z / 2 ) 2  2 (1  1/ k ) (i.e., ε = 1%) and the equivalence limit is 5% (i.e. , δ = 0.05). Assuming the
n2  if   0 standard deviation is 10% (σ = 10%). The sample size needed to achieve the
2 desired power of 80% (β= 0.20) at the 5% (α = 0.05%) for the establishment of
therapeutically equivalence between the study drug and the active control agent
( z  z )  2 (1  1/ k )
2
is given by
n2    if   0
(  |  |) 2 2(z  z /2 )2 2 2*(1.641.28)2 *0.12 2*0.2922
n1  n2    107
( |  |)2 (0.050.01)2 (0.04)2

77 78

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 EQUIVALANCE EQUIVALANCE
Two-Sample Parallel Design: PROPORTIONS
Two-Sample Crossover Design: Proportions
Example: Suppose a sponsor is interested to conducting an open label randomized crossover
The sample size needed to achieve the desired power of 1 – β trial to compare an inhaled insulin formulation manufactured for commercial usage for
is given by patients with type I diabetes to the inhaled insulin formulation utilized in phase III clinical
trials. Unlike subcutaneous injection, the efficiency and reproducibility of pulmonary insulin
delivery is a concern. As a result, a replicated crossover consisting of two sequences of
ABAB and BABA is recommended (a=1, m=2), where A is inhaled insulin formulation for
commercial usage and B is the inhaled insulin formulation utilized in phase III clinical trials.
n1  kn2 In this trail, in addition to the comparison of pharmokinetic parameters such as area under
the blood concentration time curve and peak concentration curve (Cmax), it is also of
( z  z ) 2  2 (1  1/ k )  p1 (1  p1 )  interest to compare the safety profiles between the two formultions in terms of the
n2    / 2   p2 (1  p2 )  incidence rate of adverse events.
(  |  |)2 k  Assume σd = 50%, no difference in the mean adverse event rate between the two treatments
(ε = 0), and the equivalence limit is 20% (δ = 0.2). The sample size needed in order to achieve
80% (β=0.2) is given by

( z  z / 2 ) 2  d 2 (1.64  1.28) 2 (0.5) 2

n   27
79 2 2
0.2 2 80

Suggested Readings on Sample Size

Determination

1. Stephen B Hulley, Steven R Cummings. Designing Clinical

Research : An epidemiologic approach, Williams and
Wilkins, London 1988. page 139 – 150

2. Stanley Lemshow, David W Hoshmer, Janelle Klar, Adequacy

of sample size in health studies. John Willey, and Sons. New
York
Questions ??
3. Bernard Rosner, Fundamentals of Biostatistics,
Duxbury Thomson Learning, 2000

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Thank You

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